25626ournal of Neurology, Neurosurgery, and Psychiatry 1996;60:256-274 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.3.256 on 1 March 1996. Downloaded from NEUROLOGICAL INVESTIGATIONS Investigation of muscle disease F L Mastaglia, N G Laing Various pathological processes, some geneti- such as the dystrophinopathies, encompassing cally determined and others acquired, may the Duchenne and Becker forms of muscular Australian affect the function of the skeletal muscles and dystrophy, the sarcoglycanopathies, which Neuromuscular may manifest in different ways. Some, such as include many cases of limb-girdle muscular Research Institute, the weakness University congenital myopathies, produce dystrophy, and the channelopathies comprising Departments of and hypotonia at birth whereas others do not the periodic paralyses and myotonic syn- Medicine and cause functional abnormalities until child- dromes. Department of hood, adolescence, or adult life. With the This review focuses on the modern Neurology and Clinical application of modem molecular biological approach to the clinical and laboratory investi- Neurophysiology, techniques major advances have taken place in gation of patients with muscle diseases with Queen Elizabeth II Medical Centre, Perth, the identificaton of the genetic mutations particular emphasis on the application of mole- Western Australia responsible for many of the hereditary muscle cular techniques in diagnosis. F L Mastaglia diseases and new mutations in nuclear or N G Laing mitochondrial DNA are being reported on a to Correspondence regular basis. 2 These discoveries have had a Clinical evaluation Department of Medicine, major impact on the diagnostic approach to The investigation of a patient with muscle dis- Centre, GBlock, Nedlands, patients with these disorders and have led to ease should always commence with a detailed Western Australia 6009. the definition of new categories of myopathy history which, in the case of known hereditary disorders, may provide an immediate indica- tion of the nature of the patient's condition. Table 1 Drug induced muscle disorders Moreover, a history of heavy alcohol con- Disorder Inducing drug sumption or administration of drugs with known myotoxic actions (table 1) may point to Myalgia Suxamethonium, danazol, clofibrate, salbutamol, lithium, captopril, a toxic and therefore potentially reversible colchicine, procainamide, metolazone, cytotoxics, zidovudine, http://jnnp.bmj.com/ isoetherine, zimeldine, labetalol, pindolol, cimetidine, penicillamine, aetiology for the patient's symptoms.3 A his- gold, enalapril, rifampicin, i.-tryptophan, nifedipine Myotonia Diazacholesterol, ,¢blockers,* «-agonists (fenoterol, ritodrine),* tory of a thyroidectomy or parathyroidectomy, clofibrate,t diuretics (frusemide, ethacrynic acid, mersalyl, or symptoms of hypothyroidism or hyperthy- acetazolamide)t Necrotising Alcohol, gemfibrozil, lovastatin, simvastatin, clofibrate, E-aminocaproic roidism, should alert the physician to the possi- myopathy acid, cyclosporin, zidovudine, cocaine, emetine bility of an endocrine cause whereas a history Mitochondrial myopathy Zidovudine of chronic diarrhoea, purgative misuse, or Inflammatory excessive consumption of liquorice or other myopathy D-penicillamine, i.-tryptophan, others rarely on September 23, 2021 by guest. Protected copyright. Autophagic myopathy Chloroquine, vincristine, colchicine, amiodarone, perhexiline preparations containing glycyrrhizinic acid Type 2 atrophy Corticosteroids such as snuff, chewing tobacco, and certain Localised myopathy Intramuscular antibiotics, narcotics traditional Chinese medicines, should suggest *May exacerbate myotonia. the possibility of hypokalaemic myopathy. A tMay cause myotonia in animals. history of malignancy, of a systemic connec- tive tissue disease, other autoimmune disease, or state may indicate a pre- Table 2 Disorders in which muscle pain may be a prominentfeature immunodeficiency disposition to an inflammatory myopathy. Inflammatory Hereditary When muscle is a feature, hypothyroid, Viral myositis Disorders of glycogen metabolism pain Pyomyositis Carnitine palmityl transferase deficiency osteomalacic or other metabolic myopathy, Parasitic myositis Myoadenylate deaminase deficiency infestation example, trichinosis), Polymyositis/dermatomyositis Mitochondrial myopathy parasitic (for Granulomatous myositis Dystrophinopathy or a toxic myopathy or neuromyopathy should Interstitial myositis Sodium channel myotonia be considered, (table 2), although in many Localised nodular myositis Malignant hyperthermia Vasculitis patients no specific aetiology will be found Eosinophilic fasciitis Others even with Fibromyalgia complete investigation. Myalgia, Toxic Polymyalgia rheumatica muscle