Motor Neuron Diseases Fact Sheet

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 brainstem 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.

When there are disruptions in these signals, the muscles do not work properly; the result can be gradual weakening, wasting away, and uncontrollable twitching (called fasciculations).  When upper motor neurons are affected, the manifestations include spasticity or stiffness of limb muscles and overactivity of tendon reflexes such as knee and ankle jerks.  Eventually, the ability to control voluntary movement can be lost.  MNDs may be inherited or acquired.

MNDs occur in adults and children.  The diseases are more common in men than in women.  In adults, symptoms may appear after age 40.  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.

The causes of sporadic, or noninherited, MNDs are not known, but environmental, toxic, viral, or genetic factors may be implicated.  Sporadic cases may be triggered by exposure to radiation therapy, lightning strike or other electrical injury, cancers, or prolonged exposure to toxic drugs or environmental toxins.  Scientists are investigating whether the body's autoimmune reaction to viruses such as the human immunodeficiency virus can trigger MNDs.

The major site of motor neuron degeneration classifies the disorders.  Common MNDs include amyotrophic lateral sclerosis, which affects both upper and lower motor neurons.  Progressive bulbar palsy affects the lower motor neurons of the brainstem, causing slurred speech and difficulty chewing and swallowing.  Patients with these disorders almost always have abnormal signs in the arms and legs.  Primary lateral sclerosis is a disease of the upper motor neurons, while progressive muscular atrophy affects only lower motor neurons in the spinal cord.

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 (presenting no 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, thus becoming asymptomatic carriers of the mutation.)

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 eventually disrupts signals to all voluntary muscles.  In the United States, doctors use the terms motor neuron disease and ALS interchangeably.  Both upper and lower motor neurons are affected.  Approximately 75 percent of patients with classic ALS will also develop weakness and wasting of the bulbar muscles (muscles that control speech, swallowing, and chewing).  Symptoms are usually noticed first in the arms and hands, legs, or swallowing muscles.  Muscle weakness and atrophy occur disproportionately on both sides of the body.  Patients lose strength and the ability to move their arms, legs, and body.  Other symptoms include spasticity, exaggerated reflexes, muscle cramps, fasciculations, and increased problems with swallowing and forming words.  Speech can become slurred or nasal.  When muscles of the diaphragm and chest wall fail to function properly, patients 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 ALS patients may have alterations in cognitive functions such as problems with decision-making and memory.  ALS most commonly strikes people between 40 and 60 years of age, but younger and older people 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.  (There is a familial form of ALS in adults, which often results from mutation of the superoxide dismutase gene, or SOD1, located on chromosome 21.)  A rare juvenile-onset form of ALS is genetic.  Most ALS patients die from respiratory failure, usually within 3 to 5 years from the onset of symptoms.  However, about 10 percent of ALS patients survive for 10 or more years.

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 upper motor neuron degeneration and progressive loss of the ability to speak, chew, and swallow.  Progressive weakness in facial muscles leads to an expressionless face.  Patients may develop a gravelly voice and an increased gag reflex.  The tongue may become immobile and unable to protrude from the mouth.  Patients may also experience emotional lability.

Primary lateral sclerosis (PLS) affects only upper motor neurons and is nearly twice as common in men as in women.  Onset generally occurs after age 50.  The cause of PLS is unknown.  It occurs when specific nerve cells in the cerebral cortex (the thin layer of cells covering the brain which is responsible for most higher level mental functions) that control voluntary movement gradually degenerate, causing the muscles under their control to weaken.  The syndrome -- which scientists believe is only rarely hereditary -- progresses gradually over years or decades, leading to stiffness and clumsiness of the affected muscles.  The disorder usually affects the legs first, followed by the body trunk, arms and hands, and, finally, the bulbar muscles.  Symptoms may include difficulty with balance, weakness and stiffness in the legs, clumsiness, spasticity in the legs which produces slowness and stiffness of movement, dragging of the feet (leading to an inability to walk), and facial involvement resulting in dysarthria (poorly articulated speech).  Major differences between ALS and PLS (considered a variant of ALS) are the motor neurons involved and the rate of disease progression.  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 years before making a diagnosis of PLS.  The disorder is not fatal but may affect quality of life.  PLS often develops into ALS.

