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Discover our podcast on History of Science and on health made by Florian and Yannick.

History of Amyotrophic Lateral Sclerosis

Often described as the least rare of rare diseases, which is a counter-truth, Amyotrophic Lateral Sclerosis is a neurodegenerative disease. According to the rare diseases’ portal Orphanet, this disease is characterized by:

“A weakening and then paralysis of the muscles of the legs and arms, the respiratory muscles, as well as the muscles of swallowing and speech. Intellectual and sensory functions are not affected. It is a serious progressive disease resulting from the destruction of nerve cells (neurons), which reduces the life expectancy of people affected by it. »

Amyotrophic Lateral Sclerosis, which we will call ALS to make it easier to listen to this podcast, is a highly disabling disease. Generally speaking, it breaks out quite late in life, since the average age of the person diagnosed is 60. It also affects men slightly more than women. The ratio of men to women is 1.5 to 1. It is estimated that ALS affects about 1 in 25,000 people. In France, nearly 800 people are diagnosed each year. As a reminder, in Europe, a disease is considered rare when it affects one person in 2,000. It should also be noted that there is currently no cure for this disease, but ways have been found to increase life expectancy and improve the quality of life of patients. Many other characteristics define the disease, and to find out more I invite you to listen to the podcast of Yannick, my colleague at Fondation Ipsen, on his excellent channel: Our Health! .

If we all know this disease, at least by name, it is mainly for two reasons. The first is that it was made famous in 2014 by a viral campaign on social networks: the ice bucket challenge. The premise was very simple: encourage named participants to have a bucket of ice water dumped on their heads, while being filmed, and nominate others to do the same. Often, the nominated participants had 24 hours to complete the challenge or not and therefore commit to donating to research or a charity. The second is that the disease has affected famous people such as theoretical physicist and cosmologist Stephen Hawking, who suffered from a very rare form of ALS, and baseball player Lou Gehrig. In fact, as we will see in this episode, Lou Gehrig’s story has touched the American people so much that the disease is now commonly referred to, on the other side of the Atlantic, as Lou Gehrig’s disease. ALS has indeed different names in different parts of the world. It is therefore widely known as Charcot’s disease in French-speaking countries, Lou Gehrig’s disease in North America, and motor neuron disease in the United Kingdom and in other countries such as Ireland, Australia or New Zealand. As we will see, the motor neurons, which are the nerve cells that control movement, will be fundamental in understanding the disease. In this podcast we will focus on the advances and work that led to the identification of the disease by Jean-Martin Charcot and discuss the touching story of the man who became the face of the disease, Lou Gehrig.


  1. Progress before identification

As its name suggests in France, the first true clinical description is now largely attributed to Jean-Martin Charcot, in 1865. The name Amyotrophic Lateral Sclerosis was used for the first time in 1874. However, many other scientists contributed to the development of the disease and, in part, facilitated this formal identification. One example is the Scottish anatomist and surgeon Charles Bell, who lived from 1774 to 1842. In 1824, he published a work that is fundamental for our purposes: Exposition of the natural system of the nerve. In this document, Bell was the first to distinguish between two types of root within the spinal cord: the anterior roots, which have a motor function and therefore concern movement, and the posterior roots, which have a sensory function. This discovery was therefore essential since it allowed the conclusion that certain neurological pathologies can be distinguished according to the type of spinal cord roots concerned. The idea that diseases can be purely motor is thus advanced for the first time. A first step has been taken.

Amyotrophic Lateral Sclerosis was first described in 1850 by the French physician François-Amilcar Aran. At that time, many French scientists were interested in these neurodegenerative diseases that affect motor functions but were not yet able to distinguish them completely. Why ? Because the motor neurons, which are the cells that control the body’s voluntary muscles, and whose death leads to these neurodegenerative disorders, were not yet fully understood. Guillaume Duchenne de Boulogne, who left his name to a disease similar to ALS, thought, for example, that the latter was due to a purely muscular attack. It was Duchenne, in particular, who made it possible to separate progressive muscular atrophy from other paralyses, since he was the first to note that certain paralyses “were accompanied by a fatty degeneration of the muscles”. But in 1853, real progress in the understanding of the disease was made by Jean Cruveilhier, a prominent scientist at the time, notably a member of the Académie de Médecine. During an autopsy, Cruveilhier was able to demonstrate that the disease first materialized through damage to the spinal cord and, more precisely, through atrophy of the anterior roots.

