10 Diseases of the Muscles

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Diseases of the Muscles

Note: Significant diseases are indicated in bold and syndromes in italics.

I. Muscle Physiology

1.Muscle contraction (Fig. 10–1) and neuromuscular transmission (Fig. 10–2)

2.Muscle fibers: distinguished biochemical by the expression of different isozymes of myosin

Figure 10–2 Neuromuscular transmission. SR smooth endoplasmic reticulum. (From Koolman J, Rohm KH. Color Atlas of Biochemistry. Stuttgart, Germany: Georg Thieme; 1996:309. Reprinted by permission.)

a.slow twitch/type I muscle fibers: characterized by a small diameter, a high myoglobin content, and numerous mitochondria; relies on aerobic metabolism, which is better for tonic contraction

b.fast twitch/type II muscle fibers: characterized by a large diameter, a low myoglobin content, and few mitochondria; relies on anaerobic metabolism, which is better for phasic contraction (Fig. 10–3)

c.super-fast muscle fibers: found in extraocular muscles

d.tonic muscle fibers: found in extraocular muscles, tensor tympani

3.The motor unit: composed of the motoneuron and the muscle fibers it innervates; the muscle fibers for a particular motoneuron are always of the same type, but are not necessarily located near to each other in the muscle

a.motoneurons innervate a greater number of muscle fibers in larger muscles; conversely, motoneurons for the small muscles of face and hands may innervate less than 10 muscle fibers, allowing for fine motor control

Figure 10–3 Normal gastrocnemius muscle. ATPase stain demonstrates fast-twitch (f) and slow-twitch (s) muscle fibers. (From Beltri K et al. Contribution of the distal nerve sheath to nerve and muscle preservation following denervation and sensory protection. J Recon-

struct Microsurg 2005, 21:67, Fig. 8e. Reprinted 231 by permission.)

10 Diseases of the Muscles

b.types of motor units listed in order of recruitment

i.fatigue-resistant slow-twitch motor units: respond to low levels of activation of the motoneuron pool

ii.fatigue-resistant fast-twitch motor units: respond to intermediate levels of activation of the motoneuron pool; produce only half the contraction force of fatigue-resistant slow-twitch motor units

iii.fatigable fast-twitch motor units: respond to the highest levels of activation of the motoneuron pool; generates the largest force during twitch or tetanic contraction

4.Recruitment principle: the force of a muscle contraction is produced by activating an increasingly larger number of motor units in a fixed order beginning with the weakest and progressing to the strongest; this simplifies the modulation of force, because only the magnitude of the response has to be determined, not the identity of the responding motor units

a.the recruitment principle also keeps fatigable fast-twitch motor units quiescent until they are absolutely needed, which is metabolically advantageous

b.the order of activation can be reversed under certain physiological conditions, for example, activation of cutaneous pain receptors that inhibit fatigueresistant slow-twitch motor units while promoting the fast-twitch motor units, thereby allowing rapid force modulation

II. Diagnostic Testing

1.EMG: normal motor unit potentials (MUPs) (Fig. 10–4) a. pathological MUPs

i.myopathic changes on EMG

(1)MUPs tend to exhibit a decreased, not increased, amplitude after myopathic changes, because the muscle fibers are atrophying

(2)contractions of a diseased muscle results in an increased number of MUPs that are firing at normal or slower-than-normal rates

ii.neuropathic changes on EMG: involve a lesser degree of denervation and reinnervation than do myopathic changes

(1)denervation: acutely denervated muscle fibers are electrically

inactive unless they are irritated (e.g., at the time of needle insertion), until the development of fibrillation potentials 3 weeks after injury

(a)fibrillation potentials: spontaneous, regular potentials of chronically denervated muscle fibers

(i)the most accurate indicator of axonal loss in a neuropathic disorder, but fibrillation potentials last only 2 years after denervation before they spontaneously resolve

(ii)presence of fibrillation potentials in the proximal musculature (e.g., paraspinal muscles) indicates a motor root injury (versus peripheral nerve disease), but it is not always present

(2)reinnervation: can be accomplished by regeneration of an injured axon or by collateral sprouting of nearby intact motoneuron terminals

(a)MUPs from collateral sprouts are different from those of normally innervated motor units in that they

