Motor neuron diseases

What are motor neuron diseases?
The motor neuron diseases (MNDs) are a group of progressive neurological disorders that destroy motor neurons, the cells that control essential voluntary muscle activity such as speaking, walking, breathing, and swallowing. Normally, messages from nerve cells in the brain (called upper motor neurons) are transmitted to nerve cells in the brain stem and spinal cord (called lower motor neurons) and from them to particular muscles. Upper motor neurons direct the lower motor neurons to produce movements such as walking or chewing. Lower motor neurons control movement in the arms, legs, chest, face, throat, and tongue. Spinal motor neurons are also called anterior horn cells. Upper motor neurons are also called corticospinal neurons.

When there are disruptions in the signals between the lowest motor neurons and the muscle, the muscles do not work properly; the muscles gradually weaken and may begin wasting away and develop uncontrollable twitching (called fasciculations). When there are disruptions in the signals between the upper motor neurons and the lower motor neurons, the limb muscles develop stiffness (called spasticity), movements become slow and effortful, and tendon reflexes such as knee and ankle jerks become overactive. Over time, the ability to control voluntary movement can be lost.

Who is at risk?
MNDs occur in adults and children. In children, particularly in inherited or familial forms of the disease, symptoms can be present at birth or appear before the child learns to walk. In adults, MNDs occur more commonly in men than in women, with symptoms appearing after age 40.

What causes motor neuron diseases?
Some MNDs are inherited, but the causes of most MNDs are not known. In sporadic or noninherited MNDs, environmental, toxic, viral, or genetic factors may be implicated.

How are they classified?
MNDs are classified according to whether they are inherited or sporadic, and to whether degeneration affects upper motor neurons, lower motor neurons, or both. In adults, the most common MND is amyotrophic lateral sclerosis (ALS), which affects both upper and lower motor neurons. It has inherited and sporadic forms and can affect the arms, legs, or facial muscles. Primary lateral sclerosis is a disease of the upper motor neurons, while progressive muscular atrophy affects only lower motor neurons in the spinal cord. In progressive bulbar palsy, the lowest motor neurons of the brain stem are most affected, causing slurred speech and difficulty chewing and swallowing. There are almost always mildly abnormal signs in the arms and legs.

If the MND is inherited, it is also classified according to the mode of inheritance. Autosomal dominant means that a person needs to inherit only one copy of the defective gene from one affected parent to be at risk of the disease. There is a 50 percent chance that each child of an affected person will be affected. Autosomal recessive means the individual must inherit a copy of the defective gene from both parents. These parents are likely to be asymptomatic (without symptoms of the disease). Autosomal recessive diseases often affect more than one person in the same generation (siblings or cousins). In X-linked inheritance, the mother carries the defective gene on one of her X chromosomes and passes the disorder along to her sons. Males inherit an X chromosome from their mother and a Y chromosome from their father, while females inherit an X chromosome from each parent. Daughters have a 50 percent chance of inheriting their mother's faulty X chromosome and a safe X chromosome from their father, which would make them asymptomatic carriers of the mutation.

What are the symptoms of motor neuron diseases?
A brief description of the symptoms of some of the more common MNDs follows.

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease or classical motor neuron disease, is a progressive, ultimately fatal disorder that disrupts signals to all voluntary muscles. Many doctors use the terms motor neuron disease and ALS interchangeably. Both upper and lower motor neurons are affected. Symptoms are usually noticed first in the arms and hands, legs, or swallowing muscles. Approximately 75 percent of people with classic ALS will develop weakness and wasting of the bulbar muscles (muscles that control speech, swallowing, and chewing). Muscle weakness and atrophy occur on both sides of the body. Affected individuals lose strength and the ability to move their arms and legs, and to hold the body upright. Other symptoms include spasticity, spasms, muscle cramps, and fasciculations. Speech can become slurred or nasal. When muscles of the diaphragm and chest wall fail to function properly, individuals lose the ability to breathe without mechanical support. Although the disease does not usually impair a person's mind or personality, several recent studies suggest that some people with ALS may develop cognitive problems involving word fluency, decision-making, and memory. Most individuals with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10 percent of affected individuals survive for 10 or more years.

