instrument survey administered as a clinical interview or self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). the alsfrs-r is the most frequently used outcome measure in clinical trials and is used by doctors to track disease progression. though the degree of variability is high and a small percentage of people have a much slower disorder, on average, people with als lose about 1 alsfrs-r point per month. brief periods of stabilization ("plateaus") and even small reversals in alsfrs-r score are not uncommon, due to the fact the tool is subjective, can be affected by medication, and different forms of compensation for changes in function. however it is rare (<1%) for these improvements to be large (i.e. greater than 4 alsfrs-r points) or sustained (i.e. greater than 12 months). a survey-based study among clinicians showed that they rated a 20% change in the slope of the alsfrs-r as being clinically meaningful, which is the most common threshold used to determine whether a new treatment is working in clinical trials. late stage disease management difficulties with chewing and swallowing make eating very difficult and increase the risk of choking or of aspirating food into the lungs. in later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. as the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung function such as vital capacity and inspiratory pressure diminish. in respiratory-onset als, this may occur before significant limb weakness is apparent. individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, known as locked-in syndrome. bladder and bowel function is usually spared, meaning urinary and fecal incontinence is uncommon, although trouble getting to the toilet can lead to difficulties. the extraocular muscles responsible for eye movement are usually spared, meaning that the use of eye tracking technology to support augmentative communication is often feasible, albeit slow, and needs may change over time. prognosis, staging, and survival although respiratory support using non-invasive ventilation can ease problems with breathing and prolong survival, it does not affect the progression of als. most people with als die between two and four years after the diagnosis. around half of people with als die within 30 months of their symptoms beginning, and about 20% of people with als live between five and ten years after symptoms begin. about 10% of people with als survive for 10 years or longer after onset. the most common cause of death among people with als is respiratory failure, often accelerated by pneumonia. most als patients die at home after a period of worsening difficulty breathing, a decline in their nutritional status, or a rapid worsening of symptoms. sudden death or acute respiratory distress are uncommon. access to palliative care is recommended from an early stage to explore options, ensure psychosocial support for the patient and caregivers, and to discuss advance healthcare directives. as with cancer staging, als has staging systems numbered between 1 and 4 that are used for research purposes in clinical trials. two very similar staging systems emerged around a similar time, the king's staging system and milano-torino (mitos) functional staging. comparison of kings and mitos als staging systems and prognosis at each stage stage 0 stage 1 stage 2 stage 3 stage 4 stage 5 king's staging system not used symptom onset, involvement of the first region 2a: diagnosis 2b: involvement of the second region involvement of the third region 4a: need for a feeding tube 4b: need for non-invasive ventilation not used median time to king's stage n/a 13.5 months 17.7 months 23.3 months 4a: 17.7 months 4b: 30.3 months n/a als-mitos staging system no loss of a functional domain loss of 1 domain loss of 2 domains loss of 3 domains loss of 4 domains death probability of death at each mitos stage 7% 26% 33% 33% 86% providing individual patients with a precise prognosis is not currently possible, though research is underway to provide statistical models on the basis of prognostic factors including age at onset, progression rate, site of onset, and presence of frontotemporal dementia. those with a bulbar onset have a worse prognosis than limb-onset als; a population-based study found that bulbar-onset als patients had a median survival of 2.0 years and a 10-year survival rate of 3%, while limb-onset als patients had a median survival of 2.6 years and a 10-year survival rate of 13%. those with respiratory-onset als had a shorter median survival of 1.4 years and 0% survival at 10 years. while astrophysicist stephen hawking lived for 55 more years following his diagnosis, his was an unusual case. cognitive and behavioral symptoms cognitive or behavioral dysfunction is present in 30–50% of individuals with als. around half of people with als will experience mild changes in cognition and behavior, and 10–15% will show signs of frontotemporal dementia (ftd). most people with als who have normal cognition at the time of diagnosis have preserved cognition throughout the course of their disease; the development of cognitive impairment in those with normal cognition at baseline is associated with a worse prognosis. repeating phrases or gestures, apathy, and loss of inhibition are frequently reported behavioral features of als. language dysfunction, executive dysfunction, and troubles with social cognition and verbal memory are the most commonly reported cognitive symptoms in als; a meta-analysis found no relationship between dysfunction and disease severity. however, cognitive and behavioral dysfunctions have been found to correlate with reduced survival in people with als and increased caregiver burden; this may be due in part to deficits in social cognition. about half the people who have als experience emotional lability, in which they cry, smile, yawn, or laugh for no reason or when they are feeling the opposite emotion to that being expressed; it is more common in those with bulbar-onset