1. The four components of the motor unit are the motor neuron, the axon of that motor neuron, the neuromuscular junction, and the muscle fibers innervated by the dendrites of the motor neuron.
2. The muscular dystrophies are relentlessly progressive inherited conditions with variable clinical presentation. Patients are at risk of development of cardiomyopathy, arrhythmias, and conduction disturbances, and careful preoperative assessment of cardiac function is necessary.
3. During the perioperative period, the primary consideration for the patient with neuromuscular disease is the degree of weakness, with particular attention on the patient’s ability to protect the airway and to sustain adequate alveolar ventilation.
4. Certain myopathies such as central core disease are associated with susceptibility to malignant hyperthermia. Patients with Duchenne muscular dystrophy may develop rhabdomyolysis following exposure to succinylcholine or the potent inhalational agents.
5. Malignant hyperthermia is a primary muscle disorder of deranged intracellular calcium transport leading to hypermetabolism. It is a medical emergency requiring immediate treatment (dantrolene administration, discontinuation of triggering agents, active cooling, hemodynamic stabilization).
THE MOTOR UNIT
There are four components of the motor unit: the motor neuron, the axon of that motor neuron, the neuromuscular junction, and the muscle fibers innervated by dendrites originating from that single motor neuron.
1. Myocyte development: Muscle cell development proceeds through several stages: myoblast, then myotube, followed by myocytes, and finally mature muscle fiber. Although the first recognizable muscle fibers form from primitive myoblasts independent of a connection with neurons, complete development of the muscles depends on innervation and formation of a neuromuscular unit. Once this innervation has occurred, muscle cell development progresses. At the start of the third trimester, muscle fiber subtypes are identifiable (1).
2. Motor neuron axon development: At the time the myoblasts have fused, axon terminals have just reached these primitive muscle cells. Functional synapses form once the growing axon reaches the membrane of the myotube (2). In adult muscle, motor endplates are seen in distinct bands. Later-arriving axons are limited to making contact near the site where the initial junction was formed. Acetylcholinesterase is measurable within several days of the formation of the first synapses. Programmed death of motor neurons occurs soon after the formation of the first synapses with the developing muscle cell. It appears that muscle activity plays a role in determination of which motor neurons undergo apoptosis. The last cellular event in the formation of a mature motor unit is the elimination of all save one of the axons innervating a muscle cell (3).
DISORDER: Muscular dystrophies
BACKGROUND: All the muscular dystrophies share some common characteristics.
1. They are all inherited, progressive conditions primarily involving pathology of the muscles.
2. Degeneration and death of myocytes eventually occur.
3. Although the muscular dystrophies share these characteristics, they have different genetic causes and also vary greatly in clinical severity and presentation.
Duchenne muscular dystrophy (DMD) is the most common of the dystrophies.
CLINICAL PEARL Patients with DMD may have significantly more severe cardiomyopathy than skeletal muscle weakness. This may become unmasked with intubation and positive pressure ventilation.
1. It is transmitted as an X-linked recessive trait, and the incidence is 2.9:10,000 in male infants.
2. Affected males generally have normal muscle tone at birth and usually achieve motor milestones in infancy.
3. These children often become ambulatory at the normal time, approximately 12 months of age. The classic Gower sign is apparent by the third year of life and is easily seen by the time the child is 4 or 5 years of age.
4. The weakness progresses relentlessly, although the rate of progression is different for different patients; some children retain their ability to walk until 10 or 12 years of age. These children undergo a variety of orthopedic interventions designed to improve their independence.
5. Because of muscle weakness, scoliosis is a regular feature of this condition.
6. Even with severe muscle weakness, ocular movement is preserved, as is the function of the urinary and anal sphincters. Despite the degeneration of the skeletal muscles seen in DMD, affected patients do not complain of pain.
7. All patients with DMD have cardiomyopathy.
a. The involvement of the cardiac muscle may be more severe or less severe than the observed skeletal muscle weakness.
8. Patients with DMD may also have impaired cognitive function. However, most have a measured intelligence quotient (IQ) over 70.
9. As the muscles of respiration continue to weaken along with the pharyngeal muscles, pneumonias become more frequent (4).
a. Unless there is intervention with respiratory and airway support, affected patients rarely survive beyond more than 18 years. However, with meticulous nursing care, placement of a tracheostomy tube, the provision of mechanical ventilation, and placement of a gastrostomy for nutritional support, these patients can live much longer (5).
10. Elevated serum creatine kinase (CK) is a constant feature of DMD.
a. This elevation is seen even early in life when the clinical features are not apparent.
b. In the late stages of the disease, when patients have significantly less muscle mass, the CK level may decline.
c. An elevated CK does not confirm the diagnosis.
11. Muscle biopsy and/or genetic analysis of peripheral lymphocytes can confirm the diagnosis. There is no specific therapy for DMD, and treatment is supportive.
12. Medical management includes treatment of cardiac decompensation, treatment of pulmonary infections, physical therapy, and surgical correction for contractures and scoliosis as indicated (6).
Becker muscular dystrophy is a mild form of DMD.