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 patients.

Spinal muscular atrophy (SMA) is a hereditary disease affecting the lower motor neurons.  Weakness and wasting of the skeletal muscles is caused by progressive degeneration of the anterior horn cells of the spinal cord.  This weakness is often more severe in the legs than in the arms.  SMA has various forms, with different ages of onset, patterns of inheritance, and severity and progression of symptoms.  Some of the more common SMAs are described below.

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.

Symptoms of SMA type II usually begin after the child is 6 months of age.  Features may include inability to stand or walk, respiratory problems, hypotonia, decreased or absent tendon reflexes, and fasciculations.  These children may learn to sit but do not stand.  Life expectancy varies, and some patients live into adolescence or later.

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.

Symptoms of Fazio-Londe disease appear between 1 and 12 years of age and may include facial weakness, dysphagia (difficulty swallowing), stridor (a high-pitched respiratory sound often associated with acute blockage of the larynx), difficulty speaking (dysarthria), and paralysis of the eye muscles (ophthalmoplegia).  Most patients die from breathing complications.

Kennedy disease, also known as progressive spinobulbar muscular atrophy , is an X-linked recessive disease.  Daughters of patients with Kennedy disease are carriers and have a 50 percent chance of having a son affected with the disease.  Onset occurs between 15 and 60 years of age.  Symptoms include weakness of the facial and tongue muscles, hand tremor, muscle cramps, dysphagia, dysarthria, and gynecomastia (excessive development of male breasts and mammary glands).  Weakness usually begins in the pelvis before spreading to the limbs.  Some patients 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.

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, micrognathia (unusually small jaws), and ptosis (drooping of upper eyelids).

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.

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.  This procedure also measures electrical energy to test the nerve's ability to send a signal.  This two-part test is most often done in a hospital.  A technician tapes two sets of flat electrodes on the skin over the muscles.  The first set of electrodes is used to send small pulses of electricity (similar to a jolt from static electricity) to stimulate the nerve that directs a particular muscle.  The second set of electrodes transmits the responding electrical signal to a recording machine.  The physician then reviews the response to verify any nerve damage or muscle disease.

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.  Most tests are performed in a doctor's office or at a testing facility.

Magnetic resonance imaging (MRI) uses computer-generated radio waves and a powerful magnetic field to produce detailed images of body structures including tissues, organs, bones, and nerves.  These 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 degenerative disorders such as multiple sclerosis and can document brain injury from trauma.  MRI is often used to rule out diseases other than the MNDs that affect the head, neck, and spinal cord.  This noninvasive scan usually is performed in a laboratory or hospital setting.

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 now also being used as a treatment for certain disorders.  This noninvasive procedure creates a magnetic pulse inside the brain that stimulates motor activity in a certain area of the body.  Electrodes taped to different areas of the body pick up and record the electrical activity in the muscles.  Readouts of this data may help in diagnosing MNDs and in monitoring disease progression.  Similarly, magnetic resonance spectroscopy is being used to evaluate function of the upper motor neurons.

There is no cure or standard treatment for the MNDs.  Symptomatic and supportive treatment can help patients be more comfortable while maintaining their quality of life.

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.  Glycopyrrolate and atropine may reduce the flow of saliva.  Quinine or phenytoin may decrease cramps.  Anticonvulsants and nonsteroidal anti-inflammatory drugs may help relieve pain, and other drugs can be prescribed to treat depression.  Tranquilizers often help with sleeping problems.  Some patients with PPS develop sleep apnea (a potentially life-threatening condition characterized by interruptions of breathing during sleep), which can be treated with decongestant therapy, assisted breathing at night, or surgery to remove any blockage to the airway.  Panic attacks over fears of choking to death can be treated with benzodiazepines.  Botulinum toxin may be used to treat jaw spasms or drooling.  Amitriptyline and other anticholinergic drugs can help control excess drooling.  Some patients 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 patients 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 patients retain independence.

