Amyotrophic Lateral Sclerosis (ALS) 

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. ALS was first described in 1869 by the French neurologist Jean-Martin Charcot and hence is also known as Charcot disease; however, it gained popular recognition and its best-known eponym after the baseball player Lou Gehrig announced his diagnosis with the disease in 1939.^{[1, 2, 3, 4, 5]} ALS is also known as motor neurone disease (MND).

The cause of ALS is unknown, although 5-10% of cases are familial. Some research is showing that ALS may share common biological mechanisms with Alzheimer disease, Parkinson disease, and other neurodegenerative diseases. Collaborative research is increasing.^[6]

In its classic form, ALS affects motor neurons at 2 or more levels supplying multiple regions of the body. It affects lower motor neurons that reside in the anterior horn of the spinal cord and in the brain stem; corticospinal upper motor neurons that reside in the precentral gyrus; and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons.^[7]

Loss of lower motor neurons leads to progressive muscle weakness and wasting (atrophy). Loss of corticospinal upper motor neurons may produce stiffness (spasticity), abnormally active reflexes, and pathological reflexes.

Loss of prefrontal neurons may result in special forms of cognitive impairment that include, most commonly, executive dysfunction but may also include an altered awareness of social implications of an individual’s circumstances and, consequently, maladaptive social behaviors.^[8] In its fully expressed forms, the prefrontal dysfunction meets established criteria for frontotemporal dementia.^{[9, 10]}

The term classic amyotrophic lateral sclerosis is reserved for the form of disease that involves upper and lower motor neurons. The classic form of sporadic ALS usually starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body. Ventilatory failure results in death, on average, 3 years after the onset of focal weakness.

If only lower motor neurons are involved, the disease is called progressive muscular atrophy (PMA). Although many patients with PMA have a course indistinguishable from that of classic ALS, others have a course that may be longer.

When only upper motor neurons are involved, the disease is called primary lateral sclerosis (PLS). The course of PLS differs from that of ALS and is usually measured in decades. Rarely, the disease is restricted to bulbar muscles, in which case it is called progressive bulbar palsy (PBP). In most patients who present with initial involvement of bulbar muscles, the disease evolves to classic ALS.

Worldwide, ALS occurs sporadically in 90-95% of cases and with Mendelian patterns of heredity (familial ALS) in 5-10% of cases. Most familial ALS is inherited in an autosomal dominant pattern^[7] (see Etiology.)

The diagnosis of ALS is primarily clinical. Electrodiagnostic testing contributes to the diagnostic accuracy (see Clinical and Workup).

ALS is a fatal disease, with median survival of 3-5 years (see Prognosis). Aspiration pneumonia and medical complications of immobility contribute to morbidity in patients with ALS. Although ALS is incurable, there are treatments that can prolong meaningful quality of life (see Treatment); therefore, diagnosis is important to patients and families.

ALS is named for its underlying pathophysiology. Amyotrophy refers to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. Lateral sclerosis refers to hardening of the anterior and lateral columns of the spinal cord as motor neurons in these areas degenerate and are replaced by fibrous astrocytes (gliosis).

Current research into the mechanisms resulting in sporadic and familial types of ALS has focused on excitotoxicity. This may occur secondary to overactivation of glutamate receptors, autoimmunity to calcium ion channels, oxidative stress linked to free radical formation, or even cytoskeletal abnormalities such as intracellular accumulation of neurofilaments. Apoptosis has emerged as a significant pathogenic factor, and evidence suggests that insufficient vascular endothelial growth factor may also be a risk factor for ALS in humans.

However, no direct mechanism has been identified and most researchers and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of ALS.^{[11, 12]} Why the disease is limited to the motor neurons and corticospinal tracts is still unknown, as is the reason ALS starts focally and then spreads within body regions.

Axonal degeneration

Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon.

As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin, termed myelin ovoids. Ovoids then are phagocytized by macrophages recruited into the area to clean up debris.

This type of axonal degeneration can be seen in the brain on biopsy as atrophy and pallor of myelinated motor axons in the corticospinal tracts. In cases where the disease has been active for a long time, atrophy of the primary motor and premotor cortex may be seen as well. On biopsy of the spinal cord, degeneration of the myelinated motor axons with associated atrophy of the anterior motor roots of the spinal cord can be observed.

