Neuroscience/Muscle disorders

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  • When presented with a patient s history and the results of a physical examination, students will be able to differentiate between myopathic and neurogenic muscle weakness based on the history and physical examination.
  • When presented with a patient s history and the results of a physical examination students can begin to formulate a differentiate diagnosis for myopathic weakness into broad diagnostic categories, based on the pattern of weakness. Diagnostic categories include the inflammatory myopathies, muscular dystrophies, other inherited myopathies, endocrine myopathies, toxic myopathies, and channelopathies/myotonias.
  • When asked students can list the common drugs that can cause toxic myopathies.
  • When the diagnosis of a myopathy is suggested by the history and physical examination students will be able to formulate a logical sequence of investigations which will include taking a family history, appropriate biochemical and hematological investigations, electrophysiological studies, and sometimes tissue diagnosis (muscle biopsy).



  • Lecture slides have lightbulbs
  • Myopathy patterns: 4 light bulbs
    • Limb girdle
    • Distal
    • Scapuloperoneal
    • Distal forearm, proximal leg
    • Oculopharyngeal
    • Neck extensor


Draft - Myopathy

Myopathy: Usually proximal, occasionally distal weakness (myotonic dystrophy), often symmetric, preservation of deep tendon reflexes, no sensory abnormalities.

A} Hereditary muscle diseases Congenital myopathies - rare Disorders of muscle energy metabolism e.g. McArdle s - rare Mitochondrial myopathies not so rare Myotonias and channelopathies e.g. myotonic dystrophy, periodic paralyses - uncommon Muscular dystrophies e.g. Duchenne s, Becker s, Facioscapulohumeral MD

B} Acquired myopathies Inflammatory myopathies e.g. polymyositis, dermatomyositis, inclusion body myositis Toxic myopathies e.g. steroid myopathy Endocrine myopathies e.g. hypothyroid


a) Myotonia (increased muscle irritability and contractility with decreased relaxation): Clinical: Delayed relaxation of muscles after voluntary contraction, often appreciated by the patient as stiffness . Most common disorder is myotonic dystrophy (DM1), with a prevalence of 1 per 5-10,000 population. Usually have characteristic phenotype of frontal balding, apathy, temporal wasting, slurred speech, weakness of face, neck, distal arms > distal legs. (Remember, it is one of the few myopathies with a predominantly distal weakness). One of the more common hereditary muscle diseases and often unrecognized. Many non-muscle manifestations including excessive somnolence, cataracts, cardiac conduction defects, smooth muscle involvement.

Diagnosis: The insertion of a needle into muscle (needle electromyography) discloses trains of repetitive discharges with a waxing and waning phenomenon, ie. dive-bomber phenomenon 4 as heard by the electromyographer. The gene abnormality has been localized to the long arm of chromosome 19 (19q 13.3), and specific genetic tests are available. More recently a second hereditary mytonic disorder with predominantly proximal weakness and less cardiac involvement, PROMM (Proximal myopathy with myotonia; DM2) has been recognized and is secondary to a CCTG repeat in the zinc finger 9 gene on chromosome 3.

b) Channelopathies: Rare disorders with mutations in ion channels, usually chloride, sodium or calcium. Clinical: Present with episodic muscle weakness, cramps or stiffness. Diagnosis: The clinical history of weakness or paralysis after the precipitating events listed above. The EMG may show myotonic discharges. Provocative tests to raise or lower potassium may reproduce the symptoms. Treatment: Depends on type. Dietary changes and drugs (e.g. acetazolamide) which affect channel function or the potassium level may help.

THE MUSCULAR DYSTROPHIES Definition: Progressive, genetically determined, primary degenerative myopathies. Many are now known to be secondary to abnormalities to one of the structural muscle proteins (see Figure 1, FYI). Fig 1 5 Figure 2

a) Duchenne (DMD) And Becker's (BMD) Muscular Dystrophy The two conditions are allelic disorders and are the result of a mutation at Xp21 of the gene for dystrophin. Dystrophin (~400 Kd) is localized in the sarcolemma of skeletal muscle fibres and provides mechanical stability for the surface membrane. Deletions giving rise to the severe Duchenne MD result in a disruption of the translational open reading frame and thereby in a severely truncated gene product. Dystrophin staining in sarcolemma is absent. In the milder Becker's variant, the translational reading frame is maintained, but the gene product is shorter and semifunctional. Clinical (Duchenne): The disease is present at birth; becomes symptomatic in early childhood (age 3-5 y) and leads to failure of ambulation towards the end of the first decade (age 10-14 y). Progressive respiratory involvement is fatal often in the second or third decade. " Early signs: Pelvic girdle weakness - awkward running, frequent falls, difficulty climbing stairs. Hypertrophy of calves (Figure 2) and atrophy of thigh muscles; Achilles tendon contracture - toe walking; pelvic tilt and hyperlordosis; Gower's maneuver. " Later signs: Relentless progression and involvement of shoulder girdle muscles, inability to ambulate; scoliosis and thoracic deformity, contractures. Clinical (Beckers): Later onset with progression of muscle weakness at much slower rate; patients remain ambulatory into adolescence or adult life. If they have children, female offspring have a 100% risk of carrier status. Patients often experience exercise induced muscle pain and intermittent rhabdomyolysis and myoglobinuria. Cardiac involvement, previously thought to be uncommon, is now recognized to occur in 60 to 80% of patients and is manifest by early right ventricular involvement and later left ventricular impairment, which is frequently subclinical. Intellectual impairment is rare. Female carriers may sometimes be manifesting carriers with hypertrophic calves, mild weakness, and an elevated serum CK. Diagnosis: Clinical suspicion with an appropriate family history. However many patients may represent sporadic mutations. The biopsy suggests a dystrophic process. Immunostaining for dystrophin shows an either absent or reduced staining pattern. Genetic studies are available for 60 to 70% of mutations which consist of a large deletion, but are not yet available for smaller point mutations. Treatment: Not yet available. Temporary stabilization with treatment of steroids. Gene replacement therapy, to date, is not possible.

