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 including speaking, walking, breathing, swallowing and general movement of the body.
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. Signs of lower motor neurone damage include weakness and muscle atrophy.
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. 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.
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.
|Type||UMN degeneration||LMN degeneration|
|Progressive bulbar palsy||no||yes - bulbar region|
|Pseudobulbar palsy||yes - bulbar region||no|
The "bulbar region" in the table above refers to the mouth, face, and throat.
It it possible that Transcranial Magnetic Stimulation can be used to diagnose MND.
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.
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.
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 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. 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.
There is a role in excitotoxicity and oxidative stress, presumably secondary to mitochondrial dysfunction. In animal models, death by apoptosis has also been identified.
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.
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.
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 Association football (soccer). 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. 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.
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/).