Amyotrophic Lateral Sclerosis
Webpages concerning "Amyotrophic Lateral Sclerosis"
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Wikipedia-Article "Amyotrophic Lateral Sclerosis"
| Motor neurone disease | ||
|---|---|---|
| ICD-10 code: | G122 | |
| ICD-9 code: | 335.2 | |
The motor neuron diseases (MND) are a group of progressive neurological disorders that destroy motor neurons, the cells that control voluntary muscle activity such as speaking, walking, breathing, and swallowing. Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), progressive bulbar palsy (PBP), and primary lateral sclerosis (PLS) are all motor neuron diseases.
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Terminology
MND is the term used internationally[Citation needed] while ALS is often used in the United States (where it is also known as Lou Gehrig's disease, after a famous patient) to cover all forms of MND. It was first described by Jean-Martin Charcot, a French neurologist, in 1869 and in France the disease is therefore known as Maladie de Charcot (Charcot's disease).
Signs and symptoms
Characteristic symptoms of MND include gradual weakening, wasting away, and uncontrollable twitching of the muscles; spasticity or stiffness in the arms and legs; and overactive tendon reflexes. Sensation, intellect, memory, and personality are not affected in MND. In some types of MND, such as ALS, muscle weakness is progressive and eventually leads to death when the muscles that control breathing no longer work. Other types of MND progress slowly and last over a lifetime.[1]
In adults, symptoms usually appear after age 40, and may be similar to those of other diseases, making diagnosis difficult. In children, particularly in inherited forms of the disease, symptoms are present from birth.[2]
Diagnosis
The diagnosis of ALS is established based on the history of the patient and the findings on neurological examination. There is no diagnostic test for ALS. Electromyography (EMG) examination are useful to demonstrate the diffuse loss of motor neurons innervating muscles of extremities, face and abdomen and to rule out other disorders that may mimic ALS, but interpretation of the result is not necessarily straight forward. A set of diagnostic criteria called the El Escorial criteria have been defined by the World Federation of Neurologists and are widely used by neurologists and ALS researchers.
Clinically, upper motor neuron damage signs (such as spasticity, brisk reflexes and Babinski signs) can be found, while the lower motor neurones demonstrate weakness and muscle atrophy. Weakness of bulbar musculature can also be seen (difficulty breathing, swallowing, coughing, or speaking).
Neuroimaging examinations are usually performed to rule out alternative causes, such as a mass lesion of upper parts of spinal cord
Pathology
Causes
Nonhereditary (also called sporadic) MND are caused by unknown factors. Nonhereditary MND include ALS, progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, progressive muscular atrophy, and post-polio syndrome. There are no specific tests to diagnose the MND.[3]
About 90% of cases of MND are "sporadic", meaning that the patient has no family history of ALS and the case appears to have occured sporadically in the community. The cause of sporadic ALS is unknown, though genetic factors are suspected to be important in determining an individual's susceptibility to disease. There is weak evidence to the suggestion that the onset can be triggered by a viral infection, but this is not widely believed in the ALS research community. The remaining 10% of cases are "familial", defined as more than one case of ALS in a family. Familial ALS is genetic in aetiology and the following genes are known to be linked to ALS: Cu/Zn superoxide dismutase SOD1, ALS2, NEFH(a small number of cases), senataxin (SETX) and vesicle associated protein B (VAPB).
The SOD1 gene codes for the enzyme superoxide dismutase, a free radical scavenger that reduces the oxidative stress of cells throughout the body. Mutations in SOD1 are found in at least 20% of familial ALS cases. So far over 100 different mutations in the SOD1 gene have been found, all of which cause some form of ALS (see link to ALSOD database below). In North America, the most commonly occurring mutation is known as A4V and occurs in up to 50% of SOD1 cases. In people of Scandinavian extraction there is a relatively benign mutation called D90A which is associated with a slow progression. Future research is concentrating on identifying new genetic mutations and the clinical syndrome associated with them.
Although some researchers believe that nerve cell death is caused in part by an excess of free radicals in the cell, it is more commonly thought that the SOD1 mutations confer a gain, rather than a loss, of function upon the SOD1 enzyme. There is a significant amount of evidence suggesting that many SOD1 mutations increase the propensity for the enzyme to form aggregates which may be toxic to nerve cells.