b) Facioscapulohumeral Dystrophy (FSHD) FSHD is an autosomal dominant disorder, causing a distinct pattern of weakness of variable severity. Linkage to markers on chromosome 4q35 has been well established. The disease 6 Figure 3 is common - prevalence 1:10,000, but of very variable clinical severity. Penetrance is high, but signs may only be recognized by careful clinical examination. Symptoms usually become apparent within the first 3 decades; beginning with facial weakness (asymmetrical smile, inability to whistle or suck from a straw, inability to fully close eyes or burrow eyelashes) progressing to scapular and shoulder weakness (scapular winging - Figure 3), inability to lift arms, arm weakness) and successive involvement of foot extensors (foot drop), abdominal and pelvic girdle muscles (severe lumbar lordosis and pelvic tilt). Although characteristic for this disorder, facial weakness is often very mild and may falsely suggest a limb girdle muscular dystrophy (see below). Characteristic for FSHMD is asymmetric weakness. The life expectancy is not reduced; 10% will become wheelchair bound; 30% of gene carriers are relatively asymptomatic. The progression is slow, with apparent periods of arrest. Diagnosis: Typical clinical pattern; CPK normal or mildly elevated. EMG mildly myopathic; muscle bx varies according to severity of clinical muscle involvement. Focal lymphocytic infiltrates are a common finding, yet steroids or immunosuppressive drugs are ineffective. There is a genetic test available which will detect many but not all cases. Treatment: None available

c) Limb Girdle Muscular Dystrophy (or Limb Girdle Syndrome) This diagnosis was often applied to patients with a diverse group of etiologies, sharing the common feature of proximal weakness of arms and legs. It is now known that some of these represent neurogenic disorders, while many represent other muscular dystrophies with unusual presentations (see above). Modern genetic studies have now allowed the classification of these disorders into a group of autosomal dominantly inherited LGMD s, and a rarer group of more severely affected autosomal recessively inherited LGMD s. Chromosomal localization has been established for many of these. In many, the mutation affects one of the structural proteins in muscle membrane (see Figure 1). Diagnostic features: Generally proximal, sometimes distal weakness. Sometimes other associated systemic features. EMG shows a myopathic pattern. Muscle biopsy suggest a dystrophic Differential diagnosis: Includes the dystrophinopathies (Duchenne s and Becker s) inflammatory myopathies, metabolic myopathies and spinal muscular atrophies.

INFLAMMATORY MYOPATHIES a. Polymyositis b. Dermatomyositis c. Inclusion body myositis d. Infectious 7 viral/post viral parasitic bacterial fungal protozoal e. Other sarcoid and other granulomatous focal myositis eosinophilic

a/b) Polymyositis/Dermatomyositis Etiology: The cause remains unknown. Current knowledge of pathological and immunological features justifies a separate classification. The existing evidence suggests that the muscle fibre damage in polymyositis is mediated by cytotoxic T cells (CD8+). In dermatomyositis a humoral mechanism, mediated by CD4+ T lymphocytes and B lymphocytes, with immune complex (antibody-antigen) mediated toxicity is more important. In dermatomyositis it appears to be more of a vasculitic process with involvement of intramuscular blood vessels resulting in ischemic damage to the muscle fibres. The association of the individual disorders with connective tissue diseases favors the notion of a common autoimmune etiology and pathogenesis. In older patients, dermatomyositis (and probably not polymyositis) is associated with an increased risk of an underlying malignancy. The malignancies found are those in a similar aged matched population (eg. lung, colon, breast, ovary, gastric), but appear to be present at roughly twice the rate of those in individuals who do not have dermatomyositis. Clinical Features: Subacute, insidious development (weeks to months) of symmetrical weakness of proximal shoulder and pelvic girdle muscles with difficulty rising from a seat, climbing stairs, lifting arms, etc. Characteristic neck flexor weakness and dysphagia. Distal muscles usually but not always spared. Cardiac involvement in 20%, respiratory muscle involvement in 5%. Occasional diffuse aching pain, arthralgias, positive Raynaud phenomenon.

