Lecture 42: Amyotropic Lateral Sclerosis

Question 1

What is Poliomyelitis and Syringomyelia

Answer 1

Polio: acute viral infection causing degeneration of mn and muscles which survive but go to atrophy

Syringomyelia: formation of large cysts within central portion of spinal cord; damage of pain and temperature fibres followed by damage of mn cell bodies.

Question 2

What is the difference between Amyotrophic Lateral Sclersosis/Lou Gehrig/Motoneuron disease and other muscle wasting diseases

Answer 2

Usually wasting is caused by lesions outside of the motor nuclei in the spinal cord/brainstem. However ALS affects motoneurons themselves including umn in cerebral cortex and leads to severe weakness of various groups of muscles

Question 3

What is the epidemiology: incidence, causes, onset, survival

Answer 3

~200 in NZ

• 90% sporadic, 10% caused by autosomal dominant mutation of superoxide dismutase/TDP-43/FUS
• Average onset 50yr+
• Death usually within 2-5yrs

Question 4

Describe the general progressive muscle wasting symptoms of ALS and the muscles that aren’t affected. Which motoneurons degeneration causes this

Answer 4

Caused by alpha and gamma motoneuron spinal cord degeneration

1. Progressive Wasting and weakness of legs, arms, hands

Caused by brainstem motoneuron degeneration - not CN 3,4,6 nuclei

2. Difficulty with swallowing and speech - progressive bulbar palsy (medulla): can get PEG tube
3. Impairment of respiration: diaphragm- leading to pulmonary infection (cod)

No involvement of the extra-ocular, anal and bladder sphincter. No sensory or intellectual defects.

Question 5

What are other symptoms of ALS apart from muscle wasting and which motorneuron degeneration causes this symptom

Answer 5

• Spasticity: increased tone and reflexes due to degeneration of UMN
• signs of muscle denervation:
• Fasciculations (gross)
• Fibrillations (EMG)

Question 6

What are the 6 theories of pathogenesis of ALS

Answer 6

Autoimmune, Neurotrophic, Oxidative stress, FUS/TDP43 mutation, FAS induced cytotoxicity and Excitotoxic hypothesis.

Question 7

Compare the Autoimmune and Neurotrophic hypothesis of ALS

Answer 7

Autoimmune: presence of antibodies against Ca2+ channels in some patients

Neurotrophic: reduced in level of neurotrophic factors which promote motoneuron survival: eg. BDNF, NT3

Question 8

What is the Oxidative stress hypothesis and what is form of ALS is it seen in

Answer 8

• Mutation of an antioxidant enzyme (superoxide dismutase) leads to free radical production exceeding the detoxification capacity and causing damage to motoneurons.

Seen in familial forms of ALS

Question 9

What are the 2 parts of the excitotoxicity hypothesis

Answer 9

1. Due to reduced activity of astrocytic glutamate transporter GLUT1., Extracellular glutamate increase
2. Reduced expression of GluR2 subunit of AMPA glutamate receptor in motoneurons which predisposes them to higher calcium influx and excitotoxic damage

Question 10

What is the FUS/ TDP43 mutation hypothesis theory - what form of ALS involved in

Answer 10

TDP 43/ FUS are proteins involved in RNA processing. They get mutations in some forms of familial ALS and are shifted to the cytoplasm where they form insoluble aggregates, affecting neuron function.

Question 11

What is FAS induced cytotoxicity hypothesis

Answer 11

Increased sensitivity to activation of Fas (a member of death receptor family) which increases expression of neuronal Nitric Oxide Synthase which makes toxic peroxynitrite

Question 12

What are the treatments available for ALS

Answer 12

Only symptomatic
- Riluzole can slow progression by few months as a glutamate blocker

• Edaravone is an anti-oxidant which is more effective but given as daily IV infusion
• Baclophen is a GABA agonist to reduce spasicity.
• Other treatments to reduce salivation: - muscarinic blockers
  Future will be cellular replacement therapy.