Wallerian degeneration also occurs peripherally, and collateral branches of surviving axons in the surrounding area can be seen attempting to reinnervate denervated muscle fibers. On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

In typical ALS, certain motor neurons are spared. In the brainstem, these include the oculomotor, trochlear, and abducens nerves. In the spinal cord, the posterior columns, spinocerebellar tracts, nucleus of Onuf (controls bowel and bladder function), and the Clarke column generally are spared, though the Clarke column can be affected in the familial form of the disease.

Derangements of RNA metabolism

In 2006, ubiquinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia.^{[13, 14]} TDP-43 is an RNA processing protein that is normally found mainly in the nucleus.

Shortly after their identification, TDP-43 positive inclusions were identified in patients with non-SOD1 familial ALS^{[15, 16]} , and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS^{[17, 18, 19, 20, 21, 22]} .

Mutations in the TDP-43 gene account for 5% of patients with familial ALS. TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex^[23] and in patients with familial British dementia.^[24] A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy.^[25]

In February of 2009, 2 groups^{[26, 27]} reported that mutations in the gene for another RNA processing protein, fused in sarcoma/translated in liposarcoma (FUS/TLS), which is located on chromosome 16, cause ALS-6, an autosomal dominant form of ALS. Patients with the FUS/TLS mutations have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Usually, FUS/TLS is concentrated in the nucleus.

Mutations in FUS/TLS account for 4% of patients with FALS. These observations have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS.

Other pathways

Prior to the recent observations implicating TDP-43 and FUS/TLS pathology in ALS, much of the information had been derived from studies in transgenic mice carrying the human SOD1 mutation.^[28] Mutant SOD1 exerts its effect through “gain of function” (ie, toxicity that is not related to loss of its natural activity).

Oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, growth factor expression, glial cell pathology, and glutamate excitotoxicity may all mediate the pathways, causing cell death in ALS.^[28]

Inferences from animal models, including transgenic models of familial disease, to sporadic human disease are tenuous, at best. However, recognition of the role of glutamate excitotoxicity in sporadic disease and in animal models paved the way to the testing and approval of riluzole, the only treatment that has been shown to ameliorate the course of sporadic ALS, extending life by 2-3 months.^{[29, 30]}

Disease onset

In contrast to these advances in understanding the pathophysiology of ALS, the mechanisms that lead to disease onset, which may be distinguished by the term pathogenesis, remain unknown.

Assuming that the abnormal gene or gene product plays a role in triggering disease onset in familial ALS and may have a role in disease propagation is reasonable. However, having an abnormal gene is neither a necessary nor a sufficient condition for developing ALS, since not all familial gene carriers develop the disease and having normal copies of these genes does not prevent development of sporadic ALS.

Additional factors must be postulated to intervene between birth and disease onset even in patients who develop familial ALS, because the disease does not appear to start at birth. ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiological cascades that share the common consequence of causing preferential progressive loss of motor neurons.

Making the distinction between pathogenesis and pathophysiology matters because the mechanisms underlying each of these stages are probably different, and therefore, interfering with those mechanisms likely requires different approaches. Prevention of ALS requires modifying or removing factors that are part of disease pathogenesis. A precondition is identifying probable risk factors for ALS.^[31]

Mechanism-specific treatments directed at the processes that cause the disease to evolve after it has expressed itself sufficiently to be diagnosed may, at best, have an ameliorative effect. Treatments that halt the spread of the disease may be more effective than those that try to salvage affected motor neurons. Adaptive treatments directed at the clinical manifestations of the disease are the mainstay of contemporary treatment of ALS. Acquired nucleic acid changes may trigger disease onset in sporadic ALS.^[32]

Loss of motor neurons bridges disease pathophysiology and its clinical expression. When advanced, this loss results in the characteristic picture seen in a cross-section of the spinal cord. At the level of the muscle, loss of discrete lower motor neurons results in loss of innervation of individual motor units.

Early in the disease, surviving nerve fibers establish connections and reinnervate motor units that have lost their connection to axons that have died; as a result, larger motor units are formed. These large motor units manifest in histological stains as type grouping (see the image below). They also have special characteristics on electromyographic testing. Later in the disease, when the motor neurons that supply the large motor units die, group atrophy ensues.

