Amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig’s disease, is a degenerative condition that affects the motor neurons. The axons of motor neurons are found all over the body, specifically the muscles, but the respective cell body is located in the brain and spinal cord. They originate from the central nervous system and are projected to the muscles all around the body.
“Neurodegenerative diseases impose an enormous clinical and economic burden on patients and health systems. Development of disease-modifying therapies and strategies for effective palliative care have been limited by disease heterogeneity and the presence of overlapping phenotypes. Models which reliably predict outcomes at an individual patient level may become an important factor in a precision medicine approach to find the most effective treatment for patients with neurodegenerative disease, by improving potential for prognostic counselling, stratification of patients for trials, and timing of interventions.
Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurodegenerative diseases. It predominantly affects motor neurons in brain and spinal cord, leading to weakness of voluntary muscles.3,4 Muscle weakness progresses gradually, spreading from a site of clinical onset to other regions of the body; patients eventually become paralyzed and die, usually as the result of respiratory failure. The clinical features of ALS are heterogeneous; it can occur at any adult age, up to 15% of patients develop frontotemporal dementia (FTD), 5 and 10-15% of patients have a family history of ALS or FTD.”1
The first motor neuron starts in the motor cortex, the area of the brain responsible for movement. It connects with the second motor neuron in the spinal cord and this second neuron connects with different muscle fibers. ALS affects both the first and the second motor neurons that are involved in supplying the voluntary muscles with innervation. The degeneration and death of these neurons causes paralysis.
“ALS presents in many different ways, and it has been recognized for many years that the different clinical presentations correspond with differences in survival. Bulbar palsy, in which dysarthria followed by swallowing difficulty is the main presentation, is associated with the worst prognosis, and flail arm or flail leg syndrome, in which there is symmetrical, predominantly flaccid weakness of the limbs, is associated with the best prognosis. Perhaps surprisingly, statistical methods such as latent class cluster analysis can analyze the same data and identify different clinical subtypes that predict prognosis with far more discrimination than can neurologist classifications. Most cases of ALS are focal in onset and relentlessly progressive, often to contiguous regions, although there are some exceptions. The spread could be the result of a ‘prion-like’ spread of toxic proteins through phagocytosis (consumption of cells by other cells) or possibly through a time-to-failure model. Lower motor neuron failure is the main cause of weakness in ALS and can be measured non-invasively to provide data to assess cellular patterns of spread. Understanding the mechanisms of spread will aid the development of novel therapeutics and may aid models of prognosis.”2
The disease usually appears in men and women between 50 to 70 years old. However, there are cases discovered in much younger patients, but according to research, it affects men up to 3 times more than women. There is a rare form of ALS that is inherited, which is responsible for only 10% of cases. The rest of the ALS cases are considered to be sporadic.
Amyotrophic lateral sclerosis remains a disease without a specific diagnostic test. A clinical diagnosis of ALS is based on a history of progressive, painless weakness, and examination findings of both upper and lower motor neuron dysfunction. The initial symptoms of ALS vary among patients depending on the degree of upper and lower motor neuron involvement and which regions of the body are involved. Where the neurologic deficits manifest dictates which other diseases may produce the observed symptoms and, thus, informs the differential diagnostic evaluation. Clinical presentations can range from a spastic pattern of speech caused by upper motor neuron loss to a foot drop caused by lower motor neuron loss, with numerous permutations in between. The diagnosis may, therefore, be uncertain initially, and only with the development of additional features can the diagnosis be established with greater certainty. The appropriate exclusion of other diseases in the differential diagnosis is paramount, and electrophysiologic evaluations (electromyography and nerve conduction studies) are often the most important tests to help establish a diagnosis, but neuroimaging and serologic studies can also be of great value and are indicated in most cases. Spinal fluid analysis and nerve and muscle biopsies are tests that only rarely need to be used to exclude specific diseases in the differential diagnosis.”3
The exact cause is still unknown. There are multiple theories that try to explain the origin of the disease. The most supported hypotheses point to a possible combination between alterations of the immune system and the action of environmental factors. Several studies have shown the relationship between the use of certain agricultural pesticides and the occurrence of ALS, other studies have also revealed a possible association between the disease and certain fungal infections.
On the genetics side, several mutations related to this condition have been identified, in the forms of inherited amyotrophic lateral sclerosis; it has been proven that the most frequent alteration is a mutation in the superoxide dismutase 1 (SOD1) gene. In random cases, polymorphisms have been found to possibly be related to the development of this illness.
