Overview


Amyotrophic Lateral Sclerosis (ALS), also referred to as Lou Gehrig’s disease, Motor Neuron Disease, and Charcot Disease, was first described in 1896 by the French neurologist Jean-Martin Charcot. ALS is a neurodegenerative disease that can target both upper and lower motor neurons. Amyotrophic refers to muscle atrophy, weakness and fasciculation, which are associated with the disease of the lower motor neurons. Lateral sclerosis refers to the thickening or hardening of the lateral columns in the spinal cord and result in upper motor neuron signs such as over reactive tendon reflexes, Hoffmann signs, clonus, and Babinski signs. Depending on the site of deterioration a range of symptoms will present themselves. As the disease progresses the loss of control becomes more and more severe until the patient is completely paralyzed. Those unfortunately plagued with this disease will ultimately die within an average of three years after diagnosis or onset of weakness, primarily due to loss of respiratory function. The cause of ALS is still unknown, though five to ten percent of cases have been shown to be hereditary. Many causal theories have been construed and tested in attempts to develop a cure, but have achieved very little success.


Functional Anatomy of the Motor System


Neurons and Action Potentials
Figure 1. Motor Neuron
Figure 1. Motor Neuron

Neurons are electrically excitable cells that process and transmit information through electrical and chemical signals. There are over 100 billion neurons in the human brain alone with many more branching from the spinal cord to the rest of the body. A neuron is composed of three distinct morphological regions, each with specific functions. The dendrites are where incoming connections with other neurons are made. The soma (or cell body) is where the nucleus and organelles lie, and is the center of all cellular functions. The axon can be likened to a long cable, which transmits information to the terminal regions of the neuron (called the synapse). Neurons are protected and maintained by glial cells, which surround the neurons. Glial cells hold the neurons in place, supply nutrients and oxygen, destroy pathogens, and create myelin sheath.

The language in which neurons speak is electricity, and these electrical signals are relayed via action potentials. An action potential is short lasting electrical event in which the membrane potential of a cell rapidly rises. This rise is caused by a sudden influx of ions into the cell, depolarizing it (where the inside becomes more positive). The structures that allow for this influx are called ion channels. There are many types of ion channels, including ligand gated, mechanically gated, and voltage gated ion channels. Once the neuron gains enough of a positive charge (reaches threshold) it will begin to propagate the action potential down the axon and to the terminal. It is this electrical signal that causes the release of neurotransmitters at the synapse, ultimately leading to an electrical gradient shift in the postsynaptic neuron or effector cells.

An important anatomical feature that certain neurons possess is called the myelin sheath (a type of glial cell). It is essentially a fatty, axon-enwrapping sheath that serves to speed up neural conduction. It takes a different form whether it is in the central nervous system (CNS) or the peripheral nervous system (PNS). In the CNS the enwrapping cells are called Oligodendrocytes, while in the PNS they are referred to as Schwann cells. By covering large portions of the axon, the sheath allows for the influx of ions (usually sodium) to occur at concentrated spots called nodes of Ranvier. In essence, the action potential hops down the axon, covering a much greater distance in a shorter amount of time. These sheaths are an essential component to producing quick coordinated movements.


The Motor Unit and Muscle Contraction
Figure 2. Motor Unit
Figure 2. Motor Unit

When speaking of movement, the specialized neuron of interest is the motor neuron. It is important
to first distinguish between upper motor neurons (UMN) and lower motor neurons (LMN). The UMN originates from the motor strip of the cerebral cortex, located anteriorly to the central sulcus. Specifically, motor neurons involved in voluntary movement are located in layer five of the primary motor cortex and are called Betz Cells. Meanwhile, the LMN, associated with voluntary movement, is located in the ventral horn of the spinal cord, specifically in Rexed Laminae IX. It is many times referred to as the alpha motor neuron. It runs out the ventral root, into the peripheral nerve and out to the muscle of interest.
These motor neurons therefore act as the relay between upper motor neurons and the muscles. They are clustered into columns in the anterior horn, called motor neuron pools.A pool refers the individual LMNs that innervate a single muscle. The location of these pools in the ventral horn of the spinal cord determines the location of the muscles they innervate. Those that are more anterior innervate extensors, while those more posterior innervate flexor muscles. Those that are more lateral innervate distal musculature, and those that are more medial innervate proximal musculature. Furthermore, pools are arranged so that those closer to each other most likely innervate muscles that work together for a certain type of movement.


