Upper Motor Neuron

Quadriplegia and respiratory compromise can result from acute cervical spinal cord trauma, spinal artery infarction, or compression by tumor. Injuries at or above C3 to C5 involve the phrenic nerves and can cause partial to complete bilateral hemidiaphragmatic paralysis. Intercostal muscle paralysis below the level of the lesion limits the normal outward expansion of the middle and upper rib cage, compromising inspiration further. Expiration also can be reduced because of paralysis of the abdominal and other expiratory muscles. High-level quadriplegics may be unable to generate adequate tidal volumes, and the accompanying hypoventilation and atelectasis can result in hypoxemia. Low-level cervical quadriplegics with intact phrenic nerves are able to contract their diaphragms. They, too, lack the intercostal muscle activity necessary to stabilize the rib cage for optimal inspiratory function, however. These patients also may lose the use of the abdominal and other expiratory muscles. Combined inspiratory and expiratory weakness can prevent them from effectively coughing and clearing secretions and place them at high risk for pneumonia. Initially, with spinal cord injury, the vital capacity, maximum inspiratory pressure, and maximum expiratory pressure are reduced. As the initial phase of spinal injury passes, chest wall flaccidity is replaced with spasticity, and there is an improvement in the vital capacity as the more rigid chest wall resists collapse.

Anterior Horn Cell Disorders

SMAs comprise a group of autosomal-recessive degenerative disorders of lower motor neurons classified as type I (Werdnig-Hoffman disease), type II, and type III (Kugelberg-Welander disease), based on the age of onset of muscle weakness and clinical severity. These disorders often manifest in infancy and childhood with an estimated incidence of 1:5000. SMAs are due to a mutation of the survival motor neuron gene located on chromosome 5q13. This mutation is responsible for primary degeneration of the anterior horn cells of the spinal cord and often of the bulbar motor nuclei, which leads to skeletal muscle paralysis and atrophy.

Werdnig-Hoffman disease manifests in the first 6 months of life. Infants with this disease lack head control and are nearly always unable to sit and walk. There is severe hypotonia, generalized weakness, and thin muscle mass. All of these patients have paradoxical inward rib cage movement with each inspiration, the diaphragm being relatively spared. Unless provided with nocturnal high-span BiPAP, they develop pectus excavatum and severe undergrowth of the lungs and chest wall, showing on chest radiography reduced lung volume and a bell-shaped thorax. Unless supported by respiratory muscle aids (described later), more than 90% of patients die by 2 years of age.

In SMA type 2, affected patients are usually able to suck and swallow, and respiration is adequate in early infancy. Swallowing difficulties or choking with feeds becomes apparent in the preschool years, predisposing these patients to recurrent pneumonia and chronic suppurative lung disease. These patients can sit but not walk. About 40% of these patients have paradoxical breathing and require nocturnal high-span BiPAP.

Kugelberg-Welander disease is the mildest SMA (type 3), and patients may appear normal in infancy. The progressive weakness is proximal in distribution, particularly involving shoulder girdle muscles. In the adult-onset form, SMA type 4, patients can walk for some period of time. An X-linked adult-onset type 5 SMA (which affects only men), otherwise known as Kennedy disease, is associated with gynecomastia, temporal atrophy, and endocrine disturbances and hypospermia.

Preliminary data obtained from phase 1 human studies have suggested that sodium valproate may improve anterior horn cell function in SMA. Pharmacologic therapy or gene therapy is unlikely to have a major effect on the course of the disease in older patients with advanced disease, but NIV is effective in many of these patients and may buy time for medical therapies to take effect or even undergo development.

Poliomyelitis is a poliovirus infection of young children that begins with fever and upper respiratory symptoms that are followed by signs of meningeal irritation and asymmetric, flaccid paralysis that can involve the skeletal, respiratory, and bulbar-innervated musculature. The respiratory motor nuclei can be directly involved, resulting in diaphragmatic and accessory respiratory muscle dysfunction. Involvement of lower cranial nerve nuclei can result in upper airway obstruction, pooling of secretions, and aspiration. The medullary respiratory center also can be affected, resulting in irregular respirations and apnea. Many of these patients require ventilatory and hemodynamic support during the acute phase of the illness. Although most patients show substantial muscle recovery over time, they gradually relapse to require ventilatory assistance again later in life with the senescent aging and dropping out of overworked anterior motor neurons with aging.

