Amyotrophic Lateral Sclerosis (ALS)

Question 1

What is ALS?

Answer 1

• progressive, incurable neurodegenerative disease
• causes muscle weakness and eventually death
• a disease of the motor tracts of the lateral column and the anterior horn of the spinal cord

Question 2

What factors can cause ALS?

Answer 2

• Most cases are sporatic, few are familial
• Males > females (equalizes with age)
• most pts are diagnosed between 55-75 years
• rarely occur in 20s and 30s
• white prs are 2x more likely to develop ALS
• more common among non-hispanics
• genetic factor lends to ~10% of diagnosis

Question 3

What is ALS pathophysiology?

Answer 3

• no single cause: several different hypothesis – contribute to progressive loss of motor
• excitotoxicity caused by excessive glutamate leading to entry of Ca2+ into cells (cell death via lipid peroxidation, nucleic acid damage, mitochondrial disruption)
• accumulation of toxic free radicals
• motor neruons replaced with gliosis after neuron death –> leads to scarring in CNS
• bilateral changes in white matter
• spinal cord becomes atrophic
• clear overlap with frontotemportal dementia
• impairment afferects functions in different areas (Limb, Bulbar, Axial, Respiratory)
• progresses as more neurons degenerate and die > muscles are no longer nerve pulses > muscles shrink and waste aways

Question 4

What are the critera for ALS diagnosis?

Answer 4

• Progressive upper and lower motor neuron symptoms and signs in one limb or body segment
  or
• progressive lower motor neuron symptoms and signs in at least two body segments
  and
• absesne of electrophysologic, neuroimaging, and pathologic evidence of other disease processes

Question 5

What are the signs and symptoms of ALS upper motor neuron?

Answer 5

• limb: slowness of movement, incoordiantion, stiffness, poor dexterity of arms/hands, spastic gait and poor balance
• bulbar: dysarthria, dysphagia, pseudobular affect, laryngospasm, sialorrhea
• axial: stiffness, imbalance

Question 6

What are the signs and symptoms of ALS lower motor neuron?

Answer 6

• limb: weakness, atrophy, fasciculations, cramps
• bulbar: dysathria, dysphagia, incomplete eye closure
• axial: difficulty holding up head, maintaining erect posture
• respiratory: weakness of diaghragm causes dysphenea at rest, reduced vocal volume, tachypnea, sleep disordered breathing

Question 7

What is the clinical course of ALS?

Answer 7

• diagnosis early is difficult: often >13-18 months after symptom onset
• usually starts with nerve atrophy in the hands or feet: gradual muscle weekness and wasting arms, legs; muscle fasciculations; difficulty swallowing, speaking, breathing; muscle stiffness, bodily pains, cramps
• fatal, progressive disease: average survival time is 3 years after symptom onset, stable plateus are rare

Question 8

Whar is the ALS cause of death?

Answer 8

respiratory failure, pneumonia

Question 9

What is the goal of ALS treatment?

Answer 9

• slow disease progression
• increase time to need for tracheostomy or permanent assitied ventilation
• prolong survival

Question 10

What are the three aproved agents of trearment for ALS?

Answer 10

• riluzole- start with this
• ederavone
• PB- TURSO
  (add new agents within a few weeks of eo)

Question 11

What is the the neuroprotective effect of Riluzole?

Answer 11

• blocks presynaptic release of glutamate byt bocking pre-synaptic calsium channels
• prolongs median survival by 2-3 months - better for pts with bulbar onset
• major CYP1A2 subtrate - level decreased in smokers
• high fat meal - 20% AUC decrease

Question 12

common adverse effects of riluzole?

Answer 12

• nausea
• dizziness
• general weakness
• numbness
• increased LFTs

Question 13

MoA of endaravone?

Answer 13

free radical scavenger
* efficacy in combo with riluzole

Question 14

What is the MoA of PB-TURSO?

Answer 14

• can reduce neuronal cell death in vitro
• mechanism unclear
• reactive oxygen species scavengers
• slower meadian rate of functional decline seen in trials (75% of paitents were also receivign riluzole and endaravone)

Question 15

What are the ADEs of PB-TURSO?

Answer 15

• avoid in moderate to severe hepatic/ renal impairment
• high fat meal decreases AUC by ~50%
• Common adverse effects:
  1. abdominal pain
  2. diarrhea
  3. nausea
  4. sialorrhea- excessive saliva flow
  5. fatigue
  6. dizziness