Pathophysiology
Skeletal muscles are stimulated by a group of neurons (lower motor neurons) located on the frontal portion of the spinal cord projecting to the muscle cells and these nerve cells are stimulated by a group of nerve cells (upper motor neurons) that project from a specific region called the motor area, located on the brain's frontal lobe. The latter projection is called the corticospinal tract. In MND, the nerve cells of both pathways shrink and die. On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots (shrunken in appearance). Similarly, a degeneration of the motor neurons in the brainstem is seen. Neuronal loss and astrogliosis develops as well. Degeneration of the corticospinal tracts, as well as of the neurons in the motor strip of the cerebral cortex is known.
In addition, neuroimaging and neuropathology has demonstrated extra-motor changes in the frontal lobes including the inferior frontal gyrus, superior frontal gyrus, anterior cingulate cortex, and superior temporal gyrus. The degree of pathology in these areas has been directly related to the degree of cognitive change experienced by the patient, if any. Patients with MND and dementia have been shown to exhibit marked frontotemporal lobe atrophy as revealed by MRI or SPECT neuroimaging.
There is a role in excitotoxicity and oxidative stress, presumably secondary to mitochondrial dysfunction. In animal models, death by apoptosis has also been identified (tranlocation of Bax to mitochondria, and translocation of cytochrome c to cytosol).
Extra-motor change in MND
Cognitive change can and does occur in between 33–50% of patients. A small proportion exhibit a form of frontotemporal dementia characterised by behavioural abnormalities such as disinhibition, apathy, and personality changes. A small proportion of patients may also suffer from an aphasia, which causes difficulty in naming specific objects. A larger proportion (up to 50%) suffer from a milder version of cognitive change which primarily affects what is known as executive function. Briefly, this is the ability of an individual to initiate, inhibit, sustain, and switch attention and is involved in the organisation of complex tasks down to smaller components. Often patients with such changes find themselves unable to do the family finances or drive a car. Depression is surprisingly rare in MND (around 5–20%) relative to the frequency with which it is found in other, less severe, neurological disorders e.g. ~50% in multiple sclerosis and Parkinson's disease, ~20% in Epilepsy. Depression does not necessarily increase as the symptoms progress, and in fact many patients report being happy with their quality of life despite profound disability. This may reflect the use of coping strategies such as reevaluating what is important in life.
Although traditionally thought only to affect the motor system, sensory abnormalities are not necessarily absent, with some patients finding altered sensation to touch and heat, found in around 10% of patients. Patients with a predominantly upper motor neurone syndrome, and particularly PLS, often report an enhanced startle reflex to loud noises.
Epidemiology
MND has three major subgroups: primary lateral sclerosis (PLS, only the upper motor neurons are affected), progressive muscular atrophy (PMA, only the lower motor neurons are affected) and amyotrophic lateral sclerosis (ALS, both types of motor neurons are affected). PLS and PMA each account for about 5% of cases, with the majority of diagnoses being ALS.
The incidence of MND is approximately 1–5 out of 100,000 people. Men have a 20% higher rate of incidence than women. Approximately 5,600 cases are diagnosed in the U.S. every year.
Tentative risk factors identified so far include: having a family member with the disease, exposure to severe electrical shock leading to coma, having served in the first Gulf War, and playing professional football (soccer). However, these findings have not been firmly identified and more research is needed. Residence on the island of Guam in the Pacific Ocean, increases risk of developing Guamanian ALS-PD-dementia complex, but it is not clear how this disease is related to the more classical form of ALS seen elsewhere in the world.
Prognosis
The disease usually has a grave prognosis and 50% of patients die within the first 3 years, 20% will live 5 years or more, only 10% survive for 10 years or more. There are documented cases of people living 35 years or more after diagnosis; Stephen Hawking has lived for more than 42 years since his (1963) diagnosis. The rarer subgroups of MND have better prognoses than ALS; people with PMA are more likely to be "long survivors" i.e. > 5 years, while people with PLS effectively have a normal lifespan. In ALS and PMA, mortality is typically caused by respiratory weakness or complications arising from prolonged paralysis.
Treatment
Currently, there is no cure for ALS. The only drug that affects the course of the disease is riluzole. This drug, an ion-channel blocker, can typically extend the lifespan of an ALS patient by only a few months.