a) Polymyositis: Clinical Features: See above

Figure 4 b) Dermatomyositis Clinical Features: The degree and pattern of weakness is identical to that in polymyositis, but in addition characteristic dermatological features are seen: lilac discolouration of eyelids and periorbital edema, butterfly rash, erythematous rash on anterior neck, chest, extensor surfaces of the extremities, joints, knuckles and round nail beds (Fig 4) - scaling ezcematoid dermatitis or exfoliative dermatitis. Pigmentary skin changes and 8 subcutaneous calcifications - particularly in childhood dermatomyositis. Loss of hair. Laboratory Findings: " In polymyositis and dermatomyositis the serum CPK (creatinine phosphokinase) is usually (75 to 90%) moderately to markedly elevated, although may be normal. " Elevation of erythrocyte sedimentation rate (ESR) IN 2/3 of cases. " Characteristic EMG findings: low amplitude, short duration and polyphasic motor units, ie. myopathic. Increased insertional activity, with fibrillation potentials and positive sharp waves, is more specifically suggestive of an inflammatory myopathy as opposed to other causes of a myopathy. Similar changes may be seen in neuropathic disorders. " Characteristic muscle biopsy findings (you don t need to know this): Polymyositis: Perivenular and interstitial inflammatory infiltrates (lymphocytes, plasma cells, macrophages). Scattered single-fibre necrosis mediated by cytotoxic (CD8+) T lymphocytes and macrophages. Muscle fibre regeneration. Dermatomyositis: Perivascular inflammation (CD4+ lymphocytes and B lymphocytes) Marked vascular change: endothelial cell hyperplasia, immune complex deposition, perivascular inflammation, thrombosis, capillary loss _ ischaemic perifascicular muscle fibre atrophy. Occasionally segmental infarction. Characteristic tubuloreticular inclusions within the endothelial cytoplasm. " supportive clinical and laboratory findings for associated connective tissue diseases in the overlap group. Differential Diagnosis: inclusion body myositis, metabolic myopathies (thyroid disease), myasthenic syndromes, drug-induced myopathies, post-viral myopathies, sarcoidosis, muscular dystrophy (FSHD which may occasionally have inflammatory infiltrates on biopsy). Treatment: " Corticosteroids: (prednisone 1-2 mg/kg/day). Slow tapering according to clinical response and CPK level. Maintenance dose 5 - 10 mg/alternate days for several years. " Cytotoxic Drugs: azathioprine 2-3 mg/kg/day. Cyclophosphamide or methotrexate are reserved only for poor responders. " Plasma exchange and intravenous immunoglobulin effective in dermatomyositis. " N.B.: high dose steroids may not be tolerated by the elderly patients and have the potential of causing a number of complications including steroid myopathy, which may be confusing in a patient already weak because of an inflammatory myopathy, as well as osteoporosis. 9 " immunosuppressive therapy is not effective in inclusion body myositis and therefore it is very important at an early stage to differentiate inclusion body myositis from polymyositis or dermatomyositis. Fig 5

c) Inclusion Body Myositis (IBM): Much more prevalent than thought, and likely as common as both polymyositis and dermatomyositis combined. Often elderly individuals and more common in men. A characteristic pattern of muscle weakness (proximal and distal; forearm flexors (Fig 5) and quadriceps, hand intrinsics and ankle dorsiflexors) may be seen. 40% or more of patients may have significant dysphagia. Not associated with an underlying malignancy. Rarer cases are hereditary. The serum CK may be normal or only slightly elevated. The findings on EMG are very similar to those in DM and PM, although in general the degree of insertional activity is less. On biopsy the degree of the inflammatory response is less, and characteristic rimmed vacuoles with inclusions are seen. Several trials have conclusively shown that individuals with IBM do not respond to immunosuppressive therapy, including intravenous immunoglobulin. In general this disease is slowly progressive. Fig 5

7. TOXIC MYOPATHIES Alcohol toxic+nutritional deficiencies: Excessive, especially acutely, consumption of alcohol in combination with poor nutrition may result in both focial and more diffuse muscle pain, swelling, proximal muscle weakness and myoglobinuria. This is compounded by the more frequent occurence of hypokalemia, hypophosphatemia and hypomagnesiumia. Drug induced or medication induced: Heroin, cocaine, amphetamine, prednisone, amphotericin B, HMG CoA reductase inhibitors, amiodarone, chloroquine, d-penicillamine etc. Can be associated with either insidious onset of proximal muscle weakness or bouts of myoglobinuria and reversible muscle weakness.

8. ENDOCRINE MYOPATHIES Hyperthyroidism: May be accompanied by proximal muscle weakness which is reversible with correction of the endocrinopathy. Attacks of hyperkalemic periodic paralysis may rarely occur, more commonly in oriental males. Hypothyroidism: May present with muscle weakness, stiffness and pain. 10 Steroid myopathy: Endogenous or exogenous elevations of glucocorticoids may result in profound reversible proximal muscle weakness often involving the legs more so than the arms.