**2. Some sportsmen presenting amyotrophic lateral sclerosis**

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

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.

1939. https://en.wikipedia.org/wiki/Lou\_Gehrig.

4 Update on Amyotrophic Lateral Sclerosis

In 2005, Al-Chalabi and Leigh studying this topic concluded that: 'there is no evidence that football players elsewhere in the world have an increased risk of developing ALS' [23]. Other authors said that the only really consistent epidemiological risk factors for ALS are increasing age, male sex and a family history of ALS [24–28] and we agree on that. Even in Guam, where a restricted population with high risk of developing ALS has been under intense scrutiny for over 50 years, controversy persists and no environmental (or genetic) causes have been identified beyond doubt [23, 29–31]. On the other hand, cigarette smoking may also be a risk factor [27, 28, 32] but other information should be taken into consideration. For example, it is known that complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, can involve both motor neurons and surrounding glial cells [33], and therefore is accepted that the aetiology of ALS likely involves a complex interaction between Multiple risk factors. Although no confirmation about the direct effect of stress or exercises on pathophysiology of ALS has been made, we cannot ignore the frequency of ALS in people practicing sport apart from the affirmation from some author saying that CNS injury is linked to an increased incidence of motor neuron degeneration [34], given the recognised association between neurodegenerative disease and activities that involve a higher risk for CNS trauma, including participation in professional full-contact sports and military service [35–39].

Most researchers investigating head injury and ALS did their studies in predisposed rats to ALS, including those with a more severe injury due to a stab-wound trauma (SOD1 rat spinal cord), and in all the studies done, those traumatic lesions did not accelerate motor neuron degeneration [40, 41], but these research protocols cannot apply to the real scenarios afforded by athletes that underwent more and repetitive instances of all kind of stress and repetitive CNS trauma leading to more chance of developing diffused axonal injury. Other authors supported this hypothesis as well [42–46] and we considerate that those results cannot be transferred to human beings.

Let us highlight one more time that a single injury is not able to hasten disease pathology, but there is enough evidence suggesting that brain injuries can be linked with ALS [47] and about the risk of developing ALS in football players [48, 49]. In our series of patients, we found that professional boxing and rugby players are the most common to be associated with ALS, but we have to mention that our job is done in a semi-rural setting where other sport modalities are not practiced. We support the hypotheses that cortical dysfunction caused by any kind of injury should be taken into consideration as part of the pathophysiology of ALS [50–52], until proven otherwise.

To practice sports or do strong exercises obviously do not cause a degenerative disorder, but if the above-mentioned activities are accompanied by prolonged and severe stress situation in a genetically predisposed person, then nobody can predict what is going to happen.

To provide better idea about this hypothesis, we decided to review some biographic aspects of these kinds of patients.

Because it is mainly an introductory chapter and due to limitations of space we had to remove some relevant aspects regarding ALS/sportsmen and a lot of illustrative material from the original chapter and to bring more attention to others topics.

#### **2.1. Comments about some sportsmen presenting ALS**

**Lou Henri Gehrig** is one of the most famous people affected by ALS. He was born in the Yorkville section of club and earned the nickname Columbia Lou from adoring fans. Gehrig signed his first contract with the New York Yankees Team in April 1923. Over the next 15 years he led the team to win six World Series titles. Available at the URL: http://www.biogra‐ phy.com/people/lou-gehrig-9308266.

**Figure 2.** Ezzard Mack Charles (7 July 1921-28 May 1975) was an American professional boxer and former World Heavyweight Champion. https://en.wikipedia.org/wiki/Ezzard\_Charles.

