Amyotrophic Lateral Sclerosis

Overview

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is characterized as degeneration of upper and lower motor neurons, leading to progressive muscular paralysis and death. Primarily affected are the lower motor neurons in the ventral horn of the spinal cord, the prefrontal motor neurons, and the corticospinal upper motor neurons in the precentral gyrus. Depending on the site of deterioration, different clinical signs will be present during the generation of movement. There currently is no known cause of ALS, except for about 5-10% of cases in which there is a genetic defect. After onset of the disease, there is a typical progressive deterioration until almost all voluntary muscles are affected. Patients often die within five years due to respiratory compromise related to diaphragm and intercostal weakness.

Anatomy Review

Neurons are the basic unit that makes everything possible in the nervous system. There are over a billion in the brain, and they all share common traits with one another while also being distinct from most other cells in the body. Each section has a specific function that is manifested in the shape of the various components. Dendrites are the region that receives input signals from other neurons; they can have many branches depending on how big the receptive field is. The cell body (soma) contains the nucleus and various other necessary organelles to regulate the flow of ions. There is one long axon (up to a meter long) that
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has terminal ends that can innervate other neurons. Myelination of the axon causes faster transduction of the action potential because it forces the potential to hop from node to node. In the central nervous system, myelinated axons are called oligodendrocites, whereas in the peripheral nervous system they’re referred to as Schwann cells. Innervation of the terminal endings of the axon results in a synapse, where synaptic transmission takes place.


One specific type of neuron is the alpha motor neuron, which innervates skeletal muscle and is essential for generating movement. At the synapse (neuromuscular junction), motor neurons release the neurotransmitter acetylcholine. This binds to the acetylcholine receptors on the muscle fiber, which open and allow ions to flow and create an action potential. This action potential is propagated in both directions along the muscle fiber. This action potential ultimately causes the muscle to contract. The motor neurons that control muscles in the body and limbs are located in the ventral horn of the spinal cord. Those that control muscles in the head and face are located in the motor nuclei of the brainstem.

The motor neuron is the only neuron that the central nervous system can use to send its signals to affect the muscles. Therefore pretty much all movement hinges on the effective use of these lower motor neurons. Sir Charles Sherrington referred to motor neurons as the “final common pathway” in motor processing.

In the spinal cord, motor neurons are grouped in columns called motor neuron pools. In each of those pools, all the motor neurons innervate a single muscle; for every muscle there is one motor neuron pool. Motor neurons can innervate multiple muscle fibers within a muscle; however no single muscle fiber is innervated by more than one motor neuron. A motor unit consists of the individual motor neuron and the muscle fibers that it innervates.
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Neuron Pool

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Motor Unit

The motor cortex controls various aspects of voluntary movement. The primary motor cortex, premotor cortex, and supplementary motor area collectively make up the “motor cortex” and they plan voluntary actions, coordinate sequences of movements, make decisions, and give commands to the lower motor neurons in order to carry out the desired movement. Anatomically it is located in the frontal lobe, which is just anterior to the central sulcus. The primary motor cortex is located in the precentral gyrus and on the anterior paracentral lobule on the medial surface of the brain. It’s much easier to stimulate this portion of the motor cortex, which causes many brief stimulations, usually resulting in simple movements of individual body parts. The premotor cortex and supplementary area however requires a much larger stimulus to elicit movement. Therefore more complex movements are generated with activation of these regions than the primary motor cortex.
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Motor Cortex

As seen in the figure on the right, there is a “homunculus” that shows where groups of neurons of certain muscles reside in the motor cortex. All of the neurons that control a certain body part are located in the same regions of the motor cortex (as seen with the somatosensory cortex). It does not represent the location
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Homunculus
of neurons for individual muscles because they are scattered throughout a region. For example, all the muscles of the quadriceps are located in the same area due to them all being leg muscles; however they are not further segregated based on the specific muscle they innervate.


There are two cortical systems that generally control voluntary movement. The corticospinal system controls motor neurons and interneurons in the spinal cord, while the corticobulbar system controls the brainstem nuclei and the muscles in the head and face that they innervate. The corticobulbar axons descend down the Genu of the internal capsule to the medial part of the cerebral peduncle. In the midbrain, pons and medulla,
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Corticospinal Tract
the upper motor neurons innervate the lower motor neurons in the cranial nerve nuclei. The motor cortex axons come together in the internal capsule and then travel through the cerebral peduncle in the midbrain. The medullary pyramids are formed on the ventral surface of the brainstem from these axons. At the caudalmedulla, the tract splits into two; about 90% of the axons decussate and form the lateral corticospinal tract. These continue down the lateral funiculus until they synapse on alpha motor neurons or interneurons in the ventral horn. The other 10% that do not decussate in the medulla form the anterior corticospinal tract, where they travel down the anterior faniculus. They then decussate at the segmental level of the spinal cord that contains the motor neurons that they innervate. They both decussate at some point, which explains how one hemisphere controls movement primarily on the opposite side of the body.