A motor unit is the alpha motor neuron (or LMN) cell body, its axon, and all of the muscle fibers it innervates. It has been referred to as the final common pathway where all cortical inputs as well as spinal reflexes associated with movement meet. The motor unit must be activated for any movement to be produced. Activation of the motor unit, and hence the muscle, is a multiple step process where many things have the chance to go wrong.


Figure_38_04_06f.png
Figure 3. Process of Muscle Contraction

The process of activation begins with proper innervation of the LMN by incoming UMN and interneurons. With its extensive dendritic branching, the LMN receives a variety of input that is either inhibitory or excitatory. The more excitatory input (or excitatory postsynaptic potentials) that reaches the cell body and congregates at the axon hillock, the more depolarization, and the likelier threshold will be reached. The process of temporal summation (many consecutive EPSPs from the same presynaptic neuron) and spatial summation (many EPSPs from different presynaptic neurons occurring around the same time in different places on the postsynaptic neuron) allow for the depolarization to be maintained. When the action potential is initiated at the axon hillock, it travels down the axon, to the terminal, where voltage gated calcium channels open. The influx of calcium begins the process of exocytosis of the neurotransmitter Acetocholine (ACh).ACh must then cross the synaptic cleft and bind to receptors on the individual muscle fibers. If enough ACh binds, the muscle cell will depolarize and this action potential will travel along the sarcolemma and down into to the T-tubules. The voltage change will open the calcium channels of the sarcoplasmic reticulum and it will flow out to the myofilaments. It is here that movement finally occurs. As calcium binds to the troponin found on actin strands, causing a mechanical change in tropomyosin. Under normal circumstances the tropomyosin blocks myosin from binding to actin, but with calcium present, the binding sites open up. With actin bound to myosin, the ADP and inorganic phosphate attached to myosin with break off. This will result in the power stroke as myosin pulls actin forward. With many of these reactions occurring through the muscle, a contraction occurs. If this contraction is strong enough it will result in limb movement.



Figure 5. Corticospinal Tract
Figure 5. Corticospinal Tract

Figure 4. Corticobulbar Tract
Figure 4. Corticobulbar Tract



Descending Tracts of the Voluntary Motor System
There are multiple tracts that communicate important cortical and subcortical information to various places in the CNS. Each tract caries specific information that is defined by its point of origin. All information associated with voluntary movement comes primarily from the motor cortex. There are two tracts that fall under voluntary control of movement: corticospinal and corticobulbar. The corticospinal tract can be divided into medial (or anterior) and lateral sections. This division occurs at the caudal medulla where the lateral tract decussates and the medial tract remains ipsilateral until it reaches the spinal segment at which it terminates. The medial tract is concerned with proximal musculature, while the lateral tract innervates distal musculature. 90% of the fibers in the corticospinal tract run in the lateral division and the remaining 10% in the medial division. This discrepancy reflects the greater cortical representation if distal musculature and the need of more input for finer control of movement. Damage to this tract results in a loss of all fine motor skill. It is possible to maintain possession of coarse movements if the parallel pathways are preserved. The corticobulbar tract has bilateral innervation to all cranial nerve nuclei, except VII and XII. Therefor, unless both sides of the nervous system are affected, there is no loss of motor control. This tract relays voluntary movement information to the muscles of the face, eyes, mouth, head, and neck.


