Table 1

Differential diagnosis of primary lateral sclerosis

NeurodegenerativeKey distinguishing features
Upper motor neuron-predominant amyotrophic lateral sclerosis
Hereditary spastic paraparesis
Alexander disease
Development of clinically progressive lower motor neuron involvement.
Family history or relevant genetic variant; symmetrical weakness limited to lower limbs.
Focal atrophy and MRI signal change in the medulla, or pathogenic variant in GFAP.
Neuroinflammatory
Primary progressive multiple sclerosis
Anti-amphiphysin paraneoplastic syndrome
Inflammatory lesions on MRI of the brain and cord.
Positive antibody in context of coincident malignancy.
Metabolic
AdrenomyeloneuropathyCerebral MRI white matter abnormalities; raised serum very long chain fatty acids; pathogenic variant in ABCD1.
Infectious
Tropical spastic paraparesis (Human T-cell lymphotropic virus, HTLV-1 & 2)
Syphilis
Positive IgM serology.
Positive serology.
Structural
Foramen magnum region lesions
Parafalcine meningioma
MRI appearances.
MRI appearances.
Vascular
Spinal arteriovenous malformationMRI appearances.
  • It is not a requirement that all are formally excluded, rather investigations are guided by clinical plausibility.