Motor neurone disease Classification and external resources
ICD-10	G12.2
ICD-9	335.2
DiseasesDB	8358
MeSH	D016472

The motor neurone diseases (or motor neuron diseases) (MND) are a group of progressive neurological disorders that destroy motor neurones, the cells that control voluntary muscle activity such as speaking, walking, breathing, and swallowing. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings G00-G99 - Diseases of the Nervous system (G00-G09 Inflammatory diseases of the Central nervous system ( Bacterial meningitis The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books In Vertebrates the term motor neuron (or motoneuron) classically applies to Neurons located in the Central nervous system (or CNS that project

Contents 1 Forms 2 Terminology 3 Signs and symptoms 4 Diagnosis 5 Prognosis 6 Pathology 6.1 Causes 6.2 Pathophysiology 7 Emotional lability / pseudobulbar affect 8 Extra-motor change in MND 9 Epidemiology 10 Treatment 11 Research efforts 12 Etymology 13 See also 14 References 15 External links

Forms

Forms of motor neurone disease include:

• amyotrophic lateral sclerosis (ALS) (sometimes called Lou Gehrig's disease)
• primary lateral sclerosis (PLS)
• progressive muscular atrophy (PMA)
• bulbar^[1]
  • pseudobulbar palsy - spastic
  • progressive bulbar palsy - spastic and flaccid

Spinal muscular atrophy (SMA) is sometimes (but not always) considered a form of MND. Amyotrophic Lateral Sclerosis ( ALS, sometimes called Maladie de Charcot, or in the United States Lou Gehrig's Disease) is a progressive Henry Louis "Lou" Gehrig ( June 19 1903  – June 2 1941) born Ludwig Heinrich Gehrig, was an American Primary lateral sclerosis ( PLS) is a rare Neuromuscular disease characterized by progressive muscle weakness in the Voluntary muscles. Progressive muscular atrophy (PMA is a rare subtype of Motor neurone disease (MND which affects only the Lower motor neurones This is in contrast to the most common Pseudobulbar palsy is bilateral impairment of the function of the lower Cranial nerves 9 10 11 and 12 which control the muscles of eating swallowing and talking Progressive Bulbar Palsy (also known simply as PBP) belongs to a group of disorders known as motor neuron diseases ( Lapiedra 2002) Spinal Muscular Atrophy ( SMA) is a term applied to a number of different disorders all having in common a genetic cause and the manifestation of weakness due to loss

Terminology

In this article, MND refers to a group of diseases which affect the motor neurones. In the United States, the term ALS is more commonly used, where it is also known as Lou Gehrig's disease, after the baseball player. The United States of America —commonly referred to as the Amyotrophic Lateral Sclerosis ( ALS, sometimes called Maladie de Charcot, or in the United States Lou Gehrig's Disease) is a progressive Henry Louis "Lou" Gehrig ( June 19 1903  – June 2 1941) born Ludwig Heinrich Gehrig, was an American Baseball is a Bat-and-ball Sport played between two teams of nine players each Although previously described by other neurologists of the 19th century, it was Jean-Martin Charcot, a French neurologist, who suggested grouping together a number of disparate conditions all affecting the lateral horn of the spinal cord in 1869. Jean-Martin Charcot ( 29 November 1825 – 16 August 1893) was a French Neurologist and professor of Anatomical pathology This article is about the country For a topic outline on this subject see List of basic France topics. In the Thoracic region the postero-lateral part of the Anterior column projects lateralward as a triangular field which is named the lateral column ( lateral In France the disease is sometimes known as Maladie de Charcot (Charcot's disease), although it may also be referred to by the direct translation of ALS, Sclerose Laterale Amyotrophique (SLA). To help prevent confusion, the annual scientific research conference dedicated to the study of MND is called the International ALS/MND Symposium.

Signs and symptoms

Symptoms usually present between the ages of 50-70, and include progressive weakness, muscle wasting, and muscle fasciculations; spasticity or stiffness in the arms and legs; and overactive tendon reflexes. A fasciculation (or "muscle Twitch " is a small local involuntary Muscle contraction (twitching visible under the skin arising from the spontaneous discharge Patients may present with symptoms as diverse as a dragging foot, unilateral muscle wasting in the hands, or slurred speech.

