67. Motor Neuron Disease

Question 1

Definition of ALS

Epidemiology (gender, age)

Answer 1

Amyotrophic: loss of muscle bulk
Lateral: lateral column of SC
Sclerosis: hardening of CS tract

M>F 1.5:1
Avg onset: 56 (+FamHx - 46)

• progressive neuromuscular disorder (generalizes with time)
• involves bulbar + somatic musculature
• ultimately fatal 2/2 respiratory involvement

Question 2

What does ALS look like on imaging? pathology? muscle biopsy?

Answer 2

Imaging: degeneration of UMN in motor cortex, ventral root atrophy in SC
Histo: Bunina bodies (ubiquinated proteins in LMN)
Muscle: active denervation and group atrophy, reinnervation/type grouping

Question 3

How is ALS diagnosed? what are sx of ALS?

Answer 3

Clinical dx of exclusion
Exclusion criteria: no sensory/autonomic/visual disorders

Somatic M. Sx
LMN: weakness, atrophy, FASCICULATIONS, cramps
UMN: poor coordination, spasticity, clonus, hyperreflexia

Bulbar M. Sx
LMN: dysarthria, dysphagia, sialorrhea, palatal droop, tongue weakness/fasciculations (nasally speech due to palate weakness)
UMN: dysarthria (slow, spastic speech), dysphagia, pseudobulbar affect (laughing/crying spells), hyperactive gag

Question 4

What are disease mimickers of ALS?

Answer 4

Benign Fasciculations
Progressive Bulbar Palsy: UMN > LMN deficits to bulbar muscle only
Primary Lateral Sclerosis: only UMN deficits to somatic m.
Progressive Muscular Atrophy: only LMN deficits to somatic m.
Kennedy’s Syndrome: gynecomastia, prominent chin fasciculations

Question 5

What is the prognosis of ALS? How is it monitored?

Answer 5

50% mortality within 3-5years sx onset

Prognosis depends on lung function - monitor FVC

Question 6

What are the genetics of Familial ALS?

What are the 2 biggest risk factors for Sporadic ALS?

Answer 6

SOD1 - first identified gene
C9orf72 - ALS + cognitive dysfx

Male Gender
Smoking

Question 7

What are some hypotheses for ALS pathophysiology?

Answer 7

1. Glu Excitotoxicity: astrocyte fails to remove excess Glu from cleft = excessive motor neuron firing = Ca influx = ER/mito. stress
2. Neuroinflammation
3. Altered Protein Degradation - aggregation/defect in proteostasis
4. Impaired Retrograde Axonal Transport
5. RNA Metabolism Alterations

Question 8

Treatment types of ALS

Answer 8

Symptomatic Tx:
Cramps (Gabapentin), Spasticity (Baclofen), Sialorrhea (antidepressants), Pseudobulbar affect (SSRIs), Resp mgmt (monitor FVC, non-invasive night ventilation, airway clearance), Nutrition (prevent weight loss), adaptive devices

Disease Modifying Tx:
Riluzole: improves early survival, no mortality difference
Edavarone: reduces oxidative stress (scavenges ROSs), slows progression in definitive ALS pts but administered via infusion

Question 9

What are the challenges to clinical trials for ALS tx?

Answer 9

Heterogeneous disease - hard for pts to appear similarly
Unknown pathogenesis/pathophys
Delayed dx
Absence of biomarkers
Hard to know if drug is hitting intended target
Poor preclinical studies (mice are not human)