ALS most commonly strikes people between 40 and 60 years of age, but younger and older individuals also can develop the disease. Men are affected more often than women. Most cases of ALS occur sporadically, and family members of those individuals are not considered to be at increased risk for developing the disease. Familial forms of ALS account for 10 percent or less of cases of ALS, with more than 10 genes identified to date. However, most of the gene mutations discovered account for a very small number of cases. The most common familial forms of ALS in adults are caused by mutations of the superoxide dismutase gene, or SOD1, located on chromosome 21. There are also rare juvenile-onset forms of familial ALS.

Progressive bulbar palsy, also called progressive bulbar atrophy, involves the bulb-shaped brainstem - the region that controls lower motor neurons needed for swallowing, speaking, chewing, and other functions. Symptoms include pharyngeal muscle weakness, weak jaw and facial muscles, progressive loss of speech, and tongue muscle atrophy. Limb weakness with both lower and upper motor neuron signs is almost always evident but less prominent. Affected persons have outbursts of laughing or crying (called emotional lability). Individuals eventually become unable to eat or speak and are at increased risk of choking and aspiration pneumonia, which is caused by the passage of liquids and food through the vocal folds and into the lower airways and lungs. Stroke and myasthenia gravis each have certain symptoms that are similar to those of progressive bulbar palsy and must be ruled out prior to diagnosing this disorder. In about 25 percent of ALS patients early symptoms begin with bulbar involvement. Some 75 percent of patients with classic ALS eventually show some bulbar involvement. Many clinicians believe that progressive bulbar palsy by itself, without evidence of abnormalities in the arms or legs, is extremely rare.

Pseudobulbar palsy, which shares many symptoms of progressive bulbar palsy, is characterized by degeneration of upper motor neurons that transmit signals to the lower motor neurons in the brain stem. Affected individuals have progressive loss of the ability to speak, chew, and swallow. Progressive weakness in facial muscles leads to an expressionless face. Individuals may develop a gravelly voice and an increased gag reflex. The tongue may become immobile and unable to protrude from the mouth. Individuals may have outbursts of laughing or crying.

Primary lateral sclerosis (PLS) affects the upper motor neurons of the arms, legs, and face. It occurs when specific nerve cells in the motor regions of the cerebral cortex (the thin layer of cells covering the brain which is responsible for most high-level brain functions) gradually degenerate, causing the movements to be slow and effortful. The disorder often affects the legs first, followed by the body trunk, arms and hands, and, finally, the bulbar muscles. Speech may become slowed and slurred. When affected, the legs and arms become stiff, clumsy, slow and weak, leading to an inability to walk or carry out tasks requiring fine hand coordination. Difficulty with balance may lead to falls. Speech may become slow and slurred. Affected individuals commonly experience pseudobulbar affect and an overactive startle response. PLS is more common in men than in women, with a very gradual onset that generally occurs between ages 40 and 60. The cause is unknown. The symptoms progress gradually over years, leading to progressive stiffness and clumsiness of the affected muscles. PLS is sometimes considered a variant of ALS, but the major difference is the sparing of lower motor neurons, the slow rate of disease progression, and normal lifespan. PLS may be mistaken for spastic paraplegia, a hereditary disorder of the upper motor neurons that causes spasticity in the legs and usually starts in adolescence. Most neurologists follow the affected individual's clinical course for at least 3 to 4 years before making a diagnosis of PLS. The disorder is not fatal but may affect quality of life.