Figure 6. Motor Cortex
Figure 6. Motor Cortex

Motor Cortex
The motor cortex is located in the frontal lobe of cerebral hemispheres, anterior to the central sulcus, and consist of three different areas: the primary motor cortex, the lateral premotorcortex, and the supplemental motor area. The primary motor cortex is where voluntary movement commands originate, being sent out specifically by the Betz Cells in layer V. It has many other outputs and inputs. The premotor cortex and supplementary area are important in encoding complex patterns of motor output and selecting the appropriate motor plans for specific desired results. They have input to the primary motor cortex as well as direct input to the corticospinal pathways. The primary motor cortex is somatotopically organized, meaning that sections of the cortex are associated with the movement of specific body parts. Moving from dorsomedial to ventrolateral, stimulation of the cortex will elicit movements in the legs, torso, arm, hand, face (in that order). The larger the body part is represented on the map, the larger its cortical representation. More cortical representation also means that greater acuity of movement is associated with that body part. The premotor and supplementary areas also have their own maps that function similarly. Similar to the motor neuron pools in the spinal cord, neurons in the cortex are organized into columns based on the muscles they innervate and the action performed. Therefore, UMNs in the same column innervate synergistic muscles and are involved in a specific movement. Not only are they associated with a specific movement, they also have a preferred direction. If the movement is in the preferred direction, the neuron will increase its firing rate.


Prevalence


ALS affects as many as 30,000 Americans, and it is estimated that there are an average of 5,600 cases diagnosed yearly (in the U.S.). The disease has been shown to be slightly more prevalent in men, especially at earlier onset ages (with a ratio of 1.6:1). The risk of contracting the disease increases with age, as the mean age affected is between 40 and 60 years. ALS is either “familial” or “sporadic”. The prevalence of sporadic ALS is much greater, sitting at around 90-95%, while ALS seems to be hereditary for only 5-10% of the American population. Of the cases that are “familial” nearly all show an autosomal dominant pattern of inheritance, and there is a 50% chance that each offspring will develop the disease.


Pathophysiology


Figure 8. Proliferation of Microglia
Figure 8. Proliferation of Microglia
Figure 7. ALS motor Neuron
Figure 7. ALS motor Neuron

The primary pathological hallmark of ALS is the progressive degeneration and eventual loss of the alpha motor neurons (or LMN) in the ventral horn of the spinal cord, their homologues in the brainstem nuclei (the cranial nerves), and the UMN Betz Cells in the motor cortex. With their innervation removed, the muscles begin to atrophy with time. The secondary hallmark is the gliosis and demyelination of the lateral and anterior corticospinal tracts. Gliosis is a protective mechanism of the CNS. When neurons in the CNS are injured, a reaction characterized by hypertrophic and proliferating astrocytes and microglia ensues. This causes the formation of a glial scar, a meshwork of tightly interwoven cell processes. This is why upon palpation of the lateral columns of the spinal cord in autopsy specimens there is hardness. This process of reactive gliosis is protective in nature but has detrimental effects on the potential regrowth of neuronal connection. The scarring seems to create an inhibiting environment for successful axon regrowth. Why the motor neurons begin to die in the first place is still unknown but there are many theories under process of development.


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Figure 9. Possible Causes of ALS

Theories of Causes

One theory explains that the neuronal death is a result of excitotoxicity. This is the process by which amino acid neurotransmitters, such as glutamate, become toxic when they are present at very high concentrations. It has been shown in some cases that there were increased glutamate levels in the plasma and cerebrospinal fluid of patients with ALS. An extension of this theory is that there is a reduction in astrocytic glutamate transporters in patients with ALS, therefore it cannot be cleared from the synaptic cleft fast enough (Figure ___). This excitotoxicity then triggers excessive calcium influx into the motor neuron thus starting and intra-neuronal cascade mechanism that includes free radicals, ultimately leading to cell death. It has also been hypothesized that this intracellular increase in calcium is due to mitochondrial damage.