In May 1939, he noticed that his performance has been decreasing gradually due to progressive weakness all over the body and then he decided to pull himself out of the lineup of players looking for better results of his team. At that time a diagnosis of ALS was done and he died 2 years later. Lou Gehrig, also known as 'the iron man of the baseball', played in more consecutive games than any other baseball player worldwide and his record remained unbroken until 1995 (modified from: http://www.alstexas.org/understanding-als/).

are not practiced. We support the hypotheses that cortical dysfunction caused by any kind of injury should be taken into consideration as part of the pathophysiology of ALS [50–52], until

To practice sports or do strong exercises obviously do not cause a degenerative disorder, but if the above-mentioned activities are accompanied by prolonged and severe stress situation in

To provide better idea about this hypothesis, we decided to review some biographic aspects

Because it is mainly an introductory chapter and due to limitations of space we had to remove some relevant aspects regarding ALS/sportsmen and a lot of illustrative material from the

**Lou Henri Gehrig** is one of the most famous people affected by ALS. He was born in the Yorkville section of club and earned the nickname Columbia Lou from adoring fans. Gehrig signed his first contract with the New York Yankees Team in April 1923. Over the next 15 years he led the team to win six World Series titles. Available at the URL: http://www.biogra‐

**Figure 2.** Ezzard Mack Charles (7 July 1921-28 May 1975) was an American professional boxer and former World

In May 1939, he noticed that his performance has been decreasing gradually due to progressive weakness all over the body and then he decided to pull himself out of the lineup of players looking for better results of his team. At that time a diagnosis of ALS was done and he died 2 years later. Lou Gehrig, also known as 'the iron man of the baseball', played in more consecutive

a genetically predisposed person, then nobody can predict what is going to happen.

original chapter and to bring more attention to others topics.

**2.1. Comments about some sportsmen presenting ALS**

Heavyweight Champion. https://en.wikipedia.org/wiki/Ezzard\_Charles.

proven otherwise.

of these kinds of patients.

6 Update on Amyotrophic Lateral Sclerosis

phy.com/people/lou-gehrig-9308266.

Scarmeas et al. [46] published a manuscript, concluding that subjects with ALS were more likely to be slim or had once been serious athletes. Apart from Lou Gehrig, they mentioned many famous people in U.S. history who have had ALS such as: **Ezzard Charles** (see **Fig‐ ure 2**) who was a quite famous heavyweight boxing champion. Charles was diagnosed with ALS. The disease affected Charles legs and eventually left him completely disabled. Charles died on 28 May 1975 in Chicago.

**Figure 3.** Marthinus 'Tinus' Linee (23 August 1969-3 November 2014) was a South African rugby player. https:// en.wikipedia.org/wiki/Tinus\_Linee.

Another famous baseball player affected by ALS was '**Catfish**' Hunter. From 1965 to 1979, he was a pitcher for the Kansas City Athletics, Oakland Athletics and New York Yankees. He was diagnosed with ALS in his early 50s and died of the disease about a year later. **Paul Kevin Turner** was an American professional fullback. He played eight seasons in the Na‐ tional Football League for the New England Patriots and Philadelphia Eagles. After Turner learned he had ALS in 2010, he created the Kevin Turner Foundation to raise awareness about sports-related brain trauma and to support research and treatment initiatives. He was involved in research that links chronic traumatic encephalopathy to ALS, and agreed to do‐ nate his brain and spinal cord when he died. On 24 March 2016, Turner died as a result of ALS at home in Vestavia Hills, Alabama. **Stephen Michael 'Steve' Gleason** (born 19 March 1977) is a former professional football player, a safety with the New Orleans Saints of the National Football League. In 2011, he revealed that he was battling ALS. **André Gerhardus Venter** (born 14 November 1970 in Vereeniging, South Africa) who was a former South Af‐ rican rugby union footballer and earned 66 caps playing for the South Africa national team during the mid-to-late 1990s and early 2000s. He represented South Africa during the 1999 Rugby World Cup where they finished third. Unfortunately, he was another victim of ALS. **Joost van der Westhuizen** (born 20 February 1971) was a member of the victorious South African rugby team at the 1995 World Cup. He was inducted into the International Rugby

