Amyotrophic lateral sclerosis

Diagnosis of amyotrophic lateral sclerosis (ALS) may be suspected due to symptoms and the history of the way the symptoms progressed. ALS is usually strongly considered if the symptoms suggest both upper and lower motor neurons are affected. Basically, upper motor neurons (UPN) are found in the brain, whereas lower motor neurons are found in the spinal cord (LMN). UMN problems that can be found in a physical exam include tight and stiff muscles (spasticity), quicker than normal reflexes, and the Babinski reflex, which is when stroking the bottom of the foot causes the big toe to move upward and is not normally present after the age of 2 years. LMN problems that can be found in a physical exam include loss of muscle mass (muscle atrophy), muscle weakness, and muscle twitching (fasciculations). These signs can occur in any muscle group, including the arms, legs, chest, abdomen, and back, as well as the muscles involved in breathing, speaking, and swallowing. Even if symptoms of UMN and LMN problems are found, further testing must rule out other possible causes.

Tests to rule out other possible diseases and medical causes include electromyography (EMG), nerve conduction study (NCS), magnetic resonance imaging (MRI) of brain and spinal cord, and urine and blood tests. After ALS is diagnosed, genetic testing may also be considered depending on family history, age the symptoms began, and the person's wishes.

About 90-95% percent of cases of ALS are not inherited and occur in individuals with no history of the disease in their family. The remaining 5-10% of cases are familial, and are thought to be caused by mutations in any one of several genes. The inheritance pattern associated with familial ALS varies depending on the disease-causing gene involved.

Most familial cases are inherited in an autosomal dominant manner. This means that only one altered (mutated) copy of the disease-causing gene in each cell is sufficient to cause the condition. In most of these cases, an affected individual has one parent with the condition. When an individual with an autosomal dominant form of ALS has children, each child has a 50% (1 in 2) risk to inherited the mutated copy of the gene and be affected.

Less frequently, ALS is inherited in an autosomal recessive manner. In autosomal recessive inheritance, both copies of the disease-causing gene (typically one copy inherited from each parent) must have a mutation for the individual to be affected. The parents of an individual with an autosomal recessive condition, who presumably each carry one mutated copy of the gene, are referred to as carriers. Carriers typically do not have any signs or symptoms of the condition. When two carriers for the same condition are having children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each parent, and a 25% risk to not have the condition and not be a carrier. Autosomal recessive forms of ALS may be mistaken for non-inherited (sporadic) forms due to having a negative family history of the condition.

In rare cases, ALS is inherited in an X-linked dominant manner. This occurs when the disease-causing gene is located on the X chromosome (a sex chromosome). Although females have 2 X chromosomes, having a mutation in one X chromosome is still sufficient to cause the condition. Males who have a mutation (and only one X chromosome) will have the condition. Usually, males with an X-linked dominant form of ALS experience more severe symptoms than females with the same form.

Some individuals who do inherit a mutation known to cause ALS never develop signs and symptoms of ALS, although the reason for this is unclear. This phenomenon is referred to as reduced penetrance.

Age of onset alone is not a reliable predictor of the form of ALS that an individual has. Furthermore, if an individual is found to have an inherited form of ALS, the specific inheritance pattern would depend on the disease- causing gene involved. Establishing the specific subtype of ALS in a given individual usually involves obtaining family history and performing molecular genetic testing.

Onset of ALS may occur any time from the teenage years up to the late 80s. The average age of onset for sporadic (non-inherited) ALS has been estimated to be around 56 to 65 years (estimates vary among sources). The average age of onset for familial ALS is approximately 46 years. However, onset of either form may occur years before or after these average ages.

The estimated general population risk for ALS is a small fraction of one percent. Less than 3 people in 100,000 are diagnosed with ALS each year in the United States. Studies suggest that people with a closely related relative (e.g., parent or sibling) have a small, but definite increased risk for ALS. Siblings are estimated to have a 0.5% risk, while offspring a 1% risk.

Some research has indicated that use of riluzole has prolonged survival amongst individuals with bulbar-onset ALS, but not in subjects with limb-onset ALS. It has also been demonstrated that in patients over age 70, riluzole treatment is associated with a longer median survival time and a reduction in mortality rate regardless of the site of the onset of symptoms. Bulbar- onset patients appear to particularly benefit from riluzole for unclear reasons.