Neurological examination presents specific signs associated with upper and lower motor neurone degeneration. Signs of upper motor neurone damage include spasticity, brisk reflexes and the Babinski sign. Upper motor neurons are Motor neurons that originate in motor region of the Cerebral cortex or the Brain stem and carry motor information down Spasticity or muscular hypertonicity is a disorder of the body Motor system, and especially the central nervous system (CNS in which certain Muscles continually A reflex action, also known as a reflex, is an involuntary and almost instant movement in response to stimulus. In Medicine and Neurology, the Babinski response to the plantar reflex is a Reflex, named after Joseph Babinski ( 1857 - 1932) (a French Signs of lower motor neurone damage include weakness and muscle atrophy. Lower motor neurons ( LMNs) are the Motor neurons connecting the Brainstem and Spinal cord to Muscle fibers, bringing the nerve

Note that every muscle group in the body requires both upper and lower motor neurones to function. The signs described above can occur in any muscle group, including the arms, legs, torso, and bulbar region.

The symptoms described above may resemble a number of other rare diseases, known as "MND Mimic Disorders". These include, but are not limited to multifocal motor neuropathy, Kennedy's disease, hereditary spastic paraplegia, spinal muscular atrophy and monomelic amyotrophy. Kennedy's disease (KD or X-linked spinal and bulbar muscular atrophy (SBMA is a neuromuscular disease associated with mutation of the Androgen receptor (AR Hereditary Spastic Paraplegia (HSP also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is not a single disease but is a heterogeneous group of Spinal Muscular Atrophy ( SMA) is a term applied to a number of different disorders all having in common a genetic cause and the manifestation of weakness due to loss Monomelic amyotrophy (also known as MMA, Hirayama's disease, Sobue disease or Juvenile nonprogressive amyotrophy) is an untreatable focal A small subset of familial MND cases occur in children, such as "juvenile ALS", Madras syndrome, and individuals who have inherited the ALS2 gene. However, these are not typically referred to as MND, but by their specific names.

Diagnosis

The diagnosis of MND is a clinical one, established by a neurologist on the basis of history and neurological examination. There is no diagnostic test for MND. Investigations such as blood tests, electromyography (EMG), magnetic resonance imaging (MRI), and sometimes genetic testing are useful to rule out other disorders that may mimic MND. Electromyography (EMG is a technique for evaluating and recording the activation signal of muscles Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry. However, the diagnosis of MND remains a clinical one. Having excluded other diseases, a relatively rapid progression of symptoms is a strong diagnostic factor. Although an individual's progression may sometimes "plateau", it will not improve.

A set of diagnostic criteria called the El Escorial criteria^[2][3] have been defined by the World Federation of Neurologists for use in research, particularly as inclusion/exclusion criteria for clinical trials. Owing to a lack of clinical diagnostic criteria, some neurologists use the El Escorial criteria during the diagnostic process, although strictly speaking this is functionality creep, and some have questioned the appropriateness of the criteria in a clinical setting. Scope creep (also called focus creep, requirement creep, feature creep, and sometimes kitchen sink syndrome) in Project management ^[4]

• MND in the presence of both upper and lower motor neurone degeneration is ALS.
• Where the illness affects only the upper motor neurones it is PLS.
• Where the illness affects only the lower motor neurones it is PMA.
• Progressive bulbar palsy is degeneration of the lower motor neurones innervating the bulbar region (mouth, face, and throat).
• Pseudobulbar palsy refers to degeneration of the upper motor neurones to the same region.

It it possible that Transcranial Magnetic Stimulation can be used to diagnose MND. Transcranial magnetic stimulation ( TMS) is a noninvasive method to excite neurons in the Brain: weak Electric currents are induced in the tissue by rapidly ^[5]

Prognosis

Most cases of MND progress quite quickly, with noticeable decline occurring over the course of months. Although symptoms may present in one region, they will typically spread. If restricted to one side of the body they are more likely to progress to the same region on the other side of the body before progressing to a new region. After several years, most patients require help to carry out activities of daily living such as self care, feeding, and transportation.

MND is typically fatal within 2-5 years. Around 50% die within 14 months of diagnosis. The remaining 50% will not necessarily die within the next 14 months as the distribution is significantly skewed. As a rough estimate, 1 in 5 patients survive for 5 years, and 1 in 10 patients survive 10 years. Professor Stephen Hawking is a well-known example of a person with MND, and has lived for more than 40 years with the disease. Stephen William Hawking CH, CBE, FRS, FRSA (born 8 January 1942 is a British theoretical physicist.

