Optic Neuropathy

Key points of this disease group

• Optic neuropathy is a general term for diseases that cause functional impairment of the optic nerve, including various causes such as inflammation, ischemia, compression, toxicity, nutritional deficiency, and genetics.
• Optic neuritis is a subcategory limited to inflammatory conditions and is distinguished from optic neuropathy as a whole.
• Arteritic anterior ischemic optic neuropathy (AAION/GCA) is an ophthalmic emergency. If giant cell arteritis (GCA) is suspected, high-dose steroids should be started on the same day. Without treatment, 65% develop involvement of the fellow eye within 10 days ¹⁾.
• Relative afferent pupillary defect (RAPD) is the most important finding for objectively evaluating optic nerve dysfunction and is positive in unilateral or asymmetric optic neuropathy.
• The thinning patterns of pRNFL (peripapillary retinal nerve fiber layer) and GCL (ganglion cell layer) on OCT are useful for differentiating disease types.
• In acute unilateral optic neuropathy, GCA exclusion tests (ESR, CRP, platelets) should be performed as a priority, and inquiry is mandatory in patients aged 50 years or older.
• The entry point for differential diagnosis is systematically organized along four axes: acute vs. chronic, unilateral vs. bilateral, presence or absence of pain, and optic disc findings.

1. What is optic neuropathy?

Optic neuropathy is a general term for a group of diseases in which some damage occurs to the optic nerve, leading to decreased visual function. It presents with one or more of the following: decreased visual acuity, visual field defects, color vision abnormalities, and reduced contrast sensitivity ²⁾.

The optic nerve is composed of approximately 1.2 million axons of retinal ganglion cells (RGCs). Within the eye, they bundle together as the optic disc, pass through the optic canal, and reach the optic chiasm. Damage from the optic disc to the anterior part of the optic chiasm is called “anterior visual pathway disorder,” and most clinically significant optic neuropathies correspond to this region ²⁾. Damage beyond the optic chiasm (optic tract, optic radiation, occipital lobe) is termed “posterior visual pathway disorder” and is treated as a visual pathway disorder rather than an optic neuropathy.

The optic nerve is divided into four segments. The intraocular segment (optic disc, about 1 mm) is prone to ischemic and inflammatory optic neuropathies. The intraorbital segment (about 25 mm) is often affected by compressive and inflammatory conditions. The intracanalicular segment (optic canal, about 5–8 mm) is susceptible to traumatic and bony compression. The intracranial segment (about 10 mm) is frequently compressed by pituitary adenomas and craniopharyngiomas. It is also important to distinguish between “anterior optic neuropathy,” where the optic disc can be directly observed, and “retrobulbar optic neuropathy,” where the fundus appears normal. In retrobulbar optic neuropathy, the absence of disc changes makes it easy to overlook as a cause of vision loss.

Blood flow to the optic disc is primarily provided by the short posterior ciliary arteries (SPC arteries). The SPC arteries are terminal branches of the ophthalmic artery and supply blood to the prelaminar, laminar, and retrolaminar regions of the optic disc. Circulatory disturbances in this area are the main pathological basis for NAION and AAION ³⁾. The interior of the optic nerve is protected by the blood-brain barrier, but this protective mechanism breaks down in inflammatory optic neuritis and autoimmune diseases ²⁾.

Common Pathological Pathway and Optic Atrophy

Regardless of the cause, the final common pathway involves damage to retinal ganglion cells and optic nerve axons, leading to apoptosis and eventually optic atrophy. Optic atrophy is the end-stage of optic neuropathy and is recognized as pallor of the optic disc. Once atrophy is established, recovery of visual function is severely limited ²⁾.

Optic nerve axons are a mixture of myelinated and unmyelinated fibers with diameters of 0.2–10 μm, broadly classified into P cells (responsible for luminance and contrast) and M cells (responsible for motion and contour). In optic neuropathies, P cells, which have high ATP consumption, are more susceptible to damage, which is related to the mechanism of central scotoma in toxic and nutritional optic neuropathies ²⁾.