Proper nutrition and a balanced diet are essential for individuals with ALS to maintain their weight and strength. Nutritional management, which has been shown to improve prognosis, has become a focus in managing the disease.

There is currently limited information on whether specific diets may affect the progression of ALS. The U.S. National Institutes of Health, through the National Library of Medicine, developed ClinicalTrials.gov to provide patients, family members, and members of the public with current information on clinical research studies. Currently, 4 clinical trials are identified as enrolling individuals with ALS to gain more information on the use of dietary supplements. To find these trials, click on the link above.

Yes. Studies have found "de novo" autosomal dominant gene mutations in people with ALS. A de novo gene mutation is a mutation that occurs for the first time in a family as a result of a spontaneous gene change in the egg or sperm or in a fertilized egg soon after conception.

These research findings, and rare case reports, support that this is possible. It is common for these mutations to be very unique to a family, and so very little is often known about the specific mutation. Factors such as "reduced penetrance" have also been reported in these cases, making it very difficult to predict if a person will develop ALS. Reduced penetrance means that a person with the ALS-associated gene mutation may never develop ALS.

Studies are underway to improve our understanding of how genetics plays a role in both sporadic and familial cases of ALS. Hopefully this knowledge will give families more definitive answers about recurrence risks.

The Clinical Research in Amyotrophic Lateral Sclerosis and Related Disorders for Therapeutic Development (CREATE) Consortium is an integrated group of academic medical centers, patient support organizations, and clinical research resources dedicated to conducting clinical research, including genetic studies, involving sporadic and familial forms of amyotrophic lateral sclerosis. The CREATE Consortium has a contact registry for patients who wish to be contacted about clinical research opportunities and updates on the progress of the research projects.

Riluzole and endaravone are the two therapies approved by the United States Food and Drug Administration (FDA) specifically for the treatment of amyotrophic lateral scelerosis (ALS). Riluzole has been available in tablet form for over twenty years. It is believed to reduce damage to motor neurons. Riluzole may increase survival by several months and also extend the time before mechanical breathing support (ventilation) is needed. Riluzole does not reverse damage already done to motor neurons. The tablet form is available in generic versions and has been approved by the drug regulating agencies of most countries. As of 2018, a liquid form, Tiglutik, has been approved by the FDA, which allows those who have a hard time swallowing a tablet to continue treatment.

Edaravone (Radicava) has been available in the United States since 2017. It is an antioxidant and may slow the decline of physical function in some people with ALS. Physical function is measured by ALS Functional Rating Scale-Revised (ALSDRS-R). This scale measures problems with speech, swallowing, and breathing, as well as daily functioning such as walking, holding items like a pen or fork, dressing, and general care of oneself, like bathing. Edaravone does not improve function that has already been lost. The clinical trials took place in Japan and were six months long. As of 2018, long term effects of treatment with edaravone on physical function, survival, and quality of life are not known. It can be used along with riluzole. Edaravone is delivered by IV infusion on usually a two week on, two week off cycle. The IV infusion takes about one hour and is initially given in a hospital or clinic setting, but many have been able to transition to having the IV infusions at home. Edaravone is also approved by regulating agencies in Japan and South Korea, and is waiting for approval in Canada, Switzerland, and the European Union as of 2018.

Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This type of care is known as palliative care, supportive care that is typically provided by multidisciplinary teams of health care professionals such as physicians, pharmacists, physical therapists, occupational therapists, speech therapists, nutritionists, social workers, and home care and hospice nurses. These teams along with the patients and caregivers can design an individualized plan of medical and physical therapy and provide special equipment aimed at keeping patients as mobile and comfortable as possible.

• Physicians: Can prescribe medications to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, and constipation.
• Pharmacists: Can give advice on the proper use of medications and monitor a patient's prescriptions to avoid risks of drug interactions.
• Physical therapist: Can provide physical therapy and recommend special equipment to help the patient be independent and safe during the course of their ALS.
• Occupational therapists: Can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients conserve energy and remain mobile.
• Speech therapists: Can provide speech therapy to those people with ALS who have difficulty speaking.
• Nutritionists: Can help teach people with ALS and their caregivers how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow.
• Social workers and home care and hospice nurses: Help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease.
• Respiratory therapists: Can help caregivers with tasks such as operating and maintaining respirators.
• Home care nurses: Are available not only to provide medical care but also to teach caregivers about giving tube feedings and moving patients to avoid painful skin problems and contractures.
• Home hospice nurses: Work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home.