Motor neurone disease
Encyclopedia
The motor neurone diseases (or motor neuron diseases) (MND) are a group of neurological disorder
s that selectively affect motor neuron
es, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. They are generally progressive in nature, and can cause progressive disability and death. The drug riluzole
can slow progression slightly. The condition was first described in full by the French neurologist Jean-Martin Charcot
in 1869.
The disease spinal muscular atrophy
(SMA) is classified under MND by the disease terminology classification system MeSH
, but not in the tenth International Statistical Classification of Diseases and Related Health Problems
published in 1992.
s, spasticity or stiffness in the arms and legs, and overactive tendon reflexes. 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 neuron
e damage include spasticity
, brisk reflex
es and what are referred to as pathological reflexes (reflexes that may be normal in an infant but are abnormal in an adult) including Hoffmann's sign
in the fingers and hand and the Babinski sign
. Signs of lower motor neuron
e damage include weakness, fasciculations (twitching muscles) and muscle atrophy.
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
. A small subset of familial MND cases occurs 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.
Cognitive
change occurs 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.
Neuroimaging and neuropathology have 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
.
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 , , (a small number of cases), senataxin and vesicle associated protein B .
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. 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 Scandinavia
n extraction there is a relatively benign mutation called D90A which is associated with a slow progression. In Japan, the H46R mutation is most common. G93A, the mutation used to generate the first animal model (and by far the most widely studied), is present only in a few families worldwide. 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.
s 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. These nerve cells are themselves innervated by the corticospinal tract
or upper motor neurones that project from the motor cortex
of the brain. 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
. Bunina bodies were first described in 1962; they are markers of neuronal degeneration.
The availability of mouse models has led to extensive research into the causes of SOD1
-mutant linked familial ALS
. The most commonly used mouse model is G93A, although many others have since been generated. At the gross physiological level, the mouse models faithfully recapitulate the features of human ALS (motorneuron death, muscle atrophy, respiratory failure).
Although there is no consensus as to the exact mechanism by which mutated SOD1 causes the disease (in either mice or patients), studies based largely on mouse models suggest a role for excitotoxicity
and more controversially, oxidative stress
, presumably secondary to mitochondrial dysfunction. Death by apoptosis
has also been suggested.
(EMG), magnetic resonance imaging
(MRI), and sometimes genetic testing
are useful to rule out other disorders that may mimic MND. 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 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.
. 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 therapist
s, dieticians, respiratory therapists, social workers, palliative care specialists, specialist nurses and psychologists.
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 nearly 50 years with the disease. The television film Hawking starring Benedict Cumberbatch
was made in 2004 about him and this disease.
Mortality normally results when control of the diaphragm is impaired and the ability to breathe is lost. One exception is Primary Lateral Sclerosis
(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.
There are three "hot spots" of MND in the world. One is in the Kii peninsula of Japan; another is amongst a tribal population in Papua New Guinea
. 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. Putative theories involve neurotoxins in the traditional diet including cycad
nut flour and bats that have eaten cycad nuts.
, primary lateral sclerosis
, and progressive bulbar palsy
. In the United States the most common terms used are ALS (both specifically for ALS and as a blanket term) or "Lou Gehrig's disease". 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 avoid confusion, the annual scientific research conference dedicated to the study of MND is called the International ALS/MND Symposium. ALS/MND refers to a specific subset of pathologically identical diseases; there are numerous other afflictions of motor neurones that are pathologically distinct from ALS/MND and have a different clinical course. Examples of other diseases of the motor neurone that should not be confused with ALS/MND include spinobulbar muscular atrophy, spinal muscular atrophy
, Charcot-Marie-Tooth disease
, and many others.
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.
neurologist
, Jean-Martin Charcot
, first suggested grouping together disparate conditions that affect the lateral horn
of the spinal cord in 1869.
:Category:Deaths from motor neurone disease
Neurological disorder
A neurological disorder is a disorder of the body's nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or in the nerves leading to or from them, can result in symptoms such as paralysis, muscle weakness, poor coordination, loss of sensation, seizures,...
s that selectively affect motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
es, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. They are generally progressive in nature, and can cause progressive disability and death. The drug riluzole
Riluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....
can slow progression slightly. The condition was first described in full by the French neurologist Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...
in 1869.
Classification
There are five recognized subtypes of motor neurone diseases. They are distinguished by the nerve cells affected (upper and lower motor neuron), and the symptoms that result from this damage. The "bulbar region" in the table below refers to the mouth, face, and throat.| Type | UMN Upper motor neuron Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle... degeneration |
LMN Lower motor neuron Lower motor neurons are the motor neurons connecting the brainstem and spinal cord to muscle fibers, bringing the nerve impulses from the upper motor neurons out to the muscles... degeneration >- | ALS Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input... |
yes | >- | yes | >- | no | >- | no | >- | yes - bulbar region | no |
The disease spinal muscular atrophy
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
(SMA) is classified under MND by the disease terminology classification system MeSH
Medical Subject Headings
Medical Subject Headings is a comprehensive controlled vocabulary for the purpose of indexing journal articles and books in the life sciences; it can also serve as a thesaurus that facilitates searching...
