Motor neurone disease ICD-10 code: G12.2 ICD-9 code: 335.20 Motor neurone disease (MND) is a term used to cover a number of illnesses of the motor neurone; amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), spinal muscular atrophy (SMA), progressive bulbar palsy (PBP), and primary lateral sclerosis (PLS) are all forms of MND. MND is the term used internationally 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). Contents 1 Signs and symptoms 2 Diagnosis 3 Pathology 3.1 Causes 3.2 Pathophysiology 3.3 Extra-motor change in MND 4 Epidemiology 5 Prognosis 6 Treatment 7 Etymology 8 History and prominent patients 9 See also 10 Sources and References 11 External links Signs and symptoms The onset of symptoms is usually between 40–70 years of age (average 55). Cases range from 18 to over 100. The disorder is characterized by the progressive loss of voluntary muscle contraction due to the destruction of nerve cells in the brain and the spinal cord that are responsible for the stimulation of the voluntary muscles. While the initial symptoms are subtle, the disease causes progressive physical disability. Diagnosis The diagnosis is established on both clinical grounds and an electromyography (EMG) examination, which is obligatory to demonstrate the diffuse loss of nervous stimulation of muscles of extremities, face and abdomen. Clinically, upper motor neuron damage signs (such as spasticity, lively 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 About 90% of cases of MND are "sporadic". The cause of these cases is unknown, although there is some suggestion that the onset can be triggered by a viral infection. The remaining 10% of cases are "familial" (i.e. have a clear genetic basis). At least 6 genes are known to be linked to ALS: SOD1 (a.k.a. ALS1), SOD2, SOD7, ALS2, NEFH and 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, residence on the island of Guam in the Pacific Ocean, 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. 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. Other drugs can be taken to relieve individual symptoms, but these do not affect the progression of the disease. 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. 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. See also Kennedy disease Monomelic amyotrophy Sources and References 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 of minocycline as an ALS treatment may be found at The ALS Association's Website. External links ALS Therapy Development Foundation ALS Association ALSOD Database of all known SOD1 mutations 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 Canadade:Amyotrophe Lateralsklerose Search Term: "Motor_neurone_disease" Categories: Neurology | Disability