As long as reinnervation can keep up with denervation, clinical weakness may not be detectable. However, as the motor units grow larger and as their number starts to decrease, the earliest consequence is that affected muscle may fatigue faster than muscle with normal motor units; consequently, one of the first symptoms of ALS may be fatigability of function in the region of onset (for example, “his speech got muffled toward the end of his sermons”).

As the number of motor units innervatng a muscle decreases further, reinnervation is not able to keep up with denervation, permanent weakness develops and progresses, and the affected muscles gradually shrivel (atrophy). In general, loss of cortical neurons may result also in weakness, but more commonly in ALS it results in other upper motor neuron signs.

Risk factors and triggering of onset

Acquired nucleic acid changes may trigger disease onset in sporadic ALS.^[32] This hypothesis relies on the observation that smoking is the only established risk factor for sporadic ALS^[33] and provides a mechanism by which smoking might cause the disease, namely, by induction of changes in nucleic acids. It follows a similar logic that suggests that the alkylating components in the cycad are responsible for delayed onset of Western pacific ALS/PDC.^{[34, 35]}

In support of this hypothesis, Ravits et al showed the simultaneous initial involvement of cortical and spinal motor neurons responsible for the same body part in ALS and the independent spread of disease at spinal and cortical levels.^[36] These observations have been replicated.^[37] They establish an irrefutable role for corticospinal neurons in the early spread of ALS and provide an observational foundation for postulating the existence of one or more "agents of spread."^[38]

The affirmation of spread substantiates the concept of a biological focal onset to ALS. This in turn lends credibility to the concept of a focal trigger to ALS onset that generates the production of one or more agents of spread.^[32]

Under this hypothesis, disease phenotype in each patient depends on the site of onset and the relative affinity of the specific agent of spread in that patient to motor neurons at the different hierarchical levels of the motor system (prefrontal, corticospinal, spinal/bulbar).^[38] The concept of preferential affinity of the agent of spread may apply even to specific motor neurons within a given hierarchy, resulting, for example, in the special predominantly lower motor neuron phenotypes (flail arm syndrome, flail leg syndrome).^[39]

Most of the biochemical changes found in lower and upper motor neurons of diseased patients are probably downstream from those that initiate the disease and cause its spread. Some of these changes may represent the processes by which the motor neurons die, but others may reflect the efforts of the motor neurons to survive, by compensating for the primary pathological processes driving progression of ALS.

The specific cause of ALS is unknown. Approximately 5-10% of cases are familial; the remainder are sporadic.

Familial cases

Approximately 5-10% of ALS cases are familial with a Mendelian pattern of inheritance.^[40] The disease is transmitted in an autosomal dominant fashion in most cases and is rarely autosomal recessive.

Mean age at onset is 10-20 years younger in patients with familial ALS than in patients with sporadic disease, and variability between families is greater than variability within families.^[7] While some cases of FALS are indistinguishable from sporadic disease, others have unique phenotypes.^[40]

Specific gene mutations have been described in familial ALS.^[4] (See Table 1, below.) The causative nature of the gene mutations is still unknown.

Table 1. Familial Forms of ALS (Open Table in a new window)

About 10-20% of familial ALS cases are due to a mutation in the copper/zinc superoxide dismutase 1 (SOD1) gene. SOD1-ALS is a lower motor neuron form of the disease.^[41]

More than 140 allelic variations have been seen in the SOD1 mutants, and they determine the mean age of onset and rate of disease progression. The most common SOD1 mutation in the United States is the A4V mutation, accounting for 50% of SOD1 patients. It causes rapidly progressive lower motor disease with mean survival of 1 year. The North American SOD1 A4V mutation descended from 2 founders (Amerindian and European) 400-500 years ago.^[42]

Not all individuals with an SOD1 mutation develop ALS. SOD1 ALS has been shown to be a gain-of-function disease; knockout mice who are depleted of SOD1 do not develop ALS, and transgenic mice with 1 mutated gene and 2 normal genes have worse disease than those with 1 normal and 1 mutated gene. Misfolding and precipitation of the abnormal (and normal) SOD1 proteins are thought to be part of the pathophysiology of SOD1 ALS, but why the disease begins when it does, and how it causes the lower motor neuron ALS phenotype is not clear.