Progressive muscular atrophy is marked by slow but progressive degeneration of only the lower motor neurons. It largely affects men, with onset earlier than in other MNDs. Weakness is typically seen first in the hands and then spreads into the lower body, where it can be severe. Other symptoms may include muscle wasting, clumsy hand movements, fasciculations, and muscle cramps. The trunk muscles and respiration may become affected. Exposure to cold can worsen symptoms. The disease develops into ALS in many instances.

Spinal muscular atrophy (SMA) is a hereditary disease affecting the lower motor neurons. It is an autosomal recessive disorder caused by defects in the gene SMN1, which makes a protein that is important for the survival of motor neurons (SMN protein). In SMA, insufficient levels of the SMN protein lead to degeneration of the lower motor neurons, producing weakness and wasting of the skeletal muscles. This weakness is often more severe in the trunk and upper leg and arm muscles than in muscles of the hands and feet. SMA in children is classified into three types, based on ages of onset, severity, and progression of symptoms. All three types are caused by defects in the SMN1 gene.

SMA type I, also called Werdnig-Hoffmann disease, is evident by the time a child is 6 months old. Symptoms may include hypotonia (severely reduced muscle tone), diminished limb movements, lack of tendon reflexes, fasciculations, tremors, swallowing and feeding difficulties, and impaired breathing. Some children also develop scoliosis (curvature of the spine) or other skeletal abnormalities. Affected children never sit or stand and the vast majority usually die of respiratory failure before the age of 2. However, the survival in individuals with SMA type I has increased in recent years, in relation to the growing trend toward more proactive clinical care.

Symptoms of SMA type II, the intermediate form, usually begin between 6 and 18 months of age. Children may be able to sit but are unable to stand or walk unaided, and may have respiratory difficulties. The progression of disease is variable. Life expectancy is reduced but some individuals live into adolescence or young adulthood.

Symptoms of SMA type III (Kugelberg-Welander disease) appear between 2 and 17 years of age and include abnormal gait; difficulty running, climbing steps, or rising from a chair; and a fine tremor of the fingers. The lower extremities are most often affected. Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints, caused by abnormal muscle tone and weakness, which prevents the joints from moving freely. Individuals with SMA type III may be prone to respiratory infections, but with care may have a normal lifespan.

Congenital SMA with arthrogryposis (persistent contracture of joints with fixed abnormal posture of the limb) is a rare disorder. Manifestations include severe contractures, scoliosis, chest deformity, respiratory problems, unusually small jaws, and drooping of the upper eyelids.

Kennedy’s disease, also known as progressive spinobulbar muscular atrophy, is an X-linked recessive disease caused by mutations in the gene for the androgen receptor. Daughters of individuals with Kennedy’s disease are carriers and have a 50 percent chance of having a son affected with the disease. The onset of symptoms is variable and the disease may first be recognized between 15 and 60 years of age. Symptoms include weakness and atrophy of the facial, jaw, and tongue muscles, leading to problems with chewing, swallowing, and changes in speech. Early symptoms may include muscle pain and fatigue. Weakness in arm and leg muscles closest to the trunk of the body develops over time, with muscle atrophy and fasciculations. Individuals with Kennedy’s disease also develop sensory loss in the feet and hands. Nerve conduction studies confirm that nearly all individuals have a sensory neuropathy (pain from sensory nerve inflammation or degeneration). Affected individuals may have enlargement of the male breasts or develop noninsulin-dependent diabetes mellitus.

The course of the disorder varies but is generally slowly progressive. Individuals tend to remain ambulatory until late in the disease. The life expectancy for individuals with Kennedy disease is usually normal.

