Etiology

There are numerous causes of TM.[23][24]

  • Multiple sclerosis and neuromyelitis optica spectrum disorder: these are the most common causes of TM.

  • Parainfectious causes: note that the causative organism is usually not identified.

    • Antecedent viral infection: known causative agents include herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses, HIV, influenza, human T-cell leukemia virus, West Nile virus, Zika virus, and rabies.

    • Antecedent bacterial or fungal infection: known causative organisms include Mycoplasma pneumoniae, TB, syphilis, Lyme borreliosis.

  • Post-vaccination: TM has been reported with almost all vaccines.

  • Systemic autoimmune causes: systemic lupus erythematosus and Sjogren syndrome are associated with TM.

  • Systemic inflammatory causes: sarcoidosis is associated with TM.

  • Paraneoplastic syndromes: TM can occur in the context of paraneoplastic syndromes.

Pathophysiology

Demyelinating causes of TM include multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MS is a putative central nervous system (CNS) autoimmune disease in which activated T-cells against an unknown antigen generate a cascade of inflammation, demyelination, and axonal loss.[18][25] NMOSD is now known to be distinct from MS. About 75% of cases are associated with aquaporin-4 (AQP4)-IgG, an autoantibody that targets the astrocyte water channel AQP4. NMOSD with AQP4 is an antibody-mediated astrocytopathy, in which complement activation and complement-mediated injury play a key role.[9][26][27][28][29][30] Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been found in approximately 25% of AQP4-IgG seronegative patients with an NMOSD clinical phenotype. MOG-IgG appears to target myelin and not astrocytes.[31][32]

Idiopathic complete TM is often parainfectious, leading to speculation that the immune response against the responsible organism results in an autoimmune attack on myelin or other antigens in the spinal cord.[33] Potential mechanisms include molecular mimicry, whereby T-cells or antibodies stimulated by epitopes found on the infectious agent cross-react with those in the CNS, or the induction of a superantigen response by the organism. Numerous viruses, bacteria (including some mycobacteria), fungi, and parasites have been associated with TM.

Classification

Classification based on spinal cord lesion characteristics

Acute partial TM:

  • Parainfectious, occurring at the time of and in association with an acute episode of infection at a site remote from the central nervous system

  • Characterized by asymmetric spinal cord lesions typically of 1 or 2 vertebral segments in length

  • The clinical syndrome is typically mild to moderate in severity and the motor and sensory symptoms and signs are asymmetric[6]

  • Although heterogeneous, acute partial TM is most commonly associated with high risk for multiple sclerosis when the brain magnetic resonance imaging reveals white matter lesions compatible with demyelination.[3][7][8]

Longitudinally extensive TM:

  • Characterized by asymmetric or symmetric spinal cord lesions that span ≥3 contiguous vertebral segments[4]

  • The clinical syndrome is usually moderate to very severe, and the motor symptoms and signs are typically bilateral and more symmetric than in acute partial TM

  • Although heterogeneous, longitudinally extensive TM is most commonly associated with high risk for neuromyelitis optica spectrum disorder in the setting of seropositivity for neuromyelitis optica-IgG.[5][9][8]

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