Although the clinical identification is rightly attributed to Jean-Martin Charcot, it is also important to mention the remarkable work of Augustus Jacob Lockhart Clarke, who accurately described the disease in the early 1860s. Now best known for his descriptions of the spinal cord, this British scientist wrote two detailed case reports following post-mortem neuro-pathological studies of what we now think of as cases of Amyotrophic Lateral Sclerosis. Lockhart Clarke is one of those scientists who have been somewhat forgotten by history, despite his remarkable contributions. Unambitious and above all devoted to his work, he did not hold any prestigious position, and was hardly recognized by his peers during his lifetime. Moreover, he did not hold any academic position. In an article published in The Lancet in 2000, entitled Lockhart Clarke, his role in the early history of muscular dystrophy. Neuromuscular Disorder, the Emery authors tell us that he was “a unique man, of noble independence and honesty, without any ambition… he will be remembered, not as the popular physician, but because of his patient and painstaking researches, so fruitful for medical science.”



  1. Lockhart Clarke’s descriptions: the case of patient F.P.

As mentioned, Lockhart Clarke published two reports. For the purpose of this paper, we will focus on the case of the patient F.P. on whom Clarke worked in collaboration with Charles Bland Radcliffe. This case study will also help us to understand the pathogenesis of the disease. F.P. was a 40-year-old male, which suggests that he had an early onset of ALS. In this patient, the progression of the disease was rapid. Prior to the onset of symptoms, F.P. was visibly healthy and, according to the report, “never had […] a sick day”. Clarke’s acolyte in this case, Radcliffe, described his first encounter with the patient, and his observations were as follows:

“Looking at the clinical facts, it was obvious that there was no material lesion in the seat of intelligence, and it was probable that there was a serious lesion in the parts which govern the movements of the tongue and pharynx, and the respiratory movements in general. Without this latter lesion, indeed, it was difficult to account for the state of paralysis and decay of the tongue, the difficult swallowing, the occasional disturbance of breathing. ”

Eight months later, the patient’s symptoms had spread to both arms, and more generally to the upper body. There was no increase in leg tone either, and the patient was constantly weak and tired, making it impossible for him to stand. Our two scientists did not notice any change in the face, and I quote: “the eyes were intelligent, and the features not inexpressive”. The patient therefore seemed to have retained his cerebral and cognitive capacities, which was also confirmed by the patient’s wife, Mrs P., who told our two scientists that her husband was “never tired of hearing her read books to him, requiring attention and reflection”.

F.P. eventually died, suddenly, six days after being admitted to hospital. According to Martin Turner, Michael Swash and George Ebers, author of the article Lockhart Clarke’s contribution to the description of amyotrophic lateral sclerosis, this type of death is common in ALS patients and is usually due to respiratory failure, pulmonary embolism or cardiac arrhythmia.

It was Lockhart Clarke himself who did the post-mortem examination of the patient, and he immediately noted that there was something remarkable about this case. I quote:

“All the most important symptoms of the disease – the extensive paralysis and muscular atrophy described in the patient’s history, are so clearly and satisfactorily explained by the structural lesions discovered on examination of the nerve centres, that the case before us must be regarded as one of the most remarkable and interesting ever recorded.”

Using techniques that were at the cutting edge of science at the time, Clarke carefully studied the patient’s lumbar canal, cervical canal and brain stem. In each of these areas he noted anomalies, such as cells that looked completely different from what they should have looked like. I quote: “the cells were wonderfully altered from their natural appearance … looked like aggregated granules … all more or less atrophied and shrivelled”. He also noted that the number of nerve cells was small and that some had no nuclei, in addition to their irregular shape.

