**1. Introduction**

My daughters Lorna Maria (32 years old) and Fatima Susana Adolfina (7 years old) who encouraged me all the time to continue moving forward with persistence. My son Thabo Humberto Jorge (8 years old) who pushed me to play physics games with him which helped me to relax and to find new ideas. My whole family contributed to this project in one way or another and they deserve our deep gratitude. I also want to thank the families, relatives, and friends of all contributors for their support. Special thanks to Walter Sisulu University (WSU), named in honour of an icon of the South Africa liberation struggle and close com‐ rade of Nelson Mandela, the late Walter Max Ulyate Sisulu. Many thanks to Dr. EN Cishe: Acting Director Research Development of WSU, Dr. WW Chita: Dean of the Faculty of Health Sciences (WSU), Prof. A Awotedu: Head of Department of General Medicine and Therapeutic, Dr. M Mdledle: Acting Governor General Director: Clinical Governance of Nel‐ son Mandela Central Hospital and Mrs. NP Makwedeni: Chief Executive Officer of Nelson Mandela Central Hospital for the best understanding and support. At the end, I extend my deepest sense of appreciation for the support received by Dr. Roberto Morales Ojeda: Minis‐ ter of Public Health of Cuba and Dr. Jorge Delgado Bustillo: Deputy Head of the National

**Prof. H Foyaca Sibat. MD, PhD, MSc,**

Head of Department of Neurology

Full Scientist Research

Mthatha, South Africa

Aggregate Scientist Research

First and Second Degree Specialist in Neurology

Department of Neurology, Nelson Mandela Central Hospital. Walter Sisulu University. Mthatha, South Africa.

Nelson Mandela Central Hospital, Faculty of Health Sciences, WSU

**Dr. Lurdes de Fatima Ibañez Valdés. MD, MSc, Family Physician**

Unit for International Cooperation in Health.

VIII Preface

Amyotrophic lateral sclerosis (ALS) is a progressive and almost invariably fatal neurodege‐ nerative disease that affects motor neurons cell in the cerebral hemispheres, brainstem, and the spinal cord. The disease begins focally in the central nervous system and then spreads relentlessly. This disorder of the upper and lower motor neurons (also known as Motor Neuron Disease) can be confirmed by electromyography and is characterised by a progres‐ sive muscle weakness, spastic hypertonia, hyperreflexia, muscle wasting, dysphagia, disarth‐ ria and fasciculations in most of the patients. Less than 10% of the patients have a hereditary pattern. Mostly, ALS does not affect sphincters, sexual functions, or eyes movements. There are two well-recognised varieties: sporadic (SALS) and familial (FALS).

#### **1.1. Recent updated information**

To update knowledge about ALS, it is important to bring new information which are as fol‐ lows: the FALS accounts for 5% of all ALS; an underlying mutation has been identified in approximately a third of these cases [1] and it is important to perform a screening of four principal genes (SOD1, TARDBP, FUS, C9ORF) because they cover more than 50% of FALS [2]. A recent meta-analysis of population-based studies also confirmed that 5% of ALS cases are FALS and the remaining 95% are SALS with no reported family history [3]. Both share common pathogenic mechanisms and the disease has an incidence of 2.7 cases per 100,000 people in Europe [4] and at the present moment straightforward and classical cure for ALS are not available.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

We cannot ignore the history and therefore should be mentioned that ALS is recognised back in 1850 by a British neurophysiologist Augustus Waller for the appearance of shrivelled nerve fibres and identified as a specific disease. Later, this pathological process was named and described as ALS by a French neurologist Jean-Martin Charcot. He was also a professor of anatomical pathology and is known as 'the founder of modern neurology', his name has been associated with at least 15 medical eponyms, such as: Charcot-Marie-Tooth disease, Charcot's artery (lenticulostriate artery), Charcot's joint (diabetic arthropathy), Charcot-Wilbrand syndrome (visual agnosia and loss of ability to revisualise images), Charcot-Bouchard aneurysms (tiny aneurysms of the penetrating branches of middle cerebral artery in hyper‐ tensives) and Charcot disease (better known as amyotrophic lateral sclerosis or motor neurone disease), among others. His work greatly influenced the developing fields of neurology and psychology; modern psychiatry owes much to the work of Charcot and his direct followers. He was the 'foremost neurologist of late nineteenth-century France' [5].

