Porth's Essentials of Pathophysiology, 4e

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Nervous System

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Approximately 5% to 10% of cases are familial ALS, mostly with autosomal dominant inheritance. The rest are believed to be sporadic, with no family history of the disease. The gene for a subset of familial ALS has been mapped to the superoxide dismutase 1 ( SOD1 ) gene on chromosome 21. SOD1 is a critical enzyme involved in protecting neurons from oxidative damage. Other sug- gested mechanisms of nerve injury are alterations in transport of molecules necessary for maintenance of the axon, neurofilament abnormalities, and glutamate-medi- ated excitotoxicity (see Chapter 37). Manifestations of amyotrophic lateral sclerosis include those of both UMN and LMN dysfunction. 42–45 Muscle cramps involving the distal legs often are an early symptom. The most common clinical presenta- tion is slowly progressive weakness and atrophy in dis- tal muscles of one upper extremity. This is followed by regional spread of muscle weakness, reflecting involve- ment of neighboring areas of the spinal cord. Eventually, UMNs and LMNs involving multiple limbs and the head are affected. In the more advanced stages, mus- cles of the palate, pharynx, tongue, neck, and shoulders become involved, causing impairment of chewing, swal- lowing (dysphagia), and speech. Dysphagia with recur- rent aspiration and weakness of the respiratory muscles produces the most significant acute complications of the disease. Death usually results from involvement of cra- nial nerves and respiratory musculature. There are no specific tests for ALS. Diagnosis is based on a careful medical history, detailed physical and neurological examination, and electrophysiologi- cal studies. 43,44 Currently, there is no cure for ALS. The treatment of persons with ALS, which requires man- agement of medical problems, severe disability, and psychosocial problems, is best provided by a multidis- ciplinary team. 42–44 Measures to assist persons with the disorder manage their symptoms (e.g., weakness and muscle spasms, dysphagia, communication difficulty, excessive salivation, and emotional lability), nutritional status, and respiratory muscle weakness increase sur- vival time. An antiglutamate drug, riluzole, is the only drug approved for the treatment of ALS. 42 The drug is designed to decrease glutamate accumulation and slow the progression of the disease. Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune demyelinat- ing disorder characterized by inflammation and selective destruction of CNS myelin. 37,38,46–51 It affects approxi- mately 350,000 persons in the United States and more than 1 million worldwide. 46 The age of onset is typically between 18 and 45 years. 46 Women are affected twice as frequently as men. As with other autoimmune disorders, the pathogen- esis appears to involve both genetic and environmental influences. The risk for developing MS is 15-fold higher when the disease is present in a first-degree relative, and is even greater in monozygotic twins. 37 People with the human leukocyte antigen (HLA)-DR2 haplotype (see

SUMMARY CONCEPTS (continued)

Upper Motor Neuron Disorders Upper motor neuron disorders involve neurons that are fully contained within the CNS. They include the motor neurons arising in the motor areas of the cortex and their fibers as they project through the brain and descend in the spinal cord. Disorders that affect UMNs include multiple sclerosis and spinal cord injury. Stroke, which is a common cause of UMN damage, is discussed in Chapter 37. Amyotrophic lateral sclerosis is a mixed UMN and LMN disorder. Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease after the famous New York Yankees baseball player, is a devastating neurologic disorder that selectively affects motor function. Amyotrophic lateral sclerosis has an annual incidence of about 2 cases per 100,000 population. It is primarily a disorder of middle to late adulthood, with men being affected more fre- quently than women. The disease typically follows a progressive course, with a mean survival period of 2 to 5 years from the onset of symptoms. Amyotrophic lateral sclerosis is characterized by the loss of anterior LMNs in the spinal cord and motor nuclei of the brain stem and UMNs that originate in the motor cortex and descend via the pyramidal tract to synapse with the LMNs. 42–44 The death of LMNs leads to denervation, with subsequent muscle fiber atrophy and shinkage of skeletal muscles. It is this fiber atrophy, called amyotrophy, that appears in the name of the disease. The loss of nerve fibers in lateral columns of the white matter of the spinal cord, along with fibrillary gliosis, imparts a firmness or sclerosis to this CNS tissue; the term lateral sclerosis designates these changes. A remarkable feature of the disease is that the entire sensory system, the regulatory mechanisms of control and coordination of movement, and the intellect remain intact. The neurons for ocular motility and the parasym- pathetic neurons in the sacral spinal cord are also spared. The pathogenesis ofALS is largelyunknown, despite the identification of a number of genetic associations. 18,37,42,43,45 and controlled skilled movements. Disorders of the basal ganglia are characterized by involuntary movements, alterations in muscle tone, and disturbances in posture. ■■ Parkinsonism is a disorder in which there is an imbalance between the dopaminergic inhibitory effects and excitatory cholinergic functions of the basal ganglia, and is manifested by resting tremor, increased muscle tonus and rigidity, slowness of movement (i.e., bradykinesia), gait disturbances, and impaired postural responses.