(i)have an increased duration

(ii)have an increased amplitude

(iii)have a polyphasic waveform

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(2)elderly: MUP amplitudes are larger than in young adulthood due to compensatory reinnervation caused by age-appropriate loss of motoneurons

2.Muscle biopsy

a.open biopsy allows for multiple sampling sites that may be necessary for muscle diseases that do not involve the whole muscle body (i.e., are patchy, as in the inflammatory myopathies)

b.evaluate both frozen and glutaraldehyde-fixed sections; fixed sections should be prepared by embedding in plastic (for electron microscopy, if necessary) and paraffin

c.technical limitations

i.in cases of chronic muscle diseases, avoid biopsies of severely affected muscles; in cases of relative acute muscle diseases, select severely affected muscles

ii.do not perform within 1 month of an episode of rhabdomyolysis, and avoid muscles that have suffered recent trauma (e.g., EMG testing)

III. Myasthenic Syndromes

1.Myasthenia gravis

a.pathophysiology: caused by antibodies that disrupt the function of postsynaptic nicotinic acetylcholine receptors on striated muscle; these antibodies may be derived from

i.a paraneoplastic syndrome: anti-acetylcholine receptor antibodies block acetylcholine receptor binding and crosslink the receptor proteins causing their internalization and destruction; antibodies target the gamma subunit of the receptors, which are most concentrated in the extraocular muscles

(1)antibodies on the myocytes induce (Box 10.3)

(a)complement membrane attack complexes: damage to the postsynaptic membrane initially causes loss of infoldings of the muscle fiber membranes {T tubules} and disorganization of the muscle end plate with widening of the synaptic cleft, and may ultimately cause muscle fiber death

(b)mild lymphocyte invasion of the muscle, in severe cases

(2)associated with thymoma (15% of cases) or thymic hyperplasia (80% of cases)

(a)B lymphocytes produce the anti-acetylcholine receptor antibodies but require T lymphocytes to make them in the form of IgG, therefore thymectomy changes the antibody expression from IgG to the less damaging IgM form

ii.an autoimmune reaction: antibodies against the muscle specific tyrosine kinase (MuSK) may disrupt acetylcholine receptor aggregation in the muscle end plate by deregulating the function of the intracellular protein agrin

(1)this form of myasthenia gravis is associated with HLA-B8 and –DR3 in young patients, and with other autoimmune disorders (rheumatoid arthritis, lupus, polymyositis, pernicious anemia) or immunosuppression

b.epidemiology: a bimodal prevalence with peaks at 20–30 years of age (female predominance) and 60–80 years of age (male predominance)

(1)myasthenia gravis patients greater than 40 years of age commonly have a thymoma; patients less than 40 years of age are more likely to have thymic hyperplasia

c.symptoms

Box 10.3

Thymoma paraneoplastic syndromes—

Myasthenia gravis; Isaac’s syndrome; cerebellar degeneration (CV-2 paraneoplastic autoantibody); pure red cell aplasia

i.weakness of the extraocular and facial muscles neck (particularly flexion), bulbar, and oropharyngeal muscles proximal upper extremity muscles lower extremity muscles

(1)weakness is typically asymmetric and becomes evident after prolonged use of a muscle (i.e., it is not present with immediate movements)

(a)weakness is often evident as a loss of postural tone, or as tremulousness during prolonged muscle use

(2)the weakness may be specifically limited to the extraocular muscles; the pupils are spared in myasthenia gravis, unlike botulism

ii.muscle soreness

iii.muscle atrophy occurs in only 15% of chronic cases and reflexes are always normal

(1)the tongue often exhibits longitudinal furrows in patients with MuSK antibodies, but this is a poorly understood abnormality that is not true atrophy

d.diagnostic testing

i.edrophonium (Tensilon) test: double-blinded injection of edrophonium (10 mg total in divided doses) produces improvement in a preexisting weakness within 1 minute of injection

(1)best to measure the degree of ptosis, which can be easily quantified

(2)requires a 2-mg test dose to assess tolerability; monitoring for bradycardia

(3)not as accurate as serological tests and EMG, because the response to edrophonium is not specific for myasthenia gravis

ii.serum antibodies

(1)acetylcholine receptor: present in 95% of myasthenia gravis cases

(2)striated muscle: present in 30% of myasthenia gravis cases; more common in older patients