However, ALS was not well known until 1939 when a famous American baseball first baseman player Lou Gehrig brought national and international attention to his disease. After Lou Gehrig died, a big number of sportsman have been diagnosed with ALS or Lou Gehrig's disease, and based on their experiences a lot of knowledge about the disease have been accumulated. Most patients are diagnosed with ALS between the ages of 40-70, but the disease can also develop in younger people. The average age for an ALS diagnosis is 56. Approximately 30,000 Amer‐ icans have the disease at any given time and most of them will die within 3-5 years from the beginning of the disease, although we will mention some people that are still alive. It affects people throughout the world without any racial, ethnic or socioeconomic boundaries but males are more prone to ALS. Fifty percent of affected patients live at least 3 or more years after diagnosis; 20% live 5 years or more; and up to 10% will survive more than 10 years [6]. More information is available online: http://www.hopkinsmedicine.org/neurology\_neurosurgery/ centers\_clinics/als/conditions/als\_ amyotrophic\_lateral\_sclerosis.html.

In our series of patients, complaints about visual disturbances, ophthalmoplegia, auditory disorders, vestibular dysfunction, olfactory problems, sensory loss or disorder of the auto‐ nomic nervous system related to ALS were not identified, although in late stages of the disease patients may develop a supranuclear gaze palsy or oculomotor palsy [7, 8], as anecdotic cases.

However, cognitive impairment can be seen in nearly a third of the patients with ALS in a pattern consistent with frontotemporal lobar dementia as has been proved [9]. These findings were also reported by many other authors [10–20]. Executive function, behaviour and speech are the most likely areas to be involved. Screening helpful in detecting abnormalities includes verbal or categorical fluency, behavioural inventories filled out by the caregiver and evaluation for the presence of depression and pseudo-bulbar signs [21]. Patients with ALS may have difficulty interpreting the emotions associated with facial expressions, even when they are otherwise cognitively normal; this may impact their relationships with their caregiver and possibly influence medical decision making [22]. In our opinion, this manifestation may occur even without confirmed lesion at the insular lobe and without insular lobe epilepsy. However, we have patients presenting ALS without cognitive disorder and very high intelligence coefficient level.

Unfortunately, due to reasons beyond our control no abstracts related to the therapy of ALS (which is not a single disease) is received. Therefore, we will mention some important aspects related to the therapy of ALS.

We cannot ignore the history and therefore should be mentioned that ALS is recognised back in 1850 by a British neurophysiologist Augustus Waller for the appearance of shrivelled nerve fibres and identified as a specific disease. Later, this pathological process was named and described as ALS by a French neurologist Jean-Martin Charcot. He was also a professor of anatomical pathology and is known as 'the founder of modern neurology', his name has been associated with at least 15 medical eponyms, such as: Charcot-Marie-Tooth disease, Charcot's artery (lenticulostriate artery), Charcot's joint (diabetic arthropathy), Charcot-Wilbrand syndrome (visual agnosia and loss of ability to revisualise images), Charcot-Bouchard aneurysms (tiny aneurysms of the penetrating branches of middle cerebral artery in hyper‐ tensives) and Charcot disease (better known as amyotrophic lateral sclerosis or motor neurone disease), among others. His work greatly influenced the developing fields of neurology and psychology; modern psychiatry owes much to the work of Charcot and his direct followers.

