Amyotrophic Lateral Sclerosis


What is ALS?:

Amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrig’s disease, is characterized as progressive degeneration of the motor neurons. This leads to the loss of connections between motor neurons and muscles. As these connections die, the brain is no longer able to send signals to initiate or control movement. This means that the brain is no longer in control of the body's voluntary movement. This neuronal death will also lead to muscle atrophy and paralysis because the muscles are no longer receiving the signals they require to function. Most patients die within five years of onset due to respiratory complications.


Anatomy Review:


ALS1.jpg

The body is made up of thousands upon thousands of nerve cells. These nerve cells, or neurons, are responsible for sending and receiving electrical impulses throughout the body in order to initiate or prevent movement and send other neural impulses to the brain. Neurons are made up of 3 main components: the cell body, the axon, and the dendrite. The dendrites are branches off of the cell body where neurons receive the stimulus (input). The cell body is where the impulse is processed and integrated. The axon is where the electrical impulses are sent out to other neurons (output). The speed at which the axon conducts impulses is based off of its diameter and myelination. Axons are insulated by myelin which allows for faster conduction down the axon.

The nerves most affected by ALS are those that are involved in voluntary movement and muscle power. Each muscle fiber in the body is inervated, or controlled, but one motor neuron. However, one motor neuron may inervate multiple muscle fibers. The motor neuron and the muscle fibers that is inervates are called a motor unit. When it comes to movement, there are two types of motor neurons that are important to know: upper motor neurons and lower motor neurons, also known as alpha motor neurons. The upper motor neurons are located in the ‘motor cortex’, which is made up of the premotor cortex, the primary motor cortex, and the supplementary motor cortex. The motor cortex is in control of the body’s voluntary movements. When stimulated, the motor cortex sends an action potential via the upper motor neurons to the lower motor neurons located in the spinal cord. The upper motor neuron will typically synapse with an interneuron located in the spinal cord. Once the action potential has reached the lower motor neuron, it travels through the ventral horn and then down to the muscle fibers inervated by the motor neuron. This chain of events causes the muscle fibers to contract. The lower motor neurons are those that invervate the skeletal muscles. All of this takes place in

what is referred to as the corticospinal tract. This tract is what allows the brain to control the movement in any part of the body it wants. The corticospinal tract (diagram below) consists of the lateral tract and the anterior tract. The lateral tract controls the movement of the distal muscles while the anterior tract controls the proximal muscles.


corticospinal_tract.png

Pathophysiology:


The term amyotrophic refers to the atrophy of muscle fibers and the term lateral sclerosis refers to the hardening of the lateral and anterior columns of the spinal cord. The hallmark of ALS is the death or wasting away of both the upper and lower motor neurons in the motor cortex and spinal cord. As the motor neurons waste away, their axons become thinner in diameter and lose their conductivity. This is because the myelin around the axon has been affected. In the same way, the dendrites of the affected neurons also become weaker and are unable to pick up stimulus. This wasting away inevitably leads to the weakening of the muscles innervated by the neurons affected. As the motor neurons and their corresponding cells deteriorate, the muscle fibers that they innervate become denervated, meaning that they no longer can receive input from the spinal cord. Similarly, as the motor neurons in the spinal cord deteriorate, they are replaced by fibrous astrocytes, which cause them to harden. The hardening of the motor neurons in the spinal cord

The exact cause of ALS is still unknown. However, research has shown that one of the causes of inherited ALS has to do with a mutation of the gene that produces the superoxide dismutase 1 (SOD1) enzyme.This enzyme is responsible for protecting the body’s cells from free radicals that are produced by the cells themselves. If this enzyme is affect

At this point, there is only one drug that can be administered to ALS patients. Riluzole targets the cells in the brain that are responsible for the transportation of glutamate. This particular drug is used to decrease the amount of glutamate that is produced in ALS patients. Overtime this can reduce the damage done to the motor neurons that have been affected. There has been some success in slowing down the progression of the disease with Riluzole, but it is in no way a cure as of yet. Other treatments include physical and occupation therapies that help the patient live with ALS.ed/mutated, the body loses its protection from the free radicals. There is evidence that the mutation of these gene can be toxic and can therefore cause ALS. Some doctors have also found that an excess of glutamate, a neurotransmitter in the brain, can lead to the degeneration of motor neurons. The excess of glutamate can lead the an overstimulation of neurons. There has also been studies and research done that could link genetic ALS to a mutation in the gene C9ORF72. Again, scientists are not sure how the mutation of this gene can cause ALS to occur, but the mutation is a common factor between most ALS patients.