What also leads us to understand and believe that the patient had ALS is that a signature of the disease, as we know it today, was present: degeneration of the cells of the anterior root and lateral corticospinal tract, which, simply put, is the direct link between the motor cortex and the motor neurons of the spinal cord. As Turner, Swash and Ebers tell us, it was clear from Clarke’s report that he had studied the patient with thoroughness, brilliance and a certain fascination. He ended his report by stating that he was unable to draw any “firm conclusions” from the case, again quoting Clarke: “some important facts … may be more safely or advantageously examined after some other cases of a similar nature have been similarly carefully considered”. And this is precisely where Jean-Martin Charcot comes in, as this is exactly what he would do a few years later. Clarke’s contribution to Charcot’s work was recognized by Charcot himslef, who mentioned it in his Lectures on Diseases of the Nervous System, published in 1881.


  1. The official identification by Jean-Martin Charcot

The life of Jean-Martin Charcot is a classic example of an irresistible social ascent. Born into a family of the Parisian petite bourgeoisie, he quickly decided to devote himself to medicine and passed the competitive examination for the internship in the Paris hospitals in December 1848. In 1851, he joined Pierre Rayer’s team at the Hôpital de la Charité. The latter, a very prominent doctor at the time, was appointed ordinary doctor to Napoleon III in 1852. Rayer quickly grasped Charcot’s potential and was eventually a support and mentor for him. After brilliant studies, Charcot was appointed family doctor in 1854, on Rayer’s recommendation, and passed the competitive examination to become a Paris hospital doctor in 1856. Charcot was 31 years old and assigned to the Salpêtrière Hospital, a hospital where he made his greatest discoveries. Once again recommended by Rayer, he was made an officer of the Legion of Honor in 1858 for his work, and two years later received the agrégation of medicine, where one of the most eminent members of the jury was… Pierre Drayer. Now a lecturer, Charcot quickly became a popular teacher. In the first half of the 1860s, he began to take a serious interest in neurological disorders.

In 1865, the case of a patient who died at the Salpêtrière Hospital changed the course of the history of the disease. Like many others, she was considered hysterical by many medical staff because of permanent contractures that were considered exaggerated. At the time, the lack of knowledge and understanding of unidentified diseases led some medical staff to draw hasty conclusions, to the detriment of the health of certain patients, who were considered to be ‘comedians’, whereas their suffering was very real. It was Charcot himself who performed the autopsy and he quickly understood that the patient was not in fact hysterical. He noted the sclerosis of an entire cord of neurons on the lateral bundle of the spinal cord and the presence of lesions on the anterior roots of the latter. The study of another patient with similar characteristics led him to publish, in 1869, Two cases of progressive muscular atrophy with lesions of the grey matter and the anterolateral beams of the spinal cord.

Through these two patients, Charcot understood that several diseases concerned the motor system. Having worked with Duchenne in the past, his ambition was from that point on, to distinguish these neurodegenerative diseases which seemed, at first sight, very similar. In one of his lessons he stated that in the period 1858-1867 “the role of alterations in the nerve cells themselves had not yet been elucidated”. In 1870, a new patient with the same characteristics as those already examined made him observe a bulbar impairment linked to the disease. This characteristic, which was also present in Lockhart Clarke’s F.P. patient, affected the tongue, soft palate and perioral muscles. In 1874, after studying 20 cases and performing 5 autopsies, Charcot was now certain that all these patients suffered from a rare and unique disorder. He decided to give the disease the name Amyotrophic Lateral Sclerosis.

