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ALS

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ALS
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Amyotrophic lateral sclerosis (ALS, sometimes called Lou Gehrig's disease, Maladie de Charcot or motor neurone disease) is a progressive, almost invariably fatal neurological disease.

Description

In ALS (amyotrophic lateral sclerosis), both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away (atrophy), and have fasciculations because of denervation. Eventually, the ability of the brain to start and control voluntary movement is lost. However, even patients in advanced stages of the disease may retain the same intelligence, memory, and personality they had before its onset.

Stephen Hawking, whose ALS was diagnosed in 1963

ALS causes weakness with a wide range of disabilities. Eventually, all muscles under voluntary control are affected, and patients lose their strength and the ability to move their arms, legs, and body. When muscles in the diaphragm and chest wall fail, patients lose the ability to breathe without help from mechanical ventilation. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10% of ALS patients survive for 8 or more years (like Jason Becker). Patients with a bulbar or respiratory onset generally have a worse prognosis, although this is not consistently true due to the heterogeneous nature of the disease.

Those with ALS respond differently to hypoxia (low levels of oxygen). The normal response to hypoxia is to upregulate vascular endothelial growth factor (VEGF), which promotes the growth of neurons and protects them from hypoxia-induced injury. However, the response to hypoxia in ALS is a lowering of protective VEGF, suggesting that ALS may involve VEGF dysregulation. [1] [2]

Epidemiology

As many as 30,000 Americans have ALS, and an estimated 5,000 cases of the disease are diagnosed in the United States each year. ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. ALS most commonly strikes people between 40 and 60 years of age, but younger and older people can also develop the disease. Men are affected more often than women.

In 90 to 95% of all ALS cases, the disease occurs apparently at random with no clearly associated risk factors. Patients do not have a family history of the disease, and their family members are not considered to be at increased risk for developing ALS.

About 5 to 10% of all ALS cases are inherited. The familial form of ALS usually results from a pattern of inheritance that requires only one parent to carry the gene responsible for the disease. About 20 % of all familial cases result from a specific genetic defect that leads to mutation of the enzyme known as superoxide dismutase 1 (SOD1). Research on this mutation is providing clues about the possible causes of motor neuron death in ALS. Not all familial ALS cases are due to the SOD1 mutation, therefore other unidentified genetic causes clearly exist.

Symptoms

The onset of ALS may be so subtle that the symptoms are frequently overlooked. The earliest symptoms may include twitching, cramping, or stiffness of muscles; muscle weakness affecting an arm or a leg; slurred and nasal speech; or difficulty chewing or swallowing. These general complaints then develop into more obvious weakness or atrophy that may cause a physician to suspect ALS.

The parts of the body affected by early symptoms of ALS depend on which muscles in the body are damaged first. About 75% of people experience limb onset ALS. In some of these cases, symptoms initially affect one of the legs, and patients experience awkwardness when walking or running or they notice that they are tripping or stumbling more often. Other limb onset patients first see the effects of the disease on a hand or arm as they experience difficulty with simple tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock.

About 25% of cases are bulbar onset ALS. These patients first notice difficulty speaking clearly. Speech becomes garbled and slurred. Nasality and loss of volume are frequently the first symptoms. Difficulty swallowing, and loss of tongue mobility follow. Eventually total loss of speech and ability to protect the airway when swallowing are experienced.

Regardless of the part of the body first affected by the disease, muscle weakness and atrophy spread to other parts of the body as the disease progresses. Patients have increasing problems with moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign (the large toe extends upward as the sole of the foot is stimulated in a certain way) also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). In some patients (15-45%) the Pseudobulbar affect is also experienced, which causes uncontrollable laughing or crying.[2]

To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

Although the sequence of emerging symptoms and the rate of disease progression vary from person to person, eventually patients will not be able to stand or walk, get in or out of bed on their own, or use their hands and arms. Difficulty swallowing and chewing impair the patient's ability to eat normally and increase the risk of choking. Maintaining weight will then become a problem. Because the disease usually does not affect cognitive abilities, patients are aware of their progressive loss of function and may become anxious and depressed. A small percentage of patients may experience problems with memory or decision-making, and there is growing evidence that some may even develop a form of dementia. Health care professionals need to explain the course of the disease and describe available treatment options so that patients can make informed decisions in advance.