The symptoms of ALS are the result of the destruction of motor neurons. It usually begins with weakness in the distal part of the limbs in an asymmetric way, meaning, they do not affect both hands and feet at the same time. Patients can also stumble, drop objects and some have difficulty speaking. Weakness slowly gives way to paralysis, ALS is progressive. Paralysis affects the different voluntary muscles and in a disordered manner, the only muscles that are not affected until the very advanced stages are the extrinsic muscles of the eye and the sphincters. Therefore, despite suffering from paralysis, these patients are able to move their eyes and control urination and defecation.
The paralysis developed in ALS is a ‘rigid’ type of paralysis where stiffness takes over and they cannot move. Babinski’s sign is also present. By lightly stroking the sole of the feet (as if tickling), the big toe stretches up while the rest of the fingers are fanned out. This is Babinski’s sign and is indicative of injury of the first motor neuron, so its presence is always pathological. When we tickle the feet of a healthy person, the toes point downwards, not upwards. The appearance of this sign is normal exclusively in neonates, as it should disappear during infancy and never return. Hence, an adult should never show an extended toe after stimulation, otherwise, it is indicative of a neurological disorder.
The critical point of ALS comes when paralysis affects the pectoral muscles because it compromises the respiratory function of the patient. From this moment on, the installation of respiratory supports is essential.
It has been recently discovered that in addition to motor symptoms, non-motor neurological symptoms appear. Impairment of superior functions such as loss, concentration, memory and signs of dementia, among others.
Paralysis also affects the cranial nerves, which are the ones that innervate the head and neck structures. Therefore, it brings about difficulty or inability to swallow (dysphagia), presenting a risk of choking, aspiration and difficulty or inability to articulate words (dysarthria).
ALS patients can present a neurological state called ‘lability’, which is when they lack control of emotional responses, specifically, erratic laughing and weeping. These alterations are included in the so-called ‘pseudobulbar syndrome’ which is due to a lesion of the rachidian bulb.
The diagnosis of this illness is difficult since there is no standard test that allows the obtaining of a definitive answer. Diagnosis should be based on medical criteria and the result of multiple complementary tests such as magnetic resonance, electromyography (measures the electrical activity of the muscles), tests of nerve conduction velocity and analysis of the cerebrospinal fluids. Its diagnosis usually causes a serious emotional impact, both in patients and their family. Depression at the time of diagnosis is frequent as well as during the course of the disease.
The prognosis of ALS is fatal. The estimated life expectancy is about 3 years as a maximum, there is no curative treatment. Currently, the only drug available is Riluzole which only increases the life expectancy by a few months.
“No therapy offers a substantial clinical benefit for patients with ALS. The drugs riluzole and edaravone, which have been approved by the Food and Drug Administration for the treatment of ALS, provide a limited improvement in survival. Riluzole acts by suppressing excessive motor neuron firing, and edaravone by suppressing oxidative stress. Numerous other compounds that have been investigated have not been shown to be effective. Currently, the mainstay of care for patients with ALS is timely intervention to manage symptoms, including use of nasogastric feeding, prevention of aspiration (control of salivary secretions and use of cough-assist devices), and provision of ventilatory support (usually with bilevel positive airway pressure). Some interventions raise serious ethical issues, such as whether to perform tracheostomy for full ventilation and, if so, when and how to withdraw respiratory support once it has been instituted.”4
“During the disease course, most patients develop chronic respiratory insufficiency due to progressive weakness of the diaphragm and auxiliary respiratory muscles. Early symptoms include signs of hypercapnia such as daytime fatigue, sleep disturbance, cognitive impairment, and depression, while dyspnea and orthopnea usually occur later. Respiratory disorders usually develop slowly in ALS; therefore, acute worsening should lead to diagnostic measures in order to exclude complications like atelectasis, pneumonia, or pulmonary embolism.
Noninvasive ventilation (NIV) refers to the administration of ventilatory support through the upper airways without using invasive artificial airways like endotracheal tubes or tracheostomy. It is performed by using a compact breathing device with a nasal or full-face mask. It is easy to handle and can be used at home, initially usually at night. Because of its flexible and noninvasive nature, it is usually well accepted. NIV uses room air, since administration of pure oxygen reduces the respiratory drive in ALS patients and might induce carbon dioxide narcosis.
