Pathophysiology

ALS progressively destroys the motor neurons that control voluntary muscles. Upper motor neurons, located in the brain, send messages to lower motor neurons in the spinal cord and from there to various voluntary muscle groups. In individuals affected by ALS, both the upper and lower motor neurons become sclerotic and die. Consequently, the neurons can no longer conduct impulses to the muscles, so that muscular weakness and atrophy develop. In a process called astrocytic gliosis, lost motor neurons are replaced by astrocytes, which form a kind of scar tissue that can be seen on magnetic resonance imaging (MRI) within the corticospinal tracts, brain stem, and spinal cord. Motor neuron degeneration is accompanied by a neuroinflammatory process and the proliferation of glial cells (gliosis), which do not conduct impulses.16,17

Eventually, as damage to the motor neurons increases, the brain is unable to start or adequately control voluntary muscle movement. The affected muscles become increasingly weak and atrophic, and the muscles that control speech, swallowing, and breathing slowly become impaired. Ultimately, paralysis develops, and the patient requires artificial ventilation for respiratory failure.18 ALS damages motor neurons, but the sensory neurons usually remain intact—the senses of sight, touch, hearing, taste, and smell are not affected. The eye muscles and sphincter control are spared.8 Cognitive impairment is not a major feature of ALS, and dementia does not occur in all patients. However, a link between ALS and FTD has recently been postulated because the two conditions are characterized by similar neuropathologic changes, clinical features, and genetic mutations. Some investigators refer to this overlap of features as the ALS-FTD spectrum.19-22

Clinical presentation

The initial symptoms of ALS may include cramping and weakness in the upper and lower extremities. Foot drop and clumsiness may cause the patient to fall. Twitching, stiffness, slurred speech, and difficulty walking occur.8 Symptoms of upper motor neuron involvement include muscle spasticity, hyperreflexia, and the presence of a Babinski reflex. Symptoms of lower motor neuron damage include muscle weakness, atrophy, cramping, and fasciculations.22 Emotional lability due to pseudobulbar palsy may also develop.23 Later in the disease process, dysphagia due to esophageal muscle dysfunction, inability to move the arms and legs, dysarthria, dysphonia, and respiratory failure commonly occur. In more than half of patients with ALS, hypermetabolism causes weight loss, muscle wasting, and cachexia.24

In the past, ALS was thought to spare cognitive function but is now known to cause a range of cognitive impairments. According to Gillingham et al,25 50% of persons with ALS have mild cognitive impairment with subtle executive deficits, and 10% to 15% have FTD.26,27

Diagnosis

ALS is usually diagnosed on the basis of clinical symptomatology. Alternative diagnoses can usually be ruled out with neuroimaging studies and laboratory evaluation. Because ALS is a diagnosis of exclusion, a substantial delay in diagnosis, upward of 12 months after the onset of symptoms, is common, and patients may seek health care from multiple providers early in the disease course.28 No laboratory tests can identify the disorder, no biomarkers for the condition are known, and the findings on MRI and computed tomography (CT) are unremarkable. Electromyographic (EMG) studies may be helpful to rule out muscle or neurologic conditions that can mimic ALS. The value of positron emission tomography (PET), functional MRI, and magnetic resonance spectroscopy in ALS is being studied.29

Related Articles

For a diagnosis of ALS, the patient must have signs and symptoms of both upper motor neuron and lower motor neuron damage that cannot be attributed to other causes. Two classification systems have attempted to characterize definite vs probable signs of ALS. The El Escorial criteria, which experts commonly use, rely mainly on the clinical examination findings (Table 1).30 Some investigators find that use of the Awaji criteria allows an earlier diagnosis. The Awaji criteria include EMG results for the identification of lower and upper motor neuron damage and incorporate fasciculation potentials as evidence of ALS (Table 1).31-33


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