ALS

ALS Affected neurons and muscles

Illustration of the motor neuron tract descending from primary motor cortex, via spinal cord, to skeletal muscle

ALS subtypes UMN LMN distribution

ALS Disease Pathology and Proposed Disease Mechanisms

ALS cross

ALS Coronal

Per Villand

Amyotrophic lateral sclerosis (ALS) is a group of rare neurological diseases that primarily affect the nerve cells (neurons) responsible for controlling voluntary muscle movement. Voluntary muscles enable activities such as chewing, walking, and talking. ALS is a progressive disease, meaning its symptoms worsen over time. At present, there is no cure for ALS, nor any effective treatments to stop or reverse its progression.

ALS is classified as a type of motor neuron disease (MND), which is caused by the gradual degeneration and death of motor neurons. Motor neurons are essential for communication between the brain, spinal cord, and muscles. These cells initiate and maintain the connections necessary for voluntary muscle movement. In ALS, both the upper motor neurons (located in the brain) and the lower motor neurons (located in the spinal cord and brainstem) degenerate, disrupting this communication and leading to muscle weakness, twitching (fasciculations), and atrophy.

As motor neurons die, the brain loses its ability to initiate and control voluntary movements. This can result in loss of mobility, speech, and the ability to breathe. Most people with ALS die from respiratory failure, typically within 3 to 5 years after the onset of symptoms. However, approximately 10% of people with ALS may survive for 10 years or longer.

Who Gets ALS?

In 2016, the Centers for Disease Control and Prevention (CDC) estimated that between 14,000 and 15,000 people in the United States are living with ALS. It is a rare disease that affects individuals worldwide, irrespective of race or ethnic background. However, there are several factors that may influence an individual's likelihood of developing ALS.

Risk Factors

Several risk factors for ALS include:

• Age: The disease most commonly develops between the ages of 55 and 75, although it can occur at any age.
• Gender: Men are slightly more likely to develop ALS than women, but this difference diminishes with age.
• Race and Ethnicity: Caucasians, particularly non-Hispanic white individuals, have a higher incidence of ALS.

Additionally, some studies suggest that military veterans are at a higher risk, being 1.5 to 2 times more likely to develop ALS. Possible explanations for this increased risk include exposure to environmental toxins such as lead and pesticides.

Types of ALS

• Sporadic ALS: Over 90% of ALS cases are sporadic, meaning they occur without any clear family history. Although family members of someone with sporadic ALS are at a slightly increased risk, the overall likelihood remains low.
• Familial (Genetic) ALS: Approximately 5-10% of ALS cases are familial, meaning they are inherited. Many cases of familial ALS are caused by mutations in the SOD1 gene, while others are linked to mutations in the C9ORF72 gene, which can also contribute to frontotemporal dementia (FTD). This form of ALS is referred to as ALS-FTD when both motor neuron symptoms and cognitive decline appear simultaneously.

Symptoms of ALS

The onset of ALS can be subtle, and early symptoms may be overlooked. However, as the disease progresses, the symptoms become more noticeable and can lead to a diagnosis. Early signs often include:

• Fasciculations (muscle twitches) in the arms, legs, or tongue
• Muscle cramps
• Spasticity (muscle tightness)
• Muscle weakness in the arms, legs, neck, or diaphragm
• Dysarthria (slurred or nasal speech)
• Dysphagia (difficulty chewing or swallowing)

Some individuals may first notice difficulty performing simple tasks, such as buttoning a shirt, writing, or turning a key. Others may experience awkward walking or tripping when the symptoms initially affect the legs.

ALS can begin with either of the following:

• Limb onset ALS: When symptoms begin in the arms or legs.
• Bulbar onset ALS: When symptoms first affect speech or swallowing.

As the disease progresses, muscle weakness and atrophy spread throughout the body. Affected individuals may lose the ability to walk, stand, or perform daily activities. Eventually, people with ALS may experience difficulty swallowing and eating, which increases the risk of choking and malnutrition. Weight loss is common due to rapid calorie consumption, and individuals may become malnourished.

Although ALS does not affect cognitive functions in most individuals, some may experience cognitive or behavioral changes, with a small subset developing dementia over time.

Diagnosis of ALS

ALS is diagnosed primarily based on the patient’s symptoms and a physical exam. There is no single test to confirm ALS, so a physician will typically perform a series of tests to rule out other conditions that may mimic ALS symptoms. The presence of both upper and lower motor neuron signs increases the likelihood of an ALS diagnosis.

Diagnostic Tests

Some of the diagnostic tests for ALS include:

• Electromyography (EMG): This test records electrical activity in muscles and helps detect abnormal muscle activity associated with ALS.
• Nerve Conduction Studies (NCS): Measures electrical activity in nerves and can reveal issues with nerve signals.
• Magnetic Resonance Imaging (MRI): Although MRI scans are generally normal in ALS, they can identify other conditions like tumors or spinal cord issues that could explain symptoms.

Other diagnostic tools include blood and urine tests to rule out infections or other diseases that may mimic ALS.

Causes of ALS

While the exact cause of ALS remains unknown, scientific studies suggest both genetic and environmental factors may contribute to its development.

Genetic Factors

The discovery of SOD1 mutations in 1993 marked a breakthrough in understanding ALS. Since then, additional genetic mutations have been identified. Notably, mutations in the C9ORF72 gene are linked not only to ALS but also to frontotemporal dementia (FTD), indicating a genetic overlap between these two conditions.

Other mutations affect protein recycling processes, motor neuron structure, or susceptibility to environmental toxins, shedding light on the complex causes of ALS.

Environmental Factors

Environmental influences, such as exposure to toxins, infections, or physical trauma, are under investigation. Military veterans and athletes, for example, may be at increased risk due to environmental exposures. However, no single environmental factor has been consistently linked to ALS.

Treatment of ALS

There is no cure for ALS, but various treatments aim to alleviate symptoms, manage complications, and improve the quality of life for those affected.

Medications

Two FDA-approved drugs for ALS are:

• Riluzole (Rilutek): This drug may prolong survival by a few months by reducing the toxicity of glutamate, a neurotransmitter involved in motor neuron damage.
• Edaravone (Radicava): Edaravone has shown the potential to slow the decline in motor function.

Physicians may also prescribe medications to address symptoms such as muscle cramps, saliva management, and mood disorders.

Supportive Care

Supportive care is an essential part of managing ALS and is provided by a multidisciplinary team of healthcare professionals, including:

• Physicians
• Physical therapists
• Occupational therapists
• Speech therapists
• Nutritionists
• Respiratory therapists

Therapies can help manage symptoms such as muscle stiffness, mobility issues, and swallowing difficulties. In some cases, individuals may require feeding tubes or noninvasive ventilation to aid with breathing.

Physical and Speech Therapy

Physical therapy can help strengthen unaffected muscles and improve mobility, while speech therapy assists individuals in maintaining communication as the disease progresses.

Nutritional Support

As ALS can impair the ability to eat and swallow, nutritionists play a key role in ensuring patients receive adequate nourishment, often recommending a feeding tube to prevent malnutrition.

Breathing Support

Noninvasive ventilation (NIV) may be used to help individuals breathe more easily as respiratory muscles weaken. In advanced stages, invasive mechanical ventilation may be considered.

Gallery

• 

  Using a head mounted laser to point to a communication board

• 

  Percutaneous endoscopic gastrostomy tube

• 

  Prevalence of ALS in the United States by age group, 2012-2015