Transverse myelitis pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Overview
Pathophysiology
Physiology
- The lesions in acute transverse myelitis are invariably limited to the spinal cord.[1][2]
- There is no involvement of other structures in the central nervous system.[1]
- The spinal cord involvement in patients with transverse myelitis is usually central, uniform and symmetric but in patients with multiple sclerosis it typically affects the spinal cord in a patchy way and the lesions are usually peripheral.
Pathogenesis
- In the pathogenesis of transverse myelitis, a variety of immunological mechanisms may cause pathological substrate and dysfunction of neural cells within the spinal cord.[3]
- Transverse myelitis is the result of progressive demyelination and axonal loss in addition to gray matter involvement, necrosis and cavitation.[1]
- It is understood that infections may cause transverse myelitis by: [1]
- Direct tissue damage
- Immune-mediated infection-triggered tissue damage
- Multiple sclerosis is the other cause to the transverse myelitis and it sometimes transverse myelitis can appear as the first symptom of Multiple sclerosis.[1]
- Acute partial transverse myelitis may be predictive of a subsequent diagnosis of multiple sclerosis in children.[4]
- Invariable histopathological findings of transverse myelitis include:[1]
- Perivascular spread of monocytes
- Focal areas of lymphocytes infiltrating
- Astroglial and microglial activation
- In some biopsies during the acute phases of TM, infiltrates of CD4+ and CD8+ T-lymphocytes were found to be prominent suggesting immune-mediated disease process. There is typically preservation of the subpial parenchyma suggesting ischemia as the ultimate cause of the cord lesions in TM. The pathology also differs depending on the etiology. For example, necrotizing myelitis can be seen in NMO (see below) and paraneoplastic myelitis [35]. In MS and acute disseminated encephalomyelitis (ADEM) the lesions tend to have a predilection to the white matter in comparison to the circumferential involvement in idiopathic TM [36].
Various infections precede 30-60% of the cases of TM [1, 3, 4, 7-9, 11, 37]. Reported infections include, but not limited to: herpesviridae, enteroviruses, influenza viruses, adenoviruses; coxsackieviruses; enteric cytopathogenic human orphan (ECHO) virus, hepatitis A virus; lymphocytic choriomeningitis virus (LCMV); mumps virus; measles virus, rubella virus, poliovirus, rubeola virus, dengue virus, Russian spring-summer encephalitis virus, varicella virus, mycoplasma pneumonia bacteria, legionella pneumonia bacteria, pulmonary tuberculosis, borrelia (Lyme disease), listeria, and Bartonella (cat scratch disease) [4, 11, 38, 39]. About 30% of pediatric cases are preceded with immunizations within one month of disease onset [7, 11].
Infections can cause TM through direct tissue damage, [39-41] or by immune-mediated infection-triggered tissue damage which may be due to molecular mimicry or superantigen effect. The molecular mimicry theory is based on the fact that several infectious agents are capable of encoding molecular structures (e.g. proteins, glycolipids or proteoglycans) that mimic self-antigens [4, 42-44]. Immune response to the mimic “pseudo-self” then may result in cross-reactive immune activation against self tissue. The immune response can be either T-cell mediated or antibody-mediated. Superantigens are microbial peptides that are capable of inducing a fulminant immune response by activating a large number of lymphocytes including autoreactive T- cells in a unique fashion by binding to the Vβ region of T cell receptor instead of highly variable peptide groove [45-49]. Superantigens are also capable of activating T- lymphocytes in the total absence of co-stimulatory molecules.
A non-microbial related immune dysfunction has been also proposed in the immunopathogenesis of TM. Some studies have described the presence of autoantibodies in TM [18, 22, 50]. Interleukin 6 (IL-6) levels were also markedly elevated in the spinal fluid of TM patients in comparison to control patients and to MS patients, and this also correlated with disability [4, 51]. IL-6 is secreted by astrocytes and microglia and binds to oligodendroglia and axons. High levels of IL-6 can cause direct tissue injury and indirect damage by inducing nitric oxide synthetase in microglia. Interestingly, Interferon-beta (IFN-β), a medication used to treat MS, was found to induce IL-6 [52]. IL-6 has probably a bell-shaped effect where at certain levels could cause damage and at different levels can induce repair [51, 53, 54].
One study that was conducted in Japan found that several patients with TM have much higher serum IgE levels than MS patients or controls pointing towards the immune-mediated process as well [55]. Concordant with these findings, tissue biopsies of two patients with TM and elevated total and specific serum IgE disclosed the presence of antibody deposition within the spinal cord and perivascular infiltration with eosinophils that could induce tissue damage [56].
Genetics
[Disease name] is transmitted in [mode of genetic transmission] pattern.
OR
Genes involved in the pathogenesis of [disease name] include:
- [Gene1]
- [Gene2]
- [Gene3]
OR
The development of [disease name] is the result of multiple genetic mutations such as:
- [Mutation 1]
- [Mutation 2]
- [Mutation 3]
Associated Conditions
Conditions associated with [disease name] include:
- [Condition 1]
- [Condition 2]
- [Condition 3]
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Awad A, Stüve O (2011). "Idiopathic transverse myelitis and neuromyelitis optica: clinical profiles, pathophysiology and therapeutic choices". Curr Neuropharmacol. 9 (3): 417–28. doi:10.2174/157015911796557948. PMC 3151596. PMID 22379456.
- ↑ Tavasoli A, Tabrizi A (2018). "Acute Transverse Myelitis in Children, Literature Review". Iran J Child Neurol. 12 (2): 7–16. PMC 5904733. PMID 29696041.
- ↑ Kerr DA, Ayetey H (2002). "Immunopathogenesis of acute transverse myelitis". Curr Opin Neurol. 15 (3): 339–47. doi:10.1097/00019052-200206000-00019. PMID 12045735.
- ↑ Meyer P, Leboucq N, Molinari N, Roubertie A, Carneiro M, Walther-Louvier U; et al. (2014). "Partial acute transverse myelitis is a predictor of multiple sclerosis in children". Mult Scler. 20 (11): 1485–93. doi:10.1177/1352458514526943. PMID 24619933.