(3)MuSK: present in 65% of acetylcholine receptor-negative patients; patients usually exhibit mild symptoms limited to the extraocular muscles

(4)titan: more common in patients with normal thymus glands

(5)ryanodine-sensitive voltage-gated calcium channels (Box 10.4)

iii.EMG demonstrates increased jitter, at least in facial muscles if not diffusely

iv.nerve conduction studies: repetitive nerve stimulation produces decremental responses

v.muscle biopsy can be used to demonstrate immune deposits in seronegative cases

vi.thymoma screening with CT chest, which always should be performed irrespective of the likelihood of its occurrence

e.treatment (Fig. 10–5)

i.pyridostigmine (Mestinon): better for paraneoplastic myasthenia (i.e., anti-acetylcholine receptor antibody), and is minimally effective in autoimmune myasthenia (i.e., anti-MuSK antibody)

(1)the results of edrophonium testing should not be used to adjust medication doses

ii.immunosuppressants: better for autoimmune myasthenia (Box 10.5)

(1)chronic prednisone, which may cause transient worsening of the weakness at the time of initiation of the therapy

(2)chronic cyclosporine, azathioprine, or mycophenolate in patients who are poorly responsive to glucocorticoids

(3)plasma exchange or intravenous immunoglobulin (IVIg) for severe bulbar and oropharyngeal dysfunction

Figure 10–5 Myasthenia gravis. Significant decrement at rest and postexercise potentiation followed by exhaustion. (From McKhann GM et al. Q&A Color Review of Clinical Neurology and Neurosurgery. Stuttgart, Germany: Georg Thieme; 2003: 131, Fig. 130. Reprinted by permission.)

Box 10.4

The ryanodine-sensitive voltage-gated calcium channel is also mutated in central core myopathy; not the same as the L-type dihydropyridine calcium channel that is mutated in hypokalemic periodic paralysis.

Box 10.5

Myasthenia crisis

Occurs in patients with a baseline respiratory impairment who develop a second respiratory disorder (usually infection); typically defined as a forced vital capacity (FVC) 15 cc/kg

Distinguish from respiratory failure due to acetylcholinesterase inhibitor overdose by challenging the patient with edrophonium after the patient is intubated

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iii.thymus removal for thymoma or thymic hyperplasia: thymus removal is useful only for paraneoplastic myasthenia and is not usually effective acutely, in severe disease, or in patients with anti-MuSK antibodies

(1)thymomas are generally encapsulated, but 35% may be invasive; thymoma invasion of surrounding tissues may require irradiation and/or chemotherapy

(2)in postthymectomy patients, rising antibody titers may indicate thymoma recurrence

f.prognosis: slow progression of symptoms over months with periods of exacerbation

i.no clear association exists between exacerbations and pregnancy

ii.no association between antibody titers and severity of disease

2.Pediatric myasthenia syndromes

a.transitory neonatal myasthenia—caused by transplacental passive transfer of antibodies from a myasthenic mother to the fetus; occurs in 20% of children of myasthenic mothers

i.symptoms are present at birth, and include hypotonia and poor feeding

ii.treatment: may require plasmapheresis if severe

iii.prognosis: self-limited course usually lasting 2 weeks

b.congenital myasthenia—caused by abnormalities in acetylcholine release, neuromuscular junction acetylcholinesterase function, or postsynaptic acetylcholine receptors; usually exhibits autosomal recessive inheritance

i.symptoms develop at birth, and include ptosis, ocular motor weakness, and facial weakness; limb weakness is mild

ii.treatment: as per adult myasthenia gravis

c.familial infantile myasthenia—associated with polymorphisms on chromosome 17

i.symptoms are present at birth, and include poor feeding and respiratory failure often leading to sudden death

ii.treatment: as per adult myasthenia

iii.prognosis: symptoms generally improve with age

3.Lambert-Eaton myasthenia

a.pathophysiology: a paraneoplastic syndrome caused by antibodies to the P/Q calcium channel on presynaptic motoneuron terminals, thereby reducing acetylcholine release; rarely involves antibodies against the N-type calcium channels

b.subtypes: both occur with approximately equal frequencies

i.Lambert-Eaton myasthenia without associated cancer: average age of onset 50 years of age; often associated with other autoimmune conditions (i.e., myasthenia gravis, pernicious anemia, vitiligo, diabetes, lupus)

ii.Lambert-Eaton myasthenia with associated cancer: average age of onset 60 years of age; classically associated with small-cell lung cancer or rarely associated with leukemia or lymphoma

