Are Amyotrophic Lateral Sclerosis (ALS) or Spinal Muscular Atrophy (SMA) primarily demyelinating diseases?

Neither ALS nor SMA are Demyelinating Diseases

Both Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) are fundamentally diseases of axonal degeneration affecting motor neurons, not demyelinating diseases. 1

Pathophysiology: Why These Are NOT Demyelinating Diseases

ALS Pathophysiology

• The primary pathological process in ALS is progressive degeneration and death of motor neurons themselves and their axons, not degradation of the myelin sheath 1
• ALS involves degeneration of both upper and lower motor neurons along the corticospinal tracts 2, 1
• The etiology is multifactorial, involving increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis 2
• Any demyelination seen on imaging or pathology is secondary to the primary axonal degeneration, not the initiating pathological event 1

SMA Pathophysiology

• SMA is caused by deletions or mutations in the survival motor neuron 1 (SMN1) gene 3
• Like ALS, SMA is characterized by degeneration of lower motor neurons, representing a disease of neuronal loss rather than myelin destruction 4, 3
• Both diseases share pathological hallmarks including intrinsic muscle defects, neuroinflammation, and selective motor neuron vulnerability 3

Critical Distinction from True Demyelinating Diseases

What Defines a Demyelinating Disease

• Multiple sclerosis is the classic demyelinating disease, characterized by widespread focal degradation of the myelin sheath as the PRIMARY pathological process 1
• In true demyelinating diseases like MS, NMO, and ADEM, demyelination is the initial insult, with axonal injury being variable and secondary 2, 1
• MS is characterized by lesions affecting the spinal cord and brain with clinical defects disseminated in space and time 2

Why ALS/SMA Imaging Can Be Confusing

• MRI findings in ALS show abnormal T2/FLAIR signal in the corticospinal tracts, which corresponds to underlying demyelination, axonal degeneration, AND gliosis on histopathology 1
• The "snake eyes" appearance in the anterior horns on spinal imaging reflects lower motor neuron disease, not primary demyelination 2, 1
• These imaging findings represent secondary changes from the primary axonal degeneration, which can mislead clinicians unfamiliar with the distinction 1

Common Pitfall: Rare Coincidental Overlap

• Extremely rarely, ALS patients may develop concurrent demyelinating polyneuropathy as a separate, coincidental condition 5
• This represents chance coincidence of two diseases rather than ALS being a demyelinating disease 5
• The pathomechanism for such rare demyelination in ALS patients remains unclear and does not change the fundamental non-demyelinating nature of ALS 5

Clinical Implications

Diagnostic Approach

• Electromyography and nerve conduction velocity are key diagnostic tests for ALS, with imaging used mainly to exclude other conditions rather than confirm ALS 2
• The clinical presentation must be typical of motor neuron disease (hypertonicity, hyperreflexia, muscle fasciculations, weakness, atrophy) before considering ALS 2, 1
• If a patient presents with ascending sensory disturbance or weakness, this is atypical for motor neuron disease and should raise suspicion for true demyelinating diseases like Guillain-Barré syndrome or NMOSD 6

Treatment Considerations

• Disease-modifying therapies for demyelinating diseases like MS would not be appropriate for ALS or SMA 7
• ALS and SMA require fundamentally different therapeutic approaches focused on motor neuron support, not immunomodulation for demyelination 4, 3, 8