1. The genetic defect is the same, but children with Becker muscular dystrophy have a slower progression of weakness. The onset of weakness is later in childhood, and these patients are often not confined to a wheelchair until their early 20s.
2. Cardiac involvement is similarly less severe.
Myotonic muscular dystrophy has an overall incidence of 0.3:10,000. Skeletal, cardiac, and smooth muscles are involved.
1. Most infants do not exhibit weakness. When weakness becomes apparent, it is not severe in the first few years of life.
a. Distal muscle wasting occurs first, followed by proximal muscles.
b. In addition to widespread muscle involvement, affected children often also exhibit decreased intellect, cataracts, and dysmorphic features.
c. Although children eventually develop the Gower sign, most do retain the ability to walk.
d. The characteristic myotonia is not evident initially but is apparent by approximately 5 years of age.
2. Patients do not complain of pain during the period of delayed muscle relaxation.
3. Swallowing difficulties lead to aspiration pneumonias.
4. Constipation is common, resulting from decreased peristalsis of the gastrointestinal (GI) smooth muscle.
5. Cardiac contractility is not severely decreased, but heart block does occur.
6. Other common problems in addition to dysfunction of various muscle types include cataracts, endocrine dysfunction, and decreased immunoglobulin G (IgG).
7. Serum CK is elevated in these patients but not to extremely high levels as seen in patients with DMD.
8. The diagnosis can be confirmed by muscle biopsy and genetic analysis of peripheral blood.
9. Although no specific therapy is known, the various abnormalities mentioned are amenable to treatment.
10. Medications that raise the threshold for muscle cell depolarization such as phenytoin or carbamazepine can decrease the degree of myotonia.
Limb-Girdle muscular dystrophy refers to a group of conditions that affect the muscles of the shoulder and hip.
1. These diseases are often not clinically apparent until late childhood or even early adult life. Inheritance patterns of autosomal recessive and autosomal dominant are seen.
2. The disorder is usually not associated with other syndromes.
3. Cardiac function is generally preserved.
4. As with the other dystrophies, specific treatment is not available.
Emery–Dreifuss muscular dystrophy is a rare disorder.
1. Inheritance follows an X-linked pattern, and the estimated incidence is 0.1:10,000.
2. Clinically, affected patients present in childhood with weakness of the scapular and humeral muscles but sparing of the facial muscles.
3. Hypertrophy, a prominent finding in DMD, is not seen in these individuals.
4. Cardiac involvement is severe in these patients and is often the cause of death.
5. Intellectual development is normal.
6. Treatment is supportive and should include frequent evaluation of cardiac function.
DISORDER: Congenital myopathies
BACKGROUND: Although many of these disorders are hereditary with variable inheritance patterns, some occur spontaneously. The overall incidence is approximately 1:50,000. In most affected infants the clinical picture is static, but in some there is slowly progressive loss of function. Dysmorphic features are common, especially secondary to muscle weakness, with hypotonia, hyporeflexia, and poor muscle bulk. The definitive diagnosis of a specific disorder is made with muscle biopsy and/or genetic testing. In many congenital myopathies and other disorders of the motor unit, the specific inheritance pattern and chromosomal loci have been identified (7).
1. Myotubular (centronuclear) myopathy is so named because of the ultrastructural appearance of the muscle cells.
a. The muscle cells of affected infants look similar to muscle cells at approximately 10 weeks of fetal development, the myotubular stage.
b. High levels of fetal proteins in the muscle fibers support the speculation that the disorder results when muscle cell development stops at the 10th to 15th week of fetal life.
c. Clinically, affected newborns have severe hypotonia and generalized muscle weakness. These infants are so weak that intubation and mechanical ventilation are usually needed.
d. Cardiac function is normal.
e. As this is a muscle disorder, the electromyography (EMG) and nerve conduction velocity are generally within normal limits.
f. Diagnosis is made with muscle biopsy.
g. All structures save the myocytes themselves are normal.
h. The muscle cells are small with central nuclei.
i. Because the inheritance is usually X-linked recessive, the mothers of affected newborns do not show any clinical signs of the condition. However, muscle biopsies of the mothers can show minor abnormalities.
j. There is no specific therapy. All treatment is supportive.
k. Although mortality is high in infancy, those who survive do not exhibit progression of the disease (8).
2. Nemaline-Rod myopathy has two clinical presentations, a more severe infantile form and a less severe juvenile presentation (9).
a. The nemaline rods after which the disorder is named are rod-shaped structures seen in the muscle cells only with special stains. These rods, which consist of muscle cell proteins, are rarely seen in any other disease.
b. Both autosomal dominant and autosomal recessive transmission have been described.
c. Affected infants are very weak at birth, and many do not survive the newborn period; those that do survive remain very weak.
d. Children with the less severe juvenile form do have generalized hypotonia, but these children have sufficient strength to walk and take care of themselves.
e. A characteristic feature is an open mouth because the masseter muscles are too weak to keep the jaw closed.
f. The weakness is not progressive (10).
