Table 1.

Clinical features of various ON subtypes[7,8,9,10,11,12,13,14,15,16,17]

ON subtype	Epidemiology	Etiology	ON features	Other ocular features	Fluid markers	Acute treatment	Prognosis
Infections: As reported by Petzold et al.,[1] causes of infectious and postinfectious ON include but are not limited to Bartonella, Brucella, chikungunya fever, CMV, coronavirus, Coxiella burnetii, dengue, EBV, echovirus, ehrlichiosis, hepatitis B and C, herpes simplex, Histoplasma, HIV, herpesviruses, Inoue-Melnick virus, leprosy, Lyme disease, measles, mumps, Mycoplasma pneumoniae, neurotoxocariasis, ocular cat scratch disease, post-vaccination ON, rubella, streptococcus, syphilis, tick-borne encephalitis, toxoplasmosis, TB, typhus, VZV, West Nile virus, Whipple disease, and Zika virus[1]
Syphilis	Worldwide infection. In 2022, the WHO estimated that there were 8 million adults with syphilis aged 15–49 years	Caused by Treponema pallidum and transmitted through oral, anal, or vaginal sex or contact with infectious lesions. Syphilis can also be transmitted in pregnancy.	Normal, optic disc edema, optic disc atrophy	Uveitis, neuroretinitis, retinal vasculitis, perineuritis, chorioretinopathy	Positive serum and CSF VDRL and FTA-ABS	IV aqueous penicillin 2–4 million units every 4 h for 2 weeks	Variable
TB	In 2022, it was estimated that 10.6 million had TB, with the largest number of new cases in South-East Asia, Africa, and the Western Pacific	Caused by Mycobacterium tuberculosis. Airborne transmission	Normal, optic disc edema, or pale optic nerves	Uveitis, neuroretinitis, perineuritis, compressive lesions (tuberculomas)	Serum QuantiFERON testing. Growth of tuberculous bacteria by smear or culture	Isonicotinic acid hydrazide, ethambutol, rifampin, streptomycin, and pyrazinamide (may vary between immune-competent and immune-compromised hosts)	Variable
Lyme disease	Most common tick-borne infection in the USA and Europe	Caused by Borrelia burgdorferi. Transmitted to humans by tick bites.	Normal, optic disc edema, or pale optic nerves	Neuroretinitis, cranial neuropathies	ELISA IgG and IgM, western blot assay, intrathecal antibodies	IV ceftriaxone 2 g/day or doxycycline 100 mg orally twice daily	Variable
Primary CNS inflammatory disorders
Multiple sclerosis	Incidence is highest in Europe and America with a 2 to 3:1 female to male ratio	Unknown	Acutely, the optic nerve often looks normal or shows mild optic disc edema	Usually normal retinal examination	No specific serum antibody	High-dose corticosteroids and PLEX therapy	Favorable
MOGAD	Worldwide with involvement of children and adults	Unknown	Acutely, the optic nerve may show severe swelling or appear normal	The retina is usually normal; perineural enhancement with longitudinal intraorbital lesions may be seen on MRI. Orbital inflammation has been described. Uveitis is rare.	MOG-IgG	High-dose corticosteroids, PLEX, and IVIG	Mostly favorable with treatment
NMOSD	Highest in Afro-Caribbean and Asian countries with a high (9:1) female to male ratio	Unknown	Acutely, the optic nerve may show severe swelling or appear normal	The retina is usually normal. Rarely, uveitis occurs. Longitudinal intracranial optic nerve lesions are seen on MRI	Serum AQP4-IgG	High-dose corticosteroids, PLEX, and IVIG	Poor
GFAP	Unknown	Unknown, but may be associated with underlying cancers	Unilateral or bilateral optic disc edema	Iritis or uveitis may be seen	CSF GFAP-IgG	High-dose corticosteroids followed by a slow taper	These patients tend to have good vision despite optic disc edema
CRMP5	Unknown	May be paraneoplastic	Optic disc edema is often seen	Vitritis, retinitis, macular exudates, and iritis	CV2/CRMP5 autoantibodies in serum and/or CSF IgG	Tumor removal and corticosteroids	Variable
Systemic diseases: As reported by Petzold et al.,[1] causes include but are not limited to allergic granulomatous angiitis, ANCA-associated vasculitis, ankylosing spondylitis, Behçet’s disease, Churg–Strauss disease, Cogan syndrome, giant cell arteritis, GPA, IgG4-related disease, Kawasaki disease, microscopic polyangiitis, polyarteritis nodosa, primary antiphospholipid syndrome, rheumatic disease, sarcoidosis, Sjögren’s syndrome, SLE, Susac syndrome, systemic sclerosis, Takayasu arteritis, and ulcerative colitis