Disorders of Peripheral Nerves

Hereditary motor and sensorimotor neuropathies are common. The former is often confused with and can be as severe as SMA. The most common is Charcot-Marie-Tooth disease, a demyelinating neuropathy. Almost 15% of patients are left with residual weakness, and an additional 5% experience chronic relapsing (dysimmune) polyneuropathy. Some patients are never weaned from ventilatory support.

Acute idiopathic polyradiculitis, also known as Guillain-Barré syndrome, is the most common peripheral neuropathy causing respiratory failure. It is considered to be an autoimmune disease precipitated by a preceding viral or bacterial infection, such as cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae , and Campylobacter jejuni . In 80% of these patients, there is a history of a nonspecific viral illness preceding weakness by 2 to 3 weeks. Diagnosis is mainly based on clinical grounds. It usually begins with fine paresthesias in the toes or fingertips followed by progressive muscle weakness in the lower extremities, trunk, upper limbs, and, finally, bulbar-innervated and respiratory muscles. Muscle involvement is relatively symmetric. Facial and oropharyngeal weakness are often impending signs of respiratory failure. Muscle pain is common in the initial stages. Daily bedside evaluation of vital capacity and arterial blood gases is essential for appropriate decisions regarding the need of mechanical ventilatory support, which is required in 20% of affected children. Acute respiratory failure can be avoided with the use of noninvasive aids when bulbar-innervated muscle function is adequate to prevent continuous aspiration of saliva or oxyhemoglobin desaturation. Otherwise, patients need to be intubated for ventilator use and airway secretion management. Early use of high-dose intravenous immunoglobulins or plasma exchange induces a more rapid resolution of the disease. Corticosteroids are now used sparingly because they seem to predispose to the chronic relapsing form of the disease.

Among other peripheral neuropathies leading to respiratory failure, Lyme disease can manifest with a syndrome identical to Guillain-Barré syndrome. In endemic areas, serologic testing for Lyme disease is indicated. Acute intermittent porphyria can cause a neuropathy severe enough to result in respiratory failure. Postdiphtheritic neuropathy, toxic neuropathies (thallium, phosphate, and lead) avitaminosis, paralytic shellfish (saxitoxin) poisoning, and the polyneuropathies associated with systemic lupus erythematosus and polyarteritis nodosa also can cause ventilatory failure.

Disorders of the Neuromuscular Junction

Myasthenia gravis is the most common disorder of the neuromuscular junction. It affects any age group, although clusters of cases are found in adolescent girls. Myasthenia gravis is characterized by fluctuating weakness with a predilection for the ocular muscles (ptosis, diplopia, blurred vision) and bulbar-innervated muscles (dysphagia, dysphasia, and aspiration). The pupillary response to light is preserved. Similar to the adult form, juvenile myasthenia gravis is an acquired immunologic disorder of neuromuscular transmission associated with circulating antibodies against postsynaptic acetylcholine receptors. These antibodies can be detected in the serum of 90% of patients with generalized myasthenia gravis.

Diagnosis of juvenile myasthenia gravis is based on clinical symptoms, electrophysiologic studies, a positive finding of circulating acetylcholine receptor autoantibodies, and transient improvement with anticholinesterase medication. Most patients in whom this disease is suspected but undiagnosed show a dramatic response to intravenous edrophonium chloride, a short-acting acetylcholinesterase inhibitor. Benign thymic hyperplasia or thymoma occurs in 90% of these patients. Management is primarily based on anticholinesterase medication (pyridostigmine bromide). Improvement with anticholinesterase medication is often incomplete, however, and most patients require further therapeutic measures, including thymectomy, which results in improvement or remission in 80% of patients without thymomas. Immunosuppressive drugs (prednisone, azathioprine, or cyclosporine) are frequently recommended. Other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and thyrotoxicosis, commonly complicate the clinical picture.

