What is ALS?

Every 90 minutes someone is diagnosed with amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately, respiratory failure.

ALS, also known as Lou Gehrig’s disease, Charcot's disease, and motor neuron disease (MND), attacks certain cells in the brain and spinal cord needed to keep our muscles moving. Early signs and symptoms of ALS include:

• muscle cramps and muscle twitching
• weakness in hands, legs, feet or ankles
• difficulty speaking or swallowing

The senses, including hearing, sight, smell, taste, and touch, are not affected by ALS. In most cases, people with ALS do not experience difficulties in bowel, bladder or sexual function.

There is no single diagnostic test for ALS. Instead, the disease is diagnosed by ruling out other muscle and nerve disorders using a variety of tests including:

• electromyography and nerve conduction
• magnetic resonance imaging (MRI)
• genetic tests
• muscle biopsy
• spinal tap
• blood and urine tests

Most people with ALS live 2-5 years after their first signs of disease. About 10% of people with ALS survive at least 10 years. This variable rate of disease progression makes prognosis difficult to predict and therapies challenging to develop.

Currently, there is only a single medicine for specifically treating ALS - riluzole. The drug, marketed by Sanofi-Aventis under the name Rilutek, extends survival only about 2 to 3 months.

This urgent unmet medical need for effective treatments for this devastating and fatal disease is the basis for the research and drug development effort at the nonprofit biotech organization, ALS Therapy Development Institute.

In people with ALS, the motor neurons deteriorate leading to muscle weakness and paralysis. Why these cells are particularly vulnerable remains an open question, but scientists are beginning to unravel how these cells are destroyed, leading to new ways to attack the disease.

When neurologist Jean-Martin Charcot, MD, first peered into the tissues of his patients lost to ALS in 1865, he noticed clear signs of progressive neuronal damage that stretched from the brain to the brain stem (upper motor neurons) to the spinal cord (lower motor neurons) and atrophy of neighboring muscles.

Scientists now understand that this neurodegeneration is extremely complicated and occurs through several mechanisms.

Misfolded proteins accumulate. Sodium channels act up (hyperexcitability). Epigenetic and genetic switches are thrown. Energy-producing mitochondria malfunction, leading to a power drop. Free radicals build up, increasing oxidative stress. Toxic substances accumulate (excitotoxicity).

Many cells in the nervous system contribute to ALS
Courtesy of Stanford University School of Medicine

All of these mechanisms appear to contribute to motor neuron destruction in ALS. Many more are suspected to play a key role in the onset and progression of the disease.

Since the 1980s, scientists have recognized that ALS is much more than a motor neuron disease. Astrocytes and microglia entrusted to keep motor neurons healthy and free from infection turn traitor, producing toxic substances that damage them, fuel the progression of ALS. Macrophages and certain T-cells infiltrate the nervous system potentially unleashing a storm of cytokines of their own that further contributes to the disease.

Oligodendrocytes appear to lose their ability to power motor neurons up in people with ALS, contributing to the energy drain and their destruction.

There is no single diagnostic tool for ALS. A series of clinical procedures are conducted to rule out neurological conditions whose symptoms closely resemble the disease. In the US, the diagnosis can take about 12 to 14 months. Researchers hope to expedite this process by developing tools that indicate whether people have the disease.

In people with ALS, motor neurons degenerate and become unplugged from neighboring muscles resulting in muscle weakness and muscle atrophy. Some neurological diseases, share the same conditions, to distinguish them, clinicians run tests which can include:

• Electromyography (EMG) and nerve conduction studies (NCS)
  These tests enable clinicians to check whether motor nerves are plugged into the muscles and are working properly. NCS tests whether the motor nerves can send signals of sufficient strength to enable movement of the muscles. EMG measures the abilities of these muscles in response to these signals to trigger contraction. These tests help rule out certain disorders including those of the peripheral nerves.
• Muscle Biopsy
  Clinicians may also recommend a biopsy to further investigate affected muscles. Examination of muscle tissue under the microscope can help rule out certain muscle diseases.
• Magnetic Resonance Imaging (MRI)
  MRI enables clinicians to peer into our organs and our tissues including the brain and spinal cord. MRI can help rule out a number of conditions including brain tumors, multiple sclerosis and certain disorders of the spinal cord.
• Genetic tests
  Most cases of ALS are sporadic (sALS) in nature. About 10% of cases, however, are inherited. When a familial case of ALSf (fALS) is suspected, genetic testing might also be recommended. Commercially available tests can identify alterations in 9 ALS-linked genes.

Other tests include blood and urine tests and spinal tap.

During this process, people with ALS might receive a diagnosis of suspected, possible, or probable ALS. These designations depend on which parts of the body are affected by the disease.

Without a definite diagnosis, people with possible or probable ALS nevertheless remain eligible to participate in a growing number of clinical trials evaluating emerging treatments for the disease. Check out our clinical trials page.

Emerging tools
A growing number of researchers suspect that MRI might help to do much more than exclude other diseases. Certain brain scans might indicate whether a person has ALS. Researchers hope these signatures called biomarkers can be used to identify people who are at high risk of developing fALS before they develop the disease.

