EM guidemap - Myopathy and myoglobulinuria

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Introduction

General principles

Introduction

- this short guidemap supplements the neuromuscular weakness guidemap and offers the reader supplementary information on myopathies, and a short section on myoglobulinuria

- this guidemap only consists of a few brief checklists of "causes of the different types of myopathy" that an emergency physician may encounter in clinical practice when dealing with a patient with acute/subacute muscular weakness
 
General principles

- a myopathy is suggested when generalized muscle weakness involves large proximal muscle groups, especially around the shoulder and proximal girdle, and when the diffuse muscle weakness is associated with normal tendon reflexes and no sensory findings

- a simple classification of myopathy:-

Hereditary

Acquired - a myopathy can present with fixed weakness (muscular dystrophy, inflammatory myopathy) or episodic weakness (periodic paralysis due to a channelopathy, metabolic myopathy due to certain glycolytic pathway disorders)

- a myopathy can be acute (< 4 weeks), subacute (4 - 8 weeks) or chronic (> 8 weeks)

- channelopathies and certain metabolic myopathies can produce recurrent episodes of episodic weakness, while certain toxins (eg. cocaine) can produce a single episode of episodic weakness

- abnormal weakness after exercise suggests a channelopathy, or a metabolic or mitochondrial myopathy (mimics myasthenia gravis)

-  muscle pain (myalgia) is surprisingly infrequent in many myopathies, and the presence of episodic muscle pain suggests a metabolic myopathy, while constant muscle pain suggests an inflammatory myopathy

- muscle cramps are not common in myopathic disorders, and they strongly suggest anterior horn cell disorders eg. amyotrophic lateral sclerosis, or many non-specific conditions eg. dehydration and hyponatremia, azotemia, hemodialysis, pregnancy

- muscle contractures resemble cramps, but they last longer and are usually provoked by exercise in patients with glycogenolytic enzyme defects

- myotonia is the phenomenon of impaired muscle relaxation after a forceful muscle contraction; patients complain of muscle stiffness and difficulty releasing their handgrip after a handshake

- myotonia often improves after exercise (warm-up phenomenon), in contrast to paratonia where exercise makes the myotonia worse; both myotonia and paratonia are usually worse when exposed to the cold

(* paratonia suggests frontal lobe disease and is seen in association with other signs suggestive of frontal lobe disease eg. frontal gait ataxia, "gegenhalten")

- certain myopathies may produce rhabdomyolysis and myoglobulinuria, and the combination of weakness + muscle pain + discolored red urine after mild exercise, or prolonged exercise, suggests a metabolic myopathy eg. glycolytic pathway defect or fatty acid oxidation defect

(* strenuous anaerobic exercise can produce rhabdomyolysis and myoglobulinuria even in healthy people)

- muscle atrophy is a late finding in chronic progressive myopathies, and the pattern of muscle atrophy can suggest a particular myopathy eg. atrophy of the peri-scapular muscles causing scapular winging suggests fascioscapulohumeral dystrophy, selective atrophy of the quadriceps and forearm muscles suggests inclusion body myopathy

- the pattern of muscle weakness can suggest a particular myopathy

Endocrine myopathy

Hypothyroidism

- neuromuscular findings in hypothyroidism include proximal muscle weakness, muscle stiffness and cramping, muscle hypertrophy, slow reflexes and myoedema

(* myoedema is the phenomenon of rounding up of muscle tissue after light percussion)

- lipid-lowering drugs may exacerbate hypothyroidic myopathy

- the CK may be elevated up to 10X in hypothyroidic myopathy

Hyperthyroidism

- neuromuscular findings include proximal muscle weakness with atrophy, brisk reflexes, and bulbar weakness

- respiratory muscle weakness and respiratory failure is rare

- there may be some clinical overlap with myasthenia gravis, and medical treatement of the thyroid disease may exacerbate the myasthenia

- thyrotoxic hypokalemic paralysis is a rare phenomenon in Asian patients in their third decade

Hypoparathyroidism

- usually produces muscle tetany due to hypocalemia

- a myopathy rarely occurs

Hyperparathyroidism

- a proximal muscle weakness associated with easy fatigueability, atrophy and hyperrflexia may occur

Cushings disease

- usually produces an insidious onset of proximal muscle weakness and atrophy and myalgia

- iatrogenic steroid administration may produce a similar picture, and high-dose steroids may rarely produce quadriplegia and respiratory failure

Toxic myopathy

- there are many causes of a toxic myopathy, and one system of classifying toxic myopathy is as follows:-

Painless myopathies

Painful myopathies Drugs of abuse - the CNS sedatives produce a painless myoglobulinuric myopathy due to over-sedation and immmobilization resulting in pressure necrosis

