Almost 150 years have passed since Jean-Martin Charcot first described amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, an ailment that leads to the destruction of motor neurons. Medical sciences have progressed tremendously in the last century, resulting in serious improvements in health care and our ability to manage even the most serious of conditions. However, this is not the case for ALS. The progress in understanding this disease has been slow. Even today, there is no clear diagnostic criteria, no single confirmatory diagnostic test, not to mention a cure. But that does not mean that nothing has changed. The first effective drug to slow down the progress of the disease was approved in the 1990s. This article will briefly review the progress that has been made towards combating this disease.
Our muscles are made in such a way that if the neurons that supply them fail, the muscles also start to degrade. ALS is a disease characterized by progressive weakening of muscles due to the failure of neurons until the muscles are no longer able to support the body’s vital activities. For the majority of patients, the lifespan after disease onset is only two to five years, but there are long-term survivors too. The famous physicist Stephen Hawking was diagnosed with ASL in 1963 and has lived with the condition for over 40 years already.
The worldwide incidence of ALS is not known exactly, but in Europe 2.6 cases of disease per 100,000 people are diagnosed each year. The highest onset is in the age group of 58–63 years. Not all causes of the disease are understood, but familial (~10%) and genetic (~65%) factors are usually considered to be the main causes. Old age, male gender, and genetics remain the only recognized risk factors. The risk for the disease also appears to be increased by a number of environmental and lifestyle factors. Below is the summary of all the risk factors known to date:
- Familial aggregation – persons with a family history of ALS are at increased risk.
- Genetics – several genes have been identified, although their role is not fully understood. The most common genes accepted to play a role in ALS include SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72, and PFN1.
- Chromosomes – the expanded GGGGCC repeat is associated with ALS.
- Lifestyle risk factors: Most of them are preventable.Smoking is known to be neurotoxic and increase the risk of ALS; dietary factors such as antioxidants like vitamin E may have a preventive role in ALS. Consequently, diet may have something to do with ALS; low body weight may increase risk and worsen outcomes; athleticism and chronic traumatic encephalopathy should not be misinterpreted, physical exercise decreases the risk of ALS, but the risk is higher among professional athletes who tend to be at higher risk of trauma.
- Occupations with high trauma rates – ALS prevalence has been shown to be higher in US war veterans and people working with low magnetic fields like welders and electricians.
- Pesticides – are widely used and have been suggested as a risk factor in various neurodegenerative disorders for some time.
- Some medical conditions – include head trauma, cancer, chronic inflammatory diseases, certain viral infections, and neuroinflammation.
The existence of so many factors influencing the development of the disease underlines the complex nature of ALS.
The presentation of ALS varies greatly from person to person, so does the survival rate. However, the vast majority (almost half) of patients do not live for more than 30 months after disease onset. Despite this, ~20% can survive for five to ten years, while others can expect to live even longer.
There is little clarity when it comes to predicting the chance of survival for a person with ALS. However, the odds are better when the disease starts at a younger age. Also, life expectancy depends on where in the body the disease first started. The three major early stage presentations include:
- Limb-onset ALS with the involvement of both the upper and lower motor neurons (UMNs and LMNs).
- Bulbar-onset ALS that often starts with speech and swallowing difficulties, and with limb features developing later.
- Less common is pure UMN involvement and muscular atrophy with LMN involvement.
The bulbar-onset ALS has the worst prognosis since the vital functioning of organs is affected at an early stage. This often leads to early respiratory failure.
There is also lots of controversy in the scientific literature when it comes to the question of where the disease begins. Some researchers believe that it starts in the brain and then migrates to the peripheral nerves and muscles (hence this theory is called “Dying-forward”). Other scientists believe that it all starts at the periphery at the neuromuscular junction and later affects the neurons in the brain (hence this theory is called “Dying-backward”).
Due to the lack of diagnostic tests in early disease, clinicians have to depend on clinical symptoms, identifying combinations of UMN and LMN signs. There is usually further delay with definite diagnostics, as the typical ALS symptoms can be part of many other rare neurodegenerative disorders. Thus, an elaborate clinical and laboratory analysis is required for differential diagnosis, where tests involving brain imaging are often helpful for early diagnosis.
As there is no complete understanding of why, where, and how the disease starts, finding treatment remains challenging. Further, the lack of proper early stage diagnostic techniques means that precious time is lost when the probability of effective treatment is at its highest.
To date, there is only one drug, Riluzole, that has been shown to change the course of the disease, and it only helps for a few months. But this does not mean that there is no progress. Lots of promising research has been achieved in other animals, and there is need to translate this research to humans.
At present, most of the treatment for ALS is symptomatic and supportive. They include physiotherapy, orthotics, and treatment of pain, dysphagia (difficulty in swallowing), dyspnea (difficulty in breathing), pain, constipation, loss of voice, and mental and emotional problems.
References
Armon, C., 2009. Smoking may be considered an established risk factor for sporadic ALS. Neurology 73, 1693–1698. doi: 10.1212/WNL.0b013e3181c1df48.
