Amyotrophic Lateral Sclerosis — A Brief Definition and what the Healthcare Industry is doing about it

Introduction:

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a heterogeneous neurodegenerative disease affecting primarily both upper motor neurons and lower motor neurons and the central nervous system (CNS) as well, leading to motor and extra-motor symptoms. ALS is characterized by gradual degeneration and death of motor neurons. Motor neurons extend from the brain to the spinal cord and to the muscles throughout our body. The motor neurons are responsible for communication between the brain and the voluntary muscles. Messages from the brain are transmitted by the upper motor neurons (that is, neurons that project from the cortex to the brainstem and the spinal cord) and lower motor neurons (that is, neurons that project from the brainstem or spinal cord to muscle) to the spinal cord and motor nuclei of brain and finally to a particular muscle or muscles. In ALS, this transmission of signal from the brain to the muscles is disrupted due to degeneration of both the upper and the lower motor neurons. Due to the subsequent loss of function, the muscles gradually become weak, spams (called fasciculations), and muscular atrophy occur and the brain eventually loses its ability to initiate and control voluntary movements. In most patients ALS advances relentlessly, with a median survival of about 3 years after onset, and in most cases death due to respiratory failure[1].

Nearly 50% of patients with ALS present extra-motor manifestations such as cognitive and/or behavioral impairment. About 13% patients develop concomitant behavioral variant frontotemporal dementia (FTD) while 35% — 40% patients show mild behavioral and/or cognitive changes [2, 3]. FTD causes degeneration of the frontal and anterior temporal lobes and is clinically manifested by behavioral changes, impairment of executive functioning and language impairment [4]. Overlap in the underlying molecular mechanisms has been observed in both these neurodegenerative disorders, namely ALS and FTD [5].

The global ALS prevalence and incidence are approximately 4.42 per 100,000 populations and 1.59 per 100,000 person-years, respectively. Based on U.S. population studies, approximately 30,000 Americans currently have the disease[6].

There are essentially two type of ALS:

· Sporadic ALS (sALS)

Most of the ALS cases (90 percent or more) are considered to be sporadic which means that the disease seems to occur at random with no family history of the disease. However, family members of people with sporadic ALS (sALS) are at an increased risk for the disease.

· Familial (Genetic) ALS or fALS

Only 5 to 10 percent of all ALS cases are familial, which means that the disease is inherited from parents.

Treatment:

While there are known variants of ALS and genetic studies have revealed much about the coding at the molecular level, there is still no known cure. Palliative therapy along with medication that ameliorates some of the neurodegeneration is the only current therapy.

Considering ALS as chronic neurodegenerative disease, disease modifiable measures and aids with proper equipment and patient care for symptomatic relief is the only treatment. The current FDA approved drugs such as Riluzole and Edaravone, although cannot reverse or stop progression of ALS, but it can give symptomatic benefits [7]. Report suggested the randomized trials on the safer drug Riluzole showing 35% improved twelve months’ survival rates with well toleration; however it is expensive one in the market. The other drug Edaravone used as free radical scavenger exhibited reduced motor decline, and is perfectly tolerable with minimum side effects. However, the mode of administration of the drug is a bit cumbersome considering the route, which is intravenous. Survey revealed 59% ALS patients receiving through an implanted port, 21% ALS patients receiving through peripherally inserted central catheter (PICC), whereas 18% ALS patients were administered through a peripheral line, along with rest 2% ALS patients with used other known methods. Another potential FDA approved pharmaceutical Nuedexta (dextromethorphan HBr and quinidine sulfate), is being used to target symptoms of pseudobulbar affect, which is a condition categorized by unpredictable and sudden episodes of crying or laughing seen in people with ALS [7].

Several Phase II drugs are undergoing evaluation in clinical trials. Given the various types and levels of neurodegeneration in patients these potential therapies offer some hope, long with palliative, mental and other life-long care, as no curative is yet available.

References:

1. Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918–1929. doi:10.1111/ene.14393

2. Phukan J, Elamin M, Bede P, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatr 2012; 83: 102–08.

3. Elamin M, Bede P, Byrne S, et al. Cognitive changes predict functional decline in ALS: a population-based longitudinal study. Neurology 2013; 80: 1590–97.

4. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546–1554.

5. Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain2011; 134: 2582–2594.

6. Xu L, Liu T, Liu L, et al. Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol. 2020;267(4):944–953. doi:10.1007/s00415–019–09652-y

7. Barp A, Gerardi F, Lizio A, et al. Emerging Drugs for the Treatment of Amyotrophic Lateral Sclerosis: A Focus on Recent Phase 2 Trials. Expert Opin Emerg Drugs. 2020; 25:145–164.