Another theory hypothesizes that there is a mutation in the gene for the enzyme superoxide dismutase 1 (SOD-1). The argument is that a mutation in SOD-1 may cause oxidative damage by impairing the ability of the enzyme to bind zinc. When deprived of zinc, SOD-1 can no longer effectively scavenge free radicals and break them down. This SOD-1 induced toxicity may target neurofilament proteins, impeding them in their task of axonal transport and maintaining axon structure. This in turn may lead to axon strangulation and eventually cell death. It is possible that this disorganization of neurofilaments could have been due to a mutation in their genes or due to the inflammation or injury to the axons.


Symptoms

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Figure 10. UMN and LMN signs


The parts of the body that are affected by early symptoms of ALS depend on which motor neurons are damaged or lost. The clinical features can be considered in relation to the neurological regions, specifically, bulbar, cervical, and lumbar. Patients whose neurons deteriorate along the corticobulbar tract and at the cranial nerves, present with slurring of speech (dysarthria), and difficulty swallowing (dysphagia). If the UMN of the corticobulbar tract is affected (pseudo-bulbar palsy), the patient may show pathological laughing or crying, brisk jaw jerk and difficulty speaking. If the LMN of the corticobulbar tract is effected (bulbar palsy) the patient may show upper and lower facial weakness and poverty of palatal movement. They may also show weakness and fasciculation of the tongue.

Patients whose neurons degenerate along the cervical portions of the corticospinal tract, will present with upper-limb symptoms. These symptoms could be unilateral or bilateral depending on if both left and right anterior horns are decaying at that level or not. Proximal weakness is characterized by difficulty with tasks involving shoulder abduction, while distal weakness is characterized by difficulty in tasks requiring fine motor coordination of the fingers. If it is the upper motor neurons that are affected, there will be fasciculations and brisk reflexes present in the upper limbs.

Degeneration of the anterior horn cells of the lumbar spine is linked to signs such as foot drop, where the forefoot drops due to weakness. This often causes tripping and may be associated to the development of a slapping gait in which the forefoot cannot be held up and upon heel contact with the floor it will “slap” down. If the effects are proximal, the patient will have difficulty with tasks such as walking up of down stairs due to weakness in the gluteus muscles. Again, if it is the UMNs that are degenerated, spasticity and hyperactive reflexes will be present.

Statistically, 80% of patients exhibit both UMN and LMN involvement, while only 20% exhibit one or the other. If both are involved, progression of the disease is more rapid. Ultimately all musculature will be affected by the disease but progression among individual cases will vary. The symptoms tend to move proximally with times, starting in the limbs, robbing the patient of their fine motor skills.



Figure 11. Cortical Degeneration Progression
Figure 11. Cortical Degeneration Progression

Prognosis


50% of patients die within 3 years of diagnosis. The other 50% either die before or after, with some living up to 15 years after diagnosis. The course that the disease takes is extremely variable as it can start in any muscle group and move to any other. The speed at which it does so also varies and is greatly dependent on the point at which the respiratory muscles are affected as well as those used for eating.






Treatment

Figure 12. Role of Riluzole
Figure 12. Role of Riluzole

The Food and Drug Administration (FDA) has only approved one drug for the treatment of ALS: Rilutek or Riluzole. It is a glutamate antagonist, meaning it reduces the release of glutamate. It has been shown in multiple trials to prolong survival by three to six months, extending the time until which patients needed ventilatory support.

Other drugs are being tested, such as Tirasemtiv, a fast skeletal muscle troponin activator. Hence, it acts like calcium (or increases sensitivity to calcium) and activates the troponin-tropomyosin complex, allowing myosin to bind to actin, promoting muscle contraction. With the current lack of treatment for the cause of the disease, the best option is to treat the individual symptoms to prolong life and increase comfort.

Dysphagia (difficulty swallowing) must be controlled by an adjustment in diet. There are also specific swallowing techniques that can help prevent aspiration. When oral food intake becomes too difficult with a constant risk of choking, patients can opt to have a percutaneous endoscopic gastronomy (installation of a feeding tube) performed.

For Dysarthria (difficulty speaking), speech therapy can be helpful for a little while. Otherwise, using other modes of communication should be considered. Tests have been done using highly advanced technology to capture electric brain currents and having them translated to control computers.

