Compared to other, more well-known neurodegenerative diseases like Alzheimer’s, ALS has been around for 150 years and counting, first described in the mid-to-late nineteenth century. Jean-Martin Charcot, the “father of neurology,” was the first scientist to document cases of amyotrophic lateral sclerosis. He conducted studies from 1865 to 1869, gave lectures to French scientific societies from 1869 to 1874, and eventually compiled his life’s work into Oeuvres Completes, which contained all his findings on several neurological conditions. In Oeuvres Completes, Charcot first coined the term amyotrophic lateral sclerosis (Kumar et al. 2011); his ALS research is on pages 153-272 in the original French text.
Over the next hundred or so years, regular studies of ALS were published, but none proved to be high impact in the field. One study of note looked at the possible link between sporadic ALS and chronic lead intoxication (Bruce 1907); we now know that lead exposure is a major environmental risk factor for sporadic ALS, so this study was ahead of its time. ALS as a whole gained publicity in the mid-twentieth century when New York Yankees first baseman Lou Gehrig had to retire early because of his 1939 ALS diagnosis. He was the first major public figure to be diagnosed with ALS, and for this reason many know ALS by its informal name, Lou Gehrig’s Disease. A couple decades later in 1963, young genius and future theoretical physicist Stephen Hawking was diagnosed with early-onset ALS. He would become a household name up until his death from ALS fifty-five years later, and he is still an inspiring role model for disabled people because of how he lived for many years almost completely locked-in.
The ALS field and FALS specifically were reinvigorated by two major breakthroughs only a year apart, launching the neglected disease into the genomics era. In 1993, SOD1 became the first gene and protein to be linked to ALS1 (Rosen et al. 1993). In 1994, the first animal model for ALS was developed, a transgenic mouse model (Dal Canto and Gurney 1994). This allowed for more controlled, safe, and inexpensive investigations and drug testing for ALS. Logically, the first ALS drug, riluzole, was approved in 1999 to marginally extend the prognosis of some ALS patients (Bensimon et al. 1994). All ALS research in the twenty-first century builds on these three core achievements in the 90s, such as the approval of the second ALS drug, edaravone, in 2017 (Abe et al. 2017). More events did take place; the Annotated Bibliography lists some of the others.
ALS is progressive, meaning it steadily gets worse over time. The main clinical phenotype is motor neuron death in the spinal cord and brain, especially the pyramidal tracts of the spinal cord (Davison and Wechsler 1936), which causes progressive paralysis and death (Information from NCBI 1998). Since the specific symptoms can vary between patients, a unique set of clinical diagnostic criteria is necessary.
The El Escorial and Awaji diagnostic criteria are commonly used together in clinical scenarios to diagnose ALS. Other criteria exist for more specific cases, but these are the most commonly used and accepted (Siddique and Siddique 1993). Together they are:
- The presence of all of the following:
- Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination
- Evidence of upper motor neuron (UMN) degeneration by clinical examination
- Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination
- Together with the absence of both of the following:
- Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration
- Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs
These guidelines are somewhat vague because no other noninfectious disease has the same level of motor neuron death. Note the importance of progression: if your disease is not progressing rapidly on the scale of months, you likely do not have ALS.
ALS does not affect all people equally. Men are slightly more likely to be diagnosed than women, but the difference thins out with age. Caucasians and non-Hispanics are most likely to develop ALS, though it is unclear if that is due to genetics, environmental toxins, or something else. ALS symptoms tend to first show between ages 55 and 75, but FALS patients typically show symptoms a little earlier (ALS Fact Sheet).
Here are some more symptoms of ALS in general. Several of them have simple fixes, which I will address in the next page, Treatment & Frontiers. The core symptoms are motor neuron atrophy/death (mentioned earlier), muscle weakness, loss of muscle mass, and an inability to control movement (Andersen et al. 2007). All other symptoms are resulting from progression of these.
The early symptoms include muscle fatigue, since it is easier to overwork atrophying muscle, even without exercising; muscle cramping; stiffness; muscle weakness; and slurred speech, or dysarthria. Most patients have a couple of these symptoms early in the disease, while they can still move voluntarily. Late stage symptoms include difficulty swallowing or chewing, called dysphagia, which can result in malnutrition without a feeding tube; thinning of arm and leg muscle; complete inability to walk; general loss of independence; difficulty breathing; and fatal respiratory failure (Andersen et al. 2007). In the final weeks or months, some ALS patients suffer from lock-in syndrome, which involves complete loss of ability to move voluntarily, sometimes including the eyeballs, but with normal cognitive function. Thankfully, technology has allowed lock-in patients some level of autonomy in recent years.