Amyotrophic lateral sclerosis and other motor neuron diseases are characterized by steady, relentless, progressive degeneration of corticospinal tracts, anterior horn cells, bulbar motor nuclei, or a combination. Symptoms vary in severity and may include muscle weakness and atrophy, fasciculations, emotional lability, and respiratory muscle weakness. Diagnosis involves nerve conduction studies, electromyography, and exclusion of other disorders with MRI and laboratory testing. Treatment is supportive.
(See also Overview of Peripheral Nervous System Disorders.)
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease (MND). MNDs may involve the central nervous system (CNS) as well as the peripheral nervous system. Usually, etiology is unknown. However, approximately 15% of cases are hereditary; they result from mutations in the superoxide dismutase (SOD) 1 gene (1). Nomenclature and symptoms vary according to the part of the motor system most affected.
Myopathies have similar features but are disorders of the muscle membrane, contractile apparatus, or organelles.
MNDs can be classified as upper and lower; some disorders (eg, ALS) have features of both. MNDs are more common among men, most often appearing during their 50s.
General reference
1. Abati E, Bresolin N, Comi G, Corti S: Silence superoxide dismutase 1 (SOD1): A promising therapeutic target for amyotrophic lateral sclerosis (ALS). Expert Opin Ther Targets 24 (4):295–310, 2020. doi: 10.1080/14728222.2020.1738390 Epub 2020 Mar 14.
Symptoms and Signs of ALS and Other MNDs
Upper MNDs (eg, primary lateral sclerosis) affect neurons of the motor cortex, which extend to the brain stem (corticobulbar tracts) or spinal cord (corticospinal tracts). Generally, symptoms consist of stiffness, clumsiness, and awkward movements, usually affecting first the mouth, throat, or both, then spreading to the limbs.
Lower MNDs affect the anterior horn cells or cranial nerve motor nuclei or their efferent axons to the skeletal muscles. In bulbar palsies, only the cranial nerve motor nuclei in the brain stem (bulbar nuclei) are affected. Patients usually present with facial weakness, dysphagia, and dysarthria. When anterior horn cells of spinal (not cranial) nerves are affected, as in spinal muscular atrophies, symptoms usually include muscle weakness and atrophy, fasciculations (visible muscle twitches), and muscle cramps, initially in a hand, a foot, or the tongue. Poliomyelitis, an enteroviral infection that attacks anterior horn cells, and postpolio syndrome are also lower MNDs.
Physical findings help differentiate upper from lower MNDs (see table Distinguishing Upper From Lower Motor Neuron Lesions) and weakness due to lower MNDs from that due to myopathy (see table Distinguishing the Cause of Muscle Weakness: Lower Motor Neuron Dysfunction vs Myopathy).
Amyotrophic lateral sclerosis (ALS)
Most patients with ALS present with random, asymmetric symptoms, consisting of cramps, weakness, and muscle atrophy of the hands (most commonly) or feet. Weakness progresses to the forearms, shoulders, and lower limbs. Fasciculations, spasticity, hyperactive deep tendon reflexes, extensor plantar reflexes, clumsiness, stiffness of movement, weight loss, fatigue, and difficulty controlling facial expression and tongue movements soon follow.
Other symptoms include hoarseness, dysphagia, and slurred and often nasal speech; because swallowing is difficult, salivation appears to increase, and patients tend to choke on liquids.
Late in the disorder, a pseudobulbar affect occurs, with inappropriate, involuntary, and uncontrollable excesses of laughter or crying. Sensory systems, consciousness, cognition, voluntary eye movements, sexual function, and urinary and anal sphincters are usually spared.
Death is usually caused by failure of the respiratory muscles; 50% of patients die within 3 years of onset, 20% live 5 years, and 10% live 10 years. Survival for > 30 years is rare.
Progressive bulbar palsy and progressive pseudobulbar palsy
The bulbar muscles innervated by cranial nerves are predominantly affected in patients with progressive bulbar palsy, resulting from progressive degeneration of the motor neurons innervating bulbar musculature. This disorder causes progressive difficulty with chewing, swallowing, and talking; a nasal voice; reduced gag reflex; fasciculations and weak movement of the facial muscles and tongue; and weak palatal movement. Aspiration is a risk.
The upper motor neuron equivalent of this disorder is progressive pseudobulbar palsy. This disorder affects the corticobulbar tract, descending to bulbar lower motor neurons, but spares the lower motor neurons in the brain stem, causing upper motor neuron weakness of the bulbar muscles. and thus is called pseudobulbar. Speech is spastic, patients cannot rapidly repeat syllables, (kakaka, tatata, lalala, bababa); gag reflex and jaw jerk are brisk. A pseudobulbar affect with emotional lability may also occur.
Commonly, progressive bulbar palsy spreads, affecting extrabulbar segments; then it is called bulbar-variant ALS.
Patients with dysphagia have a very poor prognosis; respiratory complications due to aspiration frequently result in death within 1 to 3 years.
Progressive muscular atrophy
In many cases, especially those with childhood onset, inheritance of progressive muscular atrophy is autosomal recessive. Other cases are sporadic. The disorder can develop at any age.
Anterior horn cell involvement occurs alone or is more prominent than corticospinal involvement, and progression tends to be more benign than that of other MNDs.
Fasciculations may be the earliest manifestation. Muscle wasting and marked weakness begin in the hands and progress to the arms, shoulders, and legs, eventually becoming generalized. Deep tendon reflexes are hypoactive. Patients may survive ≥ 25 years.