Dyspnea (difficulty breathing) can be addressed with morphine, or if the symptom is caused by anxiety benzodiazepines could be used. If the patient experiences chronic nocturnal hypoventilation, non-invasive ventilation can be an effect treatment.

Patients may experience thick mucous secretion due to the combination of diminished fluid intake and reduced coughing pressure. This can be treated with N-Acetyl Cysteine in some cases to help reduce mucous production. Manually assisted coughing techniques and mechanical insufflation-exsufflation can be of help. If nothing else is helping, there is also the option of having a tracheotomy performed.

Living with ALS




Conclusion


ALS is progressive degenerative disease affecting the motor nervous system. It currently has no cure and only one FDA approved drug that improves life expectancy by 3-6 months. Seemingly the best option for treatment is to address individual symptoms and treat them as effectively as possible. There is still hope though, as there are many theories and drugs being developed and tested daily. With the technological advances being made in this day and age, anything is possible.


Glossary of terms


Fasciculation: small involuntary muscle twitches
Glial cells: non-neuronal support cells
Myelin sheath: A fatty, axon-enwrapping sheath that serves to speed up neural conduction
Motor neuron pools: individual motor neurons that innervate a single muscle
Motor unit: An alpha motor neuron’s cell body, axon, and all the muscle fibers in innervates
Troponin: A protein that binds to calcium to mechanically effect tropomyosin
Tropomyosin: a two-stranded alpha helical protein that wraps around actin and block the myosin binding sites
Sporadic ALS: The most common type of ALS with no know cause
Familial ALS: An uncommon form of ALS that is hereditary
Gliosis: proliferation and hypertrophy of glial cells in response to nervous system injury
Astrocytes: A star-shaped glial cell that supports neurons
Microglia: A glial cell that acts as the macrophage for the nervous system
Excitotoxicity: The process by which nerve cells are damaged due to excessive stimulation by neurotransmitters
Free radicals: An atom, molecule, or ion with one or more incomplete covalent bonds
Superoxide dismutase 1: an enzyme that catalyzes the breakdown of free radicals
Neurofilament: intermediate filaments found in the neuronal cytoskeleton, important in providing structural support
Dysarthria: difficulty speaking
Dysphagia: difficulty swallowing
Pseudo-bulbar palsy: Impairment of function of cranial nerves 9-12 due to an UMN lesion; inability to control facial movement
Bulbar palsy: an impairment of function of the cranial nerves 9-12 due to a LMN lesion; difficulty eating and speaking
Foot drop: dropping of the forefoot due to weakness in the dorsiflexors
Rilutek: A drug used to treat ALS, proven to increase life expectancy for up to 6 months
Tirasemtiv: A drug being tested for treating ALS, meant to increase neuronal sensitivity to calcium, thus increase strength of contractions
Dyspnea: Difficulty breathing
Benzodiazepines: a psychoactive drug used to treat anxiety
N-Acetyl Cysteine: A drug used for patients with respiratory dysfunction
Tracheotomy: A surgical procedure in which a small hole is cut into the trachea so that a tube can be inserted to assist in breathing.


Suggested Reading


Molecular biology of amyotrophic lateral sclerosis: insights from genetics - an in depth look at the possible genetic causes of ALS
ALS Amyotrophic Lateral Sclerosis - A clear and concise overview of the disease, symptoms, and possible treatments
Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis - A look at the causes and effects of weight loss in ALS
Experience of services as a key outcome in ALS care - An interesting article discussing the satisfaction of ALS patients with the care they recieve

