ALS Flashcards
What does MND refer to?
A heterogenous group of conditions characterised by degeneration of lower motor neurons and/or upper motor neurons
Where are the upper motor neurons?
Cortex and brainstem
Where are the lower motor neurons?
SC
Which upper motor neurons can be affected by MND?
Ones that synapse with lower motor neurons
Which diseases involve upper motor neuron defects?
Primary lateral sclerosis, pseudobulbar palsy
Which diseases involve lower motor neuron diseases?
Progressive muscular atrophy, spinal muscular atrophy, progressive bulbar palsy, Kennedy disease
What is a common symptom between all MNDs involving lower motor neurons?
Muscular atrophy/loss of muscle function
Which disease is associated with upper and lower motor neuron dysfunction?
Amyotrophic lateral sclerosis
When was ALS first described in a publication?
1869
ALS stands for?
Amyotrophic lateral sclerosis
Amyotrophic meaning?
No muscle nourishment
Sclerosis meaning?
Scarring of muscle
Main cause of death as a result of ALS?
Respiratory failure
Signs that upper motor neurons are affected negatively?
Hyperreflexia, spasticity, slowing of movements
What is hyperreflexia?
Reflexes are frequent and happen in an uncontrolled way
Muscle spasticity?
Muscles become thinner and lose the stiffness
Signs that lower motor neurons are affected?
Weakness, muscle atrophy, fasciculations
What is fasiculations?
Uncontrolled, rapid movements
Why is drooling seen in ALS?
Upper motor neurons (brainstem etc) is affected–> muscles that control saliva cannot be controlled correctly
Established risk factors for ALS?
Family history and age
What % of ALS patients have inherited a mutation associated with the disease from their parents?
10%
Lifestyle choices which may be associated w/ ALS?
Manual labour, smoking, excessive exercise, exposure to toxic chemicals
Why could heavy exercise contribute to ALS?
Overuse of muscles which could lead to muscle injuries and damage of neuons
What happens as a result of cortical motor cells dissapearing?
Retrograde axonal loss and gliosis in the corticospinal tract
What does gliosis cause?
White matter changes
Effect of ALS on SC?
The SC becomes atrophic, ventral roots become thin and there is a loss of myelinated fibres in motor nerves
First step in pathogenic mechanisms of ALS?
Glutamate excitotoxicity–> if glutamate stays in the synapse for too long it is toxic. Usually astrocytes take excess glutamate up but in ALS there is too much glutamate
What does excess glutamate cause in the post N?
Excessive Ca2+
What does excessive Ca2+ in the post n cause?
Mitochondrial dysfunction
Effect of mitochondrial dysfunction?
ATP production is affected, also superoxides are produces (oxidative stress)
What happens as a result of oxidative stress and mitochondrial dysfunction?
Aggregation of SOD1 and TPD proteins which are responsible for decreasing oxidative stress
What causes neuroinflammation?
Release of inflammatory mediators by microglia
How can neuroinflammation affect RNA metabolism?
Mutation of gene expression which can dysregulated RNA metabolism
How does ALS cause axonal transport defects?
Neurofilaments that are meant to be present along the axon begin to accumulate–> too much of them
Which tools are used to diagnose ALS?
El Escorial Criteria–> set of diagnostic guidelines
Why is electromyography key in diagnosing MND?
It detects electrical activity in muscles and can reveal abnormalities indicative of motor neuron involvement e.g. denervation patterns and spontaneous muscle activity
Four steps in El Escorial criteria?
Definite ALS, Probable ALS, Probable ALS, lab results supported, possible ALS
Possible ALS criteria?
Presence of upper motor neuron and lower motor neuron signs in one region or upper motor neuron signs in 2/3 regions
Probable ALS, lab results supported criteria?
Presence of upper motor neuron and lower motor neuron signs in one region with evidence by EMG of lower motor neuron involvement in another region
Probable ALS criteria?
Presence of upper and lower motor neuron signs in at least two regions with UMN sign rostral to LMN sign
Definite ALS criteria?
Presence of upper motor neuron and lower motor neuron signs in three anatomical regions
How is a myelogram carried out?
A dye is injected into the spinal canal–> dyes areas and then does a CT scan. Look to see where the dye has deposited
Which exams can be used to diagnose ALS?
MRI, Myelogram, muscle and/or nerve biopsy
What do the three separate mechanisms of riluzole all do?
Reduce glutamate induced exciotixicity
How does riluzole work?
It inhibits glutamic acid release, noncompetitive block of NDMA receptor mediated response, direct action on the voltage dependent sodium channel
Drawbacks of riluzole?
Only extends survival rate by 2-3 months, 50% of patients experience side effects
Side effects of riluzole?
gastrointestinal disturbances (nausea, vomiting, diarrhea), fatigue, and dizziness
Serious risks of riluzole?
Neutropenia, liver dysfunction
Formulation issues w/ riluzole?
Patients cannow swallow