NIV has become an important cornerstone of ALS therapy and should be initiated as soon as clinical symptoms appear. Additional diagnostic measures such as forced vital capacity (FVC), sniff nasal inspiratory pressure (SNIP), maximal inspiratory pressure, blood gas analysis, oximetry, and capnometry can be used to justify an earlier initiation of NIV although there is no evidence or standardized procedure.”5
“Dysphagia is a common symptom of ALS and leads to increased risk of aspiration, malnutrition, weight loss and dehydration. Malnutrition and dehydration can also occur inpatients whom have severe upper limb weakness, especially if they live alone, as this leads to difficulties in meal preparation or prolonged meal times. ALS is associated with a hyper metabolic state, therefore patients require increased calorie intake. Early management of dysphagia includes dietary advice, modification of food consistency (blending solid, adding thickening agents to liquids) and educating patients on special swallowing techniques (such as supraglottic swallowing and postural changes (‘Chin tuck manoeuvre’).
Most guidelines state that supplementary enteral feeding should be considered when body weight falls by > 10% of the pre-diagnostic or baseline weight. The three options available for enteric feeding include percutaneous endoscopic gastrostomy (PEG), percutaneous radiologic gastrostomy (PRG) or radiologically inserted gastrostomy (RIG), and nasogastric tube (NGT) feeding. PEG is the standard procedure for enteral feeding, although the procedure requires mild sedation and therefore has implications in patients with respiratory weakness.”6
Nowadays, the only possible treatment is aimed at improving the quality of life of these patients. Due to the high degree of disability that they suffer, palliative and psychological support is required.
“Extending life expectancy in ALS seems to be dependent on improving our understanding of its pathogenesis, which will lead to the development of early and specific diagnostic methods. There is a crucial need to formulate therapies that not only slow disease progression, but also deal with the secondary consequences of malnutrition and respiratory failure. At present, no definitive diagnostic test or biomarker for ALS exist, and neurologists rely on only clinical criteria for diagnosis. The development of novel biomarkers to objectively assess disease progression holds the promise of greatly refining therapeutic trial design and reducing trial costs. Furthermore, the power of population registries is being increasingly recognized as an essential adjunct to improved clinical assessment techniques. These collaborative endeavors will inevitably lead to a better understanding of ALS and its often unpredictable progression, and will lead to the development of guidelines for improved care of patients.”7
As for family members, the high degree of dependency of ALS patients can bring about the appearance of ‘caregiver burnout’, so it’s also recommended for them to have psychological support from professionals, friends and other members of the family.
(1) Westeneng, H. J., Debray, T. P., Visser, A. E., van Eijk, R. P., Rooney, J. P., Calvo, A., … & Kobeleva, X. (2018). Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model. The Lancet Neurology, 17(5), 423-433. Available online at http://eprints.whiterose.ac.uk/131617/1/MND%20MODELLING%20PAPER%20LANCET%20NEUROLOGY%20ACCEPTED%20VERSION.pdf
(2) Martin, S., Al Khleifat, A., & Al-Chalabi, A. (2017). What causes amyotrophic lateral sclerosis?. F1000Research, 6. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5373425/
(3) Oskarsson, B., Gendron, T. F., & Staff, N. P. (2018, July). Amyotrophic lateral sclerosis: an update for 2018. In Mayo Clinic Proceedings. Elsevier. Available online at https://www.mayoclinicproceedings.org/article/S0025-6196(18)30266-0/pdf
(4) Brown, R. H., & Al-Chalabi, A. (2017). Amyotrophic lateral sclerosis. New England Journal of Medicine, 377(2), 162-172. Available online at https://www.mndassociation.org/wp-content/uploads/Brown-et-al-ALS-review-2017-NEJM.pdf
(5) Dorst, J., Ludolph, A. C., & Huebers, A. (2018). Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis. Therapeutic advances in neurological disorders, 11, 1756285617734734. Available online at https://journals.sagepub.com/doi/full/10.1177/1756285617734734
(6) Wijesekera, L. C., & Leigh, P. N. (2009). Amyotrophic lateral sclerosis. Orphanet journal of rare diseases, 4(1), 3. Available online at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656493/
(7) Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., … & Zoing, M. C. (2011). Amyotrophic lateral sclerosis. The lancet, 377(9769), 942-955. Available online at https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61156-7.pdf