Hall of Fame in 2007. Near the end of 2008, Van der Westhuizen first noticed weakness in his right arm. A few months later, he was play-fighting in a swimming pool with a friend who was also his personal doctor, and discovered further weakness in the arm, a diagnosis of ALS was confirmed in 2011. Modified from: http://www.eurosport.com/rugby/van-derwesthuizen-sees-a-link\_sto4476535/story.shtml. **Jarrod Cunningham** (7 September 1968-22 July 2007) was a New Zealand rugby union fullback, who died from ALS. After tests at Charing Cross Hospital, Cunningham was diagnosed with ALS in June 2002. He immedi‐ ately retired from professional rugby, and started the Jarrod Cunningham SALSA Founda‐ tion in March 2003 with the aim of providing hope, education and inspiration for fellow sufferers of ALS. He returned home to New Zealand in December 2004 and died at his home on 22 July 2007. **Herbert Krug** (21 June 1937-1 November 2010) was a German eques‐ trian who won a gold medal in team dressage at the 1984 Summer Olympics in Los Angeles. He was born in Mainz and died in Hochheim am Main due to ALS. **Krzysztof Nowak** (27 September 1975-26 May 2005) was a Polish football player, best known for his stint with the VfL Wolfsburg team. He was forced to retire from the sport in early 2002 after he learned he had ALS. **Donald George "Don" Revie** was an England international footballer. In the spring of 1986, Revie moved to Kinross, Scotland where he intended to retire, but he was diagnosed with motor neurone disease in May 1987. Revie publicly announced his illness in August of that year, and made his final public appearance on 11 May 1988 at Elland Road in a wheelchair. He died in Murrayfield Hospital in Edinburgh on 26 May 1989, aged 61. Mar‐ thinus 'Tinus' Linee (see **Figure 3**) played rugby predominantly at the centre. In April 2013, Linee was diagnosed with motor neurone disease. His deteriorating health resulted in him having financial difficulties in an attempt to cover his medical costs. Linee died on 3 No‐ vember 2014, aged 45 in his family home in Paarl, South Africa.

**John Mudgeway** was born in Masterton, he attended school in New Zealand, was an active rower and was in the school's rugby union first XV. He was diagnosed with motor neurone disease in 2002. **Ryan Walker** was born on 5 October 1978 in Pietermaritzburg (South Africa) and grew up on a beef and dairy farm in Mooi River. He was admitted in hospital for 5 days and had extensive blood tests, nerve tests, MRI and lumbar punctures. All the results came back clear. Ryan then went for his follow-up appointment with his attending doctor 4 weeks later who told him that he had ALS, and that there was no treatment available and that the prognosis was 2-5 years. More biographic information about all mentioned athletes is available at the URL: https://en.wikipedia.org.

Due to the large number of rugby players affected by ALS in South Africa, many people have questioned whether there is a link between rugby-linked head injuries and motor neuron disease in light of cases including those of Joost van der Westhuizen, Tinus Linee, John Mudgeway, Ryan Walker and Jarrod Cunningham, all professional South African rugby players who suffered from the disease [49, 53]. Due to the increasing report of sportsmen presenting ALS, of all the putative risk factors, head injury has emerged as a strong cause for initiating the neurodegenerative processes in ALS patients [38, 39].

At the present moment, there are more available facilities for confirmation of ALS, the disease is better known and the remarkable progress reached by the media and Internet has made their contribution to inform everyone about all sportsmen presenting ALS. Perhaps this is one of the reasons why we note an increase in the number of reported patients. Obviously, we also have more capacities to inform about new cases to the medical literature worldwide and this facility increase the number of reported patients.

We would like to highlight that thousands of slim athletes never developed ALS. Therefore, why a tiny few of them do develop ALS is still unknown. There is certainly no justification to avoid athletics in attempts to avoid ALS. Moreover, nothing in some authors' data can be construed as evidence that patients with ALS should not exercise [54].
