Once the diagnosis has been established, the patient should formally meet with an experienced doctor who has been involved in the care, to discuss the outcome of the investigations. Specific techniques should be used as outlined in Table 8.4, including the provision of a quiet space and adequate time to discuss the diagnosis. The patient should be accompanied by a close friend or family member. The level of information the patient has about the disease should be explored. Some patients have specific concerns including a fear of choking to death; reassurance can be provided about these and other anxieties relating to the progress of the disease. Despite the inevitable decline associated with the condition, it is important to convey hope when disclosing the diagnosis. Positive prognostic aspects of the disease can be emphasized, and the likelihood of new therapeutics in the form of future clinical trials discussed. Patients should be provided with a follow up appointment within 2–4 weeks of diagnosis. Some patients seek a second opinion. This should be facilitated.

The incidence of ALS/MND in Europe is approximately 2 per 100,000 and the overall lifetime risk is approximately 1:350. In populations of non-European or mixed ethnicity, current evidence suggests that the frequency of ALS is lower. While the reasons for this difference remain unclear, preliminary evidence suggests that genetic admixture may be protective. Careful evaluation of populations over a long period of time has indicated that the adjusted age-specific incidence of the disease is not increasing.

ALS is more common in males than females by a ratio of 1.2–1.5 to 1. This disparity is mostly due to the increased frequency of spinal onset alS in men. In contrast to Parkinson’s disease and Alzheimer’s disease, the risk of developing ALS peaks between the ages of 50–75, and declines thereafter. This suggests that ALS is not a disease of ageing, but a disease for which age is one of a number of risk factors.

As ALS is a rare disease, environmental factors that confer increased risk have been difficult to identify. Case controlled studies seeking to establish exposure risks are often inadequately powered and confounded by methodological errors. High incidences of ALS in Guam and the Kii Penninsula in Japan have been associated with cyanobacterial neurotoxins including BMAA, although definitive evidence in this regard is lacking, and more recent evidence from Kii also suggests the presence of a genetic founder effect. Clustering of ALS has been identified in certain occupations including Italian soccer players. The factors that lead to this apparent increased risk remain to be determined. Other environmental factors that have been associated with ALS have included smoking, exposure to pesticides and organic toxins, and electromagnetic radiation. With the exception of smoking, definitive evidence of risk remains to be established and will require large unbiased population-based case controlled studies for confirmation.

ALS is frequently described as being either familial or sporadic. A total of 22 genes and loci of major effect have been identified, (Table 8.5) and the majority of these are autosomal dominant in inheritance pattern. Of these, the hexnucleotide repeat expansion in C9orf72 accounts for over 50 % of known familial ALS in populations of European extraction, and up to 8 % of apparently sporadic disease. This variant is rare in other populations. The C9orf72 repeat expansion is associated with a distinct ALS phenotype with prominent cognitive and behavioural impairment, and with higher rates of neuropsychiatric conditions in kindreds of those affected. The pathogenesis of C9orf72 repeat related disease has not been established, but is thought to relate in part to aberrant RNA transcription with accumulation of sense and antisense RNA foci, coupled with proteins expressed by repeat-associated non-ATG (RAN) translation. Sense and anti-sense RNAs are thought to accumulate in nuclear foci, and RAN proteins are thought to form cytoplasmic aggregates in neurons.

Mutations in superoxide dismuatase (SOD1) account for up to 15 % of familial ALS, and up to 5 % of apparently sporadic disease in some populations. However as is the case for the C9orf72 variant, mutations in SOD1 are population specific, occurring with low frequency in familial and sporadic disease in The Netherlands and Ireland, and with higher frequency in Italy and the USA.

Mutations in two different DNA/RNA binding proteins, TDP-43 and FUS/TLS account for a further 10–15 % of familial ALS in some populations. Both TDP-43 and FUS code for proteins involved in gene regulation including transcription, RNA splicing, RNA transport, and translation, and in the regulation and processing of small regulatory RNAS (microRNAs). Of the currently known genes, only C9orf-72 SOD1, TDP-43, and FUS mutations occur with sufficiently high frequency in European populations to warrant diagnostic testing. The remainder have been described in small numbers of kindreds are often associated with unusual phenotypes.

While there is currently no accepted definition of familial ALS, up to 85 % percent of people diagnosed with ALS have no family history and are classified as having sporadic disease. The frequency of familial disease can be under-estimated by the late onset of disease phenotype, incomplete penetrance, and small kindreds. Moreover, family aggregation studies have identified an overlap between ALS, FTD and other neurodegenerative and neuropsychiatric conditions. While a proportion of these families are associated with the repeat expansion on C90rf72, some repeat-negative kindreds also exhibit prominent aggregation of neuropsychiatric disease, suggesting the presence of other gene variants with phenotypic pleotropy.

Population-based studies of “at risk” genes that increase disease susceptibility suggest that up to 17 % of those with ALS carry an “at risk” variant, although the relative contribution of each identified gene rarely exceeds an odds ratio of 2.0, and in most cases the mechanism by which the risk is conferred remains to be elucidated.

Genome-wide association studies (GWAS) in ALS have been relatively disappointing to date, primarily because of small sample size (5000 patients, 15,000 controls). Increasing the sample size to over 15,000 patients have shown to increase the number of ‘hits’ substantially in other diseases such as Parkinson’s disease, Alzheimer’s disease, Multiple Sclerosis and Schizophrenia. A combined GWAS for ALS has included over 16,000 patients and 25,000 controls is being analysed. However increased international collaboration coupled with the combination of detailed clinical phenotyping with next generation whole genome sequencing and bioinformatics technology is likely to provide a wealth of new information about ALS pathophysiology (www.​ProjectMine.​com). This in turn will provide exciting new avenues for developments in disease therapeutics.

Up to 13 % of patients with ALS have fronto-temporal dementia (FTD), and up to 30 % of those with FTD have neurophysiologic evidence of anterior horn cell degeneration (see Chap.​ 6). A smaller percentage (2–5 %) of patients with ALS have evidence of other forms of dementia including features of Alzheimer’s disease. Patients with ALS are more likely to have a family history of neurodegenerative disease – this is driven in part by the C9orf72 repeat expansion. Occasional patients with extrapyramidal syndromes and anterior horn cell degeneration have been reported and a small minority of ALS patients are ataxic. Rarely, Huntington’s disease can present with amytrophy (see Chap.​ 8).

Formal diagnosis of ALS is based upon clinical criteria that include the presence of upper motor neuron (UMN) and lower motor neuron (LMN) signs, progression of disease, and the absence of an alternative explanation. There is no single diagnostic test that can confirm or entirely exclude the diagnosis of motor neuron disease.

The El Escorial criteria were developed in 1990 by the World Federation of Neurology (WFN) for research and clinical trial purposes. These guidelines were subsequently revised in Airlie House in April 1998 (Table 8.6).