ALS is NOT a Demyelinating Disease—It Primarily Affects Axons
ALS is fundamentally a disease of axonal degeneration affecting motor neurons, not a demyelinating disease. While imaging may show changes along the corticospinal tracts that include some demyelination, the primary pathological process is progressive degeneration and death of the motor neurons themselves and their axons 1, 2.
Pathophysiology: Axonal Degeneration is Primary
ALS involves progressive degeneration of both upper and lower motor neurons along the corticospinal tracts, resulting in axonal loss rather than primary myelin destruction 2, 3.
The underlying pathological mechanisms include increased oxidative stress, glutamate toxicity, mitochondrial dysfunction, inflammation, and apoptosis—all processes that directly damage neurons and their axons 2, 4.
The disease causes progressive loss of motor neurons, resulting in atrophy of skeletal muscles including respiratory muscles, which is fundamentally different from demyelinating diseases like multiple sclerosis 3.
Imaging Findings Reflect Axonal Pathology
MRI findings in ALS show abnormal T2/FLAIR signal anywhere within the corticospinal tracts (most frequently in the posterior limb of the internal capsule and cerebral peduncles), which corresponds to underlying demyelination, axonal degeneration, AND gliosis seen on histopathology 1.
The key distinction here is that any demyelination seen is secondary to the primary axonal degeneration, not the primary disease process 1.
Spinal imaging may show abnormal T2 signal in the anterior horns with a "snake eyes" appearance, reflecting lower motor neuron disease 1, 3.
Critical Distinction from True Demyelinating Diseases
Multiple sclerosis is the classic demyelinating disease, characterized by widespread focal degradation of the myelin sheath as the PRIMARY pathological process 1.
In MS, demyelination is the initial insult, with axonal injury being variable and secondary 1.
The co-occurrence of ALS and MS is extremely rare (only 33 reported cases as of 2024), emphasizing that these are fundamentally different disease processes 5.
Clinical Implications
ALS presents with mixed upper and lower motor neuron signs (hypertonicity, hyperreflexia, muscle fasciculations, weakness, and atrophy) reflecting motor neuron death, not demyelination 2.
The relentlessly progressive nature with mean survival of 3-5 years reflects ongoing neuronal death and axonal loss 2, 4.
Immunomodulatory therapies effective for demyelinating diseases do not halt ALS progression, further confirming the distinct pathophysiology 6.
Important Caveat
Rare case reports describe ALS patients with concurrent demyelinating peripheral neuropathy, but this represents either coincidental occurrence or a poorly understood secondary phenomenon—not the core pathology of ALS 6.
The pathomechanism for any demyelinating features occasionally seen in ALS remains unclear, but ALS remains classified as a disease of progressive axonal degeneration 6.