, but not in the tenth International Statistical Classification of Diseases and Related Health Problems
ICD-10
The International Statistical Classification of Diseases and Related Health Problems, 10th Revision is a medical classification list for the coding of diseases, signs and symptoms, abnormal findings, complaints, social circumstances, and external causes of injury or diseases, as maintained by the...
published in 1992.
Muscle symptoms
Symptoms usually present themselves between the ages of 50-70, and include progressive weakness, muscle wasting, and muscle fasciculationFasciculation
A fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...
s, spasticity or stiffness in the arms and legs, and overactive tendon reflexes. 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 neuron
Upper motor neuron
Upper motor neurons are motor neurons that originate in the motor region of the cerebral cortex or the brain stem and carry motor information down to the final common pathway, that is, any motor neurons that are not directly responsible for stimulating the target muscle...
e damage include spasticity
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
, brisk reflex
Reflex
A reflex action, also known as a reflex, is an involuntary and nearly instantaneous movement in response to a stimulus. A true reflex is a behavior which is mediated via the reflex arc; this does not apply to casual uses of the term 'reflex'.-See also:...
es and what are referred to as pathological reflexes (reflexes that may be normal in an infant but are abnormal in an adult) including Hoffmann's sign
Hoffmann's sign
In medicine, Hoffmann's sign, named after the German physiologist, Paul Hoffmann is a distal sign of nerve regeneration.-Definition:...
in the fingers and hand and the Babinski sign
Plantar reflex
The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In normal adults the plantar reflex causes a downward response of the hallux...
. Signs of lower motor neuron
Lower motor neuron
Lower motor neurons are the motor neurons connecting the brainstem and spinal cord to muscle fibers, bringing the nerve impulses from the upper motor neurons out to the muscles...
e damage include weakness, fasciculations (twitching muscles) and muscle atrophy.
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
Multifocal motor neuropathy
Multifocal motor neuropathy is a progressively worsening condition where muscles in the extremities gradually weaken. The disorder, a pure motor neuropathy syndrome, is sometimes mistaken for amyotrophic lateral sclerosis because of the similarity in the clinical picture, especially if muscle...
, Kennedy's disease
Kennedy disease
Kennedy's disease or X-linked Spinal and Bulbar Muscular Atrophy or Spinobulbar Muscular Atrophy or X-Linked Bulbo-Spinal Atrophy is an X-linked recessive, slow progressing, neurodegenerative disease associated with mutation of the androgen receptor...
, hereditary spastic paraplegia
Hereditary spastic paraplegia
Hereditary Spastic Paraplegia , also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction in the lower limbs. as a result of damage to dysfunction of the nerves...
, spinal muscular atrophy
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
and monomelic amyotrophy
Monomelic amyotrophy
Monomelic amyotrophy is an untreatable, focal, motor neuron disease that primarily affects young males in India and Japan...
. A small subset of familial MND cases occurs 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.
Effects on cognition, mood, and senses
Around a third of all MND patients experience labile affect, also known as emotional lability, pseudobulbar affect, or pathological laughter and crying. Patients with pseudobulbar palsy are particularly likely to be affected, as are patients with PLS.Cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
change occurs in between 33–50% of patients. A small proportion exhibit a form of frontotemporal dementia
Frontotemporal dementia
Frontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe...
characterised by behavioural abnormalities such as disinhibition
Disinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
, and personality changes. A small proportion of patients may also suffer from an aphasia
Aphasia
Aphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
, 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
Executive functions
The executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...
. 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
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, ~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
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
despite profound disability. This may reflect the use of coping strategies
Coping (psychology)
Coping has been defined in psychological terms by Susan Folkman and Richard Lazarus as "constantly changing cognitive and behavioral efforts to manage specific external and/or internal demands that are appraised as taxing" or "exceeding the resources of the person".Coping is thus expending...
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.
Neuroimaging and neuropathology have demonstrated extra-motor changes in the frontal lobes including the inferior frontal gyrus
Inferior frontal gyrus
The inferior frontal gyrus is a gyrus of the frontal lobe . It is labelled gyrus frontalis inferior, its Latin name...
, superior frontal gyrus
Superior frontal gyrus
The superior frontal gyrus makes up about one-third of the frontal lobe of the human brain. It is bounded laterally by the superior frontal sulcus....
, anterior cingulate cortex
Anterior cingulate cortex
The anterior cingulate cortex is the frontal part of the cingulate cortex, that resembles a "collar" form around the corpus callosum, the fibrous bundle that relays neural signals between the right and left cerebral hemispheres of the brain...