Meanwhile, other scientists are developing a new method called electrical impedance myography (EIM) to diagnose ALS. This test helps identify key changes in affected muscles including atrophy. Scientists hope that this tool might also predict the spread of ALS help them to develop treatments for the disease.

Most people with ALS live about 2-5 years after experiencing their first signs of disease. At least 1 in 10 people live more than 10 years following their diagnosis. This variable rate of progression makes predicting prognosis difficult. Clinicians instead rely on regular follow-up visits to monitor people with ALS to manage their disease.

Early signs of ALS
Most people with ALS first feel muscle cramps, spasms or twitching (fasciculations) in one of their arms or legs. Other signs include weakness in the hands and feet or loss of balance. This form of the disease is called limb-onset ALS.

About 25% of people with ALS first have trouble talking clearly - slurring words. This form of the disease is called bulbar-onset ALS.

Monitoring ALS
After receiving a diagnosis, people with ALS typically attend regular clinic visits about every 3-4 months. During these visits, each patient is monitored for changes in their functional abilities. Commonly used tests include:

• ALS Functional Rating Scale-Revised (ALSFRS-R): A rating scale that measure changes including breathing, speaking, sleeping, swallowing, and walking. The score is based on answers to 12 questions using a 48-point scale.
• Spirometry: A test that measures lung function. Breathing abilities are typically estimated based on the maximum amount of air that can be blown out either slowly (slow vital capacity - SVC) or quickly (slow vital capacity - SVC).

Middle stages of ALS
As the disease spreads, many muscles weaken and start to stiffen. Range of motion exercises will likely be recommended to help keep muscles loose and prevent the formation of contractures and muscle pain.

People with ALS might tire more easily. Breathing may be affected. A BiPAP machine or a phrenic pacer might be suggested, particularly to help improve sleeping. A feeding tube might be suggested to help meet nutritional needs. Medications might be also recommended to control emotions (pseudobulbar affect) or reduce muscle spasms.

People with bulbar-onset often work with a speech therapist to keep talking longer. People with limb-onset ALS may rely on a cane, walker, or wheelchair due to difficulties walking and maintaining balance.

Late stages of ALS
As the disease progresses, muscles become paralyzed. Most people with ALS require a wheelchair to get around and may communicate through assistive devices using an eye-tracking device or a letter board.

People with late-stage ALS are often cared for in hospices or at home. Some people with ALS choose invasive ventilation to help keep them breathing. Most people lose the battle with ALS due to respiratory failure.

There is no cure or effective treatment for ALS, however scientists are working hard to develop therapies for this disease.

ALS is a complex multi-system disease. A growing number of ALS clinics are deploying multidisciplinary teams to care for people with ALS to meet their physical, emotional, and nutritional needs. These teams include physical, respiratory, speech and occupational therapists to help people with ALS breathe easier, keep moving, and stay connected. Palliative care specialists support people with ALS and their caregivers.

Today, there are dozens of clinical trials evaluating potential treatments enrolling people with ALS and their families. Check out our clinical trials page.

Emerging medicines
Researchers are developing a number of treatment strategies to fight ALS. GSK's ozanezumab hopes to keep ALS in check by protecting the neuromuscular junctions from crumbling. Immune system-modulating drugs including Neuraltus Pharmaceuticals' NP001 hope to slow ALS in its tracks by reducing neuroinflammation. Stem cell-based strategies including Neuralstem's NSI-566 and Brainstorm's NurOwn hope to shield motor neurons from destruction. And, potential muscle boosters including Cytokinetics' tirasemtiv (CK-357) hope to help people breathe easier and keep muscles moving.

The DPS might improve the QoL of people
with ALS and extend survival.

Scientists are also repurposing medicines in hopes of bringing ALS therapies more quickly to the clinic. The FDA-approved heart medicine mexiletine might slow ALS by reducing hyperexcitability, a potentially early step in the disease. The multiple sclerosis medicine, Novartis' Gilenya, aims to treat ALS by reducing neuroinflammation.

There are also a growing number of medicines that might help alleviate key symptoms of the disease. Baclofen may reduce muscle spasms. Nuedexta might help keep emotions in check (pseudobulbar affect). Mexiletine might reduce painful muscle cramps. A number of medicines including Robinul, Elavil, and Botox, may help reduce salivation.

Care and management
Breathing devices may also improve quality of life and extend survival. Non-invasive ventilators such as a BiPAP machine help people with ALS breathe better, sleep better and boost survival by about a year according to some estimates. Phrenic pacers (NeuRX DPS) might also help people sleep better and extend survival according to clinical observations about 16 months after NIV use is initiated. Clinical trials are ongoing to further evaluate the NeuRX DPS and identify which people with ALS might benefit from them.

Certain forms of exercise are also becoming routine. Range of motion (stretching) is general practice for people with ALS to prevent muscle pain and the formation of contractures. Emerging aerobic workouts might improve quality of life and help reduce functional decline. A clinical trial evaluating the benefits of certain forms of exercises including stationary cycling and weight training remains ongoing.

There is no cure or effective treatment for ALS. This urgent unmet medical need for effective ALS therapies is the basis for the research and drug development effort at the nonprofit biotech organization, ALS Therapy Development Institute.