Transient neonatal myasthenia gravis is a syndrome that affects 30% of infants born to mothers with autoimmune myasthenia gravis. Clinical features are usually noted within hours of birth and include feeding and respiratory difficulties, hypotonia, weak cry, facial weakness, and palpebral ptosis. Respiratory difficulties are related to feeding problems causing aspiration pneumonia, upper airway obstruction owing to inability to handle oropharyngeal secretions, or respiratory muscle weakness. Some patients may require ventilatory support during this period. After the abnormal antibodies disappear, the infants have normal strength and are not at increased risk for developing myasthenia gravis in later childhood. The syndrome of transient neonatal myasthenia gravis is to be distinguished from a rare, often hereditary, and often permanent, congenital myasthenia gravis not related to maternal myasthenia gravis. This disorder is characterized by an abnormality of the acetylcholine receptor, manifested as high conductance and excessively fast closure, and is probably due to a mutation affecting a single amino acid residue. Therapy for acute attacks (myasthenia crisis) includes mechanical ventilation in combination with plasma exchange, acetylcholinesterase inhibitors (pyridostigmine), and corticosteroids or other immunosuppressants.

Botulism is a rare disorder of the neuromuscular transmission blockade caused by the binding of one of the neurotoxins (A, B, E, and F) produced by Clostridium botulinum . The toxin that is carried in the bloodstream prevents the release of acetylcholine from the presynaptic terminal and affects nicotinic and muscarinic synapses. Botulism occurs in three forms: infantile botulism, the most common, in which the organism and its spores are ingested in honey or other foods, or from the environment; food-borne (classic) botulism, in which preformed toxin is ingested in nonacidic home-canned or factory-canned vegetables or meat; and wound botulism (very rare), in which C. botulinum and its spores contaminate traumatic or surgical wounds.

Infant botulism is most commonly seen in the first 4 months of life. Constipation is usually the first symptom; thereafter, neuromuscular dysfunction results in progressive descending muscle weakness, with early bulbar involvement and hypotonia. Acute respiratory failure develops in 90% of affected infants. Respiratory failure results from respiratory muscle weakness and paralysis, causing hypoventilation; bulbar palsy and upper airway muscle weakness, leading to aspiration pneumonia or upper airway obstruction; and inability to clear secretions, resulting in pneumonia and atelectasis. Endotracheal intubation is performed as soon as depression of the gag reflex is noted.

In older children with food-borne or wound botulism, the onset of neurologic symptoms follows a characteristic pattern of diplopia, blurred vision, ptosis, dry mouth, dysphagia, dysarthria, decreased gag reflex, and decreased corneal reflex followed by flaccid descending paralysis that often progresses to affect the respiratory muscles. The diagnosis should be considered if a previously healthy infant, usually younger than 6 months, has a history of constipation and then acutely develops weakness with difficulty in sucking, swallowing, crying, or breathing. It is suggested by electromyographic changes of brief, small, abundant motor unit potentials in response to high rates of stimulation similar to that seen in aminoglycoside toxicity. The diagnosis is confirmed by showing neurotoxin in the serum, stool, or contaminated food. Treatment includes positioning the head backward to open the airway and improve respiratory mechanics. Respiratory muscle aids are often required, and pneumonia is a common complication and a major cause of death. Antibiotic therapy is not part of the treatment of uncomplicated infantile or food-borne botulism because the toxin is primarily an intracellular molecule. Antibiotics are reserved for the treatment of complications. Wound botulism requires aggressive use of antibiotics and antitoxin.

The neuromuscular junction is perhaps the most common site adversely affected in drug-induced neuropathies. Several drugs have been reported to produce or potentiate unwanted neuromuscular blockade, including aminoglycosides, clindamycin, polymyxin, colistin, propranolol, calcium channel blockers, quinidine, lidocaine, corticosteroids, chlorpromazine, and lithium.

