Pathophysiology of Transverse Myelitis
Transverse myelitis results from focal immune-mediated inflammation of the spinal cord, characterized by perivascular infiltration of monocytes and lymphocytes, leading to demyelination, axonal injury, and breakdown of the blood-spinal cord barrier. 1, 2
Primary Immunopathogenic Mechanisms
The pathological substrate involves injury and dysfunction of neural cells within the spinal cord through several immunological pathways 2:
Cellular infiltration: Intraparenchymal and perivascular influx of inflammatory cells (monocytes and lymphocytes) penetrates the spinal cord parenchyma, disrupting the blood-brain barrier 1, 2
Demyelination: The inflammatory process strips myelin from axons, with variable degrees of demyelination depending on disease severity 1, 3
Direct axonal injury: Beyond demyelination, the inflammatory cascade causes direct damage to axons themselves, which correlates with permanent disability 1, 3
Molecular Pathways of Neural Injury
IL-6 serves as the critical cytokine mediator of spinal cord injury in transverse myelitis, with levels in cerebrospinal fluid directly correlating with tissue injury markers and sustained clinical disability 4:
IL-6 activates the JAK/STAT signaling pathway in spinal cord tissue 4
This activation increases iNOS (inducible nitric oxide synthase) activity and PARP (poly(ADP-ribose) polymerase) activity, both of which mediate cellular injury 4
The spinal cord demonstrates unique regional vulnerability to IL-6 compared to brain tissue, potentially due to lower expression of soluble IL-6 receptor in the spinal cord that would otherwise antagonize IL-6 signaling 4
Context-Dependent Pathophysiology
The underlying pathogenic mechanism varies based on the clinical context 2, 3:
Systemic disease-associated: In cases associated with systemic lupus erythematosus or sarcoidosis, vasculitic or granulomatous processes can be identified as the primary mechanism 2
Idiopathic cases: These demonstrate pure intraparenchymal inflammatory infiltration without identifiable systemic triggers 2, 3
Drug-induced: High antineoplastic drug levels in CSF (particularly intrathecal methotrexate, cytarabine, cisplatin) maintained for at least 24 hours can trigger the inflammatory cascade, especially when administered via lumbar route with concurrent craniospinal radiotherapy 5
Anatomical Consequences
The inflammatory process affects spinal cord gray matter, producing upper motor neuron damage 6:
This results in spastic paralysis with hyperreflexia (increased deep tendon reflexes) rather than flaccid paralysis 6
MRI demonstrates T2-weighted hyperintense lesions that appear wedge-shaped on axial views and cigar-shaped on sagittal views 6
Approximately 50% of patients develop complete paraplegia at peak deficit, with virtually all experiencing bladder dysfunction and 80-94% having sensory disturbances 1
Critical Unanswered Questions
Despite advances in understanding, three fundamental questions remain 2:
- What are the specific triggers initiating the inflammatory cascade in idiopathic cases?
- Which cellular and humoral factors are most responsible for neural injury?
- How can the inflammatory response be optimally modulated to improve outcomes?
The heterogeneity of triggers and mechanisms explains why transverse myelitis represents a syndrome rather than a single disease entity 3, 7.