Amyotrophic Lateral Sclerosis Flashcards
What is ALS?
a = no
myo = muscle
trophia, trophic = nourish
Amyotrophic = no muscle nourishment
Lateral = location on spinal cord where sclerosis (scarring, hardening) occurs.
Amyotrophic Lateral Sclerosis (ALS) is progressive degenerative disease that affects neurons controlling voluntary muscles.
- Steadily progressive;
- Evidence for slow vs. fast progressors;
- Inherited vs. sporadic cases;
- Patients eventually die of respiratory failure in 2-4 years.
Clinical Symptoms of ALS
Loss of motor neuron function results in:
- Stiff muscles;
- Muscle twitching (spasms), often overlooked;
- Weakness due to decreased muscle size;
- Difficulty speaking, swallowing and eventually breathing (typically 1st symptoms to appear);
Ultimately people lose the ability to control all voluntary movements.
Cognitive dysfunction present in less than half of cases.
What Causes ALS?
A degeneration of both upper and lower motor neurons.
Upper motor neurons motor cortex;
Lower motor neurons brainstem & spinal cord;
Cause of degeneration is unknown in ~95% of cases.
Familial cases involve genetic mutations in superoxide dismutase oxidative stress.
Extremely long neurons, such as LMN, are susceptible to damage.
Anything that happens along the axon will disrupt function of entire neuron;
Disruptions in SOD1 function anywhere along a LMN causes dysfunctional cell.
Other causes are spinal muscular atrophy, other genetic causes, Polio, West Nile virus.
No specific environmental factors have been identified.
Motor Neurons
Cell bodies located in the motor cortex, brainstem or spinal cord.
Axons (fibers) project to spinal cord or outside spinal cord to control organs, muscles and glands.
Two types:
Upper motor neuron (UMN): pyramidal cells that synapse onto interneurons in spinal cord;
Lower motor neuron (LMN): efferent nerve fibers that carry signals from spinal cord to muscles.
Upper Motor Neurons (UMN)
Cell bodies located in the motor region of the cerebral cortex.
Receive information from the neighboring somatosensory cortex.
Connects brain to appropriate level of the spinal cord.
Influences activity of LMN.
Lower Motor Neurons (LMN)
Lower Motor Neurons (LMN) are considered second order neurons.
Connect brainstem and spinal cord to muscle fibers.
Innervated with striated muscles.
- Point of contact with muscle is called a neuromuscular junction
Neuromuscular Junction (NMJ)
Motor neurons release acetyl choline (ACh) onto muscle tissue.
ACh binds to two types of receptors, and is responsible for muscle contractions
- Nicotinic ACh receptors;
- Muscarinic ACh receptors.
Many drugs and toxins target the NMJ, and interfere with normal signaling:
- Botulin Toxin;
- BlackWidowspidervenom; - Nicotine;
- Muscarine;
Drugs that act on cholinergic system
Botulin Toxin (aka Botox) is an extremely toxic compound produced by the bacteria Clostridium botulinum. These proteins are taken up selectively by peripheral cholinergic nerve terminals, including those located at the neuromuscular junction.
Botulin Toxin
Botox interferes with ACh release at nerve terminals, thereby blocking neurotransmission.
- Prevents fusion of synaptic vesicles with nerve terminal membrane;
- Results in muscle weakness or paralysis.
Face wrinkles (e.g. crows feet, worry lines, frown lines, etc.) result in chronic contraction of specific facial muscles.
- Botox can reduce these lines/wrinkles;
- Each treatment is effective for a few months;
Motor Unit
Motor Unit = LMN cell body, axon and the multiple fibers it innervates.
An action potential will depolarize one motor unit’s muscle fibers nearly simultaneously.
- Multiple action potentials will overlay on each other;
- Action potentials can be additive, leading to a larger muscle contraction.
Peripheral Nervous System
This is what you should visualize when you think of the PNS:
Afferent sensory information from somewhere in the periphery can:
- Go directly towards CNS;
- Synapse with interneurons;
- Synapse with lower motor neurons (LMN).
Efferent motor commands, synapsing somewhere in spinal cord to LMN, controlling voluntary movement.
LMN can send its axons out to nerve root, make contact with muscle and cause contraction.
Testing Reflexes
Damage to the PNS often causes a decreased or absent reflex, as part of a LMN-type lesion.
Pathophysiology of ALS
The pathological hallmarks of ALS is the presence of inclusion bodies in the cytoplasm of motor neurons.
- Abnormal aggregations of protein;
- Exactly which protein depends on the sub-type of ALS (e.g. sporadic vs. familial)
- SOD1 and TDP-43 proteins have been most studied protein aggregates.
- Aggregates lead to dysfunctional motor units.
Super Oxide Dismutase (SOD)
SOD is an enzyme that catalyzes the dismutation of the superoxide radical (O2-) into a less toxic/reactive chemical (e.g. O2 or H2O2).
O2- is produced as a by-product of oxygen metabolism, and therefore regular cellular processes.
If not regulated, O2- can cause many types of cell damage.
- SOD is an important antioxidant defense in neurons. - Mutations to SOD can lead to cell death.
Screening & Assessment
How can ALS be detected?
A good physician will take detailed history and conduct a neurological exam (including reflexes).
- Symptoms of muscle atrophy indicate LMN problem;
- Narrow down to PNS (weakness, atrophy) and refer to electromyogram (EMG) results.
Diagnosis is based on clinical features and EMG testing.