Quiz

  1. What is the role of the myelin sheath and what type of cell is it?
    • a. it speeds conduction velocity and is a neuronal cell
    • b. It secretes sodium velocity and is a glial cell
    • c. it protects the neuron from physical harm and is a glial call
    • d. all of the above
    • e. none of the above
  2. The following are true about familial ALS and Sporadic ALS except?
    • a. Familial ALS is less common than sporadic ALS
    • b. Sporadic ALS has an unpredictable prognosis and no known cause
    • c. Familial ALS has an unpredictable prognosis
    • d. Familial ALS is hereditary
    • e. All the above are true
  3. What are the two descending tracts concerned with voluntary movement?
    • a. Rubrospinal and Tectospinal
    • b. Vestibulospinal and Rubrospinal
    • c. Reticulospinal and corticobulbar
    • d. Dorsal column medial lemniscal and corticospinal
    • e. None of the above
  4. What are the differences between the two divisions of the corticospinal tract?
    • a. The medial tract doesn’t decussate, lateral one does
    • b. The medial tract innervates distal musculature, lateral innervates proximal musculature
    • c. The lateral tract represents 90% of the corticospinal tract while the medial only represents 10%
    • d. A and C
  5. Which of the following concerning steps to muscle activation are in the proper order?
    • a. Temporal and spatial summation à action potential à influx of sodium at the axon hillock à power stoke
    • b. Calcium binds to tropomyosin à actin binds to myosin à power stroke à muscle fiber contraction
    • c. Calcium influx in presynaptic terminal à exocytosis of ACh à action potential down the sarcolemma à potassium released from SR
    • d. A and C
    • e. B and C
    • f. None of the above
  6. Gliosis is a protective mechanism against neuronal cell damage and allows for rapid axonal regrowth
    • a. True
    • b. False
  7. If a patient with ALS only had degeneration in the anterior horn of the cervical spine, they would experience hyperactive reflexes and difficulty picking up a cup
    • a. True
    • b. False
  8. The supplementary motor area and the premotor cortex are important in more complex movement and motor planning and have direct projections to the alpha motor neurons of the lumbar spine
    • a. True
    • b. False
  9. What is excitotoxicity and what is the theory for its role in ALS?
  10. What is SOD-1 and what is the theory for its role in ALS?
  11. What are possible treatments for the thick mucous secretions that patients with ALS experience?
  12. Why would Tirasemtiv be helpful in treating ALS?


Answers
  1. e
  2. e
  3. e
  4. c
  5. f
  6. b
  7. b
  8. a
  9. The process by which nerve cells are damaged due to excessive stimulation by neurotransmitters. Excessive glutamate à influx of calcium à cascade involving free radicals à neuronal cell death
  10. Superoxide dismutase 1isan enzyme that catalyzes the breakdown of free radicals. Its gene was mutated à cannot break down free radicals à buildup leads to cell death
  11. N-Acetyl Cysteine, manually assisted coughing techniques, mechanical insufflation-exsufflation, tracheotomy
  12. It increases the sensitivity of the neuron to calcium à this would increase calcium’s effect on troponin-tropomyosin complex à more binding sites for myosin à more strength in contraction of muscle

References


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Rowland LP, Shneider NA. Amyotrophic Lateral Sclerosis. New England Journal of Medicine 344: 22, 13 May 2001. Retrieved from http://isites.harvard.edu/fs/ docs/icb.topic1303034.files/Case%203%20%20Supplemental%20Readings/Rowland%20and%20Shneider%202001.pdf [15 Dec. 2013]

Swenson RS. Chapter 5 – Spinal Cord in Review of Clinical and Functional Neuroscience [online]. Dartmouth School of Medicine, 2006. https://www.dartmouth.edu/~rswenson/NeuroSci/chapter_5.html [15 Dec. 2013].

Young J. (Nov. 1994) Amyotrophic lateral sclerosis patients' perspectives on use of mechanical ventilation [Online]. Health & Social Work. http://proxy2.noblenet. org/login?url=http://search.ebscohost.com/login.aspx?direct=true&AuthType=ip&db=f5h&AN=9411076019&site=ehost-live&scope=site. [Dec. 2013].

N.A. (16 Dec. 2008). X-Plain Amyotrophic Lateral Sclerosis: Reference Summary [Online]. The Patient Education Institute, Inc. http://www.nlm.nih.gov/medlineplus /tutorials/amyotrophiclateralsclerosis/nr189103.pdf [15 Dec. 2013].