Amyotrophic lateral sclerosis (ALS) is a rare progressive paralytic disorder characterised by degeneration of upper and lower motor neurons in the motor cortex, brainstem and spinal cord. ALS is the most common form of degenerative motor neuron disease [1,3,6,11].
Involvement of the upper motor neurons leads to weakness, spasticity, hyperreflexia and Babinski signs. Affection of the lower motor neurons causes weakness, muscular atrophy, fasciculations and cramps . Brain stem affection can lead to bulbar symptoms. The course of the disease varies according to the region first affected and clinical manifestation. Usually respiratory failure is the ultimate cause of death .
The worldwide incidence is approximately 1/50,000 per year and the prevalence around 1/20,000. These numbers are relatively uniform in Western countries, although foci of higher frequency have been reported in the Western Pacific . Incidence as well as prevalence increase with age . The mean age of onset for sporadic ALS is late 50s, but earlier onset may occur in familial cases. There is a slight male preponderance (male-to-female ratio of around 1.5–2:1) in sporadic cases, but an equal ratio in familial cases [1,23].
About 5–10 % of ALS cases are familial (typically autosomal-dominant inheritance), whereas the remaining 90–95 % of ALS cases occur sporadically, but these are phenotypically indistinguishable [1,6]. Over 100 genetic variants have been associated with the risk for developing ALS, but the pathogenetic mechanism(s) remain unknown . Interestingly, different gene mutations can lead to distinct phenotypes (e.g., similar age at onset, site of onset, disease duration), while other single gene mutations can lead to multiple phenotypes . Genes influencing cytoskeletal dynamics or the protein and RNA homoeostasis as well as trafficking processes play an important role in the centre of current research .
Environmental factors undoubtedly influence the complex pathogenesis, but this is incompletely understood. Environmental risk factors, which have been associated with ALS in varying levels of support include, for example, military service, different kinds of (head) trauma, smoking and exposure to heavy metals and pesticides .
There is a marked phenotypic heterogeneity between patients with respect to the onset, location and populations of involved motor neurons, resulting in diverse signs and symptoms [1,6,24]. “Classical” ALS usually begins in the limbs with focal weakness, but progresses within weeks to months to involve most muscles. Until late in the disease, neurons innervating eye muscles or the bladder are not affected [1,6]. Beside muscle weakness, muscle atrophy, fasciculations, spasticity and hyperreflexia may appear .
However, one-third of patients present with bulbar symptoms, e.g., difficulties in chewing, speaking, swallowing; drooling of saliva as well as a slurred speech [1,26]. Dysphagia can result in a symptomatic aspiration of solids, liquids and later of solid food . Furthermore, emotional lability due to involvement of frontopontine motor neurons may indicate pseudobulbar palsy, which is characterised by facial spasticity and a tendency to laugh or cry excessively in response to minor emotional stimuli .
Up to 20 % of ALS patients show progressive cognitive abnormalities marked by behavioural changes, leading to (frontotemporal) dementia .
Beside “classical” ALS, there are several atypical ALS forms such as cases with pure limb involvement and these may have longer survival. In these atypical ALS forms, the pathological burden is predominantly at one (upper or lower) motor neuron level. These forms include primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA), in which their independency or entity as a variant of ALS is under debate .
The degree of involvement of the upper and the lower motor neurons, the body regions affected, the degrees of involvement of other systems (e.g., cognition, behaviour) and the progression rates vary among patients . The time from the first symptom of ALS to diagnosis is approximately 12 months. The diagnosis is primarily based on clinical examination. Imaging of the head and spine, electromyography and laboratory test particularly serve to exclude structural lesions and other causes for paralysis . The ALSFRS-R questionnaire can be used to evaluate the course of the disease and especially the patients’ functional impairment .
Unfortunately, there is no causal therapy for ALS. Treatment options are usually palliative directed towards managing symptoms with temporary interventions (e.g., nasogastric feeding, surgical improvement of speech disorders, cough-assist devices, diaphragmatic pacing, ventilatory support or tracheotomy). Whether feeding via gastrostomy tube has a significant survival benefit is controversial [13,22,30]. Furthermore, pros and cons as well as consequences of a tracheostomy are part of an ethical discussion in the advanced care planning of ALS patients. Tracheostomy and ventilation may allow the patient to survive despite increasing paresis, but ALS may ultimately lead to a locked-in state with the inability to communicate. Drugs like edaravone and riluzole provide limited improvement .
Because no therapy offers substantial clinical benefit for ALS, the prognosis is poor [1,19]. As ALS progresses, there is further weakening of the diaphragm and respiratory muscles leading to dyspnoea, orthopnoea, hypoventilation, pneumonia and finally to death due to respiratory paralysis/failure or complications such as dysphagia or immobility within 3 to 5 years [1,11,24]. Mean life expectancy after symptom onset is about three years .