Porth's Essentials of Pathophysiology, 4e

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Disorders of Neuromuscular Function

C h a p t e r 3 6

as a thymoma (i.e., thymus tumor) or thymic hyper- plasia (i.e., increased thymus weight from an increased number of thymus cells). 16 Clinical Manifestations. In persons with myasthenia gravis who have a loss of functional acetylcholine recep- tors, each release of acetylcholine from the presynaptic membrane results in diminished motor response. This results in both muscle weakness and fatigability with sustained effort. Most commonly affected are the eye and periorbital muscles, with ptosis (drooping of eye- lids) due to eyelid weakness or diplopia (double vision) due to weakness of the extraocular muscles as an ini- tial symptom. 14–16 The disease may progress from ocu- lar muscle weakness to generalized weakness, including respiratory muscle weakness. Chewing and swallowing may be difficult. Weakness in limb movement usually is more pronounced in the proximal rather than distal parts of the extremity, so that climbing stairs and lift- ing objects are difficult. As the disease progresses, the muscles of the lower face are affected, causing speech impairment. In most persons, symptoms are least evi- dent when arising in the morning, but grow worse with effort and as the day proceeds. Persons with myasthenia gravis may experience a sudden exacerbation of symptoms and weakness known as myasthenic crisis. Myasthenic crisis occurs when muscle weakness becomes severe enough to compro- mise ventilation to the extent that respiratory support and airway protection are needed. This usually occurs during a period of stress, such as infection, emotional upset, pregnancy, alcohol ingestion, cold exposure, or surgery. It also can result from inadequate or excessive doses of the anticholinesterase drugs used in treatment of the disorder. Diagnosis andTreatment. The diagnosis ofmyasthenia gravis is based on history and physical examination and confirmed by the response to a short-acting anti- cholinesterase test. Edrophonium (Tensilon) com- monly is used for the test. 14–16 The drug, which is administered intravenously, decreases the breakdown of acetylcholine in the neuromuscular junction. When weakness is caused by myasthenia gravis, a dramatic transitory improvement in muscle function occurs. Electrophysiologic studies can be done to demonstrate a decremental muscle response to repetitive motor nerve stimulation. An immunoassay test can be used to detect the presence of antiacetylcholine receptor anti- bodies circulating in the blood. Treatment methods include the use of pharmacologic agents; immunosuppressive therapy, including corticoste- roiddrugs;managementofmyastheniccrisis;thymectomy; and plasmapheresis or intravenous immunoglobulin. 14–16 Medications that may exacerbate myasthenia gra- vis, such as the aminoglycoside antibiotics, should be avoided. Pharmacologic treatment with reversible anti- cholinesterase drugs (i.e., neostigmine, pyridostigmine) inhibits the breakdown of acetylcholine. Corticosteroid drugs, which suppress the immune response, are used in cases of a poor response to anticholinesterase drugs

The aminoglycoside antibiotics (e.g., gentamicin) may produce a clinical disturbance similar to botulism by preventing the release of acetylcholine from nerve endings. The symptoms usually subside rapidly once the drug is eliminated from the body. These drugs are particularly dangerous in persons with preexisting dis- turbances of neuromuscular transmission, such as myas- thenia gravis. The organophosphates (e.g., malathion, parathion) that are used in some insecticides bind acetylcholines- terase to prevent the breakdown of acetylcholine. They produce excessive and prolonged acetylcholine action with a depolarization block of cholinergic receptors, including those of the neuromuscular junction. 12 The organophosphates are well absorbed from the skin, lungs, gut, and conjunctiva of the eye, making them particularly effective as insecticides but also potentially dangerous to humans. Malathion and certain other organophosphates are rapidly metabolized to inactive products in humans and are considered safe for sale to the general public. The sale of other insecticides, such as parathion, which is not effectively metabolized to inac- tive products, has been banned. Other organophosphate compounds (e.g., soman) were developed as “nerve gases”; if absorbed in high enough concentrations, they produce lethal effects through depolarization block and loss of respiratory muscle function. Myasthenia Gravis Myasthenia gravis is a disorder of the neuromuscu- lar junction that affects impulse transmission between the motor neuron and the innervated muscle cell. 8,14–16 Women are affected nearly three times as often as men during early adulthood (age < 40 years), whereas the incidence is roughly equal during puberty and between ages 40 and 50. After 50 years of age, the incidence is higher in men. The Lambert-Eaton myasthenic syn- drome is a special type of myasthenic syndrome that develops in association with neoplasms, particularly small cell carcinoma of the lung 8 (see Chapter 7). Now recognized as an autoimmune disease, the dis- order is caused by an antibody-mediated loss of acetyl- choline receptors in the neuromuscular junction 8,14–16 (see Fig. 36-6B). Three mechanisms are thought to underlie the loss of functional acetylcholine receptors: (1) complement-mediated injury to the postsynaptic muscle membrane, (2) accelerated acetylcholine recep- tor degradation by receptor-specific antibodies, and (3) blockade of the receptors by antibodies attached to the acetylcholine-binding sites. Neonatal myasthenia gravis, caused by placental transfer of the acetylcholine recep- tor antibody, occurs in about 10% to 15% of infants born to mothers with the disease. 14,15 Spontaneous reso- lution of symptoms usually occurs within a few months of birth. The trigger or inciting factor leading to the autoim- mune derangement in myasthenia gravis remains unclear, but several lines of evidence implicate the thymus gland in the process. Approximately 75% of persons with myasthenia gravis also have thymic abnormalities, such