Etiology
The etiology of optic neuritis (ON) can be idiopathic, or causes including inflammation, infection, hereditary, nutrition, toxins (ingestion or drug adverse effects), and radiation.
Idiopathic ON has no known etiology. When ON occurs in isolation, it is considered a forme fruste of multiple sclerosis (MS), and the etiology of ON is thought to be identical to that of MS. The most common view of this inflammatory, primary demyelinating disease is that it is the result of interplay between genetic susceptibility and an environmental factor, most likely a virus. Of the many viruses that have been implicated, the Epstein-Barr virus is the strongest contender for an etiologic role, based on both epidemiologic and, to a lesser extent, biologic studies.[8]
Acute disseminated encephalomyelitis (ADEM), MS, and neuromyelitis optica spectrum disorders (NMOSD [Devic disease]) are known inflammatory demyelinating diseases that cause optic neuritis. ON, typically bilateral, is also part of NMOSD, where frequently there are some features of systemic lupus erythematosus (SLE) and other autoimmune conditions, chronic relapsing inflammatory optic neuropathy (CRION, where there is recent evidence of an overlap with NMOSD), and ADEM causing postinfection or postvaccine conditions.
Inflammatory optic neuropathies outside the context of primary demyelinating diseases (ON in the wider sense) include systemic autoimmune diseases such as SLE (where up to 5% of patients may have optic neuropathy), sarcoidosis, Sjogren syndrome, and Behcet disease.
Infectious etiologies are rare but include Lyme disease and syphilis.
Pathophysiology
The pathophysiologic mechanisms of ON and MS are identical.[9] MS and ON are thought to have autoimmune mechanisms triggered by an environmental factor (such as a virus) in susceptible people. T helper and T cytotoxic cells (CD4+ and CD8+ respectively) are key effector cells. These are activated in the periphery by an environmental factor and cross the blood-brain or blood-optic nerve barrier. Inside the CNS they encounter neural autoantigens, proliferate, activate and recruit other inflammatory cells, and stimulate local immune and parenchymal cells such as microglia and astrocytes to produce proinflammatory cytokines. The neural damage involves complex pathways also involving B cells, antibody, and complement. This leads to the key pathologic features of MS/ON: inflammation, demyelination, axonal loss, and gliosis. The signals for resolution of inflammation are not well known. Neural recovery represents a combination of resolution of inflammation, remyelination, and neural plasticity. The loss of axons, neurons, and myelin can be assessed using quantitative MRI and optical coherence tomography techniques. Free radical damage and glutamate excitotoxicity are thought to play an important role in the axonal and myelin damage, and have been linked to mitochondrial dysfunction.[10][11]
Classification
Optic Neuritis Study Group
In 1991, the Optic Neuritis Study Group classified ON as an inflammatory optic nerve disorder. In the most strict sense, it refers to idiopathic primary demyelinating ON, while in a broader sense it is at times used to mean all inflammatory optic neuropathies, that is, optic neuropathy associated with systemic lupus erythematosus, sarcoid, etc. ON is also sometimes divided into papillitis (inflammation affecting the visible optic nerve head) and retrobulbar ON (affecting the portion of the optic nerve behind the globe). At times, ON may be the presenting sign of multiple sclerosis and is then referred to as a clinically isolated syndrome.
International Consensus Classification
In 2023, a panel of over 100 experts provided a consensus view on the diagnosis and classification of optic neuritis, who together assessed cases of optic neuropathy with different disease characteristics. They provided a new classification scheme based on clinical, serologic, and anatomical approaches.[3]
Autoimmune (usually relapsing):
Aquaporin 4 antibody associated ON (AQP4-ON): positive AQP4-antibody test required. Isolated AQP4-ON is a forme fruste of NMOSD.
Collapsin response mediator protein 5 ON (CRMP5-ON): positive CRMP5-antibody test in patients with prelaminar ON, associated with paraneoplastic ON.
Myelin oligodendrocyte glycoprotein antibody associated ON (MOG-ON): positive MOG-antibody test required. Isolated MOG-ON is a forme fruste of myelin oligodendrocyte glycoprotein antibody-associated disease.
Multiple sclerosis associated ON (MS-ON): first presentation as a clinical isolated syndrome with MRI or CSF findings compatible with MS; may also occur as an MS relapse. Isolated MS-ON is a form fruste of MS.
Single isolated ON (SION): a single event of optic neuritis which is restricted to the optic nerve and negative for known optic neuritis related auto-antibodies.
Relapsing isolated ON (RION): a spontaneous relapse of optic neuritis which is restricted to the optic nerve and negative for known optic neuritis related auto-antibodies.
Chronic relapsing inflammatory optic neuropathy (CRION): requires demonstration of dependence on immunosuppressive treatment to prevent relapses in ON.
Infectious and systemic (normally monophasic):
Postinfectious ON or postvaccination ON: includes ADEM
Infectious ON: infection directly involving the optic nerve
Systemic conditions (e.g., Behcet syndrome, giant cell arteritis, granulomatosis with polyangiitis, sarcoidosis, Sjogren syndrome, systemic lupus erythematosus)
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