Amyotrophic Lateral Sclerosis (ALS)

What Is It, Causes, Treatment, and More

Author:Lily Guo

Editors:Alyssa Haag,Ian Mannarino, MD, MBA,Kelsey LaFayette, DNP, ARNP, FNP-C

Illustrator:Jessica Reynolds, MS

Copyeditor:David G. Walker

What is amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, refers to a progressive, neurodegenerative disorder of the upper and lower motor neurons of the corticospinal tract. It is the most common form of motor neuron disease, with a worldwide incidence of approximately 1.5 per 100,000 individuals. As the disease progresses, it ultimately involves the death of motor neurons and is characterized by muscle cramps, muscle twitching, spasticity, and gradually worsening muscle weakness over time. This results in difficulty with ambulation, speaking, swallowing, and eventually breathing. Most cases are sporadic; however, there can be a genetic mutation in zinc-copper superoxide dismutase 1 (SOD1), which leads to free radical damage to neurons. There are several subtypes of ALS, including progressive motor atrophy, which is lower motor neuron degeneration predominant; primary lateral sclerosis, upper motor neuron degeneration predominant; and progressive bulbar palsy, cranial nerve predominant. Progressive bulbar palsy ALS, also known as bulbar ALS, has the worst prognosis with a mortality rate of greater than 50% at two years due to rapid degeneration of nerve cells in the brain.

Dying motor and sensory neuron.

What causes amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis may be sporadic (i.e., idiopathic), or it may be inherited genetically (also referred to as familial ALS). Sporadic ALS is more common, whereas familial ALS occurs in 5-10% of cases. Several genes have been implicated in familial ALS, including superoxide dismutase 1 (SOD1),  C9orf72, and TARDBP. Overall, genetic mutations can cause protein aggregation, leading to neuronal degeneration and death. 

Mutations in SOD1, which is an antioxidant protein encoded on chromosome 9 has been found in up to 20% of cases of familial ALS. SOD1 mutations are gain-of-function mutations that result in protein misfolding and aggregation, leading to direct neuronal injury and cell death. 

Another mutation identified in up to 40% of cases of familial ALS is in C9orf72, which is a gene that codes for a protein whose significance and role is currently unknown. Mutations in C9orf72 similarly result in aberrant protein aggregation and accumulation. 

Lastly, mutations in the gene TARDBP, which encodes for making the transactive response DNA binding protein 43 (TDP-43), has been associated with unusual ribonucleic acid processing, leading to neuronal injury. In response to neuronal injury, the central nervous system mounts an inflammatory response which is mediated by microglia and astrocytes, two types of neuronal support cells. Microglia secrete nitric oxide, oxygen radicals, cytokines, and glutamate, which are all molecules responsible for motor neuron cell death. Additionally, T-cells and natural killer cells contribute to inflammation in ALS. 

There are several risk factors tied to ALS, including having a family member with a history of ALS, advanced age, and cigarette smoking. Although occasionally some individuals present with ALS before the age of 25, the incidence increases after age 40. It is also 1.5 times more likely to develop in those assigned male at birth.

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What are the signs and symptoms of amyotrophic lateral sclerosis?

The signs and symptoms of amyotrophic lateral sclerosis include asymmetric hand weakness, upper extremity cramping, ataxia, muscle atrophy, and respiratory weakness and failure. Other neurological signs associated with ALS include apathy (i.e., lack of interest or enthusiasm) and disinhibited behavior (i.e., lack of control in social situations), which can manifest as sudden outbursts of involuntary laughter or crying that is excessive or incongruent to mood. 

Earlier on in the disease, an individual may find themselves dropping objects, such as glasses of water. As the disease progresses, one may experience decline of strength in both upper and lower extremities with muscle fasciculations (i.e., twitching). Motor strength may decline to the point where a wheelchair is required. Weakness may occur in muscles required for swallowing, speech, and articulation, resulting in dysarthria (i.e., difficulty speaking), dysphagia (i.e., difficult swallowing), and dysphonia (i.e., hoarseness of voice). In later phases of the disease, one may experience respiratory weakness, leading to recurrent respiratory infection associated with cough, fever, and chills.

How is amyotrophic lateral sclerosis diagnosed?

Diagnosis of amyotrophic lateral sclerosis may be made based on physical examination and a thorough medical history and review of symptoms. The El Escorial World Federation of Neurology criteria may be used by the clinician, which looks at evidence of lower motor neuron disease by clinical or electrophysiological neuropathic examination; evidence of upper motor neuron disease by clinical examination; the absence of electrophysiological, pathological, and neuroimaging evidence of an alternative medical diagnosis; and the progressive spread of symptoms throughout the body determined by exam and interview. The clinician may also ask questions regarding family members with similar histories of disease, and assess the individual’s mental status for signs of apathy and disinhibition. 

Diagnostic tests may be performed, such as laboratory testing to measure levels of creatinine kinase (CK). CK will typically be increased in ALS due to muscle wasting and atrophy. Tests can be used to rule out other diseases that may present in a similar manner, such as testing the blood for Lyme disease and heavy metal poisoning. Nerve conduction studies (NCS) and needle electromyography (EMG) may be ordered to assess the function of muscles and nerve cells. During NCS, a brief electrical shock is administered to the skin over the nerves being tested to give an estimate of how fast the nerves are conducting the electrical impulse. Nerve conduction will typically be slowed on NCS in those with ALS. During EMG, a fine needle is inserted into different parts of the body, including the neck, lower back, the torso, arms, and legs. On EMG, ALS may present as fibrillations and positive sharp waves, which reflect the characteristic spontaneous depolarization of denervated muscle fibers at rest. 

How is amyotrophic lateral sclerosis treated?

Amyotrophic lateral sclerosis is managed using disease-modifying agents, though there is currently no known cure. Riluzole and edaravone are currently the only two approved medications in the United States. Riluzole blocks the transmission of glutamate in the central nervous system, thereby decreasing the rate of neuronal degeneration and symptom progression. Riluzole is indicated for mild to moderate disease of less than five-years’ duration. On the other hand, edaravone is a drug for the treatment of ALS that acts as a free-radical scavenger and reduces oxidative stress on neurons. While neither riluzole or edaravone may be used to cure ALS, they may be used to prolong survival for those in the early stages of the disease or help extend the time until a tracheostomy (i.e., breathing tube) is needed. In addition to disease modifying agents, ALS can be treated using symptom management, including quinine or muscle relaxants to help control muscle spasms and spasticity. 

What are the most important facts to know about amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) refers to a progressive neurodegernative disorder of motor neurons. There are three main forms of ALS, including progressive motor atrophy, primary lateral sclerosis, and progressive bulbar palsy. ALS occurs mainly in those over 40 years of age and is due to a sporadic mutation in 90% of cases. Genes implicated in the development of ALS include SOD1,  C9orf72, and TARDBP. The symptoms of ALS include progressively worsening muscle weakness of the upper and lower limbs as well as the trunk and muscles used for speech and articulation. ALS progresses, and eventually, an individual may need a wheelchair for ambulation and a ventilator for respiratory support. Diagnosis of ALS may be made on patient examination and history taking, including family history of disease. Diagnostic tests, such as measurement of creatinine kinase levels and an EMG, may be performed. Though there is currently no cure, treatment involves disease-modifying drugs, including riluzole and edaravone, which can help slow progression of disease. 

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Resources for research and reference

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