Proper nutrition and a balanced diet are essential to maintaining weight and strength.  Some patients who cannot eat or swallow may require insertion of a feeding tube.  Patients may also require assisted ventilation due to muscle weakness in the neck, throat, and chest.

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.

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 (using human participants) are testing whether different drugs are safe and effective in slowing the progression of MNDs.  Drugs currently under investigation include creatine (a naturally occurring substance that may slow neurodegeneration) and coenzyme Q10 (an antioxidant that may slow neuronal death).

• The amino acid creatine and the antibiotic minocycline, which have been studied in animal models, can significantly slow neurodegeneration, improve motor performance, and prolong survival. Clinical trials of the drugs, sponsored by the NINDS, will measure change in motor function, strength, pulmonary function, survival, and quality of life.
• 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. A multi-center human clinical trial of ceftriazone is being planned.
• Interrupting the inflammation process -- which plays an important role in the development and course of ALS -- might improve outcome in ALS patients. Research using mice found that the anti-inflammatory drug pioglitazone improved motor performance and reduced weight loss and the loss of motor neurons. Another study found that the drug also slowed disease progression. Pioglitazone is well tolerated in humans and is currently used to treat diabetes.
• Increased doses of vitamins E and C may benefit some patients, according to studies using animal models of MND. Additional research is needed before vitamin therapy is tested in humans.

Growth factors are proteins that aid cell survival. Growth factors have had some success in fighting MNDs. Investigators overseas found that vascular endothelial growth factor (VEGF) delivered to spaces in the brain can delay symptom onset in a rat model of ALS.

• Scientists are studying a number of possible treatments for PPS, including a number of growth factors such as insulin-like growth factor (IGF-1). IGF-1 is essential for normal development of the nervous system and has been shown to protect motor neurons in animal models and cell culture studies. Scientists are also trying to determine if there is an immunological link to PPS. And some experimental drug treatments, including pyridostigmine and seligiline, show promise in treating symptoms of PPS.
• Researchers also hope to determine whether IGF-1 slows progression of weakness in ALS.
• Scientists are studying how neurotrophic factors may be used to fight MNDs. Neurotrophic factors are chemicals found in the brain and spinal cord that are essential to neuron development and protection. The drug xaliproden may improve the release of neurotrophic factors. Ciliary neurotrophic factor and brain-derived neurotrophic factor have been shown to slow neuron degeneration in animal models but are not effective in humans.

Cellular and molecular studies, some of which involve stem cells, seek to understand the mechanisms that trigger selective motor neurons to degenerate. This work includes studies in animals to identify the means by which SOD1 mutations lead to the destruction of neurons.

• In July 2006, NINDS-funded scientists announced a study in which -- for the first time -- transplanted embryonic stem cell-derived motor neurons connected with muscle in the spinal cords of adult paralyzed rats to restore limited function. The researchers used a combination of transplanted motor neurons, drugs that block naturally occurring signals that hinder axon grown, and a nerve growth factor to attract axons to muscles. The preliminary results of this study will be tested in larger animals to determine if the nerves can reconnect over longer distances and to insure that the treatment is safe before any trials in humans can begin. Results suggest that similar techniques may be useful for treating other conditions such as spinal cord injury, transverse myelitis, ALS, and SMA.
• Researchers have used gene therapy to halt motor neuron destruction and slow disease progression in a mouse model of inherited ALS. Cell culture experiments have shown increased production of the proteins that can reduce the severity of the disease following gene therapy on skin cells of patients with SMA.
• An international study found that RNA interference-used to target and silence a messenger gene-can improve motor neuron survival in a mouse model of ALS.
• The excessive accumulation of free radicals, which has been implicated in a number of neurodegenerative diseases including ALS, 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.