However, ALS was not well known until 1939 when a famous American baseball first baseman player Lou Gehrig brought national and international attention to his disease. After Lou Gehrig died, a big number of sportsman have been diagnosed with ALS or Lou Gehrig's disease, and based on their experiences a lot of knowledge about the disease have been accumulated. Most patients are diagnosed with ALS between the ages of 40-70, but the disease can also develop in younger people. The average age for an ALS diagnosis is 56. Approximately 30,000 Amer‐ icans have the disease at any given time and most of them will die within 3-5 years from the beginning of the disease, although we will mention some people that are still alive. It affects people throughout the world without any racial, ethnic or socioeconomic boundaries but males are more prone to ALS. Fifty percent of affected patients live at least 3 or more years after diagnosis; 20% live 5 years or more; and up to 10% will survive more than 10 years [6]. More information is available online: http://www.hopkinsmedicine.org/neurology\_neurosurgery/

In our series of patients, complaints about visual disturbances, ophthalmoplegia, auditory disorders, vestibular dysfunction, olfactory problems, sensory loss or disorder of the auto‐ nomic nervous system related to ALS were not identified, although in late stages of the disease patients may develop a supranuclear gaze palsy or oculomotor palsy [7, 8], as anecdotic cases.

However, cognitive impairment can be seen in nearly a third of the patients with ALS in a pattern consistent with frontotemporal lobar dementia as has been proved [9]. These findings were also reported by many other authors [10–20]. Executive function, behaviour and speech are the most likely areas to be involved. Screening helpful in detecting abnormalities includes verbal or categorical fluency, behavioural inventories filled out by the caregiver and evaluation for the presence of depression and pseudo-bulbar signs [21]. Patients with ALS may have difficulty interpreting the emotions associated with facial expressions, even when they are otherwise cognitively normal; this may impact their relationships with their caregiver and possibly influence medical decision making [22]. In our opinion, this manifestation may occur even without confirmed lesion at the insular lobe and without insular lobe epilepsy. However, we have patients presenting ALS without cognitive disorder and very high intelligence

He was the 'foremost neurologist of late nineteenth-century France' [5].

2 Update on Amyotrophic Lateral Sclerosis

centers\_clinics/als/conditions/als\_ amyotrophic\_lateral\_sclerosis.html.

coefficient level.