The main purpose of the corticospinal tract is to carry the motor commands that drive voluntary movement. It enables higher level processing from the cortex to reach the muscles that the cortical regions want to contract. The lateral corticospinal tract controls distal muscles whereas the anterior corticospinal tract controls the proximal muscles. The corticospinal tract is the only descending pathway that has direct innervation on alpha motor neurons. This probably allows the cortex to control the fine movements of fingers and hands with such great precision and accuracy. If the corticospinal tract is damaged, there is a permanent loss of fine control of the extremities; however possibly course movements will be preserved if parallel pathways remain intact.

Pathophysiology

Amyotrophy refers to the atrophy, or wasting away, of muscle fibers; they are denervated as their corresponding ventral horn cells deteriorate. Lateral sclerosis occurs when the anterior and lateral columns of the spinal cord harden and the motor neurons deteriorate and get replaced by fibrous astrocytes. The major problem that occurs with ALS is the loss of the motor neurons due to Wallerian degeneration. Due to death of the ventral horn, the motor neurons that reside in that spinal segment break down. Schwann cells will then catabolize the axon’s myelin sheath and break it into fragments after engulfing it. Macrophages are recruited to the area in order to clean up the debris, so they phagocytize the small compartments formed from the fragments. Often this kind of axonal degeneration can be seen in the corticospinal tracts on a biopsy of the brain. If the disease has been present for a significant amount of time, atrophy of the primary and premotor cortices may be seen also. Doing a biopsy on the spinal cord can show atrophy of the ventral horn as well. Wallerian degeneration occurs in peripheral neurons as well, where surviving axons in close proximity are shown to try and reinnervate denervated muscle fibers. Some motor neurons in the brainstem and spinal cord are typically unaffected by ALS. The oculomotor, trochlear, and abducens cranial nerves in the brainstem are preserved; as well as the posterior columns, Spinocerebellar tract, nucleus of Onuf, and Clarke's column.

It is believed that one of the causes of familial ALS has to do with a mutation of the gene that produces the superoxide dismutase 1 (SOD1) enzyme. Free radicals are produced normally by cells through metabolism. They are highly reactive and must be neutralized or else they can accumulate and cause damage to the DNA and proteins within cells. SOD 1 is an antioxidant that helps protect the body from damage caused by these free radicals. Other possible causes of cell death include oxidative damage, mitochondrial dysfunction, apoptosis, defects in axonal transport, growth factor expression, glial cell pathology, and glutamate excitotoxicity. Glutamate excitotoxicity was found in sporadic disease and led to the only approved treatment on the market, riluzole. Though it is a deemed a “treatment”, it can only extend life of a patient by 2-3 months.

Weakness is a clear clinical signs of movement impairment due to loss of motor neurons. This loss causes the lack of innervation of individual motor units. Looking at the individual motor units as a group, it is easy to determine whether the disease is in the early stages or if it has progressed significantly. At the early stages in the disease, neurons that do not degenerate establish connections with motor units that have lost connections to their neurons that have died. This causes larger motor units to form, which later in the disease die and group atrophy proceeds.
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If reinnervation can keep up with denervation, muscle weakness may not be detected. Muscle fatigue is an early indicator of ALS, which may be observed just from talking too much. As the motor units become larger, the total amount of motor units will decrease and cause the muscle to fatigue faster. As the number of motor units innervating a muscle decreases further, reinnervation lags behind denervation, thus resulting in permanent weakness until the muscle gradually shrivels (atrophies).

Clinical Signs/Symptoms

Degeneration is seen in the ventral horn and its corresponding axons, as well as the corticobulbar and corticospinal tracts. Therefore a combination of lower and upper motor neuron signs will be present. In early stages of the disease, lower motor neuron contribution would show in fasciculations (mainly in the tongue). Upper neuron involvement would show as hyperreflexia. Further loss of lower motor neurons results primarily in progressive muscle weakness and atrophy, as mentioned earlier. Additional loss of upper motor neurons in the corticospinal tract may present with spasticity, abnormally active reflexes, and pathological reflexes. Loss of prefrontal neurons will show cognitive impairment that may include social behavior that doesn't take into account the implications of various actions; not being able to plan or relate well with others. A number of patients also present with emotional manifestations such as involuntary laughing or crying and depression. Patients with bulbar origins for the disease commonly present problems of slurred speech, hoarseness, or decreased volume of speech. Also aspiration or choking may occur during meals. Those with a lower limb origin for the disease typically complain of tripping, stumbling, or awkwardness when running. A “slapping gait” is often present as well. Patients with an upper limb source will frequently experience reduced finger dexterity, cramping, stiffness, and weakness or wasting of intrinsic hand muscles. This will make buttoning clothes, picking up small objects, and turning a key difficult. Since certain motor neurons are preserved, sensory functions as well as bowel and bladder control are among those that are maintained.

