Optic neuritis

Pathogenesis and pathophysiology
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During an attack of optic neuritis, lymphocytes and monocytes infiltrate the optic nerve, an extension of the central nervous system containing a million myelinated fibers. Immune cells directly damage myelin or indirectly cause dysfunction by secreting proteases, nitric oxide, and cytokines that interfere with neuronal function (“conduction block”). Experimental injection of lymphokines into the posterior eye causes an inflammatory response and slowing of visual evoked potentials within hours (Arezzo et al 1988). Soluble ICAM, a product of activated white blood cells and endothelial cells, is increased in CSF at the first attack of optic neuritis (Petersen et al 1998). Serum interferon-gamma, interleukin-6 and interleukin-2 receptors, and CSF interleukin-2 are increased in patients with optic neuritis (Deckert et al 1992), indicating that T cells are activated and are secreting cytokines in both compartments. These inflammatory cytokines also induce major histocompatibility complex antigens that could provoke chronic inflammation. In 6 patients who had optic neuritis 10 years earlier, mononuclear cells expressed more major histocompatibility complex class II protein than cells from healthy controls (Kinnunen et al 1989).

Myelin basic protein-reactive and proteolipid protein-reactive T cells that produce interferon-gamma, tumor necrosis factor, or lymphotoxin are increased in the CSF in optic neuritis and multiple sclerosis (Soderstrom et al 1993a; Navikas 1996). However, cells secreting the antiinflammatory cytokines, IL-10, IL-4, and TGF-beta are also more frequent, resulting in a complex mix of cytokines (a “cytokine storm,” H link). The number of CSF cells producing inflammatory cytokines in optic neuritis does not correlate with MRI abnormalities or oligoclonal bands (Kivisakk et al 1998).

The inflammation is reversible. Surprisingly, high expression of the activation markers, HLA-DR and CD45RO, on T cells correlates with fewer oligoclonal bands in the CSF and with better visual recovery (Roed et al 2005a). Activation may mark beneficial regulatory T cells, or it may make activated helper cells more susceptible to apoptosis. The vitreous is highly immunosuppressive, so local factors may inhibit inflammation and even enhance repair.

B cells that recognize myelin basic protein are at normal levels in the periphery but are increased 100-fold in the cerebrospinal fluid in both multiple sclerosis and optic neuritis, compared to normal controls (Soderstrom et al 1993b). In individual patients, this oligoclonal response is often directed against multiple myelin basic protein epitopes, but more frequently against proteolipid protein (Sellebjerg et al 1995). In mice transgenic for T cell receptors that recognize myelin oligodendrocyte glycoprotein, 30% spontaneously develop optic neuritis without any signs of experimental allergic encephalomyelitis (Bettelli et al 2003). Immunization with oligodendrocyte-specific protein induces an intense optic neuritis. Optic neuritis has appeared in several cases of anti-GQ1b antibody-positive Miller-Fisher syndrome (ophthalmoplegia, ataxia, and areflexia in Guillain-Barré syndrome), suggesting there is a reaction to this ganglioside that amplifies or causes the neuritis. In multiple sclerosis, anti-myelin basic protein responses are more common than anti-proteolipid protein responses. The antigen-specific response may change over time in demyelinating disease. This suggests there is no single target antigen and that the response to myelin basic protein follows earlier immune activation of unknown cause. In summary, immune changes in optic neuritis are similar to those in relapsing-remitting multiple sclerosis.

The oligoclonal bands are from expanded B cell clones that produce the same type of immunoglobulin from ongoing mutation. This suggests there is an antigen, but a specific optic neuritis or multiple sclerosis antigen has not been defined.

Myeloid dendritic cells, which present antigen to T cells, are mature and activated in optic neuritis (Tsakiri et al 2010). They induce a Th1 bias and T cell proliferation. They are deactivated by simvastatin, but caution must be exercised in the use of statins in conjunction with interferons in demyelinating diseases. Statins increase disease activity when added to ongoing interferon treatment (Birnbaum et al 2008; Sorensen et al 2011) and block interferon signaling in vitro (Dhawan et al 2007) and in vivo (Feng et al 2009).

Markers of axonal injury and nitric oxide metabolites are increased in plasma. Antioxidant enzymes suppress the demyelination in the optic nerves in experimental allergic optic neuritis, probably by interfering with the effects of inflammatory monokines (Guy et al 1989). Uric acid, an antioxidant, is reduced in serum of patients with optic neuritis, a phenomenon also seen in multiple sclerosis. Functional recovery follows resolution of inflammation and of conduction block, expression of new sodium channels on demyelinated axons, and cord remyelination that can continue for up to 2 years. Immune cells are also capable of secreting neurotrophic factors that induce repair.

Magnetic resonance spectroscopy of normal-appearing white matter after optic neuritis is the same as in normal controls, unless there are visible MRI lesions outside the optic nerve (Tourbah et al 1999). In other cases, MRI lesions are present in multiple areas of the CNS, suggesting an overlap between the 2 demyelinating diseases. During recovery of the affected nerve, functional MRI shows extreme activation of areas other than the occipital cortex (extra-striate) including insula, claustrum, thalamus, as well as lateral temporal and posterior parietal cortex (Werring et al 2000). After optic neuritis, there is trans-synaptic degeneration in the lateral geniculate nucleus. Fiber tracking with fast marching tractography shows dystrophy and lost connectivity in the optic radiations beyond the lateral geniculate (Ciccarelli et al 2005).

Functional MRI shows that optic neuritis decreases afferent stimuli to the visual cortex, and reduces functional activation of the cortex (Toosy et al 2005). Disruption of the ventral visual stream from the V1 cortical area and the posterior parietal cortex interferes with construction of the visual world—recognition and identification. At 3 months, visual activation reverses, and there is more activity in the occipital and lateral temporal cortices and the hippocampus.

Histologically, in the scattered plaques of multiple sclerosis, axons are usually preserved (although some subtypes of multiple sclerosis differ). In isolated optic neuritis, more axons are usually destroyed along with the demyelination, although myelin loss does exceed axonal loss. Ninety-five percent to 99% of patients with multiple sclerosis have lesions in the optic nerves at autopsy.

In This Article

Historical note and nomenclature
Clinical manifestations
Clinical vignette
Pathogenesis and pathophysiology
Differential diagnosis
Diagnostic workup
Prognosis and complications
References cited
Web resources