Amyotrophic Lateral Sclerosis (ALS) · What Is It, Causes, Treatment, and More

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’s 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 causes the death of motor neurons and is characterized by muscle cramps, muscle twitching, spasticity, and gradual worsening of muscle weakness over time. This results in difficulty with ambulation, speaking, swallowing, and eventually breathing.  

Motor neurons are responsible for initiating and controlling muscle activity, and they can be divided into upper and lower motor neurons. Upper motor neurons originate in the cerebral cortex, with axons that descend through the white matter and synapse with lower motor neurons in the brainstem and spinal cord. In turn, lower motor neurons send axons out of the central nervous system via the cranial nerves or spinal nerve roots to innervate different skeletal muscles. Some conditions affect only lower motor neurons, while others can affect both upper and lower motor neurons, such as amyotrophic lateral sclerosis.  

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, which initially affects the muscles involved in speech and swallowing. Progressive bulbar palsy ALS, also known as bulbar ALS, has the worst prognosis with a mortality rate of greater than 50% at 2 years due to rapid degeneration of nerve cells in the brain. 

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, these genetic mutations can cause protein aggregation, leading to neuronal degeneration and cell death.   

Specifically, mutations in SOD1, an antioxidant protein located on chromosome 9, have been found in up to 20% of cases of familial ALS. SOD1 mutations 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 codes for making the transactive response DNA binding protein 43 (TDP-43), have been associated with unusual ribonucleic acid (RNA) processing, leading to neuronal injury. In response to neuronal injury, the central nervous system mounts an inflammatory response which is mediated by different types of neuronal support cells, like astrocytes and microglia. These cells secrete inflammatory mediators such as nitric oxide, oxygen radicals, cytokines, and glutamate, all of which can contribute to motor neuron cell death. Additionally, other immune cells like 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 significantly after age 40. It’s also more likely to develop in those assigned male at birth. 

The signs and symptoms of amyotrophic lateral sclerosis include asymmetric hand weakness; upper extremity cramping; ataxia, or clumsy movement; 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. Some individuals may also develop cognitive impairment as a result of frontotemporal dementia.   

Earlier on in the disease, an individual may find themselves dropping objects, such as glasses of water. As the disease progresses, one may experience a 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 difficulty speaking, swallowing problems, and hoarseness of voice. In later phases of the disease, one may experience respiratory muscle weakness, leading to recurrent respiratory infections associated with cough, fever, and chills. 

Diagnosis of amyotrophic lateral sclerosis is made based on a combination of clinical findings and results of electrophysiological and neuroimaging tests. The diagnostic criteria for ALS requires evidence of both upper and lower motor neuron involvement, such as spasticity and overactive reflexes, as well as muscle weakness, fasciculations, and atrophy, respectively. These signs need to be present in different body regions, including the arms, trunk, legs, and bulbar muscles. Finally, ALS diagnosis requires ruling out other conditions that may mimic its symptoms, such as myasthenia gravis, spinal cord lesions (e.g., tumors, herniated discs), and other neurodegenerative or autoimmune diseases. 

While there are no definitive tests for ALS, diagnostic tests may be performed to assist the diagnosis, such as laboratory testing to measure levels of creatinine kinase (CK). CK will typically be increased in ALS due to muscle wasting and atrophy. 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, demonstrating nerve damage. During an EMG, a fine needle is inserted into different parts of the body, including the neck, lower back, the torso, arms, and legs to detect anomalies in muscle activity. On EMG, ALS typically presents with fibrillations and positive sharp waves, which reflect the characteristic spontaneous depolarization of denervated muscle fibers at rest.  

Even though there is currently no known cure, amyotrophic lateral sclerosis can be managed using disease-modifying agents. As of January 2025, there are several FDA-approved medications in the United States, including riluzole, edaravone, combination therapy with sodium phenylbutyrate and taurursodiol, and more recently, tofersen.  

Riluzole (Rilutek®) 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 5-years’ duration. On the other hand, edaravone (Radicava®) is a drug for the treatment of ALS that acts as a free-radical scavenger and reduces oxidative stress on neurons. Similarly, combination therapy with sodium phenylbutyrate and taurursodiol (Relyvrio®) is thought to protect motor neurons by reducing metabolic stress and cellular dysfunction. Finally, tofersen (Qalsody®) is designed to reduce the production of SOD1 protein in patients with known SOD1 gene mutations, which account for a subset of familial ALS cases.  

While none of these medications can be used to cure ALS, they may be able 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. Supportive care may also include management of respiratory failure with non-invasive ventilation and airway clearance with specific devices that simulate the coughing mechanism. As ALS progresses, individuals may need to make decisions regarding life-sustaining treatments (e.g., tracheostomy and artificial feeding) and end-of-life care.