Some cases only have upper or lower motor neuron symptoms. When the upper motor neuron signs are predominantly shown, it is called primary lateral sclerosis (PLS). This form however progresses and evidence of lower motor neuron involvement increase until it is nearly indistinguishable from typical ALS. The same progression occurs with lower motor neurons (progressive muscular atrophy-PMA) and cranial musculature (progressive bulbar palsy), resulting in a typical ALS pattern. The main indicator of ALS is a combination of both lower and upper motor neuron dysfunction. An example is having a weak, atrophic, fasciculating muscle that also has increased tone and hyperreflexia.

Conclusion

There currently is no definitive treatment for ALS, except for drugs that can help extend a patient’s life a few more months. Degradation of intercostal and diaphragm muscles contributes to death, which usually comes within 3-5 years of onset of the disease. In order to prevent ALS, there has to be a modification or removal of factors that are part of the generation of the disease. As seen with the SOD 1 enzyme in protection against the free radicals mentioned earlier. Treatments that aim to stop the spread of the disease will probably be more effective than those that try to save damaged motor neurons. Currently researchers are looking into over activation of glutamate receptors, autoimmunity to calcium ion channels, and cytoskeletal abnormalities. Apoptosis and insufficient vascular endothelial growth factor have grown as possible significant risk factors. No single direct mechanism has been identified for ALS, and it seems that there isn’t one. Many would agree that it is a combination of some or all of the processes mentioned throughout this article that may lead to ALS.

Glossary of Terms

Astrocyte: star-shaped glial cells in the brain and spinal cord; provide biochemical support of endothelial cells that form the blood-brain barrier and repair brain and spinal cord following trauma

Catabolize: to break down molecules into smaller units and release energy

Fasciculation: “muscle twitch”; small involuntary muscle contraction

Hyperreflexia: overactive or over responsive reflex; ex. twitching or spastic tendencies

Atrophy: partial or complete wasting away of a part of the body

Spasticity: unusual tightness of muscles due to a lack of inhibition from the CNSS resulting in excessive contraction of the muscles

Excitotoxicity: process by which neurons are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances

Suggested Readings

In Depth Article on Wallerian Degeneration

Corticobulbar Tract Involvement in ALS

Psychosocial Factors and Cognition in ALS

Article on Glutamate Excitotoxicity

Quiz

1) T/F - A myelinated neuron in the peripheral nervous system is called an oligodendrocyte.
2) T/F - The premotor cortex and supplementary area generate complex movements due to their high voltage requirement.
3) T/F - The homunculus sorts the neurons in the motor cortex by placing the neurons with the same muscle near each other.
4) T/F - The main problem with ALS is Wallerian degeneration, where death of the dorsal horn leads to motor neuron deterioration.
5) T/F - The best way to determine if ALS is present is a combination of lower and upper motor neuron involvement.
6) What neurotransmitter is primarily used at the neuromuscular junction?
A) Dopamine
B) Acetylcholine
C) Serotonin
D) Glycine
7) How many motor neurons innervate a single muscle fiber?
A) Many
B) 100
C) 10
D) 1
8) Short Answer - What are characteristics of lower motor neuron involvement in ALS?
9) Short Answer - How does the mutation of the SOD 1 enzyme affect ALS?
10) Essay - Why is there no cure for ALS? Give some examples of the mechanisms that researchers are looking into.


Answers: FTFFTBD


References

Cohen, J., Camilo, F., Lawrence, J., & Thomas, W. (2008). Amyotrophic lateral sclerosis. Chapter 24 - Degenerative diseases of the nervous system. Retrieved from
http://www.dartmouth.edu/~dons/part_3/chapter_24.html#chpt_24_ALS

Sigurdson, L. (2011). Amyotrophic lateral sclerosis presenting as upper limb weakness in a 35 year old female: a case report. Journal of the Canadian Chiropractic Association, Vol. 55 (Issue 4), pp. 204-210. Retrieved from http://web.ebscohost.com/ehost/pdfviewer/pdfviewer?sid=9cdae18f-8ee3-4999-a519-94065762ec0e%40sessionmgr112&vid=4&hid=108

(2002). Pyramidal Motor System Corticobulbar tract. Motor Systems. Retrieved from
http://pathology.mc.duke.edu/neuropath/nawr/motor-systems.html

Moldovan, M., Alvarez, S., & Krarup, C. (2008). Motor axon excitability during Wallerian degeneration. Brain: A Journal of Neuroogy, Issue 132, pp. 511-523. doi:10.1093/brain/awn332

Knierim, J. Motor Systems. Neuroscience Online. Retrieved from http://neuroscience.uth.tmc.edu/index.htm
***All Pictures with no link in the caption is from this source

Armon, C., & Lorenzo, N. (2011). Amyotrophic Lateral Sclerosis (ALS). Medscape Reference. Retrieved from
http://emedicine.medscape.com/article/1170097-overview#a0104