In 1881, in his Lectures XI, XII and XIII, he mentioned two forms of degeneration of the motor system, which lead to muscle atrophy and weakness. He called these forms “protopathic” and “deuteropathic”. What does this mean? The first, protopathic, is characterized by muscle atrophy and degeneration of the anterior root of the spinal cord. The second, deuteropathic, describes degeneration of the anterior root of the spinal cord, associated with degeneration of the lateral beams of the spinal cord. Charcot based his conclusions not only on the cases examined at the Salpêtrière, but also on other cases already recorded at the time, such as the two patients of Lockhart Clarke.

Jean-Martin Charcot not only examined the signature features of the disease, but also observed its slow evolution, which he was the first to do, since he now knew that it was a single and unique disease. He recognized it as progressive, and as a condition that starts in adulthood, at a fairly advanced age. He also noted that the disease sometimes runs in families and suggested that the disease may be hereditary. He also understood that the disease can develop more or less gradually, and that some patients may survive for up to 20 years after the first symptoms appear, while others will succumb within five years. In both cases, the progression of the disease is slow, and according to him, is characterized by progressive muscle weakness in one arm, which eventually spreads to the second. The disease, in its early stages, rarely affects the legs. Nor does he note any stiffness in the muscles.

A prolific scientist, Charcot was not content with his work on ALS and made important contributions to the identification and understanding of many other disorders. A true medical superstar in the 1880s, and a famous figure in French society, he was celebrated in France and abroad, where he embodied the excellence and influence of French science, along with the no less famous Louis Pasteur. In 1882, the first chair in the world to focus on diseases of the nervous system was created for him, on the initiative of the then President of the Council of Ministers: Léon Gambetta. The following year, he was elected member of the Academy of Medicine. He died of a pulmonary edema on 16 August 1893 and was given a national funeral three days later, as well as military honours.


  1. After Charcot

As mentioned above, Jean-Martin Charcot had suggested that hereditary forms of the disease might exist. Although he was unable to confirm this feeling, another scientist did so 15 years after Charcot’s first remarks. This was William Osler, another iconic figure in the history of medicine. Remember, we already mentioned Osler in our episode on the History of Stress in Medicine. In 1880, he was the first to report a typical ALS with autosomal dominant inheritance in a family in Vermont, a state in the north-eastern United States. Again, what does this mean? Well, an autosome is a non-sexual chromosome, which is likely to carry a gene with an abnormality. According to the AFM Telethon, and I quote: “In these so-called autosomal dominant diseases, an abnormality affecting only one copy of the gene is sufficient for the disease to develop. This anomaly is transmitted by one of the parents, the father or the mother. The latter is himself ill: he has the genetic anomaly in one copy on one of his chromosomes.” The family studied was called Farr, and Osler published a paper in 1880 dealing with this particular case, entitled Heredity in Progressive Muscular Atrophy as illustrated in the Farr family of Vermont. In this article, he focused on Erastus Farr, whose father, uncle, aunt and four cousins died at an early age from a form of ALS that is now known as Familial Amyotrophic Lateral Sclerosis. This Farr family represented a very rare case of a disease that is already considered rare. Today, we know that 5-10% of ALS is hereditary. It took more than 100 years to find one of the genes involved, SOD1, which was identified in 1993. As the Orphanet portal for rare diseases and orphan drugs tells us: “the majority of cases [of ALS] are sporadic, but 5-10% are familial and 20% of them have mutations in the SOD1 gene (21q22.11).” According to Dr. Robert H. Brown, Professor and Chair of Neurology at the University of Massachusetts Medical School, I quote:

“This family [Farr] has been of immense importance to ALS studies. Thanks to this family, and others like it, it was possible to discover the first genes for the disease. These genes have made it possible to create cell models of the disease that have been essential in the search for treatments for ALS. It is possible that the first treatable types of ALS will be those that have been so devastating to this wonderful family.”