Periodic paralysis

- there are many different types based on varying genetic abnormalities of the sodium, calcium or potassium channel

- this basic outline is a summary of some of the major types, which are most likely to produce severe episodes of  muscle weakness

Hypokalemic periodic paralysis

- due to a disorder of voltage-gated calcium (Ca2+) channel gene, CACNL1A3, chromosome 1q

- often runs in families (2/3 of cases)

- develops in early childhood and always < 30 years of age (otherwise consider thyrotoxic hypokalemic periodic paralysis or secondary hypokalemia-induced paralysis)

- attacks often occur during sleep in the early morning hours => on awakening the patient may have profound weakness and be unable to get out of bed

- attacks may be precipitated by a "trigger" on the preceding day - triggers include cold, strenuous exercise followed by rest, large carbohydrate meal

- proximal limbs and truncal musculature weak, cranial nerves and respiratory muscles usually spared

- attack lasts hours-days; usually 3 - 6 hours

- the serum potassium is usually low during attacks; however, the serum potassium may be normal

- over the years, in the absence of treatment, weakness may develop between attacks

- treatment in the ED should be oral potassium; avoiding IV potassium or IV glucose solutions

Thyrotoxic hypokalemic paralysis

- male predominance (80 - 95%)

- onset 20 - 40 years

- proximal weakness > distal weakness, legs > arms; weakness may selectively involve exercised muscles

- severe attacks may involve respiratory and bulbar muscles

- attacks last hours-days

- attacks often occur randomly without an obvious stimulus; attacks may be precipitated by rest after heavy exercise, a carbohydrate challenge and muscle cooling; attacks may be aborted by mild exercise

- underlying thyrotoxicosis, which may be sub-clinical (diagnosed by low TSH and increased radioiodine uptake by thyroid), is present; sporadic condition and not familial

- the serum potassium is usually low during attacks

- treatment of attacks includes propanolol +/- small amounts of oral potassium + treatment of thyrotoxicosis (IV potassium should not be used because the hypokalmia is a redistributive hypokalemia and hyperkalemia may occur if excess potassium is administered IV)

Andersen's syndrome

- onset 2 - 18 years

- presents with cardiac arrhythmia (bidirectional tachycardia) and prolonged QT interval due to kypokalemia, and/or episodic muscle weakness (1 hour - few days)

- associated clinical findings include hypertelorism, hypoplastic mandible, low-set ears, malar hypoplasia, short stature, scoliosis, lateral or medial curvacture of a finger or toe

- serum potassium may be low, normal or high during attacks, and the attacks can be precipitated by exercise or potassium loading (in contrast to hypokalemic periodic paralysis, where potassium loading improves strength)

- raising serum potassium may precipitate weakness, but normalize the ECG; while lowering serum potassium may improve strength but worsen the ECG abnormalities

- permanent weakness occasionally occurs

- no known optimum treatment

Hyperkalemic periodic paralysis

- onset during infancy and childhood (< 10 years) with no sex predisposition

- dues to a sodium channel gene abnormality

- attacks of weakness occur during periods of hyperkalemia (which defines the disease)

- attacks may be precipitated by potassium loading, exercise, fasting, cold temperatures and emotional stress; attacks last 1 - 3 hours and rarely days; attacks occur more frequently than they occur in hypokalemic periodic paralysis and are usually less severe and shorter in duration

- serum potassium level may actually be normal, or even low, after the onset of an attack (which does not define the disease)

- weakness usually involves proximal muscles, and occasionally only the exercising muscles

- weakness may be relieved by carbohydrate loading (opposite of hypokaleic periodic paralysis) and mild exercise

- patients may have evidence of myotonia (inability to relax muscles) or paramyotonia (muscle stiffness worsened by exercise and cold) between attacks

- permanent weakness may eventually develop if not treated prophylactically between attacks (responds to acetazolamide)

Myoglobinuria

Myoglobinuria refers to an abnormal pathologic state in which an excessive amount of myoglobin is found in the urine causing the urine to appear coca-cola colored, usually in association with severe muscle injury and a clinical picture of muscle weakness +/- myalgias +/- muscle tenderness and swelling

- the myoglobinuria usually reflects an underlying state of rhabdomyolysis and associated laboratory abnormalities may include hyperkalemia, hyperphosphatemia, hypocalcemia and hyperuricemia, and laboratory evidence of secondary renal failure (increased serum BUN and creatinine and brownish casts containing renal tubular cells)

(* hemoglobinuria may also cause a brownish urine and be secondary to hematuria or intravascular hemolysis - in hematuria red cells are present in the urine + serum is clear, while in IV hemolysis the urine contains no red cells, the serum is pink and the serum CK is negative)

