Clinical Manifestations of Amyotrophic Lateral Sclerosis

Cognitive dysfunction is present in up to 60% of patients with ALS and can range from mild impairment of word fluency to frontotemporal lobe dementia. This discovery has led to the recognition of ALS as a multisystem disorder extending beyond the motor neurons.

The pathophysiologic basis underlying the progressive degeneration of motor neurons in these disorders is incompletely understood. Defects in glutamate clearance, ubiquitinproteosome pathways, ribonucleic acid (RNA) processing, mitochondrial function, axonal transport, apoptosis, and several other mechanisms have been advanced.

Progressive muscular atrophy (PMA) is a MND variant that accounts for approximately 5% of adult-onset acquired MND. Patients with PMA initially report symptoms of weakness and muscle atrophy, sometimes associated with cramping. Most commonly, onset is asymmetric and in the distal musculature, beginning in either the upper or the lower extremity. Fine movements of the hands may be impaired, or a foot may become weak. Sensory symptoms and pain are absent. Patients may also note spontaneous twitching (fasciculations) of muscles at rest. Some patients with apparent PMA develop upper motor neuron (UMN) symptoms over time, requiring reclassification as ALS. Even in the absence of clinical UMN signs, approximately half of the patients diagnosed with PMA have autopsy evidence of corticospinal tract involvement, again implying ALS. Whether these disorders represent distinct entities or points on a continuum is unclear.

Primary lateral sclerosis (PLS) is a syndrome of progressive upper motor neuron dysfunction. It is an uncommon diagnosis and accounts for less than 5% of patients with MND. PLS is pathologically characterized by corticospinal degeneration, with sparing of the anterior horns that distinguishes it from ALS. The typical clinical presentation is characterized by leg weakness and spasticity or predominant bulbar involvement, with an upper extremity presentation less common. Symptoms usually start unilaterally and tend to spread to the contralateral side first, before involving a new region. Stiffness, clumsiness, and poor coordination are prominent complaints. A patient with a MND who presents with idiopathic spasticity and does not develop wasting and other clinical or electrophysiologic evidence of lower motor neuron (LMN) involvement within 4 years likely has PLS; before 4 years has elapsed, it is more uncertain whether such a patient will or will not eventually evolve to a diagnosis of ALS (i.e., a diagnosis of upper motor neuron–predominant ALS). The course of PLS is very slowly progressive, with average disease duration of 8 years or more, in contrast to a shorter average life span for patients with ALS.

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