Pearls & Pitfalls
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Primary lateral sclerosis
In primary lateral sclerosis, progressive muscle stiffness in the arms and legs occurs with spasticity and hyperreflexia during examination. Fasciculations and muscle atrophy are atypical for this predominantly upper motor neuron disorder.
Survival is prolonged because risk of aspiration and pneumonia is low; several years must pass to result in total disability.
Symptoms and signs reference
1. Chiò A, Logroscino G, Hardiman O, et al: Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler 10 (5–6):310-23, 2009. doi: 10.3109/17482960802566824
Diagnosis of ALS and Other MNDs
Electrodiagnostic tests
MRI of the brain and, if no cranial nerve involvement, cervical spine
Laboratory tests to check for other, treatable causes
Diagnosis of motor neuron diseases is suggested by progressive, generalized motor weakness without significant sensory abnormalities.
Differential diagnosis
Other disorders that cause pure muscle weakness should be ruled out:
Various myopathies (including noninflammatory and drug-induced)
Spinal muscular atrophies (mostly in children)
Electrolyte abnormalities (eg, hypokalemia, hypercalcemia, hypophosphatemia)
Various infections (eg, syphilis, Lyme disease, hepatitis C)
Autoimmune-mediated motor neuropathies
Behavioral variant of frontotemporal dementia (15 to 20% develop motor neuron disease)
Heavy metal toxicity (eg, lead, mercury)
When cranial nerves are affected, a treatable cause is less likely. Upper and lower motor neuron signs plus weakness in facial muscles strongly suggest amyotrophic lateral sclerosis.
Pearls & Pitfalls
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Testing
Electrodiagnostic tests should be done to check for evidence of disorders of neuromuscular transmission or demyelination. Such evidence is not present in MNDs; nerve conduction velocities are usually normal until late in the disease. Needle electromyography (EMG) is the most useful test, showing fibrillations, positive waves, fasciculations, and sometimes giant motor units, even in unaffected limbs.
Brain MRI is required. When there is no clinical or EMG evidence of cranial nerve motor weakness, MRI of the cervical spine is indicated to exclude structural lesions that may be compressing the spinal cord.
Tensor diffusion brain MRI may show a pattern of iron deposition along the motor pathways; although the association requires confirmation, this pattern seems consistent with upper motor neuron involvement and supports a diagnosis of ALS in the appropriate clinical setting (1).
Laboratory tests are done to check for treatable causes. Tests include complete blood count, electrolytes, creatine kinase, and thyroid function tests.
Serum and urine protein electrophoresis with immunofixation is done to check for a paraprotein that is rarely associated with MNDs. Discovering an underlying paraproteinemia may indicate that the MND is paraneoplastic, and treatment of the paraproteinemia may ameliorate the MND.
Antimyelin-associated glycoprotein (MAG) antibodies are associated with a demyelinating motor neuropathy, which may mimic ALS.
A 24-hour urine collection is done to check for heavy metals in patients who may have been exposed to them.
Lumbar puncture may be done to exclude other clinically suspected disorders; if white blood cells or the protein level is elevated, an alternative diagnosis is likely.
Serum tests for syphilis, erythrocyte sedimentation rate, and measurement of certain antibodies (rheumatoid factor, Lyme titer, HIV, hepatitis C virus, antinuclear [ANA], anti-Hu [to check for anti-Hu paraneoplastic syndrome]) are indicated only if suggested by risk factors or history.
Genetic testing (eg, for superoxide dismutase gene mutation or genetic abnormalities that cause spinal muscular atrophies) and enzyme measurements (eg, hexosaminidase A for Tay-Sachs disease) should not be done unless patients are interested in genetic counseling; disorders detected by these tests have no known specific treatments.
Diagnosis reference
1. Baek, S-H Park J, Kim YH, et al: Usefulness of diffusion tensor imaging findings as biomarkers for amyotrophic lateral sclerosis. Sci Rep 10 (1):5199, 2020. doi: 10.1038/s41598-020-62049-0
Treatment of ALS and Other MNDs
Supportive care
SOD1 mutation)
The mainstay of care for patients with amyotrophic lateral sclerosis is timely intervention to manage symptoms.
A multidisciplinary team approach helps patients cope with progressive neurologic disability.
3). It may be given in addition to other medications.
SOD1 mutation; it has been shown to delay progression and must be given intrathecally (4).
The following medications may help reduce symptoms:
In patients with progressive bulbar palsy, surgery to improve swallowing has had limited success.
Treatment references
1. Saitoh Y, Takahashi YNeurodegener Dis Manag 10 (6):343–355, 2020. doi: 10.2217/nmt-2020-0033 Epub 2020 Aug 27.
2. Shefner J, Heiman-Patterson T, Pioro EP, et alMuscle Nerve 61 (2):218–221, 2020. doi: 10.1002/mus.26740 Epub 2019 Nov 11.
3. Paganoni S, Macklin EA, Hendrix S, et alN Engl J Med 383 (10):919–930, 2020. doi: 10.1056/NEJMoa1916945
4. Miller TM, Cudkowicz ME, Genge A, et alN Engl J Med 387:1099–1110, 2022. doi: 10.1056/NEJMoa2204705
Key Points
Consider motor neuron disease in patients who have diffuse upper and/or lower motor weakness without sensory abnormalities.
Suspect ALS in patients with upper and lower motor neuron signs plus weakness in facial muscles.
Do MRI of the brain and electrodiagnostic and laboratory testing to exclude other disorders.
The mainstay of treatment is supportive measures (eg, multidisciplinary support to help cope with disability; pharmacotherapy for symptoms such as spasticity, cramps, and pseudobulbar affect).