, and superior temporal gyrus
Superior temporal gyrus
The superior temporal gyrus is one of three gyri in the temporal lobe of the human brain, which is located laterally to the head, situated somewhat above the external ear.The superior temporal gyrus is bounded by:* the lateral sulcus above;...
. 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
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
or SPECT
Single photon emission computed tomography
Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera. However, it is able to provide true 3D information...
neuroimaging
Neuroimaging
Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
.
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 , , (a small number of cases), senataxin and vesicle associated protein B .
Of these, SOD1 mutations account for some 20% of familial MND cases. The SOD1 gene codes for the enzyme superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
, a free radical
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
scavenger that reduces the oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
of cells throughout the body. 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 Scandinavia
Scandinavia
Scandinavia is a cultural, historical and ethno-linguistic region in northern Europe that includes the three kingdoms of Denmark, Norway and Sweden, characterized by their common ethno-cultural heritage and language. Modern Norway and Sweden proper are situated on the Scandinavian Peninsula,...
n extraction there is a relatively benign mutation called D90A which is associated with a slow progression. In Japan, the H46R mutation is most common. G93A, the mutation used to generate the first animal model (and by far the most widely studied), is present only in a few families worldwide. 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 muscleSkeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
s 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. These nerve cells are themselves innervated by the corticospinal tract
Corticospinal tract
The corticospinal or pyramidal tract is a collection of axons that travel between the cerebral cortex of the brain and the spinal cord....
or upper motor neurones that project from the motor cortex
Motor cortex
Motor cortex is a term that describes regions of the cerebral cortex involved in the planning, control, and execution of voluntary motor functions.-Anatomy of the motor cortex :The motor cortex can be divided into four main parts:...
of the brain. 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
Spongiosis
Spongiosis is mainly intercellular edema between the keratinocytes in the epidermis, and is characteristic of eczematous dermatitis, manifested clinically by vesicles, "juicy" papules, and/or lichenification....
, the presence of astrocytes, and a number of inclusions including characteristic "skein-like" inclusions, Bunina bodies, and vacuolisation
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...
. Bunina bodies were first described in 1962; they are markers of neuronal degeneration.
The availability of mouse models has led to extensive research into the causes of SOD1
SOD1
Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases.- Function :...
-mutant linked familial ALS
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
. The most commonly used mouse model is G93A, although many others have since been generated. At the gross physiological level, the mouse models faithfully recapitulate the features of human ALS (motorneuron death, muscle atrophy, respiratory failure).
Although there is no consensus as to the exact mechanism by which mutated SOD1 causes the disease (in either mice or patients), studies based largely on mouse models suggest a role for excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
and more controversially, oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, presumably secondary to mitochondrial dysfunction. Death by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
has also been suggested.
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, electromyographyElectromyography
Electromyography is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph, to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle...
(EMG), magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI), and sometimes genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
are useful to rule out other disorders that may mimic MND. 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 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
Scope creep
Scope Creep in project management refers to uncontrolled changes or continuous growth in a project's scope. This phenomenon can occur when the scope of a project is not properly defined, documented, or controlled...
, and some have questioned the appropriateness of the criteria in a clinical setting.
Treatment
Currently there is no cure for ALS. The only drug that affects the course of the disease is riluzoleRiluzole
Riluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....
. 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 therapist
Occupational therapist
An occupational therapist is trained in the practice of occupational therapy. The role of an occupational therapist is to work with a client to help them achieve a fulfilled and satisfied state in life through the use of "purposeful activity or interventions designed to achieve functional...
s, dieticians, respiratory therapists, social workers, palliative care specialists, specialist nurses and psychologists.
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
Stephen Hawking
Stephen William Hawking, CH, CBE, FRS, FRSA is an English theoretical physicist and cosmologist, whose scientific books and public appearances have made him an academic celebrity...
is a well-known example of a person with MND, and has lived for nearly 50 years with the disease. The television film Hawking starring Benedict Cumberbatch
Benedict Cumberbatch
Benedict Timothy Carlton Cumberbatch is an English film, television, and theatre actor. His most acclaimed roles include Stephen Hawking in the BBC drama Hawking ; William Pitt in the historical film Amazing Grace ; the protagonist Stephen Ezard in the miniseries thriller The Last Enemy ; Paul...
was made in 2004 about him and this disease.
Mortality normally results when control of the diaphragm is impaired and the ability to breathe is lost. One exception is Primary Lateral Sclerosis
Primary lateral sclerosis
Primary lateral sclerosis is a rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases...
(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.
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.There are three "hot spots" of MND in the world. One is in the Kii peninsula of Japan; another is amongst a tribal population in Papua New Guinea
Papua New Guinea
Papua New Guinea , officially the Independent State of Papua New Guinea, is a country in Oceania, occupying the eastern half of the island of New Guinea and numerous offshore islands...
