Aetiology

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

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

  • Para-infectious 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 leukaemia 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's 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 auto-antibody 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 para-infectious, 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 super-antigen 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:

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

  • Characterised 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:

  • Characterised 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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