Signs/Symptoms:


There is no test to determine whether or not someone has ALS. Primarily, the only way to be diagnosed is by studying and monitoring symptoms over time. The main symptoms include: muscle weakness, atrophy of muscles, hyperreflexia, and spasticity. Some also present with ‘thick speech’ and difficulty swallowing or breathing. Another common sign of ALS is the appearance of fasciculations, or small involuntary muscle twitches. The hands and feet are typically the first to be affected and seen as early symptoms. Patients diagnosed with ALS lose things such as dexterity in the hands, and are unable to perform fine motor tasks. They may also have trouble walking and will tend to trip over things. Not everyone with ALS will present with the same symptoms, but in general muscle weakness and paralysis are known to be present in all cases. As the disease spreads, the muscles that control breathing and swallowing will become affected, along with speech. The loss of these functions is what leads ALS patients to their demise.


Conclusion:


Those who have been diagnosed with ALS will be able to live with the disease for about 3 years. Patients usually lose their battle with this disease due to the loss of ability to control the muscles they need to breathe. Most will need ventilators towards the end of their life. Unfortunately, there is no known cause for this disease or a cure on the horizon. There are many different factors that could contribute to the onset of this disease. Scientists are currently doing research on other medications and treatments to improve the quality of life of those who have been diagnosed with ALS.


Sources/ Suggested Readings:


Extent of Cortical Involvement in Amyotrophic Lateral Sclerosis

Diagnosis Pathway for Patients With Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis: A 2013 Update

Genetics of Amyotrophic Lateral Sclerosis

Glossary:


Atrophy: The wasting away or decrease of parts of the body; in this case the wasting away of motor neurons.


Fasciculations: A small muscle twitch or involuntary muscle contraction.


Glutamate: A neurotransmitter involved in maintaining brain functions such as movement.


Hyperreflexia: Overactive or over responsive reflexes or twitching.


Spasticity: Tightness or stiffness of muscles due to excessive muscle contraction.


Quiz:


1). T/F - An axon is the main receptive area of a neuron
2). T/F - Myelin helps improve conductivity speed
3). T/F - ALS affects both the upper and lower motor neurons involved in voluntary movement
4). T/F - The Corticospinal Tract is directly involved in initiating and preventing voluntary movement
5). T/F - Riluzole can repair damage done to the motor neurons affected by ALS
6). What neurotransmitter is involved in activating motor neurons:
a). Dopamine
b). Glutamate
c). Acetylcholine
d). GABA
7). A symptom of ALS is:
a). Muscle weakness
b). Spasticity
c). Hyperreflexia
d). Muscle twitches
e). All of the above
8). The motor cortex sends impulses via
a). Lower motor neurons
b). The ventral horn
c). Upper motor neurons
d). Interneurons
9). Explain the process of motor neuron degeneration
10). What are the possible causes of ALS?
11). How does the Corticospinal Tract play into movement?


References:



Thorns J, Jansma H, Münte T, et al. Extent of cortical involvement in amyotrophic lateral sclerosis - an analysis based on cortical thickness. BMC Neurology [serial online]. November 2013;13(1):1-22. Available from: Academic Search Premier, Ipswich, MA. Accessed November 30, 2013. http://www.biomedcentral.com/1471-2377/13/148.

Williams J, Fitzhenry D, Grant L, Martyn D, Kerr D. Diagnosis pathway for patients with amyotrophic lateral sclerosis: retrospective analysis of the US Medicare longitudinal claims database. BMC Neurology [serial online]. November 2013;13(1):1-15. Available from: Academic Search Premier, Ipswich, MA. Accessed December 1, 2013. http://www.biomedcentral.com/1471-2377/13/160.

Sheng C, Sayana P, Xiaojie Z, Weidong L. Genetics of amyotrophic lateral sclerosis: an update. Molecular Neurodegeneration [serial online]. September 2013;8(1):1-15. Available from: Academic Search Premier, Ipswich, MA. Accessed December 1, 2013.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766231/.

Gordon P. Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials. Aging & Disease [serial online]. October 2013;4(5):295-310. Available from: Academic Search Premier, Ipswich, MA. Accessed November 28, 2013.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794725/.

Gordon P. Amyotrophic Lateral Sclerosis Pathophysiology, Diagnosis and Management. CNS Drugs [serial online]. January 2011;25(1):1-15. Available from: Academic Search Premier, Ipswich, MA. Accessed December 1, 2013.
http://www.ncbi.nlm.nih.gov/pubmed/21128691.

NINDS. Amyotrophic Lateral Sclerosis Fact Sheet. Accessed November 30, 2013. Retrieved from: http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/detail_ALS.htm.

Armon, C., & Lorenzo, N. Amyotrophic Lateral Sclerosis (ALS). Medscape Reference. Accessed: November 30, 2013. Retrieved from: http://emedicine.medscape.com/article/1170097-overview#a0104.

Quiz Answers:


1. False

2. True
3. True
4. True
5. False
6. B
7. E
8. C