. Chamorro inhabitants from the island of Guam
Guam
Guam is an organized, unincorporated territory of the United States located in the western Pacific Ocean. It is one of five U.S. territories with an established civilian government. Guam is listed as one of 16 Non-Self-Governing Territories by the Special Committee on Decolonization of the United...
in the Pacific Ocean
Oceania
Oceania is a region centered on the islands of the tropical Pacific Ocean. Conceptions of what constitutes Oceania range from the coral atolls and volcanic islands of the South Pacific to the entire insular region between Asia and the Americas, including Australasia and the Malay Archipelago...
have an increased risk of developing a form of MND known as Guamanian ALS-PD-dementia complex
Lytico-Bodig disease
Lytico-Bodig disease, sometimes spelled Lytigo-bodig is a neurological disease of uncertain aetiology that exists in the United States territory of Guam....
or "lytico bodig"
Lytico-Bodig disease
Lytico-Bodig disease, sometimes spelled Lytigo-bodig is a neurological disease of uncertain aetiology that exists in the United States territory of Guam....
, although the incidence rate has declined over the last 50 years and the average age of onset has increased. Putative theories involve neurotoxins in the traditional diet including cycad
Cycad
Cycads are seed plants typically characterized by a stout and woody trunk with a crown of large, hard and stiff, evergreen leaves. They usually have pinnate leaves. The individual plants are either all male or all female . Cycads vary in size from having a trunk that is only a few centimeters...
nut flour and bats that have eaten cycad nuts.
Etymology
Terminology regarding the motor neurone diseases can be confusing; in the UK "motor neurone disease" refers to both ALS specifically (the most common form of disease) and to the broader spectrum of motor neurone diseases including progressive muscular atrophyProgressive muscular atrophy
Progressive muscular atrophy is a rare subtype of amyotrophic lateral sclerosis or motor neurone disease which affects only the lower motor neurones. PMA is thought to account for around 4% of all ALS/MND cases...
, primary lateral sclerosis
Primary lateral sclerosis
Primary lateral sclerosis is a rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases...
, and progressive bulbar palsy
Progressive bulbar palsy
Progressive bulbar palsy is a medical condition. It belongs to a group of disorders known as motor neuron diseases . PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the degeneration of motor neurons in the cerebral cortex, spinal cord,...
. In the United States the most common terms used are ALS (both specifically for ALS and as a blanket term) or "Lou Gehrig's disease". 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 avoid confusion, the annual scientific research conference dedicated to the study of MND is called the International ALS/MND Symposium. ALS/MND refers to a specific subset of pathologically identical diseases; there are numerous other afflictions of motor neurones that are pathologically distinct from ALS/MND and have a different clinical course. Examples of other diseases of the motor neurone that should not be confused with ALS/MND include spinobulbar muscular atrophy, spinal muscular atrophy
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
, Charcot-Marie-Tooth disease
Charcot-Marie-Tooth disease
Charcot–Marie–Tooth disease- , known also as Morbus Charcot-Marie-Tooth, Charcot-Marie-Tooth neuropathy, hereditary motor and sensory neuropathy , hereditary sensorimotor neuropathy , or peroneal muscular atrophy, is an inherited disorder of nerves that takes different forms...
, and many others.
Amyotrophic comes from the Greek language
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
: A- means "no", myo refers to "muscle", and trophic means "nourishment"; amyotrophic therefore means "no muscle nourishment," which describes the characteristic atrophication
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
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
Sclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
") in the region.
History
Although other 19th century neurologists previously described the disease, a FrenchFrance
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
neurologist
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
, Jean-Martin Charcot
Jean-Martin Charcot
Jean-Martin Charcot was a French neurologist and professor of anatomical pathology. He is known as "the founder of modern neurology" and is "associated with at least 15 medical eponyms", including Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis...
, first suggested grouping together disparate conditions that affect the lateral horn
Lateral horn
In the thoracic region, the postero-lateral part of the anterior column projects lateralward as a triangular field, which is named the lateral column .-Nerve Cells in the Lateral Column:...
of the spinal cord in 1869.
See also
:Category:People with motor neurone disease:Category:Deaths from motor neurone disease
- Kennedy's disease
- Monomelic amyotrophyMonomelic amyotrophyMonomelic amyotrophy is an untreatable, focal, motor neuron disease that primarily affects young males in India and Japan...
- Primary lateral sclerosisPrimary lateral sclerosisPrimary lateral sclerosis is a rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases...
- Progressive muscular atrophyProgressive muscular atrophyProgressive muscular atrophy is a rare subtype of amyotrophic lateral sclerosis or motor neurone disease which affects only the lower motor neurones. PMA is thought to account for around 4% of all ALS/MND cases...
- RiluzoleRiluzoleRiluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....