3. Central core disease is named because of the lack of myofibrils and organelles in the cytoplasm of the muscle cells, leaving only cytoplasm in the center (11).
a. Affected infants have proximal muscle weakness and muscle wasting, but the weakness does not worsen over time.
b. The weakness is not so severe as in some of the other congenital myopathies, and patients are usually able to ambulate.
c. Cardiomyopathy is rare.
d. Serum CK is usually within normal limits.
4. Benign congenital hypotonia is a diagnosis of exclusion.
a. Infants and children with nonprogressive mild hypotonia in whom no etiology is found are given this diagnosis.
b. Muscle strength is normal as is development.
c. No specific treatment is needed, and affected children do not develop contractures. Some children with this condition, due to the hypotonia, develop recurrent dislocations of joints.
DISORDER: Spinal muscle atrophy (SMA)
CLINICAL PEARL All forms of spinal muscular atrophy are progressive and affected individuals require respiratory support, splinting and physical therapy.
BACKGROUND: This group of disorders is characterized by progressive degeneration of the spinal lower motor neurons. Overall incidence is 1 to 1.6:10,000, with an autosomal recessive inheritance pattern. As the motor neurons become nonfunctional the clinical picture of flaccid paralysis and muscle atrophy becomes increasingly profound. The different forms are distinguished only by the age at onset and the severity of the weakness. However, in all forms the disease is progressive (12). The muscle biopsies of all variants show the same pathology. Intellect is normal in children with SMA. Nerve conduction velocity is normal in these children while the EMG shows the expected signs characteristic of muscle denervation. Both muscle biopsy and detection of the characteristic genetic marker can confirm the diagnosis. There is no definitive treatment. Therapy is supportive, with splinting, physical therapy, mechanical ventilation, mobility aids, and surgical correction of contractures and/or scoliosis (13,14).
SMA type I (Werdnig–Hoffmann disease) is the most severe form of the disease.
1. The condition is clinically apparent early in infancy, and progression is relatively rapid. Clinically, these infants have muscle atrophy, severe weakness, and absent deep tendon reflexes.
2. The extraocular muscles are spared.
3. These infants have a characteristic bright-eyes appearance with a distinct lack of movement of the limbs.
4. Infants with SMA type I develop respiratory distress early in life accompanied by feeding difficulties (15).
5. They also exhibit paradoxical breathing due to weak intercostals and diaphragmatic sparing.
6. Untreated, these infants generally do not survive beyond early infancy (16,17).
SMA type II (intermediate type) is similar to type I in that the condition appears in infancy. However, onset is later, usually at around 7 to 18 months of age, and the progression is slower.
1. In infancy, children with this condition are usually able to suck, swallow, and breathe.
2. As the weakness progresses more slowly than in patients with SMA type I, these infants often survive into childhood and may be able to sit and stand, but are usually unable to ambulate.
3. They can have joint contractures and kyphoscoliosis due to muscle weakness.
4. With proper supportive measures, these children may survive into late childhood.
SMA type III (Kugelberg–Welander disease) is the least severe variant of spinal muscular atrophy (18).
1. Affected children may not have symptoms in infancy and may develop the ability to walk at or near 12 months of age.
2. In SMA type III, the weakness is more severe in the upper extremity and shoulder.
3. A minority of children with SMA type III exhibits muscular hypertrophy, not atrophy.
4. Patients may survive into adulthood.
ANESTHETIC CONSIDERATIONS: For patients with myopathies, muscular dystrophies, and spinal muscular atrophies
1. For all patients with myopathy, the primary consideration is the degree of weakness. The pediatric anesthesiologist should be particularly concerned with the patient’s ability to protect the airway and to sustain adequate alveolar ventilation. Some of these patients may be so weak that they would not meet extubation criteria prior to induction of anesthesia (19–22).
2. Although regional anesthesia has the advantage in these patients that airway manipulation is avoided, many anesthesiologists are wary of neuraxial blockade in patients with any type of preexisting neuromuscular compromise (23).
3. Possible malignant hyperthermia (MH) susceptibility: Patients with central core disease are known to be MH susceptible. Although DMD has not been linked to true MH, these patients may exhibit MH-like responses to triggering agents (24). Management of MH is described in the subsequent text.
4. Patients with DMD should have a careful evaluation for evidence of cardiac involvement.
5. These patients always have some degree of cardiomyopathy. Because their activity is so limited by skeletal muscle weakness, it is easy to underestimate the severity of cardiac dysfunction (25,26).
6. Heart block and arrhythmias can develop due to fibrosis of the conduction system.
7. Patients with DMD may develop rhabdomyolysis following exposure to succinylcholine or the potent inhalational agents (27,28).
8. The responses of these patients to nondepolarizing muscle relaxants can be variable and have been reported to be either mildly prolonged or similar to those without DMD (29).
DISORDER: Mitochondrial myopathies
CLINICAL PEARL The term mitochondrial myopathy is used to describe a variety of conditions, all with abnormalities in mitochondrial respiration, weakness, and developmental delay. Different specific diagnoses will have specific anesthetic issues.
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