(1)3% of small-cell lung cancer patients with develop Lambert-Eaton myasthenia

(2)symptomatic onset of myasthenia precedes the diagnosis of cancer in 80%

c.symptoms: usually is subacute at onset, but may be acutely precipitated by exposure to calcium channel blockers, iodinated contrast agents, and muscle paralytic agents

i.weakness in the proximal lower extremities upper extremities oropharyngeal muscles respiratory muscles

(1)weakness improves with brief exercise but then worsens with sustained exercise; similarly, patients are initially hyporeflexic but the reflexes improve with repetition

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(1)weekly glucocorticoid treatment delays loss of ability to walk by 2–3 years

(2)androgenic steroids to increase muscle bulk

(3)splints and release surgery for contractures

v.prognosis: death by 25 years of age from respiratory or cardiac failure

b.Becker’s muscular dystrophy

i.pathophysiology: caused by mutations of dystrophin gene that do not completely eliminate its functional activity; 70% of mutations are point mutations, and novel mutations are rare (unlike Duchenne’s muscular dystrophy)

ii.symptoms: as for Duchenne’s muscular dystrophy; the severity of symptoms correlates with the residual level of dystrophin activity

(1)onset of symptoms 7 years of age, progressing slowly to the loss of the ability to walk in late adolescent or even adulthood

(2)cardiomyopathy and mental retardation are not as common as they are in Duchenne’s muscular dystrophy

iii.diagnostic testing

(1)elevated CK ( 10-fold normal levels)

(2)muscle biopsy exhibits high levels of muscle regeneration and reduced (but present) dystrophin staining

(a)must rule out reduced levels of sarcoglycans as a cause for decreased dystrophin levels, as occurs in limb-girdle muscular dystrophies

(3)cannot rely on genetic testing to establish the diagnosis because decreased expression of an otherwise normal dystrophin protein may cause the disease

iv.treatment: as for Duchenne’s muscular dystrophy

c.Emery-Dreifuss muscular dystrophy

i.subtypes

(1)Emery-Dreifuss muscular dystrophy type 1: caused by an X-linked mutation of the emerin gene, which encodes a protein located on the inner surface of the nuclear membrane that (in association with lamin A/C and nuclear actin) forms the nucleoskeleton

(2)Emery-Dreifuss muscular dystrophy type 2: caused by an autosomal mutation of the gene for lamin A/C (Box 10.8)

ii.symptoms: onset in childhood or adolescence

(1)weakness of the shoulders, brachium, and calf muscles (a distinctive pattern for Emery-Dreifuss muscular dystrophy)

(2)contractures, which develop earlier than would be expected given the weakness

(3)cardiomyopathy with conduction block

iii.diagnostic testing: elevated CK ( 10-fold normal levels)

iv.treatment: cardiac pacing; contracture release

2.Autosomal-dominant congenital myopathies

a.myotonic dystrophy

i.subtypes

(1)myotonic dystrophy type I (98% of cases): caused by an expanded trinucleotide repeat in the 3 untranslated region of the myotonin protein kinase gene, which encodes a protein that regulates actinmyosin interaction and voltage-gated ion channel activity

(a)disease usually develops with 100 trinucleotide repeats

(2)myotonic dystrophy type II: mutation on chromosome 3

Box 10.8

Lamin A/C

Other mutations cause autosomal-recessive Charcot-Marie-Tooth disease type 2A and autosomal-dominant limb-girdle dystrophy.