Ascherio, A., Weisskopf, M.G., O’Reilly, E.J., Jacobs, E.J., McCullough, M.L., Calle, E.E., Cudkowicz, M., Thun, M.J., 2005. Vitamin E intake and risk of amyotrophic lateral sclerosis. Ann. Neurol. 57, 104–110. doi: 10.1002/ana.20316.
Beard, J.D., Kamel, F., 2015. Military Service, Deployments, and Exposures in Relation to Amyotrophic Lateral Sclerosis Etiology and Survival. Epidemiol. Rev. 37, 55–70. doi: 10.1093/epirev/mxu001.
Das, K., Nag, C., Ghosh, M., 2012. Familial, environmental, and occupational risk factors in development of amyotrophic lateral sclerosis. North Am. J. Med. Sci. 4, 350–355. doi: 10.4103/1947-2714.99517.
Gallo, V., Wark, P.A., Jenab, M., Pearce, N., Brayne, C., Vermeulen, R., Andersen, P.M., Hallmans, G., Kyrozis, A., Vanacore, N., Vahdaninia, M., Grote, V., Kaaks, R., Mattiello, A., Bueno-de-Mesquita, H.B., Peeters, P.H., Travis, R.C., Petersson, J., Hansson, O., Arriola, L., Jimenez-Martin, J.-M., Tjønneland, A., Halkjær, J., Agnoli, C., Sacerdote, C., Bonet, C., Trichopoulou, A., Gavrila, D., Overvad, K., Weiderpass, E., Palli, D., Quirós, J.R., Tumino, R., Khaw, K.-T., Wareham, N., Barricante-Gurrea, A., Fedirko, V., Ferrari, P., Clavel-Chapelon, F., Boutron-Ruault, M.-C., Boeing, H., Vigl, M., Middleton, L., Riboli, E., Vineis, P., 2013. Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: the EPIC cohort. Neurology 80, 829–838. doi: 10.1212/WNL.0b013e3182840689.
Gordon, P.H., 2013. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging Dis. 4, 295–310. doi: 10.14336/AD.2013.0400295.
Gordon, P.H., Cheng, B., Katz, I.B., Pinto, M., Hays, A.P., Mitsumoto, H., Rowland, L.P., 2006. The natural history of primary lateral sclerosis. Neurology 66, 647–653. doi: 10.1212/01.wnl.0000200962.94777.71.
Hardiman, O., Kiernan, M.C., Berg, L.H. van den, 2016. Amyotrophic Lateral Sclerosis, in: Neurodegenerative Disorders. Springer, Cham, pp. 145–165. doi: 10.1007/978-3-319-23309-3_8.
Ingre, C., Roos, P.M., Piehl, F., Kamel, F., Fang, F., 2015. Risk factors for amyotrophic lateral sclerosis. Clin. Epidemiol. 7, 181–193. doi: 10.2147/CLEP.S37505.
Kiernan, M.C., Vucic, S., Cheah, B.C., Turner, M.R., Eisen, A., Hardiman, O., Burrell, J.R., Zoing, M.C., 2011. Amyotrophic lateral sclerosis. The Lancet 377, 942–955. doi: 10.1016/S0140-6736(10)61156-7.
Logroscino, G., Traynor, B.J., Hardiman, O., Chiò, A., Mitchell, D., Swingler, R.J., Millul, A., Benn, E., Beghi, E., Eurals, F., 2010. Incidence of amyotrophic lateral sclerosis in Europe. J. Neurol. Neurosurg. Psychiatry 81, 385–390. doi: 10.1136/jnnp.2009.183525.
Marangi, G., Traynor, B.J., 2015. Genetic causes of amyotrophic lateral sclerosis: New genetic analysis methodologies entailing new opportunities and challenges. Brain Res., The multifaceted nature of ALS. Discoveries and Challenges of the last 5 years 1607, 75–93. doi: 10.1016/j.brainres.2014.10.009.
Poppe, L., Rué, L., Robberecht, W., Van Den Bosch, L., 2014. Translating biological findings into new treatment strategies for amyotrophic lateral sclerosis (ALS). Exp. Neurol., Special Issue: ALS genetics and pathogenesis 262, 138–151. doi: 10.1016/j.expneurol.2014.07.001.
Renton, A.E., Chiò, A., Traynor, B.J., 2014. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23. doi: 10.1038/nn.3584.
Talbot, K., 2009. Motor neuron disease: THE BARE ESSENTIALS. Pract. Neurol. 9, 303–309. doi: 10.1136/jnnp.2009.188151.
Vergara, X., Kheifets, L., Greenland, S., Oksuzyan, S., Cho, Y.-S., Mezei, G., 2013. Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis. J. Occup. Environ. Med. 55, 135–146. doi: 10.1097/JOM.0b013e31827f37f8.
Xu, Z., Poidevin, M., Li, X., Li, Y., Shu, L., Nelson, D.L., Li, H., Hales, C.M., Gearing, M., Wingo, T.S., Jin, P., 2013. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl. Acad. Sci. 110, 7778–7783. doi: 10.1073/pnas.1219643110.
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Source: Brain Blogger
