Overview of Myopathies: Clinical Approach


The history provides clinical clues. In most myopathies, weakness is proximal, affecting movements of the hips, thighs, shoulders, and upper arms. Typically, these patients have difficulty climbing stairs, arising from low chairs, and carrying out tasks above their head, such as placing a book on a high shelf or brushing their hair. Less commonly, weakness is distal (affecting movements of the feet/toes and hands/fingers), manifested by tripping over uneven terrain because of footdrop or difficulty opening jars. Much less commonly, weakness affects the cranial muscles so that patients report ocular symptoms (lid drooping, or ptosis), difficulty swallowing (dysphagia), effortful speech (dysarthria), and sometimes inability to keep the neck straight up, leading to a head-drop.


Associated “negative” symptoms of muscle disease include fatigue, exercise intolerance, and muscle atrophy. “Positive” symptoms often point in the direction of a specific myopathy. For example, myalgias tend to be associated with a toxic or infectious myopathy, with certain forms of inflammatory myopathy (associated with connective tissue disease) and with some myotonic myopathies. Cramps suggest metabolic or endocrine myopathies; stiffness or impaired relaxation of muscle points to the possibility of myotonia, as seen in the myotonic disorders; episodic tea-colored urine or myoglobinuria is strongly suggestive of a metabolic myopathy; and complaints of muscle enlargement, deemed muscle hypertrophy by the clinician, is often associated with muscular dystrophy, notably the dystrophinopathies.


Determining onset, duration, and evolution of muscle disease enhances the effectiveness of the diagnostic process. For example, weakness presenting at birth suggests some forms of congenital myopathy and infantile myotonic dystrophy; weakness emerging in childhood is typical of most types of muscular dystrophy, congenital myopathy, metabolic and mitochondrial myopathy, and rarely, inflammatory myopathy; and later-onset weakness, coming on in adulthood, is often seen in inflammatory, toxic and endocrine myopathies, and less commonly, is a first manifestation of muscular dystrophy and metabolic and mitochondrial myopathies.


In the vast majority of myopathies, weakness, once established, is fairly stable or constant over the course of a 24-hour period and is relatively uninfluenced by physiologic state (for example, active or resting, or fasting or postprandial). There are certain muscle diseases, however, such as the periodic paralyses and the metabolic myopathies, that are characterized by episodic weakness of varying intervals and intensity, and with or without concomitant metabolic derangements such as myoglobinuria. Disorders of neuromuscular transmission, particularly myasthenia gravis, have a diurnal variation that is worse in the evening.


The rate of the progression of weakness over time offers a clue to the character of the myopathy. Acute to subacute progression (that is, weakness evolving over weeks to several months) is typically seen in inflammatory myopathies (polymyositis/dermatomyositis). Chronic progression (with weakness developing over many months to years) is typical of most muscular dystrophies and the inclusion body myositis (IBM) form of inflammatory myopathy. Nonprogressive or mildly progressive weakness over the course of decades is characteristic of most forms of congenital myopathy, which explains why, in some rare instances of mild congenital myopathy, diagnosis is not established until adulthood.


Obtaining a detailed family history in any patient with a suspected myopathy is crucial to unlocking an underlying inherited disorder and identifying its pattern of inheritance. Patients are asked to reflect on certain details of their relatives’ medical history, such as overall strength, functional capacity, ability to walk and run, whether there was a need for assistive devices or orthoses to walk, need for a wheelchair or scooter, history of cardiac disease, whether the patient’s (i.e., proband’s) symptoms were shared by males and females or were gender specific. Armed with such information, the clinician may have a heightened index of suspicion for an inherited muscle disease. This places the physician in the position to hypothesize the pattern of inheritance (autosomal dominant, autosomal recessive, X-linked, or mitochondrial) and thereby improve the ability to provide genetic counseling.


