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 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.
(http://207.204.17.60/schwann-cell-transplants-human-clinical-trials)
-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.
-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
-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 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, 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 caudal
medulla, 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 (link) 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 (link), nucleus of Onuf (link), and the Clarke column
(link).
-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 (link). Glutamate
excitotoxicity was found in sporadic disease and led to the only approved treatment on
the market, riluzole (link). Though it is a deemed a “treatment”, it can only extend life
of a patient by 2-3 months.
-An important step toward finding the causes of ALS came in 1993, when research
scientists discovered that mutations in the gene that produces the superoxide
dismutase 1 (SOD1) enzyme were associated with some cases of familial ALS. The
SOD1 enzyme is a powerful antioxidant that protects the body from damage caused
by free radicals. Free radicals are highly reactive molecules that are produced by
cells during normal metabolism. If these free radicals are not neutralized, they can
accumulate and cause random damage to the DNA and proteins within cells.
Although it is not yet clear how the SOD1 gene mutation leads to motor neuron
degeneration, researchers have theorized that an accumulation of free radicals may
result from the faulty functioning of this gene. (http://als.emedtv.com/als/causes-ofals.html)
-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.
-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).
Acquired nucleic acid changes may trigger disease onset in sporadic ALS.[32] This hypothesis relies on the
observation that smoking is the only established risk factor for sporadic ALS[33] and provides a mechanism
by which smoking might cause the disease, namely, by induction of changes in nucleic acids. It follows a
similar logic that suggests that the alkylating components in the cycad are responsible for delayed onset
of Western pacific ALS/PDC…They establish an irrefutable role for corticospinal neurons in the early
spread of ALS and provide an observational foundation for postulating the existence of one or more
"agents of spread."
The affirmation of spread substantiates the concept of a biological focal onset to ALS. This in turn lends
credibility to the concept of a focal trigger to ALS onset that generates the production of one or more
agents of spread. Under this hypothesis, disease phenotype in each patient depends on the site of onset
and the relative affinity of the specific agent of spread in that patient to motor neurons at the different
hierarchical levels of the motor system (prefrontal, corticospinal, spinal/bulbar).[38] The concept of
preferential affinity of the agent of spread may apply even to specific motor neurons within a given
hierarchy, resulting, for example, in the special predominantly lower motor neuron phenotypes (flail arm
syndrome, flail leg syndrome).
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” (link?video) 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
Suggested Readings
Quiz
References
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-a51994065762ec0e%40sessionmgr112&vid=4&hid=108
(http://pathology.mc.duke.edu/neuropath/nawr/motor-systems.html)
(http://www.dartmouth.edu/~dons/part_3/chapter_24.html#chpt_24_ALS)