- the serum CK is characteristically elevated (often > 10 - 100x normal)

Causes of myoglobinuria

Hereditary causes of myoglobinuria

- metabolic myopathies with identified enzyme defects and non-identified defects, and includes disorders of glycolysis or glycogenolysis or fatty acid oxidation or mitochondrial oxidation defects

- myoglobinuria may occur following exercise, infection, fasting, or exposure to an offending drug

Disorders of glycolysis or glycogenolysis

- an attack of myoglobinuria may be the presenting complaint in patients with glycogen storage myopathies, and the disorders are characterized by recurrent episodes of muscle pain, muscle weakness and muscle cramps +/- myoglobinuria

- the attacks may be precipitated by intense exercise, especially under anaerobic conditions, and the muscle symptoms may be localized to the exercising muscles

- the disorder usually presents in childood, and the patients often have a family history, a mild baseline elevation of CK and low-level myoglobinuria

- the disorders are all characterized by abnormal glycogen accumulation in muscle biopsy specimens

- specific identified enzyme defects include phosphorylase (McArdle's disease), phosphofructokinase, phosphoglycerate kinase, phosphoglycerate mutase, lactate dehydrogenase, phosphorylase b kinase and debrancher

Disorders of fatty acid oxidation

- characterized by recurrent attacks of myoglobinuria and exercise-induced myalgia that occur during prolonged activity, particularly when glycogen stores have been depleted and the exercising muscle is dependent on fatty acid fuel

- cold temperatures, fever and infection may also precipitate attacks

- seven specific fatty acid oxidation defects have been identified - carnitine palmitoyltransferase II deficiency, long chain acyl-conenzyme A dehydrogenase deficiency, medium chain acyl-coenzyme A dehydrogenase deficiency, short chain L-3 hydroxyacyl-CoA dehydrogenase deficiency, very long chain acyl-CoA dehydrogenase deficiency, trifunctional protein deficiency and medium chain 3-ketoacyl-CoAthiolase deficiency

- carnitine palmityl transferase deficiency is the most common hereditary metabolic cause of recurrent myoglobinuria => patients presents in adolescence with exercise intolerance (muscle stiffness and myalgia and muscle weakness without warning muscle cramps) - which can also be provked by a prolonged fast, stress, infection, cold or infection

Mitochondrial and respiratory chain disorders

- also produce recurrent attacks of myoglobinuria

- deficiency of aconitase and succinate dehydrogenase produce exercise intolerance and myoglobinuria

Dystrophinopathies

- include Duchenne's muscular dystrophy, Becker's, fascioscapulohumeral dystrophy and myotonic dystrophies

- these patients may have a low baseline level of myoglobinuria

Malignant hyperpyrexia

- characterized by attacks of myoglobinuria, hyperpyrexia, muscle rigidity and lacticacidosis

- prdisposing conditions include central and multicore myopathies, myotonic disorders, Duchenne's, Becker's and congenital muscular dystrophies

- triggered by succinylcholine or halogenated hydrocarbon anesthetic agents

Acquired causes of myoglobinuria

Extreme physical exertion

- increased risk associated with high intensity exercise of prolonged duration + high ambient temperature + impaired heat dissipation (humidity, anticholinergic drugs) + lack of training (training is exercise-specific and well-trained athletes can develop myoglobinuria during high intensity novel physical activities)

Vigorous involuntary activities can also induce myoglobinuria:-

Heat stroke

Thyroid storm

Neuroleptic malignant syndrome

Prolonged exposure to extreme cold

Hypokalemia-induced

- secondary to diuretics, renal tubular acidosis, amphotericin B, licorice, alcoholism ... etc.

Chronic hypophosphatemia

Hypernatremia

Hyperosmolar ketotic states

Diabetic ketoacidosis

Crush syndrome

High voltage electrical burns and lightning injury

Prolonged immobilization

Arterial insufficiency and acute limb ischemia

Compartment syndromes

Infections

Viruses

Bacteria and rickettsia Parasites Inflammatory myositis Drug-induced myopathy Biological toxins Non-biological toxins Disclaimer: My EM guidemaps reflect my personal approach to problem-solving/managing clinical cases in an ED setting and they should not be regarded as the standard of care. They merely represent the personal opinions of the author and they should only be used in clinical practice if the reader-user has substantial reason to believe that the clinical advice contained in the guidemaps is valid and accurate. The guidemaps are not meant to be "authoritative" and the reader-user should consult standard medical textbooks and expert opinion articles/guidelines for more authoritative advice. The reader-user should particularly confirm all drug doses, their indications and contra-indications, prior to their use.