Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease (Table 188-1). ALS is caused by degeneration of motor neurons at all levels of the CNS, including anterior horns of the spinal cord, brainstem motor nuclei, and motor cortex. Familial ALS (FALS) represents 5–10% of the total and is inherited usually as an autosomal dominant disorder.
TABLE 188-1Sporadic Motor Neuron Diseases ||Download (.pdf) TABLE 188-1 Sporadic Motor Neuron Diseases
|CHRONIC ||ENTITY |
|Upper and lower motor neuron ||Amyotrophic lateral sclerosis |
|Predominantly upper motor neuron ||Primary lateral sclerosis |
|Predominantly lower motor neuron ||Multifocal motor neuropathy with conduction block |
| ||Motor neuropathy with paraproteinemia or cancer |
| ||Motor predominant peripheral neuropathies |
|Other || |
|Associated with other neurodegenerative disorders || |
|Secondary motor neuron disorders (see Table 188-2) || |
|Acute || |
|Poliomyelitis || |
|Herpes zoster || |
|Coxsackie virus || |
|West Nile virus || |
Onset is usually midlife, with most cases progressing to death in 3–5 years. In most societies there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per 100,000. Presentation is variable depending on whether upper motor or lower motor neurons are more prominently involved initially.
Common initial symptoms are weakness, muscle wasting, stiffness and cramping, and twitching in muscles of hands and arms, often first in the intrinsic hand muscles. Legs are less severely involved than arms, with complaints of leg stiffness, cramping, and weakness common. Symptoms of brainstem involvement include dysphagia, which may lead to aspiration pneumonia and compromised energy intake; there may be prominent wasting of the tongue leading to difficulty in articulation (dysarthria), phonation, and deglutition. Weakness of ventilatory muscles leads to respiratory insufficiency. Additional features that characterize ALS are lack of sensory abnormalities, pseudobulbar palsy (e.g., involuntary laughter, crying), and absence of bowel or bladder dysfunction. Dementia is not a component of sporadic ALS; in some families ALS is co-inherited with frontotemporal dementia characterized by behavioral abnormalities due to frontal lobe dysfunction (Chap. 185).
Pathologic hallmark is death of lower motor neurons (consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons (originating in layer five of the motor cortex and descending via the pyramidal tract to synapse with lower motor neurons). Although at onset ALS may involve selective loss of only upper or lower motor neurons, it ultimately causes progressive loss of both; the absence of clear involvement of both motor neuron types should call into question the diagnosis of ALS.
The cause of sporadic ALS is not well defined. Genetic causes of ALS can be grouped into three general categories. In one, the primary problem is inherent instability of mutant proteins, with perturbations in protein degradation (SOD1, ...