Transverse myelitis

Pathogenesis and pathophysiology
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By Anthony T Reder MD

At autopsy, the lesions in acute transverse myelitis are restricted to the cord. The histology differs somewhat from multiple sclerosis. In cord lesions from multiple sclerosis, many axons are usually preserved and the lesions are scattered (primary demyelination). In acute transverse myelitis, although myelin loss does exceed axonal loss, axons are usually destroyed along with the demyelination, and secondary demyelination may result. In severe transverse myelitis, the lesions may be cavitary. Scattered lesions are less common and suggest multiple sclerosis. The lesions in acute idiopathic transverse myelitis are bilateral and somewhat symmetrical. In transverse myelitis, lesions are typically central, and there is relative preservation of tissue at the periphery; in multiple sclerosis, lesions often begin at the pial surface (Partial cord lesions, or transverse myelitis plus scattered CNS lesions on MRI, frequently evolve into multiple sclerosis or are exacerbations of established multiple sclerosis). There is perivascular spread of monocytes, lymphocytes infiltrate focal areas of the cord, and there is astroglial and microglial activation. In acute cases of transverse myelitis, polymorphonuclear leukocytes and lymphocytes infiltrate the meninges, and macrophages infiltrate the parenchyma. The pattern of spread is difficult to discern based on autopsy findings, but at autopsy and on MRI there is relative preservation of subpial parenchyma. This suggests ischemia, possibly from small vessel arachnoid vasculitis, as the ultimate cause of the cord lesions in transverse myelitis and in the possibly related Devic disease.

Related syndromes show somewhat distinct pathology. In multiple sclerosis, lesions appear at different times and have different distributions. The lesions in acute disseminated encephalomyelitis are monophasic. In acute disseminated encephalomyelitis and associated conditions (perivenous encephalomyelitis, postinfectious encephalomyelitis, and postvaccinal encephalomyelitis), there is widespread perivenous lymphocytic-histiocytic inflammation, mostly within the white matter. There are small foci of demyelination (0.1 to 1 mm), but the contiguous demyelination of acute transverse myelitis is not seen (Alvord 1985).

Some other related conditions are necrotizing, in addition to having the inflammatory and demyelinating components of disseminated encephalomyelitis, eg, acute hemorrhagic leukoencephalitis, progressive necrotizing myelopathy, and Devic disease. Distinction between these diseases rests on more than the degree of inflammation accompanying the demyelinating process. The clinical course, the histology, and the dissemination of the lesions in space and time all differ.

Acute hemorrhagic leukoencephalitis is a monophasic, possibly post-viral syndrome that affects the cord, hemispheres, and brainstem. The CSF contains elevated protein and up to 3000 cells. Mononuclear cells appear first, followed by polymorphonuclear leukocytes. There are widespread perivascular cellular infiltrates, small perivascular hemorrhages, and necrosis, often to the point of liquefaction.

In Devic disease, as well as in transverse myelitis, axons and myelin are destroyed in the center of the cord; there is some preservation in subpial areas. Are Devic disease and transverse myelitis forms of multiple sclerosis? In contrast to multiple sclerosis, in both Devic disease and transverse myelitis, the CSF contains elevated protein and tends to have transient or no oligoclonal bands, and a swollen cord is often visible on MRI. Antibodies to myelin-associated glycoprotein are present in all cases of Devic neuromyelitis optica (Haase and Schmidt 2001). Most patients with Devic disease have antibodies to aquaporin 4 (NMO-IgG). This antibody defines a subpopulation of optic neuritis and myelitis cases separate from multiple sclerosis; therapies differ between the 2 entities (Lennon et al 2004).

Paraneoplastic necrotizing myelitis is acute or subacute and causes a necrotic "carcinotoxic myelodegeneration," with patchy bilateral destruction of myelin, axons, and neurons. Necrosis is massive and hemorrhagic. Inflammation is mild. The blood vessel walls are thickened and contain occasional fibrin thrombi (Ojeda 1984).

The MRI appearance of acute transverse myelitis at times suggests arterial or venous ischemia in combination with demyelination (Tartaglino et al 1996). Another group of myelopathies has pronounced vascular changes (Foix-Alajouanine syndrome) (Foix and Alajouanine 1926). Many of these patients do have arteriovenous malformations.

Anti-ganglioside GM1 antibodies are common in childhood acute transverse myelitis (46% of 15 monophasic cases versus 7% of matched controls) (Kalra et al 2009). This suggests prior exposure to Campylobacter jejuni is related, perhaps in a fashion similar to Guillain-Barré syndrome.

Immune cells secrete inflammatory cytokines that affect spinal cord cells. For instance, IL-6 is increased in CSF in multiple sclerosis and inflammatory neurologic diseases (Maimone et al 1993). It is elevated 300-fold in idiopathic transverse myelitis compared to mixed neurologic controls (Kaplin et al 2005). IL-6 is secreted by astrocytes, and to a lesser extent microglia, and binds to oligodendroglia and axons and also induces more IL-6 production by astrocytes. High levels of IL-6 in the spinal cord directly cause death and dysfunction and indirectly are toxic by inducing nitric oxide synthetase in microglia, which elevates nitric oxide. Moderate to high levels of IL-6 damage spinal cord cells in organotypic cultures. In contrast, brain cells are spared, and low IL-6 doses are actually neuroprotective, possibly because the brain has higher levels of the soluble IL-6 receptor that blocks IL-6 toxicity (Kaplin et al 2005). IL-6 and IL-17 are secreted by peripheral blood cells at high levels in transverse myelitis, and moderate levels in multiple sclerosis (Graber et al 2008).

High IL-6 levels correlate with tissue injury and with sustained clinical disability. IL-6 and other cytokines induced by interferon beta could also enhance spasticity, especially in multiple sclerosis patients with preexisting cord lesions (Bramanti et al 1998). In parallel interferon-induced IL-6, levels correlate with fever (Montalban et al 2000). Interferon-beta induces IL-6 and other members of the IL-6 superfamily, such as neurotrophic leukemia inhibitory factor, LIF (Byskosh and Reder 1996). An “inverted U” effect of IL-6 induced by inflammation or interferon-beta could cause spinal cord repair, dysfunction, or damage depending on local IL-6 levels.

In This Article

Introduction
Historical note and nomenclature
Clinical manifestations
Clinical vignette
Etiology
Pathogenesis and pathophysiology
Epidemiology
Prevention
Differential diagnosis
Diagnostic workup
Prognosis and complications
Management
Pregnancy
Anesthesia
References cited
Contributors