The lack of effective medications to slow the progression of ALS does not mean that patients with ALS cannot be medically cared for. Instead, treatment of patients with ALS focuses on the relief of symptoms associated with the disease. This involves a variety of health professionals including neurologists, physical therapists, occupational therapists, dieticians, respiratory therapists, social workers, palliative care specialists, specialist nurses and psychologists. Recent research indicates that such a multi-disciplinary team approach to the care of the ALS patient can prolong patient survival. A list of neurology clinics that specialize in the care of patients with ALS can be found on the World Federation of Neurology website (http://www.wfnals.org/clinics/).
The search for a drug that will slow ALS disease progression is underway. For example, recent research using mouse models suggests that minocycline, a common antibiotic, may also be effective in extending the lifespan of ALS sufferers. This drug must pass clinical trials with ALS patients before it may be used as a general treatment for ALS. It should be noted that minocycline extends the lifespan of ALS mice with SOD1 mutations, but it does not prevent their eventual death. Other agents that are currently in trials include ceftriaxone, arimoclomol, IGF-1 and coenzyme Q10 to name but a few. A list of US-based clinical ALS trials may be found at www.clinicaltrials.org or by contacting your local ALS/MND charity.
Etymology
Amyotrophic comes from the Greek language: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophication of the sufferer's disused muscle tissue. Lateral identifies the areas in a person's spinal cord where portions of the nerve cells that are affected are located. As this area degenerates it leads to scarring or hardening ("sclerosis") in the region.
History and prominent patients
U.S. baseball player Lou Gehrig brought national and international attention to the disease in 1939 when he abruptly retired after being diagnosed with ALS/MND. Former guitar virtuoso Jason Becker, theoretical physicist Stephen Hawking, and ex-Celtic football player Jimmy Johnstone also suffer from the disease.
Founder of care homes Leonard Cheshire VC, owner from 1957-1966 of Athelhampton House in Dorset Sir Robert Cooke F.R.C.S., theoretical physicist Victor Emery, Rangers footballer Sam English, Hall of Fame pitcher Jim "Catfish" Hunter, blues singer and guitarist Leadbelly, jazz giant Charles Mingus, Hollywood actor David Niven, legendary Leeds United manager Don Revie, teacher and book subject Morrie Schwartz, American television actor Lane Smith, linguist Larry Trask, American soap opera veteran Michael Zaslow, and Chinese Chairman Mao Zedong died from the disease.
Diane Pretty was a British woman with the disease who was involved in a prominent right-to-die case in the early 2000s.
See also
Sources and References
- Motor Neuron Diseases information sheet compiled by the National Institute of Neurological Disorders and Stroke (NINDS).
- ALSOD Database of all known SOD1 mutations
- Some information gathered from Dr. M Norenberg, University of Miami (October 26, 2004).
- Crossing the Finishing Line—Last Thoughts of Leonard Cheshire VC, ed. Reginald C. Fuller (London 1998).
- De Standaard (Dutch language newspaper), 12 September 2005.
- Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, Sarang S, Liu AS, Hartley DM, Wu du C, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM. "Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice." Nature. 2002 May 2;417(6884):74-8.
- Van Den Bosch L, Tilkin P, Lemmens G, Robberecht W. "Minocycline delays disease onset and mortality in a transgenic model of ALS." Neuroreport. 2002 Jun 12;13(8):1067-70.
- Kriz J, Nguyen MD, Julien JP. "Minocycline slows disease progression in a mouse model of amyotrophic lateral sclerosis." Neurobiol Dis. 2002 Aug;10(3):268-78.
Information about Clinical Trials
- List of government funded clinical trials relating to MND
- Information on the ALS Association's Website about clinical trials of minocycline as an ALS treatment
Other Resources
- ALS Therapy Development Foundation
- ALS Association
- ALS/MND Alliance
- MND Association
- ALS Liga Belgium (dutch and french language)
- The Hereditary Motor Neurone Disease Foundation - Australian group seeking to find a cure for familial Motor Neurone Disease.
- BrainTalk Communities Forum for people with ALS/MND (US-Based)
- BUILD-UK Forum for people with ALS/MND (UK-Based)
- ALS Canada
- Project A.L.S