Recent work in animal models suggests that silencing from birth the expression of mutant SOD1 using silencing RNA molecules (siRNA) may prevent disease onset in transgenic mouse models.^[43] This is an exciting direction for research in humans with the SOD1 mutations, but major barriers need to be overcome first, including demonstrating that this approach is effective in halting the disease after its clinical onset. Additional forms of familial ALS are summarized elsewhere.^[40]

Abnormal genes resulting in abnormalities in proteins that regulate RNA metabolism have been discovered in patients with autosomal dominant familial ALS. Mutations in the ALS1 gene, which codes for TDP-43, have been found in 5% of patients with familial ALS.^{[15, 16, 17, 18, 19, 20, 21, 22]} Mutations in the ALS6 (fused in sarcoma/translated in liposarcoma [FUS/TLS]) gene are found in 3-4% of familial ALS cases.^[40]

The mechanism by which these mutations cause ALS is distinct from that which takes place in the SOD1 mutants. Although ubiquinated pathological TDP-43 aggregates have been found in motor neuron cytoplasm of sporadic ALS, they are not specific for this disease and have been found in affected nonmotor cells in patients with Guamanian parkinsonism-dementia complex^[23] , British familial dementia^[24] , and Alzheimer disease.^[44]

Thus, formation of pathological TDP-43 and its ubiquination may prove to be a mechanism of cell death that is not specific to ALS and is triggered by upstream processes, causing clinical pathology that depends on the cells affected. Conversely, TDP-43 deposition may prove to be a nonspecific defense mechanism, trying unsuccessfully to mitigate the action of the true instigators of cell death in a spectrum of neurodegenerative diseases, or it may be an epiphenomenon common to many forms of neurodegenerative diseases.

Finland has one of the highest rates of ALS in the world. A recent population-based study there found a mutation on chromosome 9p21 as a major cause of familial ALS in that country. The mutation was found in 44 of 93 patients with familial ALS, a number larger than those who had the known D90A SOD1 mutation (27 of 93 patients).^[45] If these findings are generalizable to all Finland, this leaves only 24% of Finnish familial ALS cases where the genetic cause is not known.

The high presence (19%) of a familial ALS gene in Finnish patients with sporadic ALS may be attributed to a relatively closed population pool.^[45]

Another study from FInland suggests the existence of clusters of cases.^[46] This genome-wide association study showed peaks corresponding (1) to the site corresponding to the D90A SOD1 allele (a known cause of familial ALS in Finland) and (2) to a region of chromosome 9 previously identified in linkage studies of patients with familial ALS.

A second, 7-country genome-wide association study also identified the same 2 single-nucleotide polymorphisms on chromosome 9p21.2 seen in the Finnish study in patients with sporadic ALS. Those authors comment also that the region had been associated previously with some forms of familial frontotemporal dementia.

The penetrance of the 9p21 associated risk allele rs3849942 in sporadic ALS in the 7-country study was only slightly higher than the background risk of ALS. There is discussion regarding evidence suggesting a founder effect for the 9p21 mutation in Finland, but not in the sporadic 7-country series.^[47] These findings suggest that continued research on the area of chromosome 9p21.2 is needed.

One possible explanation for these research findings is that the culprit is not an exon (an area of DNA that codes for a protein), but rather a variation in an intron (an area of DNA that might influence the rate of transcription of an exon) or in an area of DNA coding for a microRNA or a nonannotated gene. The failure to find other peaks in both studies is consistent with the failure of previous studies to find reproducible peaks and suggests that most sporadic ALS is mediated by acquired, rather than genetic, causes.

Sporadic amyotrophic lateral sclerosis

No single cause for sporadic amyotrophic lateral sclerosis explains its entire pathology; indeed, there may be multiple causes resulting in phenotypic similarity. While ALS is ultimately a diffuse disease, onset is often focal and asymmetric.

