Diagnostic work-up in steroid myopathy
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Steroid myopathy is a well-known sign of endogenous Cushing’s syndrome as well as a side effect of glucocorticoid administration. The clinical finding of muscle weakness and the clinical inspection of the muscle size are the most commonly used diagnostic tools, sometimes in combination with needle electromyography, but there are no means to detect the myopathy before the appearance of clinical or electrodiagnostic signs. Until now, no guidelines have been produced for a disease-specific evaluation of muscle impairment in patients with Cushing’s syndrome.
We reviewed the measurement properties and limitations of the following tools that are currently adopted in clinical research and routine care for diagnosis and monitoring of steroid myopathy: muscle strength assessment; needle biopsy; intramuscular and surface electromyography; laboratory assays; muscle mass assessments (through bioelectrical impedance analysis, dual-energy X-ray absorptiometry, and computed tomography).
We suggest that the management of steroid myopathy patients in clinical research and practice would benefit from a multidisciplinary approach based on the combined assessment of muscle mass, strength, and performance. However, further studies are required to establish an operational definition of steroid myopathy and to identify population-specific criteria for diagnosis of the myopathic process.
KeywordsGlucocorticoids Steroid myopathy Sarcopenia Muscle weakness Muscle atrophy
Steroid myopathy is a non-inflammatory toxic myopathy affecting the postural muscles more than the non-postural ones and the proximal part of a limb more than the distal one [1, 2]. Clinical features presented by patients include muscle wasting, weakness, and fatigability [1, 2]. In exogenous Cushing’s syndrome, the glucocorticoid dose that can induce myopathy varies greatly among patients . However, the lowest recommended dose should be used , especially for fluorinated glucocorticoid preparations that have a greater propensity for producing myopathy than non-fluorinated compounds [1, 3].
The clinical management of steroid myopathy is complicated as there are no means to detect the onset of the myopatic process before the appearance of clinical signs . In this contribution, we reviewed the different tools currently adopted for diagnosis and monitoring of steroid myopathy in order to examine their limitations and measurement properties and to highlight the need of establishing an operational definition of steroid myopathy in order to make studies comparable and for implementation in the clinical care.
Muscle strength assessment
Most physicians evaluate the muscle impairment in steroid myopathy patients by manual muscle testing that consists in a semiquantitative assessment in which muscle strength is subjectively given a grade: the lowest grade indicates no contractility and the highest grade represents normal motion [5, 6].
An approach alternative to the semiquantitative strength assessment is the direct quantification of the isometric muscle strength . Although isometric activity is rare in daily life, measurement of isometric strength is simple, valid, reliable, and has a strong predictive relationship to functional capacity [5, 7]. Moreover, normative data for isometric strength measurements are available [6, 8, 9].
Khaleeli et al.  investigated the quadriceps isometric strength in patients with endogenous (n = 6) and exogenous (n = 3) Cushing’s syndrome and documented bilateral quadriceps weakness. Another study by Khaleeli et al.  documented, in a small (n = 4) group of patients with Cushing’ syndrome studied before and after surgery, a pre-to-post-intervention increase in quadriceps maximal isometric force (that was paralleled by the recovery of muscle atrophy).
Although not only muscular but also neural mechanisms may underlie the muscle weakness of steroid myopathy patients , we suggest that the systematic incorporation of dynamometers into routine examinations of patients can be useful for diagnosis and monitoring of the myopathic process.
Pathological changes induced by glucocorticoid excess have been extensively analyzed [10, 11, 13, 14]. The commonest histopathological findings are a preferential atrophy of type 2 muscle fibers and a distinct lack of necrosis or regeneration [1, 10, 13, 14]. Atrophy of oxidative (type 1) fibers can also be observed, although to a lesser degree . In general, a great variability in the muscular pathology is observed and may depend on many factors including disease duration or duration/dosage of glucocorticoid treatment, basal levels of physical activity, clinical status, and nutrition. The worsening or the correction of the glucocorticoid excess can be paralleled by changes in biopsy findings: in fact, also type 1 fibers show reduction in size and lipid droplets in severe steroid myopathy , while the recovery of the fiber atrophy usually occurs after correction of the hormonal disorder or glucocorticoid withdrawal [11, 14].