At the beginning of this year (29 January 2016), the following information is released: 'Results in a new mouse model of ALS indicate that delivering copper to the central nervous system can be therapeutic, according to a study published in the journal Neurobiology of Disease', and we all became very enthusiastic until Dr. Bruijn (Ph.D., M.B.A., Chief Scientist for The ALS Association) said: 'But in the meantime, it is critical to remember that oral copper supplements do not reach the central nervous system and thus cannot provide any benefit and can be quite toxic' (http://www.alsa.org/news/archive/new-copper-therapy.html), just to remind everyone that all results from animals cannot be applied to our patients. However, last year we were informed about Progress in Drug Development Reviewed at The ALS Association Drug Company Working Group Meeting (5 May 2015), where news about a new drug, a new delivery method, a new trial and a new approach to working with the Food and Drug Administration (FDA) were the highlights of the ALS Association's annual Drug Company Working Group meeting, held in April in Washington, D.C., in conjunction with the American Academy of Neurology (AAN) Meeting. From this meeting, we can summarise: (1) Induced pluripotent stem cells have been used as a drug discovery tool, leading to an upcoming clinical trial that will test a drug shown to be effective in cells derived from people with ALS. (2) Retigabine (AED) help to normalise the over-excitability of ALS cells in cell culture, and this treatment improves the survival of these cells. (3) The system to deliver glial-derived neuro‐ trophic factor (GDNF) in ALS, based on experiments showing that GDNF can promote survival of motor neurons, is being developed. (4) A biologically based system that encapsulates protein-based growth factors or DNA-based antisense molecules can cross the blood-brain barrier, allowing peripheral administration for a drug that acts in the brain, is being developed. (5) Tirasemtiv increases muscle output at mid-levels of exertion, temporarily restoring some lost strength for everyday activities such as picking up an object, but did not meet its major objective of showing a change in the ALS Functional Rating Scale score at the end of treatment, although it improves the slow vital capacity (modified from: http://www.alsa.org/news/ archive/progress-in-drug-development.html). Other results were: (6) Mexiletine is a cardiac medication that reduces hyperexcitability of motor neurons, which may help protect them from toxic excitation and it was safe to use in ALS (modified from: http://www.alsa.org/news/ archive/new-clinical-pilot-studies.html). (7) One research showed that motor neurons can be protected from disease-related toxicity by human up-frameshift protein 1 (hUPF1). Promoting hUPF1 might be therapeutic and therapies for SOD1-related ALS might require different strategies and that clinical trials may have the greatest chance of success if they target people with similar forms of ALS (modified from: http://www.alsa.org/news/archive/new-therapyrna-processing.html). All these results were preceded by the following results (2012-2015): (1) The immune system continues to grow as a target of interest in therapy design. (2) Several groups have made progress on finding biomarkers that can track disease. (3) The entire ALS community was disappointed in the negative results from the dexpramipexole trial. (4) 'Antisense' therapy against the mutation reduces the amount of aggregated RNA and may be therapeutic, according to experiments in cell culture. Antisense against the SOD1 gene has been shown to be safe in people with ALS progression. (5) The journal *The Lancet* indicates that high caloric intake is safe and tolerable in people with ALS with a feeding tube. This research sets the stage for a larger trial testing whether high caloric intake can slow progression of the disease (modified from http://www.alsa.org/news/archive/research-shows-high-calo‐ rie.html). (6) Brain storm cell therapeutics said the U.S. Food and Drug Administration has approved the start of a mid-stage clinical trial of its adult stem cell treatment for people with ALS, which have shown that it was well tolerated and safe (modified from: http:// www.alsa.org/news/archive/fda-approves-brainstorm-trial.html). (7) Tocilizumab interacts with microglia to convert them from the Microglia1 to Microglia2 state. In a recent small, openlabel trial in eight people with ALS, there was some evidence that the drug may be able to reduce neuroinflammation (modified from: http://www.alsa. org/news/archive/2014-drugcompany-working-group.html). (8) The trial with ceftriaxone was stopped in early 2012 because data analysis indicated that it was not effective at changing the rate of progression of ALS (http://www.alsa.org/news/archive/ceftriaxone-statement.html). (9) Unexpectedly, a drug (Nuedexta) that is approved for the treatment of labile emotionality that occurs in association with ALS and other neurological disorders has been observed to improve bulbar function, primarily speech and swallowing, in a number of neurological disorders, including ALS (http://www.alsa.org/news/archive/news-from-the-international.html).

**Figure 1.** Henry Louis 'Lou' or 'Buster' Gehrig (Born Heinrich Ludwig Gehrig; 19 June 1903-2 June 1941) was an Amer‐ ican baseball first baseman who played 17 seasons in Major League Baseball for the New York Yankees, from 1923 to 1939. https://en.wikipedia.org/wiki/Lou\_Gehrig.

ALS is better known since 1939, when a famous American baseball first baseman player Lou Gehrig (see **Figure 1**) brought national and international attention to his disease; since then, in America this neurodegenerative disorder is better known as a Lou Gehrig's disease.

Since Gehrig died, a big number of sportsmen have been diagnosed with ALS or Lou Gehrig's disease. At this point, we like to highlight that Lou Gehrig was a very famous baseball player, but two other baseball players from the same New York Yankees team such as his friend and teammate Babe Ruth (1895-1948) who set numerous baseball records (famous for his big hitting) and won many titles with the New York Yankees, and Joe DiMaggio (1914-1999) who won the title World Series Champion nine times with the New York Yankees, were even more famous than him and they did not suffer from ALS.