As the diaphragm and intercostal muscles weaken, forced vital capacity and inspiratory effort diminish. In bulbar onset ALS, this may occur before significant limb weakness is apparent. In limb onset ALS it is usually a much later effect. Bilevel positive pressure ventilation (frequently referred to by the tradename BiPAP) is frequently used to support breathing, first at night, and later during the daytime as well. It is recommended that long before BiPAP becomes insufficient, patients (with the eventual help of his/her family) must decide whether to have a tracheotomy and long term mechanical ventilation. Most patients do not elect this route, and instead choose palliative hospice care at this point. Most people with ALS die of respiratory failure or pneumonia, not the disease itself.

Because ALS affects only motor neurons, the disease does not impair a person's mind, personality, intelligence, or memory. Nor does it affect a person's ability to see, smell, taste, hear, or feel touch. Patients usually maintain control of eye muscles and bladder and bowel function.

Diagnosis

No test can provide a definitive diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. The physician may order magnetic resonance imaging (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, a herniated disk in the neck, syringomyelia, or cervical spondylosis.

Based on the patient's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases as well as routine laboratory tests. In some cases, for example, if a physician suspects that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.

Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), and Lyme disease can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, and spinal muscular atrophy also can mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.

Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients may wish to obtain a second neurological opinion.

Recently researchers from Mount Sinai School of Medicine identified three proteins that are found in significantly lower concentration in the cerebral spinal fluid of patients with ALS than in healthy individuals. These are the first biomarkers for this disease and may be first tools for confirming diagnosis of ALS published in Feb 2006's issue of Neurology. With current methods, the average time from onset of symptoms to diagnosis is two years . Testing for these protein concentrations may provide a means of early diagnosis, allowing patients to receive relief from symptoms years earlier. [3]

Cause

The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others. An important step toward answering that question came in 1993 when scientists discovered that mutations in the gene that produces the SOD1 enzyme were associated with some cases of familial ALS. This enzyme is a powerful antioxidant that protects the body from damage caused by free radicals. Free radicals are highly reactive molecules produced by cells during normal metabolism. If not neutralized, free radicals can accumulate and cause random damage to the DNA and proteins within cells. Although it is not yet clear how the SOD1 gene mutation leads to motor neuron degeneration, researchers have theorized that an accumulation of free radicals may result from the faulty functioning of this gene. In support of this, animal studies have shown that motor neuron degeneration and deficits in motor function accompany the presence of the SOD1 mutation.

Studies involving transgenic mice have yielded a different theory about the role of SOD1 in amyotrophic lateral sclerosis. Mice lacking the SOD1 gene entirely do not customarily get ALS, or exhibit any adverse reactions to the missing gene. This and the presence of SOD1 mutant proteins in amyloid-like neurofilaments indicates that SOD1 may act as an amyloid protein. Amyloid proteins exhibit a mutant conformation that can associate with other amyloids to form higher order structures. These structures are believed to block cellular transport and other machinery necessary to the cell's proper function.

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the chemical messengers or neurotransmitters in the brain. Scientists have found that, compared to healthy people, ALS patients have higher levels of glutamate in the serum and spinal fluid. Laboratory studies have demonstrated that neurons begin to die off when they are exposed over long periods to excessive amounts of glutamate (excitotoxicity). Now, scientists are trying to understand what mechanisms lead to a buildup of unneeded glutamate in the spinal fluid and how this imbalance could contribute to the development of ALS. Failure of astrocytes to sequester glutamate from the extracellular fluid surrounding the neurones has been proposed as a possible cause of this glutamate-mediated neurodegeneration.

Autoimmune responses which occur when the body's immune system attacks normal cells have been suggested as one possible cause for motor neuron degeneration in ALS. Some scientists theorize that antibodies may directly or indirectly impair the function of motor neurons, interfering with the transmission of signals between the brain and muscles.

In searching for the cause of ALS, researchers have also studied environmental factors such as exposure to toxic or infectious agents. Other research has examined the possible role of dietary deficiency or trauma. However, as of yet, there is insufficient evidence to implicate these factors as causes of ALS.

Future research may show that many factors, including a genetic predisposition, are involved in the development of ALS.

Treatment

No cure has yet been found for ALS. However, the Food and Drug Administration (FDA) has approved the first drug treatment for the disease: Riluzole (Rilutek). Riluzole is believed to reduce damage to motor neurons by decreasing the release of glutamate. Clinical trials with ALS patients showed that riluzole prolongs survival by several months, mainly in those with difficulty swallowing. The drug also extends the time before a patient needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and patients taking the drug must be monitored for liver damage and other possible side effects. However, this first disease-specific therapy offers hope that the progression of ALS may one day be slowed by new medications or combinations of drugs.

Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; and home care and hospice nurses. Working with patients and caregivers, these teams 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 therapy and special equipment can enhance patients' independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical therapists can recommend exercises that provide these benefits without overworking muscles. Occupational therapists can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients conserve energy and remain mobile.

ALS patients who have difficulty speaking benefit from working with a speech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as alphabet boards or yes/no signals. These methods and devices help patients communicate when they can no longer speak or produce vocal sounds. With the help of occupational therapists, speech-generating devices can be activated by switches or mouse emulation techniques controlled by small physical movements of, for example, the head, finger or eyes.

Patients and caregivers can learn from speech-language pathologists and nutritionists 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. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.

When the muscles that assist in breathing weaken, use of nocturnal ventilatory assistance (intermittent positive pressure ventilation (IPPV) or bilevel positive airway pressure (BIPAP)) may be used to aid breathing during sleep. Such devices artificially inflate the patient's lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time.

Patients may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the patient's windpipe through an opening in the neck. Patients and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the patient's quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support.It must be pointed out that some patients under long-term tracheostomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheostomy tubes (leak ventilation) are able to speak.This technique preserves phonation in some patients with long-term mechanical ventilation.

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. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Home care nurses are available not only to provide medical care but also to teach caregivers about tasks such as maintaining respirators, 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. The home hospice team can also counsel patients and caregivers about end-of-life issues.

Recent research in an animal model of ALS suggests that calorie restriction may accelerate the clinical onset of ALS and death. [4] A previous study using the same animal model also found that CR "accelerates the clinical course" of the disease and had no benefits. [5] Other research suggests a ketogenic diet may slow the progress of ALS in mice. [6]

Resources

There are many organizations set up across the world to help people with ALS. Internationally there is the ALS MND alliance, in the United States there is the ALS Association, in the United Kingdom the Motor Neuron Disease Association, in Canada the ALS Society of Canada, and in Australia there is the Motor Neurone Disease Association of Australia [1]. These organizations and others work to eliminate the disease through fund raising and grant giving and to assist people with ALS and those around them. ALSforums is an all-volunteer driven, human moderated, online support group for anyone directly or indirectly affected by ALS/MND. Organizations like Extra Hands for ALS exist to connect students who volunteer to help with household chores with ALS patients and their families, whilst The ALS Therapy Development Foundation focuses on finding treatments for today's patients.

Notable people with ALS

References

  1. ^ Li B, Xu W, Luo C, Gozal D, Liu R. VEGF-induced activation of the PI3-K/Akt pathway reduces mutant SOD1-mediated motor neuron cell death. Brain Res Mol Brain Res. 2003 Mar 17;111(1-2):155-64 PMID 12654515.
  2. ^ Moreau C, Devos D, Brunaud-Danel V, Defebvre L, Perez T, Destee A, Tonnel AB, Lassalle P, Just N. Paradoxical response of VEGF expression to hypoxia in CSF of patients with ALS. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):255-7 PMID 16421133.
  3. ^ http://www.eurekalert.org/pub_releases/2006-02/tmsh-fdi022206.php EurekAlert!
  4. ^ Hamadeh MJ, Rodriguez MC, Kaczor JJ, Tarnopolsky MA. Caloric restriction transiently improves motor performance but hastens clinical onset of disease in the Cu/Zn-superoxide dismutase mutant G93A mouse. Muscle Nerve. 2005 Feb;31(2):214-20. PMID 15625688.
  5. ^ Pedersen WA, Mattson MP. No benefit of dietary restriction on disease onset or progression in amyotrophic lateral sclerosis Cu/Zn-superoxide dismutase mutant mice. Brain Res. 1999 Jun 26;833(1):117-20. PMID 10375685.
  6. ^ Zhao Z, Lange DJ , Voustianiouk A, et. al. A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis. BMC Neuroscience 2006, 7:29. (PMID 16584562). Media report on Zhao et al.

This article incorporates public domain text from The U.S. National Institute of Neurological Disorders and Stroke

  1. Stephen Hawking's Website [2]
  2. Clinical Trial of Neurodex for Pseudobulbar Affect in People with Amyotrophic Lateral Sclerosis
  3. Lou Gehrig's Website [3]
  4. ALS-Project - Free communication software for people suffering from ALS [4]
  5. ALS Therapy Development Foundation [5]
  6. PatientsLikeMe - a free online tool for ALS patients to track and share progress [6]
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