Post-polio syndrome (PPS) is a condition that can strike polio survivors decades after their recovery from poliomyelitis. PPS is believed to occur when injury, illness (such as degenerative joint disease), weight gain, or the aging process damages or kills spinal cord motor neurons that remained functional after the initial polio attack. Many scientists believe PPS is latent weakness among muscles previously affected by poliomyelitis and not a new MND. Symptoms include fatigue, slowly progressive muscle weakness, muscle atrophy, fasciculations, cold intolerance, and muscle and joint pain. These symptoms appear most often among muscle groups affected by the initial disease. Other symptoms include skeletal deformities such as scoliosis and difficulty breathing, swallowing, or sleeping. Symptoms are more frequent among older people and those individuals most severely affected by the earlier disease. Some patients experience only minor symptoms, while others develop SMA and, rarely, what appears to be, but is not, a form of ALS. PPS is not usually life threatening. Doctors estimate the incidence of PPS at about 25 to 50 percent of survivors of paralytic poliomyelitis.

How are motor neuron diseases diagnosed?
There are no specific tests to diagnose MNDs. Symptoms may vary among individuals and, in the early stages of the disease, may be similar to those of other diseases, making diagnosis difficult. Patients should first have a physical exam followed by a thorough neurological exam. The neurological exam will assess motor and sensory skills, nerve function, hearing and speech, vision, coordination and balance, mental status, and changes in mood or behavior.

Tests to rule out other diseases or to measure muscle involvement may include the following:

Electromyography (EMG) is used to diagnose muscle and nerve dysfunction and spinal cord disease. It is also used to measure the speed at which impulses travel along a particular nerve. EMG records the electrical activity from the brain and/or spinal cord to a peripheral nerve root (found in the arms and legs) that controls muscles during contraction and at rest. Very fine wire electrodes are inserted one at a time into a muscle to assess changes in electrical voltage that occur during movement and when the muscle is at rest. The electrodes are attached to a recording instrument. Testing usually takes place at a testing facility and lasts about an hour or more, depending on the number of muscles and nerves to be tested.

EMG is usually done in conjunction with a nerve conduction velocity study. Nerve conduction studies measure the speed and size of the impulses in the nerves from small electrodes taped to the skin. A small pulse of electricity (similar to a jolt from static electricity) is applied to the skin to stimulate the nerve that directs a particular muscle. The second set of electrodes transmits the responding electrical signal to a recording machine. Nerve conduction studies help to differentiate lower motor neuron diseases from peripheral neuropathy and can detect abnormalities in sensory nerves.

Laboratory screening tests of blood, urine, or other substances are used to help diagnose disease, better understand the disease process, and monitor levels of therapeutic drugs. Certain tests can rule out muscle diseases and other disorders that may have symptoms similar to those of MND. For example, analysis of the fluid that surrounds the brain and spinal cord can detect a number of disorders, including PPS. Blood tests may be ordered to measure levels of the protein creatine kinase (which is needed for the chemical reactions that produce energy for muscle contractions); high levels may help diagnose muscle diseases such as muscular dystrophy.

Magnetic resonance imaging (MRI) uses a powerful magnetic field to produce detailed images of tissues, organs, bones, nerves, and other body structures. MRI is often used to rule out diseases that affect the head, neck, and spinal cord. MRI images can help diagnose brain and spinal cord tumors, eye disease, inflammation, infection, and vascular irregularities that may lead to stroke. MRI can also detect and monitor inflammatory disorders such as multiple sclerosis and can document brain injury from trauma. Magnetic resonance spectroscopy is a type of MRI scan that measures chemicals in the brain and may be used to evaluate the integrity of the upper motor neurons.

Muscle or nerve biopsy can help confirm nerve disease and nerve regeneration. A small sample of the muscle or nerve is removed under local anesthetic and studied under a microscope. The sample may be removed either surgically, through a slit made in the skin, or by needle biopsy, in which a thin hollow needle is inserted through the skin and into the muscle. A small piece of muscle remains in the hollow needle when it is removed from the body. This procedure is usually performed at an outpatient testing facility. Although this test can provide valuable information about the degree of damage, it is an invasive procedure that may itself cause neuropathic side effects. Many experts do not believe that a biopsy is always needed for diagnosis.

