Clinical Features

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 Alzheimer's Disease and Other Dementias).

Pathophysiology

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, ubiquilin-1 and 2, p62). In the second category, the mutant genes perturb RNA processing, transport, and metabolism (C9orf73, TDP43, FUS); for C9orf72, there is expansion of an intronic hexanucleotide repeat. In the third group of ALS genes, the primary problem is defective axonal cytoskeleton and transport (dynactin, profilin-1).

Laboratory Evaluation

EMG provides objective evidence of extensive muscle denervation not confined to the territory of individual peripheral nerves and nerve roots. CSF is usually normal. Muscle enzymes (e.g., CK) may be elevated.

Several types of secondary motor neuron disorders that resemble ALS are treatable (Table 188-2 Etiology of Motor Neuron Disorders); therefore, all pts should have a careful search for these disorders.

MRI or CT myelography is often required to exclude compressive lesions of the foramen magnum or cervical spine. When involvement is restricted to lower motor neurons only, another important entity is multifocal motor neuropathy with conduction block (MMN). A diffuse, lower motor axonal neuropathy mimicking ALS sometimes evolves in association with hematopoietic disorders such as lymphoma or multiple myeloma; an M-component in serum should prompt consideration of a bone marrow biopsy. Lyme disease may also cause an axonal, lower motor neuropathy, typically with intense proximal limb pain and a CSF pleocytosis. Other treatable disorders that occasionally mimic ALS are chronic lead poisoning and thyrotoxicosis.

Pulmonary function studies may aid in management of ventilation. Swallowing evaluation identifies those at risk for aspiration. Genetic testing is available for superoxide dismutase 1 (SOD1) (20% of FALS) and for rare mutations in other genes.