Lecture 13; Movement disorders 2 Flashcards
What conditions affect neuron cell bodies?
ALS (mainly looked at)
Poliomyelitis
What is poliomyelitis?
Oral viral infection that acutely degenerates motor neurons
What is polio?
RNA virus, highly contagious
When and how was polio brought under control?
1950s by vaccination
What is a modern application now of polio virus?
Genetically modified polio virus treatment of glioblastoma.
- Rapid growing tumor
- Stereotaxic injection
What are some other names for ALS?
MND motor neuron disease
Lou Gehrigs disease
What is ALS?
Motor neuron disease
- Affects cell bodies
Describe the progression of ALS;
Develops slowly over months/years
Progressive disease
Starts at a very young age
How does polio affect MNs?
Acute damage to cell bodies
- Virus is specific to cell bodies and these dont regenerate
What is the symptoms of polio?
Paralysis, atrophy, but do survive
Describe where ALS affects;
Sclerosis = hardening
ALS = Hardening of the lateral aspect of the spinal cord, glial cells replace dead motor neurons (gliosis)
Whats the incidence of ALS?
5/100,000
Typically onsets at 5th decade of life
Is ALS genetic?
90% non family history
Describe the genetic variant of ALS;
Rare familial form of ALS with dominant inheritance
Mutation of some genes i.e superoxide dismutase
Describe the symptoms of ALS;
Progressive wasting, weakness and atrophy of muscles leading to paralysis
- Weakness of legs, arms and hands
- Difficulty with speech and swallowing
- Impairment of respiration
Smooth muscle affected
Muscle stretch reflexes exaggerated and muscle (tone) spasticity
Whats the survival outcomes of ALS?
Death usually 2-3 years, rare benign forms that last 10+ years
What are some EMG affects of ALS?
Muscle denervation; Fasiculations and Fibrillations
Fasciculation’s : Twitching ; electrophysiologically unstable motor units
Fibrillation ; Individual muscle fibres (spontaneous AP)
What are the exceptions in ALS?
- No involvement of extraocular muscles
- No involvement of sphincters
- Usually no intellectual or sensory deficits
Motor neurons of extraocular muscles are protected, this is unknown why
Lots of other diseases have sensory affects
Describe specifically what is degenerated that leads to the muscle wasting and atrophy?
a) Motor neurons of the spinal cord with the exception of those controlling sphincters
b) Motor neurons in the brain stem ; with the exception of CN 3,4,6
a+b degeneration = muscle wasting + paralysis
What does the degeneration of upper motor neurons lead to?
** misleading, it is actually pyramidal cells in the cortex, they become more excitable = increase reflexes, tone, spasticity DESPITE degeneration
What is the current pathogenesis hypothesis regarding ALS?
Oxidative stress hypothesis
Excitotix hypothesis
TDP 43 / FUS mutation
Describe the oxidative stress hypothesis;
Damage to neurons by free radicals (reactive oxygen and nitrogen species) when radical production exceeds the detoxification capacity of the specific enzymes (glutathione oxidase, superoxide dismustase, catalase
What is a rare familial form of ALS?
Mutations of superoxide dismutase (10%)
What is the excitotoxic hypothesis?
Excessive AMPA and NMDA activation by glutamate
What is the first possible cause of the excitotoxic hypothesis?
1) Increased EC glutamate because of decreased activity of astrocytic glutamate transporter GLT-1
What is the second possible cause of the excitotoxic hypothesis?
Decreased GluR2 expression (as a subunit of the AMPA receptor)
Motor neurons of ALS have lower GluR2 subunits in their AMPA receptors, predisposing them to higher Ca influx
(GluR2 mutation results in the AMPA becoming permeable to Ca)
What is the TDP-43/FUS mutation hypothesis?
TDP-43 and FUS are proteins involved in protein processing and are normally found in the nucleus.
In some forms of FAMILIAL ALS genes for these proteins mutate and they are shifted to the cytoplasm and form agregates the affect motorneuron function (Choke Function)
What are the treatments for ALS?
No effective drugs available to alter or halt the disease progress
but can fix symptoms and improve the quality of life.
Do antioxidants help?
No clear effects (vitamin C,E)
Whats a drug that can target glutamate release?
Riluzole (small benefit) blocks glutamate release and can slow the disease progress by a couple of months
Whats a drug that is in phase 3 clinical trial?
Dexpramipexole; improves mitochondiral function and reduces oxidative stress
Whats a drug that reduces spasticity?
Baclophen (GABA-B agonist), reduces spasticity
What is some other experimental treatments?
Experimental replacement or trophic therapy using genetically modified cells or stem cells. (replace the defective astrocytes that dont transport glutamate)