Disorders of Muscles

DMD is the most common and severe of the muscular dystrophies that affect humans. Inherited as an X-linked recessive trait, it has an estimated incidence of 1:3000 male births. The gene responsible for DMD and Becker muscular dystrophy has been localized on the short arm of the X chromosome (Xp21). The dystrophin gene regulates the expression of dystrophin, a protein that links the normal contractile apparatus to the sarcolemma in skeletal muscle. DMD usually manifests in boys with proximal muscle weakness at 2 to 4 years of age. Poor head control in infancy may be an early sign of weakness. Clinical diagnosis is made after consideration of history, physical findings, and elevated serum creatine kinase level. Diagnosis is confirmed by finding an abnormality in the dystrophin gene by mutation analysis of blood leukocyte DNA. By inducing specific exon skipping during messenger RNA splicing, antisense compounds were shown to correct the open reading frame of the DMD gene and to restore dystrophin expression in vitro and in animal models in vivo .

Respiratory disease in DMD is the major cause of morbidity and mortality. Loss of lung function progresses linearly after the initiation of wheelchair use; increasing hypoxemic dips are seen during sleep in subsequent teenage years, and respiratory failure occurs between 18 and 20 years of age. Unless properly managed with respiratory muscle aids, these patients invariably die before age 30. The deterioration in pulmonary function in DMD parallels the progression of the disease. A FVC of less than 1 L is a predictor of poor outcome, with a 5-year survival rate of only 8% if assisted ventilation is not provided. Death is due to respiratory failure in 80% of cases or to cardiac failure in 10% to 20% of cases.

A restrictive syndrome secondary to muscle weakness characterizes the pulmonary compromise in patients with DMD. When daytime hypercapnia develops in DMD patients, life expectancy without noninvasive ventilatory assistance is approximately 9 to 10 months. Chest wall muscle weakness and contractures, spinal deformity, and vertebrocostal ankylosis also occur. When assisted PCF decreases to less than 300 L/min, a pulse oximeter and Cough-Assist ^TM (JH Emerson Company, Cambridge, MA) are prescribed for the oximetry protocol as described subsequently. Patients with DMD eventually require 24-hour use of noninvasive inspiratory muscle aids, but can live well into their 40s using them.

Congenital myotonic dystrophy is the second most common muscular dystrophy. Myotonic dystrophy is an autosomal dominant inherited disease that occurs with an estimated frequency of 1:7500 to 1:18,500. The mutation responsible is an expansion of trinucleotide (CTG) repeats in the region of the myotonic dystrophy protein kinase ( DMPK ) gene, on the long arm of chromosome 19. Myotonia, a very slow relaxation of muscle after contraction, and muscle weakness are the prominent clinical features, but many organ systems can be affected, including the cardiac, endocrine, and ophthalmologic systems. Involvement of the respiratory system is the major contributor to morbidity and mortality.

Neonatal myotonic dystrophy is a severe form of myotonic dystrophy that develops in a few infants born to mothers, and rarely to fathers, with myotonic dystrophy. Prominent manifestations include hypotonia without myotonia, feeding difficulties, and respiratory distress. Respiratory failure is common and may result in death in the neonatal period. Examining the parents and finding the repeat segment of DNA on the myotonic dystrophy gene can confirm the diagnosis. Polyhydramnios and decreased fetal movements are common. Prematurity, hydrops fetalis with pleural effusions, and pulmonary hypoplasia can increase respiratory difficulties owing to diaphragmatic weakness at birth. Fifty percent of neonates with congenital myotonic dystrophy need respiratory support at birth.

The diagnosis of this disease is suspected when the newborn is recognized to be difficult to wean from the ventilator for unknown reasons. Thin ribs and an elevated right diaphragm on the chest radiograph may hint at the diagnosis. The breathing pattern of these patients is similar to that of any patient with a restrictive syndrome secondary to respiratory muscle weakness—increased rate with small tidal volumes at rest. Myotonia and weakness of the respiratory muscles and the muscles of deglutition, decreased ventilatory drive, and failure of myotonic muscles to benefit from inspiratory muscle support (ventilatory assistance) make these patients very prone to chronic hypoventilation and cor pulmonale.