Clues to the diagnostic process are often found in exploring the patient’s medication list, exercise experience, dietary preferences, and motor function in a cool or cold environment. For example, subacute myopathies in adulthood may have a toxic etiology, caused by a cholesterol-lowering agent (statin), colchicine use for gout, or chronic alcohol use. Corticosteroids prescribed for a wide spectrum of medical disorders may be responsible for a subacute or chronic myopathy. In susceptible individuals with a glycolytic pathway defect, short bursts of intense activity sometimes lead to muscle cramping, weakness, and myoglobinuria. In contrast, patients having lipid oxidation disorders generally require longer periods of low-intensity exercise to predispose to muscle weakness and myoglobinuria. In individuals with a genetic predisposition to periodic paralysis, a high-carbohydrate meal is sometimes the trigger for an attack of severe muscle weakness. Muscle stiffness worsening with cold exposure is typical of paramyotonia congenita.


The physical examination provides additional important clues that help in the diagnostic process. Some myopathies affect tissues other than skeletal muscle per se, because they are multisystem disorders, such as myotonic dystrophy. In this instance, extramuscular involvement may be truly multiorgan and multisystem, including cataracts, arrhythmia, cognitive impairment, and glucose intolerance. In others, concomitant cardiac muscle skeletal muscle involvement occurs as in the dystrophinopathies, Emery-Dreifuss muscular dystrophy (EDMD), and polymyositis/dermatomyositis, and there may be a serious concomitant cardiomyopathy, with a clinical course punctuated by arrhythmia and congestive heart failure. Although the diaphragm is a striated muscle, it is infrequently involved in muscle disease, with notable exceptions, including myotonic dystrophy type I, centronuclear myopathy, nemaline myopathy, and acid maltase deficiency.


Muscle thinning, or hypertrophy, especially enlarged calves, are important clinical signs that often suggest a dystrophinopathy or congenital myopathy. Dysmorphic features may be associated with congenital myopathies; nemaline myopathy is a good example, especially exhibiting an elongated facies, high-arched palate, and foreshortened toes. Skin changes, especially a rash over the face and hands, are typical of dermatomyositis. Musculoskeletal contractures indicate long-standing, usually inherited myopathies: Emery-Dreifuss muscular dystrophy and Bethlem myopathy. Myopathies presenting within the context of pronounced multiorgan involvement suggest sarcoidosis, amyloidosis, endocrinopathies, connective tissue, infectious disorders, and mitochondrial cytopathies.


Distribution of muscle weakness provides a clue to the diagnostic process. In most myopathic disorders, the proximal and limb-girdle muscles bear the brunt of involvement; but there are important exceptions. Distal muscle involvement is quite characteristic of classic myotonic dystrophy type I and dysferlinopathy. Ocular weakness is often an early manifestation of mitochondrial myopathy and oculopharyngeal muscular dystrophy (OPMD).


Laboratory tests often provide diagnostic confirmation in the clinical context of a patient with suspected myopathy. These tests include serum creatine kinase (CK) levels, which are elevated in myopathic disorders marked by muscle fiber necrosis and normal in muscle disorders with little injury to the muscle fiber membrane. Electrodiagnostic studies will show early recruitment of short-duration, low-amplitude motor unit potentials in weak muscles, irrespective of the cause of the myopathy. However, fibrillation potentials and positive sharp waves primarily occur in aggressive myopathies, including inflammatory, toxic, or dystrophic types. These potentials are less commonly seen in most congenital and endocrine myopathies.


Muscle biopsy analysis by light microscopy usually provides information that helps corroborate the classification into inherited and acquired myopathy and often provides further diagnostic specificity (for example, acquired myopathy that is inflammatory with features of dermatomyositis). Immunohistochemical analysis of frozen muscle tissue sections identifies specific muscle proteins when muscular dystrophy is suspected. In cases where muscular dystrophy is suspected but cannot be confirmed by immunohistochemical studies, molecular genetic testing by deoxyribonucleic acid (DNA) analysis of leukocytes can sometimes confirm the diagnosis of a muscular dystrophy by identifying a specific known mutation. In selected cases, when metabolic myopathy is suspected, biochemical analysis of frozen muscle tissue for analysis of the glycolytic, oxidative, or mitochondrial metabolic pathways can be performed.


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Sep 2, 2016 | Posted by in NEUROLOGY | Comments Off on Overview of Myopathies: Clinical Approach

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