Amyotrophic Lateral Sclerosis (ALS)

Question 1

Poliomyelitis (polio)

Answer 1

Like ALS it also affects the neuronal cell bodies.

• Acute, usually ‘focal’ degeneration of motoneurons due to a viral infection (polio)
• Atrophy of muscle as seen on the patients right leg
• Brought under control since the introduction of a polio vaccination by John Salk!! Huge success!

Question 2

How is the polio virus being used in a positive way?

Answer 2

Using polio to fight cancer!

Genetically modified polio virus for treatment of glioblastoma (brain cancer), by injecting virus into the tumour by a neurosurgeon.

The modified virus can only replicate in cancer cells (oncolytic virus, very important!)

Acts by triggering an immune response to cancer cells!
Recent phase 1 clinical study at Duke university

Question 3

What is ALS?

Answer 3

‘Amyotrophic Lateral Sclerosis’ or ‘Motoneuron Disease -MND”

“something hardening laterally in the brain (spinal cord) which causes atrophy of the muscles”

• The onset is usually rapid and irreversible but sometimes there are rare benign cases that cause very slow degeneration of muscle (eg; stephen Hawking!)

Question 4

What’s the incidence of ALS?

Answer 4

• ~5/100,000 (~200 in NZ)
• 90-95% have no family history of illness; (only one rare ‘familial form of ALS with dominant inheritance mutation of superoxide dismutase enzyme)
• ~5th decade is average age of onset.
• Death within 2-5years usually (‘benign’ forms >10yrs)

Question 5

The symptoms of ALS?

Answer 5

• Progressive wasting, weakness and atrophy of muscles ⇒ paralysis.
• Weakness of legs, arms and hands
• Difficulty with speech (DYSARTHRIA) and swallowing (DYSPHAGIA) (‘progressive bulbar (medulla oblongata) palsy’)
• Impairment of respiration (resp muscles +diaphragm gone as phrenic+IC MN gone) → pulmonary infection
• ‘Spasticity’: muscle stretch reflexes exaggerated and muscle tone increased (even though paralysis is occuring!)

Question 6

Why is the spasticity symptom, where you get exaggerated reflexes and increased muscle tone, so confusing? What is it telling us!

Answer 6

Complex because at the same time we are developing paralysis of the muscles!

The muscle paralysis is due to the degeneration of LMN to innervate the muscles.

However the spasticity indicates that the UMN are also degenerating within the corticospinal tract!

Both LMN and UMN involved!

Question 7

How is the symptom of dysphagia (difficulty swallowing) treated?

Answer 7

Via a ‘PEG’ a Percutaneous Endoscopic Gastrostomy tube.

Tsis is inserted into the stomach so the patient gets adequate nutrition!

Question 8

What signs of Muscle denervation can be seen to confirm the disorder in a non-physical way?

Answer 8

1. Fasciculations: twitches of some motor-units which survived atrophy. These resistant units are stable and fire out APs randomly to large groups of muscle fibres → twitch, which can be seen via the naked eye through the skin. (these can occur physiologically too so don’t freak out)
2. Fibrillations: Spontaneous AP’s generated in individual muscle fibres in EMG recordings. Normal subject ~0 APs so easily seen in ALS patients.

**No involvement of extraocular muscles, anal + bladder sphincters

Usually no sensory +intellectual deficits.

Question 9

Pathology/cause of ALS?

Answer 9

Progressive Degeneration of:

1. Motoneurons (a and delta) in the spinal cord: exception of those controlling the sphincters.
2. Motoneurons in the brain stem: exception of III, IV and VI which control extraocular muscles
   
   • (1) + (2): LMN muscle wasting/paralysis
3. ‘Upper’ Motoneurons (cortico-spinal neurons): increased ‘stretch reflexes, tone and spasticity + babinski reflex

Question 10

Although the Pathogenesis is unknown, what are a few of the Hypothesis???

Answer 10

1. Oxidative Stress Hypothesis
2. Excitotoxic Hypothesis
3. TDP-43/FUS mutation Hypothesis

Question 11

Explain the Oxidative Stress Hypothesis

Answer 11

• Damage of neurons by free radical (reactive O₂ and Nitrogen species •OH, •O₂ and NO•) when radical production exceeds the detoxification capacity of specific defence enzymes. (eg; superoxide dismutase, catalase).
• Mutation of superoxide dismutase due to free radicals leads to oxidative stress, and can be noted in some forms of familial ALS

Question 12

Explain the Excitotoxic Hypothesis

Answer 12

• Excessive activation of AMPA and NMDA receptors by glutamate.
  
  • Increase in extracellular glutamate due to decreased activity of glutamate transporter GLT1 in astrocytes (bc they’ve been damaged by free radicals released from surrounding motoneurons)
  • Or decrease of GluR2 subunit expression in their AMPA receptors, which normally prevents excessive Ca²⁺influx. Lack of this predisposes motoneurons to high Ca²⁺ influxes and excitotoxic damage

Question 13

Explain the TDP-43/FUS mutation hypothesis

Answer 13

TDP-43 and FUS are proteins (involved in RNA processing) normally only found in the nucleus.

If genes coding for these mutate in some forms of ALS the 2 proteins are shifted to the cytoplasm where they form insoluble aggregates, affecting neuronal functions

Question 14

What are the current treatments available for ALS?

Answer 14

No drugs available to alter/stop the course of the disease!

• Riluzole: has small beneficial effect (blocks glutamate release), can slow disease process by a few months (confirms excitotoxic theory)
• Stage II clinical study of Dexpramipexole (improving mitochondrial function, could confirm oxidative stress)
• Baclophen (agonist of GABA-B receptors)→ reduces spasticity/pain

**​Other symptomatic treatments (eg controlling excess saliva due to dysphagia)

*no clear effect of antioxidants (vit C, E), but how many get to the brain, maybe it could help oxidative stress

**experimental replacement therapy using genetically modified stem cells but hard due to the larger targets!