Lecture 31: ALS

Question 1

Poliomyelitis (polio) features?

Answer 1

Acute, usually focal degeneration of motorneurons resulting from viral (oral) infection.

Question 2

ALS stands for? What is it?

Answer 2

Amyotrophic lateral sclerosis =MND = motorneuron disease

Hardening of the spinal cord in the lateral portion, leading to lack of trophic effects of muscles

aka: Lou Gehrig’s disease

Question 3

Incidence and symptoms of ALS?

Answer 3

• approx 5/100,000
• 90-95% have NO FAMILY HISTORY (rare familial ALS does exist with dominant inheritance)
• average age of onset is 50s
• Progressive in nature: wasting, weakness, atrophy
• difficulty speaking and swallowing
• impariment of respiration > pulmonary infection
• Muscle stretch reflexes exaggerated and increased muscle tone: Spasticity = painful and stiff muscles
• Death within 2-5 years (rare benign forms >10years)

Question 4

Other signs of ALS?

Answer 4

Signs of muscle denervation: fasciculations and fibrilations

Fasciculations: twitches of some motorunits which survive atrophy

Fibrilations: Spontaneous action potentials generated in individual muscle fibres in EMG (electromyograph)

Question 5

Muscles never or almost never effected?

Answer 5

• No extraocular muscles (CN 3,4,6)
• No anal and bladder sphincter
• No sensory or intellectual defecits (quite sad as people are still fully aware when they live their last few days)

Question 6

Causes of the disease?

Answer 6

Progressive degeneration of:

a) Motorneuron in the spinal cord: exception being those motorunits of sphincters

b) Motorneurons in the brain: except the 3,4,6 CN

a + b = LOWER motorneurons

c) UPPER motorneurons (cortico-spinal neurons): Increased stretch reflexes and spasicity

Question 7

Pathogenesis of ALS?

Answer 7

unknown

Question 8

oxidative stress hypothesis?

Answer 8

Oxidative stress hypothesis:

• free radicle damage when radicle production exceeds the detoxification capacity of specific enzymes (mutation of superoxide dismutase in some forms of familial ALS)

Question 9

Excitotoxic hypothesis?

Answer 9

Excitotoxic hypothesis: excessive activation of AMPA and/or NMDA receptors by glutamate (leading to increased Ca2+ that damages neurons via activation of proteolytic enz)

a) Increased extracellular glutamate due to decreased activity of astrocytic glutamate transporter GLT1
b) decreased GluR2 subunit expression (a subunit of the AMPA receptor) majing them permeable to Ca2+

Question 10

TDP - 43 / FUS mutation hypothesis?

Answer 10

• TDP-43 and FUS (proteins involved in RNA processing) are normally found in the nucleus
• The genes that code for these proteins are mutated in some forms of familial ALS
• The two proteins are shifted to the cytoplasm where they form insoluable aggregates affecting neuronal function

Question 11

Treatment of ALS?

Answer 11

• NO effective drugs available to arrest or alter the course of the disease
• No clear effect of antioxidants (vitamin C and E)
• Small beneficial effect of Ruluzole (blocks glutamate release) - Can slow the disease process by about 3 months
• Stage II: dexpramipexole (improving mitochondrial function)
• Baclophen (agonist of GABA-b receptors) > reduces spasticity
• Other symptomatic treatment: eg. control excessive salivation