Mortality normally results when control of the diaphragm is impaired and the ability to breathe is lost. One exception is PLS, which may last for upwards of 25 years. Given the typical age of onset, this effectively leaves most PLS patients with a normal life span. PLS can progress to ALS, decades later.

Pathology

Causes

About 90% of cases of MND are "sporadic", meaning that the patient has no family history of ALS and the case appears to have occurred with no known cause. Genetic factors are suspected to be important in determining an individual's susceptibility to disease, and there is some weak evidence to suggest that onset can be "triggered" by as yet unknown environmental factors (see 'Epidemiology' below).

Approximately 10% of cases are "familial MND", defined either by a family history of MND or by testing positive for a known genetic mutation associated with the disease. 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).

Of these, SOD1 mutations account for some 20% of familial MND cases. The SOD1 gene codes for the enzyme superoxide dismutase, a free radical scavenger that reduces the oxidative stress of cells throughout the body. The enzyme superoxide dismutase ( SOD,) catalyzes the Dismutation of Superoxide into Oxygen and Hydrogen peroxide. In Chemistry, radicals (often referred to as free radicals) are atoms molecules or ions with Unpaired electrons on an otherwise Open shell Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily So far over 100 different mutations in the SOD1 gene have been found, all of which cause some form of ALS(ALSOD database). 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. Terminology and usage As a cultural term "Scandinavia" has no official definition and is subject to usage by those who identify with the culture in question as well Future research is concentrating on identifying new genetic mutations and the clinical syndrome associated with them. Familial MND may also confer a higher risk of developing cognitive changes such as frontotemporal dementia or executive dysfunction (see 'extra-motor change in MND' below).

It is thought that SOD1 mutations confer a toxic gain, rather than a loss, of function to the enzyme. SOD1 mutations may increase the propensity for the enzyme to form protein aggregates which are toxic to nerve cells.

Pathophysiology

Skeletal muscles are innervated by a group of neurones (lower motor neurones) located in the ventral horns of the spinal cord which project out the ventral roots to the muscle cells. Skeletal muscle is a type of Striated muscle, which usually attaches to tendons These nerve cells are themselves innervated by the corticospinal tract or upper motor neurones that project from the motor cortex of the brain. Motor cortex is a term that describes regions of the Cerebral cortex involved in the planning control and execution of voluntary motor functions On macroscopic pathology, there is a degeneration of the ventral horns of the spinal cord, as well as atrophy of the ventral roots. In the brain, atrophy may be present in the frontal and temporal lobes. On microscopic examination, neurones may show spongiosis, the presence of astrocytes, and a number of inclusions including characteristic "skein-like" inclusions, bunina bodies, and vacuolisation.

There is a role in excitotoxicity and oxidative stress, presumably secondary to mitochondrial dysfunction. In animal models, death by apoptosis has also been identified.

Emotional lability / pseudobulbar affect

Main article: labile affect

Around a third of all MND patients experience labile affect, also known as emotional lability, pseudobulbar affect, or pathological laughter and crying. Labile affect or pseudobulbar affect refers to the pathological expression of Laughter, Crying or smiling. Labile affect or pseudobulbar affect refers to the pathological expression of Laughter, Crying or smiling. Patients with pseudobulbar palsy are particularly likely to be affected, as are patients with PLS.

Extra-motor change in MND

Cognitive change can and does occur in between 33–50% of patients. Cognition is a concept used in different ways by different disciplines but is generally accepted to mean the process of awareness or thought A small proportion exhibit a form of frontotemporal dementia characterised by behavioural abnormalities such as disinhibition, apathy, and personality changes. Frontotemporal dementia (FTD is a clinical Syndrome caused by degeneration of the Frontal lobe of the Brain and may extend back to the Temporal lobe Disinhibition is a term in Psychology used to describe conditions of a person being unable (rather than disinclined to control their immediate impulsive response 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. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression g. ~50% in multiple sclerosis and Parkinson's disease, ~20% in Epilepsy. Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the Central nervous system that often impairs the sufferer's 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. Quality of life is the degree of well-being felt by an individual or group of people This may reflect the use of coping strategies such as reevaluating what is important in life. The psychological definition of coping is the process of managing taxing circumstances expending effort to solve personal and interpersonal problems and seeking

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.