Sarcoid	Sarcoidosis may be more common in people of African or Caribbean extraction and may affect women more than men	An autoimmune-mediated disorder characterized by noncaseating granulomas affecting one or multiple organs	Normal, edematous, or atrophic optic nerve	Conjunctival nodules, keratitic precipitates, iris nodules, uveitis, perineuritis, and lacrimal gland enlargement	Chest imaging, ACE, gallium scan, 24-h urine calcium, PET study, tissue diagnosis	Corticosteroids and long-term immunosuppression as needed	Variable
SLE	More commonly affects women relative to men, with a ratio of 9:1, typically affecting young adults (20–30 years)	An autoimmune-mediated condition that upregulates antibody production and causes deposition of immune complexes in tissues	Optic nerves may be normal, may show, atrophy, or may manifest edema	Retinal vasculitis, perineuritis, retinal arterial occlusions	ANA, anti-double stranded DNA, anti-Smith nuclear antigen, urinalysis	Corticosteroids and long-term immunosuppression as needed	Variable, often poor
GPA	The incidence rate has been estimated at 12.8 per million person-years with a slight female predominance	A form of vasculitis involving small and medium-sized arteries, primarily in the lung and kidneys	Optic nerves may be normal, may show atrophy, or may manifest edema	Orbital signs and lacrimal gland involvement	Cytoplasmic antineutrophil cytoplasmic antibodies, tissue diagnosis	Corticosteroids and long-term immune suppression	Variable
IgG4 disease	In Japan, the incidence has been estimated to be 0.28-1.08 per 100,000 population. Subjects tend to be aged 50–70 years (predilection for male sex)	IgG4 plasma cells infiltrate various organs and anatomic sites	Optic nerves may be normal, may show atrophy, or may manifest edema	Orbital signs and lacrimal gland involvement	The diagnosis is based on clinical, histopathologic, and serologic findings including increased IgG4 serum concentration, infiltration of IgG4 cells	Corticosteroids and immune suppression as needed	Variable
Sjögren’s syndrome	Sjögren’s syndrome affects 1–2 million people worldwide, with a female to male ratio of 9:1	An autoimmune disease affecting the lacrimal and salivary glands	Normal, edematous, and atrophic optic nerves	Keratoconjunctivitis and dry eyes	Rheumatoid factor (50% of patients) and antibodies against antigens known as Ro (SSA) and La (SSB)	Corticosteroids with or without immune suppression	Variable
Medications
ICIs	Our understanding of the incidence of ICI-related ON is still evolving, with most reports associated with ipilimumab and pembrolizumab	ICIs overactivate the immune system	Normal, edematous, and atrophic optic nerves	Uveitis, endo-ophthalmitis	Increased NMDA receptor, GFAP, CRMP5 antibodies may be detected in serum and CSF	Consider drug cessation and corticosteroids	Variable
TNF-alpha blockers	The incidence of ON among users of TNF-alpha blockers (in patients without prior CNS demyelination) has been estimated to be 5–10 per 100,000 persons	These agents suppress the body’s natural response to TNF	Normal, edematous, and atrophic optic nerves	Uveitis	None	Drug cessation and corticosteroids	Variable

ACE: angiotensin converting enzyme, ANA: antinuclear antigen, ANCA: anti-neutrophil cytoplasmic antibodies, AQP4: aquaporin-4, CMV: cytomegalovirus, CNS: central nervous system, CRMP5: collapsin response mediator protein 5, CSF: cerebrospinal fluid, ELISA: enzyme-linked immunosorbent assay, GFAP: glial fibrillary acidic protein, GPA: granulomatosis with polyangiitis, HIV: human immunodeficiency virus, ICIs: immune checkpoint inhibitors, IV: intravenous, IVIG: intravenous immunoglobulin, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated disease, MRI: magnetic resonance imaging, NMDA: N-methyl-d-aspartate, NMOSD: neuromyelitis optica spectrum disorders, ON: optic neuritis, PLEX: plasma exchange, TB: tuberculosis, TNF: tumor necrosis factor, VDRL: venereal disease research laboratory, VZV: varicella zoster virus, WHO: World Health Organization, EVB: Epstein–Barr virus, FTA-ABS: Fluorescent treponemal antibody absorption test, CV2: Cerebellar Veil 2