Congenital Myopathies

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i.pathophysiology: caused by a transpositional insertion into the fukutin gene, the protein of which may be necessary for proper extracellular glycosylation of the protein dystroglycan that is necessary for cell–cell adhesions

(1)fukutin protein is highly expressed in the developing brain but is not apparently expressed in muscle

(a)abnormal function of fukutin protein in the brain likely explains the frequently associated developmental abnormalities (polymicrogyria, lissencephaly, disruption of gray matter lamination, hypomyelination)

ii.symptoms: onset 1 year of age

(1)hypotonia and weakness

(2)mental retardation, seizures, hydrocephalus

(3)retinal hypoplasia

iii.diagnostic testing

(1)neuroimaging of the brain exhibits multiple developmental abnormalities

(2)muscle biopsy demonstrates internal nuclei, and disrupted and increased connective tissue

iv.treatment: none specific

v.prognosis: death by 10 years of age

4.Inherited metabolic diseases of the muscle

a.carnitine palmitoyl transferase deficiency

i.pathophysiology: autosomal recessive mutations of carnitine palmitoyl transferase that links fatty acids to carnitine for transportation into the mitochondria where they are oxidized

ii.symptoms: fatigue and muscle pain developing well after the onset of exercise; episodes may present in childhood or adulthood

iii.diagnostic testing: significant myoglobinuria; increased respiratory

exchange ratio ( expired [CO2]/inspired [O2]) at rest, reflecting the use of glucose for resting metabolism rather than fatty acids

iv.treatment: glucose intake during periods of exercise

b.McArdle’s disease

i.pathophysiology: autosomal recessive mutations in myophosphorylase, which cleaves glycogen into free glucose for glycolysis

ii.symptoms: rapid-onset fatigue that can be overcome with continuing activity; muscle pain with forced muscle contraction or exercise; normal acute muscle strength and bulk

iii.diagnostic testing

(1)mild myoglobinuria

(2)EMG during ischemic contraction demonstrates no electrical activity

(3)increased CK occur only with significant muscle contractions

(4)minimal rise in serum lactate levels with anaerobic exercise

iv.treatment: none specific

c.phosphofructokinase deficiency

i.pathophysiology: caused by autosomal recessive mutations of phosphofructokinase, which phosphorylates fructose-6-phosphate prior to its cleavage into glyceraldehyde that then enters the Krebs cycle

(1)the rate-limiting enzyme for metabolism of glucose for the Krebs cycle

ii.symptoms: as per McArdle’s disease, although more severe; also hemolytic anemia

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Acquired Muscle Diseases

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a.subtypes

i.paraneoplastic neuromyotonia: exhibits antibodies against voltagegated potassium (Box 10.14) channels and the nicotinic acetylcholine receptor that are located on peripheral nerves (Box 10.15)

(1)associated with small cell lung cancer and lymphoma as well as myasthenia gravis

ii.neuromyotonia associated with human immunodeficiency virus (HIV) infection and penicillamine use

b.symptoms: onset typically 60 years of age; the severity of symptoms fluctuates with the patient’s level of physical activity

i.neuromyotonia: prolonged muscle contraction induced by physical stimulation

ii.myokymia: rhythmic rippling of the muscles that is not sensitive to physical stimulation (e.g., percussion) as is myotonia

iii.stimulation-independent muscle cramping that may involve the face and oropharynx

iv.stiffness but little weakness (if any); normal reflexes

v.abnormal limb posturing similar to dystonias

vi.hyperhidrosis

vii.insomnia

c.diagnostic testing

i.EMG: shows spontaneous motor unit potentials, fasciculations, and myokymia and neuromyotonia potentials

ii.nerve conduction studies demonstrates axonal motor neuropathy

iii.CK is not reliably elevated

iv.muscle biopsy: demonstrates type I fiber predominance and hypertrophy

d.treatment: antiepileptics (phenytoin, carbamazepine); plasmapheresis

Box 10.14

Antibodies against voltage-gated potassium channels are also seen in limbic encephalitis paraneoplastic syndrome

Box 10.15

Other diseases of potassium channels—

Paraneoplastic limbic encephalitis; Hashimoto’s encephalopathy; Morvan syndrome ( Isaac’s syndrome encephalopathy)

VI. Channelopathies of Muscle

1.Diseases of sodium channels

a. hyperkalemic periodic paralysis

i.pathophysiology: caused by mutations in a voltage-gated sodium channel (Box 10.16) that increase its open time and slow its inactivation once it is open, thereby allowing prolonged membrane depolarization

(1)an increased extracellular potassium concentration depolarizes the cell and activates the abnormal channels, which then causes efflux of potassium from the cell that further depolarizes the cell and maintains the sodium channel in an open state