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. Single photon emission computed tomography (SPECT or less commonly SPET is a Nuclear medicine tomographic imaging technique using Gamma rays. Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/ Pharmacology of the Brain

Epidemiology

The incidence of MND is approximately 1–5 out of 100,000 people. Men have a slightly higher incidence rate than women. Approximately 5,600 cases are diagnosed in the U. S. every year. By far the greatest risk factor is age, with symptoms typically presenting between the ages of 50-70. Cases under the age of 50 years are called "young onset MND", whilst incidence rates appear to tail off after the age of 85.

Tentative environmental risk factors identified so far include: exposure to severe electrical shock leading to coma, having served in the first Gulf War, and playing professional Association football. Association football, more commonly known as football or soccer, is a Team sport played between two teams of eleven players and is widely considered However, these findings have not been firmly identified and more research is needed.

There are three "hot spots" of MND in the world. One is in the Kii peninsula of Japan, one amongst a tribal population in Papua New Guinea. Papua New Guinea (or ˈpæpjuːə in Tok Pisin: Papua Niugini) officially the Independent State of Papua New Guinea, is a country in Oceania Chamorro inhabitants from the island of Guam in the Pacific Ocean have an increased risk of developing a form of MND known as Guamanian ALS-PD-dementia complex or "lytico bodig", although the incidence rate has declined over the last 50 years and the average age of onset has increased. Guam ( Chamorro: cha Guåhån) officially the Territory of Guam, is an island in the western Pacific Ocean and is an organized unincorporated ^[6] Putative theories involve neurotoxins in the traditional diet including cycad nut flour and bats that have eaten cycad nuts. Cycads are a group of Seed plants characterized by a large crown of compound leaves and a stout trunk. ^[7][8]

Treatment

Currently there is no cure for ALS. The only drug that affects the course of the disease is riluzole. Riluzole is a drug used to treat Amyotrophic The drug functions by blocking the effects of the neurotransmitter glutamate, and is thought to 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, speech-language pathologists, physical therapists, occupational therapists, dieticians, respiratory therapists, social workers, palliative care specialists, specialist nurses and psychologists. 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/).

Research efforts

The search for a drug that will slow MND progression is under way. For example, recent research using mouse models suggests that minocycline, a common antibiotic, may also be effective in extending the lifespan of MND sufferers. Minocycline hydrochloride, also known as minocycline, is a member of the broad spectrum Tetracycline antibiotics, and has a broader spectrum than the other members ^[9][10][11] This drug must pass clinical trials with ALS patients before it may be used as a general treatment for MND. In health care clinical trials are conducted to allow safety and Efficacy data to be collected for new drugs or devices

Minocycline extends the lifespan of MND mice with SOD1 mutations, but it does not prevent their eventual death. Minocycline hydrochloride, also known as minocycline, is a member of the broad spectrum Tetracycline antibiotics, and has a broader spectrum than the other members Other agents that are currently in trials include ceftriaxone, arimoclomol, IGF-1 and coenzyme Q10 to name but a few. Ceftriaxone ( INN) (ˌsɛftraɪˈæksoʊn/ /ˌkɛf- is a third-generation Cephalosporin Antibiotic. Arimoclomol is an experimental drug compound developed by CytRx Corporation, a biopharmaceutical company based in Los Angeles California. Insulin-like growth factor 1 (IGF-1 that was once called somatomedin C is a Polypeptide Protein Hormone similar in Molecular structure Coenzyme Q10 (also known as ubiquinone ubidecarenone coenzyme Q and abbreviated at times to CoQ10 CoQ Q10 or Q is a Benzoquinone, where Q

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. Greek (el ελληνική γλώσσα or simply el ελληνικά — "Hellenic" is an Indo-European language, spoken today by 15-22 million people mainly Atrophy is the partial or complete Wasting away of a part of the Body. 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.

See also

• Category:People with motor neuron disease
• Category:Deaths from motor neurone disease
• Kennedy disease
• Monomelic amyotrophy
• Primary lateral sclerosis
• Progressive muscular atrophy
• Riluzole

References

External links

• ALS Therapy Development Foundation
• ALS Association
• Scottish Motor Neurone Disease 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.
• BUILD-UK Forum for people with ALS/MND (UK-Based)
• ALS Society of Canada
• MND Association of Australia
• Project A.L.S
• 644546567 at GPnotebook
• List of United States government funded clinical trials relating to MND
• motor_neuron_diseases at NINDS
• ALSOD Database of all known SOD1 mutations

GPnotebook is a British medical database for General practitioners (GPs The National Institute of Neurological Disorders and Stroke is a part of the U

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