After Charcot’s work, there were very few advances. Attempts at treatment were even less frequent. Let us nevertheless mention the identification of a variant form of ALS, pseudopolynevritis, in 1918 by Pierre Marie and his student Patrikios. Remember, we had already mentioned Pierre Marie in our two episodes on Acromegaly, another rare disease. Pierre Marie was the one who definitively named the disease, and went to meet patients in the 1880s at the request of… Jean-Martin Charcot. This variant form of ALS discovered by these two men is therefore characterized by an involvement of the legs, whereas the vast majority of forms of ALS first affect the arms, by a slow progression due to a slow death of the upper motor neurons, and by a life expectancy estimated at five years from the appearance of the first symptoms. Until advances would be made in modern molecular biology, there would be little change in the understanding of the disease or in the prospects for treatment. Again, there is currently no cure for ALS. However, several celebrities were affected by the disease in the 20th century and helped to bring it to light. It is now one of the most well-known rare diseases in the world, for the reasons mentioned in the introduction to our first episode. Let’s focus on one of these personalities.

  1. Lou Gehrig, the face of ALS

If the name Lou Gehrig doesn’t ring a bell, it’s because, like the vast majority of Europeans, you have very little interest in baseball. However, the sport is extremely popular in the United States and, according to a 2017 study by the American polling institute Gallup, is the favourite sport of Americans after American football, neck and neck with basketball. Lou Gehrig is a legendary figure across the Atlantic. In 2019, Eurosport focused on the story of Lou Gehrig, in its series The Great Tales, and this is how journalist Maxime Dupuis began his article: “Lou Gehrig is the story of one of the greatest players in the history of baseball. An athlete that America cherished for his modesty and humility. And whom it imagined to be invincible. At the age of 36, illness unjustly took him. It took his life, he gave it his name.”

Lou Gehrig was born on June 19, 1903 in New York, a city he would never really leave. Coming from a very modest background, he began to play American football before focusing on baseball, where he was quickly talked about on the youth teams. Lou had indeed impressive technical and physical qualities. As an adult, he was 1.83 meters tall and weighed 91 kilos. Very quickly, once entering the professional circuit, he was given the nickname of Iron Horse. Powerful and enduring, Lou Gehrig was a modern athlete. After a stint in the minor league to acclimatize at the top level, he quickly joined the first team of the legendary New York Yankees franchise, where he would wear the white jersey throughout his entire career. His association with Babe Ruth, considered today to be the greatest player in the history of the sport, was working wonders. In 1927, he was one of the strongmen of the team which many consider to be the best in history, culminating in a landslide World Series final victory over the Pittsburgh Pirates. Maxime Dupuis tells us about his career:

“We could pour a flood of statistics to sum up his immense career, tell you that he won the World Series 6 times, was elected MVP twice, 7 times All Star and remains to this day among the 18 players in history to have hit 4 home runs in a single game. But a number better sums up the man that Gehrig was: 2130. As the number of matches played in a row by the New Yorker with his franchise of always. A record that lasted fifty-six years.”

But after 2130 matches, Lou was forced to say stop. Accidents, he had known. But he always continued, never flinching. In April 1933, when wearing a helmet was not yet compulsory, he was hit in the head during training. Later, an x-ray would show that he suffered from 17 fractures during his career, without taking the time to treat them. He knew how to play an entire match despite lumbago. Lou knew how to take it. A tough guy. But no matter how big a superhero he was, the disease made him say stop. In 1938, Gehrig saw his performance drop. Worse, he had the very unpleasant feeling that his physique was starting to fail him. A top athlete, he was 34 years old at the time, and one thought his golden years were over. But Lou could tell that the loss of his physical capacities was too brutal. He sometimes lost consciousness. It was not normal, and he knew it. In June 1939, after a complicated season with the Yankees, he visited the Mayo Clinic in Rochester, Minnesota, on the advice of his wife, Eleanor. A few days later, on June 19, he emerged from the clinic, probably with a heavy heart. Under his arm, a file including a letter from Dr. Harold C. Habein. The diagnosis fell. Lou suffered from Amyotrophic Lateral Sclerosis, Charcot’s disease. Dr. Habein’s letter stated that “the nature of this disorder is such that Mr. Gehrig will be unable to continue his active participation as a baseball player to the extent that it is desirable that he retain. his muscle energy”. Optimistic by nature, Lou Gehrig tried to reassure his close ones, telling them that he had a one in two chance of being able to continue living a normal life, despite the illness. In truth, he probably knew he was doomed. The announcement of the end of his athletic career loomed, and the time for farewells arrived, two weeks after the diagnosis. It happened on a symbolic date for the United States, July 4, the national holiday. Before the game against the Washington Senators, Lou Gehrig was celebrated, it must be said that he represents, as Maxime Dupuis specifies to us, the “legend next door”, a simple, humble and approachable man, adored by his teammates and fans. Already very weakened, he found it difficult to carry the many gifts that he was presented with on the path which was supposed to take him to the center of the pitch. He dropped these presents, one by one, before taking the microphone, in front of the 62,000 fans present at Yankee Stadium. 4 minutes of a legendary speech, marked by the total silence of the crowd. A rare moment suspended in time. Lou Gehrig told them:

“For the past two weeks you have been reading about a bad break. Yet today I consider myself the luckiest man on the face of the earth. I have been in ballparks for seventeen years and have never received anything but kindness and encouragement from you fans. When you look around, wouldn’t you consider it a privilege to associate yourself with such a fine looking men as they’re standing in uniform in this ballpark today? Sure, I’m lucky. […] When everybody down to the groundskeepers and those boys in white coats remember you with trophies – that’s something. When you have a wonderful mother-in-law who takes sides with you in squabbles with her own daughter – that’s something. When you have a father and a mother who work all their lives so you can have an education and build your body – it’s a blessing. When you have a wife who has been a tower of strength and shown more courage than you dreamed existed – that’s the finest I know. So I close in saying that I might have been given a bad break, but I’ve got an awful lot to live for. Thank you.”

His health gradually declining, as the disease progressed, Gehrig wanted to stay active, but he eventually succumbed to the disease on June 2, 1941, sixteen years to the day after his debut as a starter with his long-standing team, the Yankees. One of America’s most famous and beloved men had passed. Since then, Amyotrophic Lateral Sclerosis has been commonly referred to as Lou Gehrig’s Disease in the United States. As we saw in our last episode with Valérie Delattre, this baseball player, through his touching story, managed to put the human before the disease. He who preferred to leave megalomania to others and who sometimes seemed almost embarrassed by his immense popularity, had become, paradoxically, eternal.

And it is with this beautiful and tragic story that we end the History of Amyotrophic Lateral Sclerosis, or Charcot disease, or of course, Lou Gehrig disease. This history is marked by a late discovery and identification, but an absolutely remarkable one. As Turner, Swash, and Ebers tell us, it’s worth, and I quote:

“To salute the remarkable progress made in our knowledge of motor neuron diseases in the 19th century. Reading these reports, one cannot help but be impressed by the clarity of the clinical and scientific questions formulated so many years ago. They are as relevant today as they were then; indeed, it is sobering to note that many of these questions are still the subject of current debates.”

Although little progress followed the remarkable work of Lockhart Clarke and Jean-Martin Charcot until the era of modern molecular biology, the disease was embodied, as it has rarely been the case in history, by famous scientists and patients, making it possible to highlight it and attract the attention of the general public. Research continues and represents the best hope for patients and the 800 people who are diagnosed with this disease each year in France. We all hope that treatments will be found to help thm. As such, I allow myself once again to redirect you to the channel of my friend and colleague at Fondation Ipsen, Yannick, who offers in his program Our Health, an interview with Dr. Maria Grazia Biferi who heads a research team at the Institute of Myology in Paris, and who is dedicated to the preclinical development of gene therapy for motor neuron-related diseases, such as ALS.


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  1. Lou Gehrig: Luckiest Man [Lou Gehrig: l’homme le plus chanceux], US National Baseball Hall of Fame


  1. Gallup News Service: December 4-11, 2017 – Final Topline? What is your favorite sport to watch? [Quel sport préférez-vous regarder?]



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