Allbutt believed that optic atrophy in multiple sclerosis, tabes dorsalis, and cerebellar diseases were caused by traveling degeneration that propagated rostrally from a primary lesion in the spinal cord (Allbutt 1870). Other putative causes of optic neuritis and multiple sclerosis have included antecedent illnesses, cold temperatures, grief, dysplastic glia, myelinotoxic factors, heavy metals, spirochetes, viruses, venular thrombosis, and vasospasm (DeJong 1970). Current belief is that optic neuritis is immune-mediated, although the specific mechanism and target antigen (if one exists) are unclear.
Antibodies to brain antigens are neither the cause nor the consequence of optic neuritis. During an acute attack of optic neuritis, free anti-myelin basic protein antibodies appear in the serum. These antibodies become complexed to myelin basic protein within 4 months. The antibodies bind residues 61 to 106 of myelin basic protein (Warren et al 1992). In a small subset of cases, antibodies recognize only proteolipid protein (Warren 1994). Proteolipid protein induces experimental allergic optic neuritis in mice (Potter and Bigazzi 1992), indicating that this antigen induces region-specific immune responses. Cell-mediated cytotoxicity against lymphocytes coated with myelin basic protein, cerebrosides, and gangliosides also correlates with disease activity (Frick 1988). However, in optic neuritis, the target of the activated T cells and monocytes is unknown.
Optic neuritis can be a primary idiopathic inflammation of the optic nerve. It can also be a result of diverse inflammatory conditions, including multiple sclerosis, Devic disease, allogeneic bone marrow transplantation, postvaccinal or postinfectious reactions (eg, following ehrlichiosis, tularemia, viral encephalitis, measles, mumps, chickenpox, hepatitis A and B, herpes zoster, HIV, HTLV-I, infectious mononucleosis, mumps, West Nile virus), or contiguous inflammation (fungus, sarcoidosis, tuberculosis, Angiostrongylus cantonensis, brucellosis, chlamydia pneumoniae, or syphilis), or intraocular inflammation. After virus infections, the disease is often bilateral (Farris and Pickard 1990). When vaccination or virus infections are followed by optic neuritis in children, most have CSF oligoclonal bands and intrathecal antiviral antibody synthesis (Riikonen et al 1988). Despite multiple case reports of linkage to vaccination, well-controlled epidemiologic studies show no increase in optic neuritis after vaccination for hepatitis B, influenza, measles, mumps, rubella, or tetanus. Many postvaccinal and postinfectious cases (9 of 21) subsequently develop multiple sclerosis within a year of the optic neuritis (Riikonen et al 1988). The fever and inflammation from these infections may expose preexisting optic neuritis or multiple sclerosis. Patients with virus-specific oligoclonal IgG antibodies in CSF are more likely to develop multiple sclerosis. These epidemiologic data raise the question of whether optic neuritis and infectious antigens are connected, or whether optic neuritis is a nonspecific response to immune activation.
There is some genetic influence in susceptibility to multiple sclerosis. Optic neuritis is frequently associated with multiple sclerosis, and by implication, there is an increased risk (undefined) for family members. There is an increased frequency of HLA-DR2, DR3, and Dqw1 (Francis et al 1987), and DR15, DQA-1B, and DQB-1B (Frederiksen et al 1996) in patients with optic neuritis. Compared to Caucasian patients, patients of African descent have worse visual acuity at onset and after 1 year (Phillips et al 1998). The neuromyelitis optica form of multiple sclerosis is more common in those of African ancestry. This suggests genetic influences that parallel the link of HLA-DRB/*1501 to Western, but not Asian (neuromyelitis optica), forms of multiple sclerosis (Kira et al 1996). The Leber mutation may be a genetic risk factor for developing multiple sclerosis (Vanopdenbosch et al 2000).