The most widely accepted hypothesis regarding the cause of sporadic ALS posits that interactions between genetic, environmental, and age-dependent risk factors trigger disease onset. (See the image below.) With the exception of smoking,^[33] no specific genetic or environmental risk factors for sporadic ALS have been identified. Evidence supports the paraoxonase gene cluster as a possible susceptibility gene (PON 1, 2, and 3).^[48]

An increased frequency of non-ALS neurodegenerative diseases has been reported in relatives of patients with ALS. This observation supports the hypothesis that genetic risk factors may influence disease initiation in sporadic ALS with a non-Mendelian pattern of inheritance.^{[49, 50]}

However, a methodologically superior population-based study in incident cases^[51] did not confirm excess non-ALS neurodegenerative disease in relatives of patients with ALS. Genome-wide analyses looking for allelic variations have produced some loci of interest, but different series have tended to identify different loci.^{[52, 53]}

The lack of reproducibility suggests that non-Mendelian patterns of inheritance may have a more limited role than had been expected in triggering sporadic ALS, possibly increasing the lifetime risk by no more than 50%.

Environmental risk factors

Cigarette smoking is the only exogenous risk factor that may be considered an established risk factor for ALS^[33] (level A conclusion, based on 3 Class II studies^{[54, 55, 56]} and 1 Class III study^[57] ). Some aspects of the findings suggest that smoking may be implicated directly in causing the disease. Active smokers have approximately double the risk of developing ALS compared with never smokers. Former smokers have an intermediate risk.

Identifying smoking as an established risk factor for ALS has the following 4 major implications:

• First, the findings provide a link between the environment and the occurrence of sporadic ALS; no link has previously been identified with this level of certainty
• Second, since smoking has no redeeming features, avoidance of smoking may reduce the future occurrence of ALS
• Third, future studies of risk factors in ALS need to be designed to precisely quantify active and passive smoking, to ensure that other putative risk factors confer a risk that is independent of their association with smoking
• Fourth, since some of the mechanisms by which smoking causes other diseases in humans are understood fairly well, recognizing its role in the occurrence of ALS may help pinpoint the biological processes that initiate the disease

Focusing on processes at the initiation of sporadic ALS and close to its initiation, accounting for its early spread within the motor system, may provide new avenues to treatments to stop its progression. This may augment the current focus on processes that occur relatively late in the course of the disease and cause the death of motor neurons directly.

No other risk factor has attained this level of certainty regarding its association with ALS. Trauma, physical activity, residence in rural areas, and alcohol consumption are probably not risk factors for ALS.^[31]

Putative risk factors that have gained recent attention include service in the US military during World War II, the Korean War, and Vietnam,^[58] and deployment to the Persian Gulf in the 1991 Persian Gulf War.^[59] However, close scrutiny generates doubts about the quality of the evidence supporting the role of these factors in triggering ALS.^{[60, 61, 59, 62, 63]}

A possible increased risk of ALS in Italian soccer players has also been reported.^{[64, 65]} In fact, this may have been due to underestimation of the expected number of cases of ALS, which led to the appearance that the observed number of cases was excessive.^{[66, 67, 68] [69, 70]} .

However, the appearance of preferential presentation of cases with bulbar onset in this population^{[64, 65, 71]} merits attention, even if no increased incidence is shown overall. In that regard, a report of an upper motor neuron phenotype in young Italian male patients^[72] is of great interest.

Other putative exogenous risk factors, such as postmenopausal hormone use^{[31, 73]} , also have not risen to the level of probable.

Western Pacific amyotrophic lateral sclerosis

Most of the research on Western Pacific ALS has focused on Guam. Ingestion of food products derived from the false sago palm Cycas micronesica (recently separated from Cycas Circinalis) was proposed by Marjorie Whiting as the process implicated in predisposing to the development of this form of ALS.^[74] An epidemiologic study in Guam appears to have confirmed that hypothesis^[75] ; its conclusions have been challenged,^[76] but the challenges themselves have been questioned.^[77]

The nature of the precise toxic component of cycad responsible for delayed-onset neurodegenerative disease has also been a matter of intense debate. One hypothesis is that excitotoxic components of cycad do not exert an effect until many years after they have been ingested.^{[78, 79]} An alternative hypothesis is that alkylating components induce changes in nucleic acids^{[34, 35]} that increase the likelihood that subsequent, additional, age-dependent nucleic acid changes trigger disease onset in Guamanian ALS/PDC.

United States statistics

Approximately 5,600 people in the United States are diagnosed with ALS each year. The annual incidence is 2-3 per 100,000 population; this is 5 times higher than that of Huntington disease and about equal to that of multiple sclerosis. It is estimated that as many as 16,000 Americans may have the disease at any given time.

