Nearly 80 years after his death, ALS is still eponymous with the record-setting New York Yankee, Lou Gehrig. Gehrig brought nationwide attention to ALS, as spectators watched their baseball hero battle a disease that quickly took his power at bat and prowess at first.
Today, there are few who know Gehrig’s impressive batting average or who remember the entirety of his heartfelt speech upon retirement from baseball at the age of 36, yet ALS is still known by way of the Hall-of-Famer. Lou Gehrig’s disease, people call it – Gehrig and ALS paired as closely in our minds as baseball and apple pie.
But half a world away, ALS goes by another name, Charcot’s Disease. Named after a different sort of Hall-of-Famer: renowned French neurologist Jean-Martin Charcot who, in 1869, was the first to make an ALS diagnosis.
Dismissed and Undiagnosed
In the 19th century, amyotrophic lateral sclerosis (ALS) was completely unknown. Well, let me rephrase. The term ALS was completely unknown. The symptoms though, were unfortunately known.
In fact, the first written record of ALS-like symptoms comes from the Scottish physician Charles Bell in 1824, but there were almost certainly unrecorded cases of progressive muscle atrophy, contractures, and other neuropathological symptoms in patients who maintained cognitive ability (1). But doctors had no diagnosis to give, and no treatments to apply.
Enter Jean-Martin Charcot
It wasn’t until Charcot entered the field of medicine in the mid-19th century that these symptoms were given a closer look. Charcot was born in Paris in 1825, attained his medical degree in 1853, and began work at the Hospital of the Salpêtrière outside Paris in 1862.
When Charcot arrived at Salpêtrière, a hospice with over 5,000 patients, the facility was not known for advanced medical research. Patients were often left undiagnosed with poorly understood chronic rheumatological or neurological issues. These were issues that doctors once thought to be connected due to similar effects on joints and movement, but which scientists now know are completely unrelated (“two trees living side by side,” in Charcot’s words) (2). Many more patients were misdiagnosed as suffering from “hysteria”, a catch-all term applied to a variety of indefinable illnesses (2). All were largely dismissed as chronically ill with little hope of recovery.
It was clear that the diagnostic abilities of the late 19th century medical community were lacking. Charcot directly took on the challenge of improving them. He took over 2,000 patients under his direct care, began evaluating their illnesses, and quickly became the first Professor of Diseases of the Nervous System in Europe (2).
Method to the Madness
Medical diagnoses, at their core, are a way to categorize and subcategorize illnesses in order to group similar cases and focus treatment. At Salpêtrière, Charcot developed an improved method for diagnosing. The anatamo-clinical method, he called it (2).
His method combined detailed clinical records taken over the course of the patient’s life. This included photographs, notes, drawings, and tremor recordings, with post-mortem anatomical analysis of the brain and spinal cord (2). His clinical observations allowed for cases to be categorized at a symptomatic level. While the anatomical, bodily observations provided another layer of understanding, differentiating diseases that presented similarly, but affected separate regions of the body. More accurate diagnoses could be made.
A Disease by Any Other Name
In 1865, Charcot saw a “young woman diagnosed as hysteric” who had “developed profound weakness, and showed increased muscle tone, with contractures of all extremities during life,” though her intellect and urinary control were preserved (2). Several years later, he saw another patient with similar neurological symptoms including muscle weakness and wasting, but with no contractures. Whereas many doctors would have given the same broad diagnosis to both, Charcot’s methods painted a clearer picture.
After their deaths, Charcot conducted an autopsy on both patients. The woman was revealed to have “specific and isolated lateral column degeneration in the spinal cord.” However, the other patient’s degeneration was focused on the anterior horn of the spinal cord (2).
Over the years, Charcot used these cases as reference points and found patients who presented nearly identical clinical and anatomical symptoms. Through the anatamo-clinical method, Charcot had distinguished these cases as two different neurological diseases: amyotrophic lateral sclerosis (ALS) and a paralytic form of infantile paralysis, or polio (2). It was the first breakthrough in ALS research.
Charcot would go on to diagnose and identify more neurological diseases than any other clinician before or after. He sparked “almost revolutionary progress in neuropathology” (2). “It will hardly be an exaggeration to say that at least one-third of the maladies now actually defined, catalogued, and diagnosed” would not be known were it not for Charcot, a British doctor wrote in 1889 (3). His influence spread beyond his hospital and throughout Europe, bringing patients from around the world to Salpêtrière in hope of receiving a diagnosis.
Charcot, Gehrig, and ALS TDI
Charcot’s legacy still abounds in neurology today. Charcot’s emphasis on clinical documentation takes modern form in our ALS Research Collaborative (ARC), the most comprehensive and longest running translational research study in ALS. This year, ALS TDI plans to launch a blood collection program as part of ARC. This will improve our ability to discover blood-based biomarkers and better track individual ALS progression. If Charcot were alive today, he surely would have developed his anatamo-clinical method into something similar.
In his anatomical studies of neurology, Charcot was the first to apply the use of microscopes to neurology. Now, researchers can observe the minute details of ALS through daily use of highly powered microscopes. Modern scientists have seen how proteins can misfold, how demyelination can interfere with the transmission of signals along the axon, and how an overabundance of free radicals might cause oxidative stress that damages the cells. Researchers at ALS TDI and around the world have made countless additions to the understanding of ALS through clinical, genetic, cellular, and animal model experiments.
ALS diagnosis, too, has remained rooted in Charcot’s observations, though over the years diagnosis has become more precise, more nuanced. Doctors now know that bulbar and limb-onset ALS are anatomically similar, though their symptoms appear in different regions. They know that 10% of ALS cases are familial and that 90% are sporadic. In the last century they have come from understanding nothing about genetics and cell biology (4), to discovering the first genetic mutation related to ALS, SOD1, in 1993, to identifying over 30 genetic mutations related to familial ALS (FALS).
ALS is still extraordinarily complex. It involves many interrelated anatomical processes and evolves due to a plethora of environmental and genetic factors. Patients still wait too long for diagnosis, and misdiagnosis still occurs. Only two modest treatments exist for ALS. There’s an obvious need for more investment in ALS research.
But ALS research has come a long way. 150 years ago, scientists didn’t know that ALS was a disease. 80 years ago, Lou Gehrig didn’t know that he was one of 30,000 people in the U.S. affected by ALS each year. And just 5 years ago, ALS TDI wasn’t sure if it was possible for a nonprofit biotech to advance a therapeutic compound into clinical trials.
But what has always been known, what ALS TDI shares with Charcot, Gehrig, and all impacted by ALS through history, is that there is hope through research, that a treatment is possible.
Science Sunday blogs aim to make ALS research and the work of the ALS Therapy Development Institute more accessible to people with ALS, families, friends, and health care providers. ALS TDI believes in open-source science accessible to all, with the goal of empowering the public with knowledge of ALS. Comments or feedback? Email info@als.net.
References:
(1) Saberi S, Stauffer J, Ravits J. Neuropathology of amyotrophic lateral sclerosis and its variants. Neurol Clin, 205: 33(4) 855-876. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628785/#!po=1.78571.
(2) Goetz, C. Jean-Martin Charcot and the anatomo-clinical method of neurology. Handbook of Clinical Neurology; 2010, Vol 95, 203-211.
(3) Hart E. Medical Paris of Today [Letter from Mr. Ernest Hart]. The British Medical Journal; 1889.
(4) Mott, F. The Croonian Lectures on Degeneration of the Neurone. The British Medical Journal, 1900; 2:2063, 82-90.
(5) Ray J. “Lou Gehrig”. Society for American Baseball Research. https://sabr.org/bioproj/person/ccdffd4c.