(2)exhibits autosomal dominant inheritance with complete penetrance

ii.symptoms: provoked by cold exposure, by resting after exercise, or by

(1)acute onset of symmetric proximal weakness that is generally less severe and of shorter duration than in hypokalemic periodic paralysis, but that occur more frequently than in hypokalemic periodic paralysis

(2)myotonia (an uncommon feature)

iii.diagnostic testing: provoke an attack with oral potassium supplements or exercise

(1)genetic testing

(2)increased serum and urinary potassium during attacks

Box 10.16

Other mutations in the voltage-gated sodium channel cause paramyotonia congenita.

iv.treatment

(1)avoid provocative stimuli, but during an attack

(a)consume glucose, which drives cellular potassium uptake to be absorbed

(b)administer intravenous calcium gluconate or sodium chloride

(2)chronic prophylaxis with acetazolamide or thiazide diuretics

b.paramyotonia congenita

i.pathophysiology: caused by mutations in a voltage-gated sodium channel (the same one as in hyperkalemic periodic paralysis)

ii.symptoms: stiffness provoked by cold exposure, exercise, or hypokalemia; severe cold exposure or strenuous exercise can also evoke weakness that outlasts the stiffness

iii.diagnostic testing

(1)EMG demonstrates fibrillation potentials or repetitive MUPs induced by cooling or exercise that disappears with further cooling or exercise

(2)muscle biopsy demonstrates only variable-sized muscle fibers

iv.treatment

(1)avoid provocative stimuli, but during attacks treat as hyperkalemic periodic paralysis

(2)prophylaxis with mexiletine in severe cases

2.Diseases of calcium channels

a.hypokalemic periodic paralysis

i.caused by

(1)mutations in the L-type (dihydropyridine) voltage-gated calcium channel (Box 10.17) that excessively depolarizes the myocyte

(a)voltage-gated calcium channel mutations are associated with reduced expression of voltage-gated sodium channels for unknown reasons

(b)exhibits autosomal dominant inheritance with incomplete penetrance particularly in women; onset of symptoms in early childhood

(2)hyperthyroidism, which increases expression of the sodiumpotassium ATPase in muscle that would excessively hyperpolarize the myocyte; exhibits an autosomal dominant pattern of inheritance

(3)hypokalemia from metabolic acidosis, hyperaldosteronism, or urine alkalinization

ii.symptoms: provoked by resting after exercise, carbohydrate consumption, or the use of aminergic agents or steroids

(1)acute attacks involve soreness in back and thighs that progresses to the extremities; muscle swelling, firmness, and weakness then develop

(a)episodes may last several hours, but have an acute onset and resolution

(2)chronic symptoms: residual weakness following an acute attack accumulates to symptomatic level by 40 years of age

iii.diagnostic testing: potassium levels during an attack are not reliable for the diagnosis

(1)muscle biopsy demonstrates vacuolation and tubular aggregates in the myocytes

iv.treatment

(1)correct underlying hypokalemia-inducing disorders, if any

(2)oral potassium supplementation

Channelopathies of Muscle

Box 10.17

Not the same as the ryanodine calcium channel, which is mutated in central core disease and malignant hyperthermia.

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Table 10–2 Comparison of Myotonic Conditions

(3)low sodium, low carbohydrate diet

(4)spironolactone for prophylaxis; avoid acetazolamide unless a calcium channel mutation is known to be the cause

3.Diseases of chloride channels

a. myotonia congenita/Thomsen’s disease (Table 10–2)

i.pathophysiology: caused by mutations in a chloride channel that decrease chloride conductance; the reduced chloride efflux during membrane depolarization allows accumulation of potassium in the T tubules, which induces repetitive membrane depolarizations by activation of the voltage-gated sodium channels

(1)exhibits autosomal dominant inheritance

ii.symptoms

(1)muscle stiffness and myotonia that is pronounced after inactivity but that improves after exercise

(2)normal strength and tone that temporarily decreases with exercise before returning to normal

(3)muscle hypertrophy, in the autosomal recessive form

iii.diagnostic testing: EMG demonstrates myotonic discharges

iv.treatment: mexiletine; quinine; phenytoin

VII. Diseases of Absent Muscles (Table 10–3)

Table 10–3 Diseases of Absent Muscles