It is, however, worth mentioning that the above reported biopsy findings can also be found in other conditions characterized by preferential type 2 fiber atrophy, such as ageing, neuropathic processes, muscle wasting of chronic disorders [15, 16, 17]. Therefore, the test sensitivity is high, but its specificity is low. In addition to the qualitative inspection of biopsy samples, quantitative analyses of skinned single muscle fibers can be useful in diagnosis of steroid myopathy [18, 19]. Reliability of these measurements has been proved [15, 18]: therefore, they can be used to add objectivity and sensitivity (through the quantification of fiber cross sectional area, specific force, unloaded shortening velocity, myosin concentration) to the “impression” of type 2 fiber atrophy that may result from the qualitative inspection of biopsy samples. However, to our knowledge, no previous study investigated the possible correlations between these histopathological findings and surrogate markers of disease severity.
Needle electromyography (EMG) is normal in most steroid myopathy patients and only a mild reduction of the amplitude of the motor unit action potentials with low-grade spontaneous activity can be observed in few patients . This is the result of a limitation of the examination with respect to this particular disease: the paucity of electrophysiological signs is understandable given the histopathologic finding of preferential type 2 fiber atrophy. The first motor units that are recruited during a voluntary contraction are composed of type 1 fibers (slow motor units). Because these fibers are not affected as severely as type 2 fibers, there is little electrophysiological dysfunction to observe. If the patient is asked to increase the contraction force to recruit also motor units composed of type 2 fibers (fast motor units), abnormalities could occur but cannot be observed. In fact, when fast motor units are recruited, too many slow motor units are concurrently activated, creating overlap of motor unit action potentials and loss of information. However, when the disorder is severe enough to compromise also type 1 fibers, abnormalities may occur and may be observed also for low contraction forces.
Motor and sensory nerve conduction studies are typically normal and also repetitive stimulation studies do not reveal significant changes in steroid myopathy patients [14, 20]. On the contrary, surface EMG could unravel a muscle abnormality in patients with steroid myopathy: in fact, we previously observed in healthy subjects after short-term glucocorticoid administration  as well as in patients with Cushing’s disease  a slowing of the muscle fiber conduction that was related to the glucocorticoid-induced atrophy of muscle fibers. However, the same electrophysiological abnormality can also be observed in several other physiological (i.e., immobilization) or pathological (i.e., ageing, medication use, neuromuscular disorders) conditions that reduce muscle fiber size . Therefore, the test sensitivity is high, but its specificity is low, thus surface EMG investigation cannot be recommended for the assessment of the glucocorticoid-related muscle impairment in daily clinical practice.
Elia et al.  measured the urinary 3-methyl histidine (3-MH) to creatinine ratio in several pathological conditions and found normal ratio in one patient with Cushing’s disease and increased ratio in two glucocorticoid-treated patients and in one patient with ectopic ACTH production. Khaleeli et al.  showed in patients with Cushing’s syndrome increased 3-MH/creatinine ratio and reduced plasma creatine kinase (CK) activity. Consistent with the latter finding, we observed a decrease in circulating levels of CK and myoglobin in patients with Cushing’s disease compared to healthy controls . Possible explanations for the observed findings are increased muscle protein degradation (that increases the 3-MH/creatinine ratio) and decreased muscle protein synthesis (that decreases the circulating levels of CK and myoglobin). However, the urinary excretion of 3-MH is influenced by dietary meat intake and its increase can also be the result of drug-induced skeletal muscle toxicity , while the decreased circulating levels of muscle proteins can be masked by exercise-induced muscle damage. To our knowledge, no reliable (urinary or circulating) biomarker that could be utilized in clinical and research settings to identify steroid myopathy, track its progression over time, and monitor its response to interventions is currently available.