weakness, or fatigue developing after Acute alcoholic myopathy Postviral myalgia/fatigue an acute viral infection also raises the possibil- Acute/subacute drug induced myopathies Muscle overuse syndromes Myopathies due to envenomation Myopathy with tubular aggregates ity of an inflammatory myopathy but in many Endocrine such patients when fatigue and reduced exer- Hypothyroidism cise tolerance are the major symptoms, a diag- Osteomalacia nosis of postviral chronic fatigue syndrome Hyperparathyroidism will usually be reached. Investigation of muscle disease 257 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.60.3.256 on 1 March 1996. Downloaded from In certain instances it may be possible to other types of muscular dystrophy or spinal reach a definitive diagnosis on the basis of the muscular atrophy, whereas more generalised pattern of muscle involvement found on clinical hypertrophy is common in myotonia con- examination or the finding of other distinctive genita. A hypertrophic myopathy may occa- features such as myotonia, fatiguability, muscle sionally occur in patients with amyloidosis, contractures, or other systemic features. sarcoidosis, or cysticercosis. Muscle contrac- Although the distribution of muscle involve- tures occur, especially in Emery-Dreifuss mus- ment in most of the acquired myopathies is rel- cular dystrophy, and are also a feature of the atively non-selective, in the genetic myopathies fibrosing myositis associated with scleromyx- certain patterns of muscle weakness are distinc- oedema.8 It is always worth looking for muscle tive and may be diagnostically helpful although it tenderness, which, when confined to certain is being increasingly recognised that the pheno- muscles such as those of the calves, may indi- typic manifestations of specific genetic defects cate a focal inflammatory or vasculitic process, may be very variable (for example, the dys- whereas the characteristic pattern of myofas- trophinopathies). Involvement of the extraocu- cial tenderness in patients with fibromyalgia is lar and eyelid muscles is seen characteristically virtually diagnostic of that condition. in oculopharyngeal muscular dystrophy, usually Depressed deep tendon reflexes or sensory associated with dysphagia and often with limb abnormalities in a patient with a myopathy muscle involvement. They are also involved in suggest the presence of an associated periph- the syndrome of chronic progressive external eral neuropathy. This combination can occur ophthalmoplegia, which is usually due to a in patients with drug induced neuromyopathy, mitochondrial myopathy and may occur in iso- connective tissue disease, inclusion body lation, or with a limb myopathy, or other sys- myositis, a paraneoplastic syndrome, or mito- temic features such as pigmentary retinopathy, chondrial myopathy. heart block, cerebellar ataxia, and sensorineural hearing loss as in the Kearns-Sayre syndrome. Involvement of the facial muscles is usually a Biochemical studies prominent feature in facioscapulohumeral mus- CREATINE KINASE cular dystrophy but may also occur in myasthe- The serum concentration of creatine kinase is nia gravis, when it is usually associated with the most reliable biochemical indicator of involvement of the extraocular muscles, and muscle disease. The highest concentrations often of the bulbar and limb muscles; fatigua- occur in patients with acute rhabdomyolysis, bility is a prominent feature. In myotonic dys- inflammatory or drug-induced myopathies, trophy there is often also involvement of the and Duchenne muscular dystrophy in the facial muscles and, characteristically, there is early stages when the patient is still ambulant. atrophy and weakness of the sternomastoids High concentrations may also occur in some and of the distal limb muscles in the later stages metabolic myopathies such as hypokalaemic or of the disease. Other systemic features which hypothyroid myopathy. Moderately raised point to the diagnosis include cataracts and, in concentrations may also be found in patients men, frontal baldness and testicular atrophy. with chronic neuropathic conditions such as Severe weakness of the neck extensor muscles spinal muscular atrophy or motor neuron dis- http://jnnp.bmj.com/ leading to the "dropped head syndrome"6 may ease, although it is rare for the creatine kinase occasionally be the presenting feature in to exceed 10 times the normal maximum con- patients with inflammatory myopathy and may centration in these conditions.9 Raised crea- also occur in motor neuron disease and long- tine kinase concentrations may also be found standing myasthenia gravis. Weakness confined in some people, without clinical evidence of to or most severe in the distal limb muscles also neuromuscular disease'0 and