Transcranial magnetic stimulation was first developed as a diagnostic tool to study areas of the brain related to motor activity. It is also used as a treatment for certain disorders. This noninvasive procedure creates a magnetic pulse inside the brain that evokes motor activity in an area of the body. Electrodes taped to different areas of the body pick up and record the electrical activity in the muscles. Measures of the evoked activity may help in diagnosing upper motor neural dysfunction in MND or monitoring disease progression.

How are motor neuron diseases treated?
There is no cure or standard treatment for the MNDs. Symptomatic and supportive treatment can help people be more comfortable while maintaining their quality of life. Multidisciplinary clinics, with specialists from neurology, physical therapy, respiratory therapy, and social work are particularly important in the care of individuals with MNDs.

The drug riluzole (Rilutek®), the only prescribed drug approved by the U.S. Food and Drug Administration to treat ALS, prolongs life by 2-3 months but does not relieve symptoms. The drug reduces the body's natural production of the neurotransmitter glutamate, which carries signals to the motor neurons. Scientists believe that too much glutamate can harm motor neurons and inhibit nerve signaling.

Other medicines may help with symptoms. Muscle relaxants such as baclofen, tizanidine, and the benzodiazepines may reduce spasticity. Botulinum toxin may be used to treat jaw spasms or drooling. Excessive saliva can be treated with amitriptyline, glycopyolate, and atropine or by botulinum injections into the salivary glands. Combinations of dextromethorphan and quinidine have been shown to reduce pseudobulbar affect. Anticonvulsants and nonsteroidal anti-inflammatory drugs may help relieve pain, and antidepressants may be helpful in treating depression. Panic attacks can be treated with benzodiazepines. Some individuals may eventually require stronger medicines such as morphine to cope with musculoskeletal abnormalities or pain, and opiates are used to provide comfort care in terminal stages of the disease.

Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce spasticity, increase range of motion, and keep circulation flowing. Some individuals require additional therapy for speech, chewing, and swallowing difficulties. Applying heat may relieve muscle pain. Assistive devices such as supports or braces, orthotics, speech synthesizers, and wheelchairs may help some people retain independence.

Proper nutrition and a balanced diet are essential to maintaining weight and strength. People who cannot chew or swallow may require insertion of a feeding tube. In ALS, insertion of a percutaneous gastronomy tube (to help with feeding) is frequently carried out even before it is needed, when the individual is strong enough to undergo this minor surgery. Non-invasive ventilation at night can prevent apnea in sleep, and some individuals may also require assisted ventilation due to muscle weakness in the neck, throat, and chest during daytime.

What is the prognosis?
Prognosis varies depending on the type of MND and the age of onset. Some MNDs, such as PLS, are not fatal and progress slowly. Patients with SMA may appear to be stable for long periods, but improvement should not be expected. Some MNDs, such as ALS and some forms of SMA, are fatal.

What research is being done?
The NINDS supports a broad range of research aimed at discovering the cause(s) of MNDs, finding better treatments, and, ultimately, preventing and curing the disorders. Various MND animal models (animals that have been designed to mimic the disease in humans) are being used to study disease pathology and identify chemical and molecular processes involved in cellular degeneration.

Research options fall largely into three categories: drugs, growth factors, and stem cells.

Clinical trials are testing whether different drugsor interventions are safe and effective in slowing the progression of MNDs in patient volunteers.

• The antibiotic ceftriaxone has been shown to protect nerves by reducing glutamate toxicity—believed by many scientists to play a critical role in the development of ALS—in a mouse model of the disease. One study found that cellular ability to manage glutamate can alter the course of ALS. The drug is currently being tested in a multi-center human clinical trial.
• The novel compound dexpramipexole has shown neuroprotective properties in multiple preclinical studies of ALS, and may work by increasing the efficiency of mitochondria—the energy-producing portion of the body’s cells. Mitochondria in the motor neurons undergo significant stress in ALS patients. The compound is currently being tested in an industry-sponsored multi-center clinical trial.
• Several early-stage clinical trials are testing the safety and feasibility of novel treatment strategies for ALS. These include cell-based approaches such as the transplantation of neural precursor cells into the spinal cord of ALS patients, and the infusion of so-called “anti-sense” compounds into the fluid that surrounds the spinal cord and brain to block production of toxic SOD1 protein in ALS patients who carry SOD1 mutations.