Muscle mass assessment: dual-energy X-ray absorptiometry and bioelectrical impedance analysis
Dual-energy X-ray absorptiometry (DXA)-derived measures of lean mass and bioelectrical impedance analysis (BIA)-derived estimations of muscle mass are extensively used in clinical research and in routine assessments of nutritional status and sarcopenia [26, 27]. The basic measurement output parameters from DXA devices include whole body and regional measurements of bone mineral density, lean soft tissue mass, and fat mass . BIA measures the impedance when an alternating potential is applied to the body. The impedance measure is used to estimate total body water, fat free mass, muscle mass , and appendicular muscle mass  by means of predictive equations. Normative data of total body and appendicular muscle mass are available for different populations [30, 31, 32, 33]. Moreover, the reliability of these methods for body composition assessment in healthy subjects and patients has been documented [27, 31, 32, 33]. Overall, the use of DXA- or BIA-derived indices for identification of muscle atrophy is practical for clinical purposes, but they do not seem very accurate . This is because muscle atrophy is not a uniform condition as it affects postural muscles more than non-postural ones [35, 36]. Moreover, the two methods require the assumption of constant (for DXA) or normal (for BIA) hydration of the fat free mass . Therefore, sensitivity and responsiveness of these methods in Cushing’s syndrome (and/or other conditions associated to changes in the hydration of the fat free mass) are poor. Consistently, Kemink et al.  found in patients under glucocorticoid replacement therapy that BIA underestimated and DXA overestimated fat free mass in comparison to a four-compartment model combining different techniques (underwater weighing, deuterium dilution, and DXA). In addition, Pirlich et al.  found a low agreement between BIA and total body potassium counting for body composition assessment in patients with Cushing’s syndrome. They also found that the BIA-derived fat free mass remained on a constant low level and did not increase (to normal values) within the 6 months after surgical intervention . Moreover, to our knowledge, no previous study investigated the possible correlations between DXA- and BIA-derived indices and surrogate markers of disease severity in steroid myopathy.
On the bases of the considerations above, we suggest that DXA- and BIA-derived estimations of muscle mass cannot be recommended for the assessment of the glucocorticoid-induced reduction of muscle mass in daily clinical practice.
Muscle mass assessment: imaging techniques
Khaleeli et al.  showed in patients with Cushing’ syndrome a pre-to-post-intervention increase in cross sectional area of thigh and calf muscles investigated through computed tomography (CT). In a more recent study, Miller et al.  assessed, in CT scans of patients with hypercortisolism and healthy controls, cross sectional area and density of the psoas muscles that resulted lower in the former compared to the latter group. Moreover, they found a significant negative correlation between psoas muscle density and urinary free cortisol. However, the use of CT for the assessment of muscle size (i.e., muscle cross sectional area) and structure (i.e., muscle density) is complicated by high costs and unnecessary exposure to radiation.
Another recent tool for the investigation of myopathy is magnetic resonance imaging (MRI) that has been used in diagnosis and follow-up of inflammatory myopathies [3, 41] as well as in sarcopenia investigation as it enables to investigate not only muscle size but also muscle fat infiltration . Unfortunately, no study thus far has been conducted to investigate the usefulness of MRI for diagnosis and monitoring of steroid myopathy.
An alternative technique for measuring muscle size is ultrasonography: although it is simple, valid, reliable [43, 44] and it has been previously adopted to quantify the muscle size changes in different physiological and pathological conditions [45, 46, 47, 48], we are not aware of previous studies investigating the glucocorticoid-induced impairment of muscle mass through ultrasonography.
Different investigations are available for diagnosis and monitoring of steroid myopathy, while no tools are currently available for prediction and prognosis of the myopathic process.
Given the available evidences on the usefulness of the quantitative assessments of muscle mass and strength for detecting and tracking the progression of muscle atrophy and weakness in different disorders, we suggest these measurements should be systematically incorporated also into routine examinations of steroid myopathy patients.
We also suggest that the clinical experimental paradigm that has established for diagnosis of sarcopenia in the elderly through the combined assessment of muscle mass, strength (by isometric dynamometry), and performance (through one or more of the following assessments: Short physical performance battery, usual gait speed measurement, 6-min walking test, stair climb power test) [49, 50] could also be applied in the routine examination of steroid myopathy patients. It is, however, worth mentioning that the use of cutoff points (for low mass, strength, and performance) proposed to identify elderly sarcopenic patients could underestimate the mass, strength, and performance impairments of steroid myopathy patients. Therefore, further studies are required to establish an operational definition of steroid myopathy and to identify population-specific criteria for diagnosis of the myopathic process.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
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