The lifetime risk for developing ALS for individuals aged 18 years has been estimated to be 1 in 350 for men and 1 in 420 for women.^[66] These estimates are close to those reported from 2 European databases, using different methods.^{[80, 81]}

International statistics

Age-adjusted European incidence data are similar to those in the US population of European descent.^[80] Most variability between countries has been attributed to different age composition or differences in case finding. However, recent data suggest that there may be ethnic variability in disease incidence^{[82, 83]} that may not be explained entirely by differences in case finding, with lower incidence in nonwhites or individuals of mixed ethnicity. This area merits further study.

Finland has one of the highest rates of ALS in the world. A recent population-based study there found a mutation on chromosome 9p21 as a major cause of familial ALS in that country.^[45]

Investigators identified a population in Guam in the mid 20th century that had an annual incidence of ALS (often in association with Parkinsonism and dementia) as high as 70 cases per 100,000. The incidence has since decreased to 7 cases per 100,000, but this is still higher than other places in the world.

The reason for the higher rate in Guam has been hypothesized to be from a toxin in the cycad nut. The cycad nut had to be subjected to an elaborate preparation process to rid it of toxins, after which it was used as a substrate for flour; presumably, some toxic factor remained, affecting preferentially those most likely to consume products made from cycad flour.^[77] In addition, the cycad nut was consumed by the flying fox (a bat), which used to be part of the Charmorro peoples' diet. Toxins from the cycad nut may have been concentrated (“bioamplified”) in the bat and delivered to the human consumer. The consumption of the flying fox was higher in the mid 20th century than it is now.^[76] Most flying foxes consumed in Guam currently are imported.

Racial differences in incidence

In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.^[82] Uncertainty surrounds this finding, as it may be an artifact of reduced case-finding in non-whites. More convincing evidence for racial differences has come from an epidemiological study in Cuba.

Small population clusters have been identified that have higher rates of ALS. The Chamorro people of Guam and Marianas Island, the Kii peninsula of Honshu Island, and the Auyu and Jakai people of southwest New Guinea, have a higher incidence of ALS than other regions.^[4]

Sexual and age-related differences in incidence

The incidence of ALS is higher in men than in women, with an overall male-to-female ratio of 1.5-2:1.^[7] After the age of 65-70 years, the gender incidence is equal.

Onset of ALS may occur from the teenage years to the late 80s, but peak age at onset occurs from 55-75 years. Mean age of onset of sporadic ALS is 65 years; mean age of onset of familial ALS is 46 years.

ALS is a fatal disease. Median survival is 3 years from clinical onset of weakness. However, longer survival is not rare. About 15% of patients with ALS live 5 years after diagnosis, and about 5% survive for more than 10 years. Long-term survival is associated with a younger age at onset, being male, and limb rather than bulbar symptom onset. Rare reports of spontaneous remission exist.^[84]

In familial ALS that results from an alanine-to-valine mutation in codon 4 of the Cu, Zn superoxide dismutase 1 (SOD1) gene (A4V mutation), survival is on average 12 months from disease onset.^[42]

Regionally limited forms of motor neuron disease, PMA, PBP, and PLS, that do not convert to classic ALS have a much slower rate of progression and survival is measured in decades.

The most effective predictor of survival is the rate of observed disease progression. Estimates derived as a ratio, in which the numerator is loss according to various measures and the denominator is time elapsed from disease onset to the time of measurement, may provide more individualized prognostic information.

Patients the author has surveyed have indicated ambivalence about being offered individualized information early in the course of the disease (when it may matter most).^[85] The author does not offer patients individualized prognostic information when he sees them first. When patients do request it, he asks them to consider the possible implications of the answers they might receive and then they can ask him again at a subsequent visit.

The following education resources are available to patients:

• ALS Association, Living With ALS Manuals
• Muscular Dystrophy Association: MDA ALS Caregiver’s Guide
• ALS 1996 and Beyond: New Hopes and Challenges. A Manual for Patients, Families and Friends (Fourth edition, 2007)^[86]
• ALS newsletter of the Muscular Dystrophy Association

Informational web sites include the following:

• Muscular Dystrophy Association
• ALS Association of America
• National Institute of Neurological Disorders and Stroke (NINDS)

For patient education information, see the Brain and Nervous System Center, as well as Amyotrophic Lateral Sclerosis (Lou Gehrig Disease) and Advance Directives.