als. cause nobody knows what causes als, hence it is described as an idiopathic disease. though its exact cause is unknown, genetic and environmental factors are thought to be of roughly equal importance. the genetic factors are better understood than the environmental factors; no specific environmental factor has been definitively shown to cause als. a liability threshold model for als proposes that cellular damage accumulates over time due to genetic factors present at birth and exposure to environmental risks throughout life. als can strike at any age, but its likelihood increases with age. most people who develop als are between the ages of 40 and 70, with an average age of 55 at the time of diagnosis. als is 20% more common in men than women, but the difference will disappear after age 70. genetics and genetic testing main article: genetics of amyotrophic lateral sclerosis als can be classified as being either genetic or sporadic, depending on whether or not there is a family history of the disease or whether an als-associated genetic mutation has been identified on testing. genetic als is usually said to account for around 10% of all cases of als, though estimates range from 5% to 20%. in sporadic als, there is no family history of the disease. sporadic als and genetic als appear identical clinically and pathologically. there is considerable variation among clinicians on how to approach genetic testing in als, and only about half discuss the possibility of genetic inheritance with their patients, particularly if there is no discernible family history of the disease. historically, genetic als was most commonly referred to as "familial" als and genetic counseling and testing only offered to those with a family history, though again there was a lack of consensus in the field as to what constituted a positive finding. the strictest definition was that a person with als must have two or more first-degree relatives (children, siblings, or parents) who also have been diagnosed with als. a less strict definition was that a person with als must have at least one first-degree or second-degree relative (grandparents, grandchildren, aunts, uncles, nephews, nieces or half-siblings) who also had a diagnosis of als. as a result of population-level genetic screening, we now know about 10% of people thought to have sporadic als also have mutations in genes that are known to cause als. the lack of family history may be caused by incomplete family history, older generations dying earlier of other causes than als, genetic non-paternity, or the occurrence of de novo mutations. there have been calls in the research community to routinely counsel and test all diagnosed als patients for genetic als, particularly as there is now a licensed gene therapy (tofersen) specifically targeted to carriers of sod-1 als. more than 40 genes have been associated with genetic als, of which four account for the majority of familial cases: c9orf72 (40% of genetic cases, 7% sporadic), sod1 (12% of genetic cases, 1-2% sporadic), fus (4% of genetic cases, 1% sporadic), and tardbp (4% of genetic cases, 1% sporadic), with the remaining genes mostly accounting for fewer than 1% of genetic or sporadic cases. the genetics of familial als are better understood than the genetics of sporadic als; as of 2016, the known als genes explained about 70% of familial als and about 15% of sporadic als. overall, first-degree relatives of an individual with als have a 1% risk of developing als. als has an oligogenic mode of inheritance, meaning that mutations in two or more genes are required to cause disease. als and frontotemporal dementia (ftd) are now considered to be part of a common disease spectrum (als–ftd) because of genetic, clinical, and pathological similarities. genetically, c9orf72 repeat expansions account for about 40% of genetic als and 25% of genetic ftd. clinically, 50% of people with als have some cognitive or behavioral impairments and 5–15% have ftd, while 40% of people with ftd have some motor neuron symptoms and 12.5% have als. pathologically, abnormal aggregations of tdp-43 protein are seen in up to 97% of als patients and up to 50% of ftd patients. other genes known to cause als-ftd include c2orf72, ccnf, chmp2b, chchd10, fus, matr3, sqstm1, tardbp, tbk1, tia1, tuba4a, ubqln2, and vcp. environmental factors where no family history of the disease is present – around 90% of cases – no cause is known. possible associations for which evidence is inconclusive include military service and smoking. although studies on military history and als frequency are inconsistent, there is weak evidence for a positive correlation. various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service. a 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to lead; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-3 fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid. in a 2017 study by the united states centers for disease control and prevention analyzing u.s. deaths from 1985 to 2011, occupations correlated with als deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs. other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock. there is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, ddt, and toxaphene. head injury a 2015 review found that moderate to severe traumatic brain injury is a risk factor for als, but whether mild traumatic brain injury increases rates was unclear. a 2017 meta-analysis found an association between head injuries and als; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed als, rather than the cause of als. physical activity a number of reviews prior to 2021 found no relationship between the amount of physical activity and the risk of developing als. a 2009 review found that the evidence for physical activity as a risk factor for als was limited, conflicting, and of insufficient quality to come to a firm conclusion. a 2014 review concluded that physical activity in general is not a risk factor for als, that