Other compounds, including minocycline, coenzyme Q10, and lithium, have been tested and found ineffective in treating motor neuron diseases.

Cellular and molecular studies seek to understand the mechanisms that trigger motor neurons to degenerate. Examples include the following:

• Scientists are developing a broad range of model systems in animals and cells to investigate disease processes and expedite the testing of potential therapies. Among these efforts, a NINDS-sponsored consortium of scientists is deriving a type of stem cell from ALS patients and using these stem cells to form motor neurons and surrounding support cells.
• Scientists have used gene therapy to halt motor neuron destruction and slow disease progression in mouse models of SMA and inherited ALS. The NINDS supports research to further explore this method and to provide a path toward clinical tests in patients.
• Scientists have found that a specific class of compounds referred to as anti-sense oligonucleotides can either block or correct the processing of RNA molecules, which are the intermediates between genes and proteins. These compounds have shown therapeutic promise in model systems of ALS and SMA, and early-stage clinical testing is underway in ALS patients who carry SOD1 mutations.
• Scientists are using advance sequencing technologies to identify new gene mutations that are associated with MNDs. These gene discoveries have provided new insights into the cellular disease processed and identified possible intervention points for therapy.

The excessive accumulation of free radicals, which has been implicated in ALS and a number of other neurodegenerative diseases, is being closely studied. Free radicals are highly reactive molecules that bind with other body chemicals and are believed to contribute to cell degeneration, disease development, and aging.

Where can I get more information?
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov

Information also is available from the following organizations:
ALS Association
1275 K Street NW, Suite 1050
Washington, DC 20005
http://www.alsa.org
202-407-8580

Muscular Dystrophy Association
3300 East Sunrise Drive
Tucson, AZ 85718-3208
http://www.mda.org
520-529-2000 / 800-572-1717

ALS Therapy Development Institute
300 Technology Square, Suite 400
Cambridge, MA 02139
http://www.als.net
617-441-7200

Les Turner ALS Foundation
5550 W. Touhy Avenue, Suite 302
Skokie, IL 60077-3254
http://www.lesturnerals.org
888-ALS-1107 / 847-679-3311

Project ALS
3960 Broadway, Suite 420
New York, NY 10032
http://www.projectals.org
212-420-7382 / 800-603-0270

Spastic Paraplegia Foundation
4 Sherwood Hill Rd
Sherman, CT 06784
http://www.sp-foundation.org
877-773-4483

Families of Spinal Muscular Atrophy
925 Busse Road
Elk Grove Village, IL 60007
http://www.curesma.org
800-886-1762

Fight SMA
1321 Duke Street, Ste 304
Alexandria, VA 22134
http://www.fightsma.org
703-647-5032

Kennedy's Disease Association
P.O. Box 1105
Coarsegold, CA 93614-1105
http://www.kennedysdisease.org
559-658-5950

Spinal Muscular Atrophy Foundation
888 Seventh Avenue, Suite 400
New York, NY 10019
http://www.smafoundation.org
877-FUND-SMA (877-386-3762) / 646-253-7100

Post-Polio Health International
4207 Lindell Blvd., #110
St. Louis, MO 63108-2930
http://www.post-polio.org
314-534-0475

This information was developed by the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Office of Communications and Public Liaison, National Institute of Neurological Disorders and Stroke, National Institutes of Health. Motor Neuron Diseases Fact Sheet. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Motor-Neuron-Diseases-Fact-Sheet. Accessed September 4, 2018.

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