Overview of Epidemiology

The annual incidence rates of major optic neuropathies (per 100,000 adults) are summarized. NAION is the most common, with rates of 2.3–10.2 in the United States³⁾. Idiopathic optic neuritis has an incidence of 1.6 in Japanese adults¹³⁾, and LHON (Leber hereditary optic neuropathy) has approximately 117 new cases per year in Japan (2014 survey), making it a rare disease¹⁴⁾. The estimated annual incidence of AAION/GCA is 0.36 per 100,000 in individuals aged 50 and older, and it is more common in Northern European Caucasians (approximately 30 per 100,000 in Norway). Visual complications of GCA occur in 10–30% (up to 70% in some reports), and AAION accounts for 60–90% of these¹⁾. The annual incidence of MOGAD is estimated at 1.6–4.8 per 1,000,000⁶⁾.

Classification of Optic Neuropathies

Optic neuropathies can be classified from multiple perspectives. The most clinically useful classification is shown below.

Classification by Onset Pattern

• Acute (hours to days): NAION, AAION, traumatic
• Subacute (days to weeks): Idiopathic optic neuritis, LHON, compressive (some)
• Chronic (months to years): ADOA, chronic compressive, radiation-induced (late-onset)

Classification by cause

• Ischemic: NAION, AAION, PION
• Inflammatory (optic neuritis): Idiopathic, MS-related, NMOSD-related, MOGAD-related, infectious
• Compressive: Tumor, cyst, aneurysm, thyroid eye disease
• Toxic: ethambutol, amiodarone, alcohol, etc.
• Nutritional: vitamin B12/B1/folate/copper deficiency
• Hereditary: LHON, ADOA, Wolfram syndrome
• Traumatic: optic canal fracture, direct injury
• Radiation-induced: delayed ischemic degeneration

Classification by location

• Anterior optic neuropathy (with disc changes): NAION, AAION, anterior optic neuritis
• Retrobulbar optic neuropathy (normal disc): toxic, hereditary, MS-related optic neuritis (most cases)
• Chiasmal lesions: pituitary adenoma, craniopharyngioma (bitemporal hemianopia)

Diagnostic Framework for Optic Neuropathy

The diagnosis of optic neuropathy proceeds in five steps.

Step 1: Confirm optic nerve dysfunction Objectively confirm optic nerve dysfunction using RAPD, visual acuity, color vision, and visual field testing.

Step 2: Localization of the lesion Anterior (with optic disc changes) or retrobulbar (normal optic disc), intraorbital, intracanalicular, or intracranial. Estimate localization based on the visual field defect pattern.

Step 3: Unilateral or bilateral, acute or chronic This allows significant narrowing of the differential diagnosis.

Step 4: Exclusion of dangerous types Prioritize exclusion of GCA (ESR, CRP), compressive (MRI), and infectious (syphilis, fungal) causes.

Step 5: Specific tests Add anti-AQP4 antibody, anti-MOG antibody, mtDNA testing, and nutritional testing depending on the type.

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2. Differences from optic neuritis (conceptual clarification)

“Optic neuritis” and “optic neuropathy” are often confused in clinical practice, but they have a relationship of subordinate and superordinate concepts.

Concept clarification

Optic neuropathy = a superordinate concept of optic nerve disorders. It includes any cause such as inflammation, ischemia, compression, toxicity, and genetics.

Optic neuritis = a subordinate concept limited to inflammatory causes among optic neuropathies. It includes idiopathic, MS-related, NMOSD-related, and MOG antibody-associated types.

Confusing non-inflammatory optic neuropathies (ischemic, compressive, toxic, hereditary) with optic neuritis can lead to erroneous steroid administration. In particular, steroid therapy is contraindicated in invasive aspergillosis ²⁾, and administering steroids in the acute phase of LHON is not only ineffective but also delays definitive diagnosis.

Main clinical features of optic neuritis

Optic neuritis (inflammatory) has the following features that help differentiate it from non-inflammatory causes.

• Acute onset: progresses over days to 2 weeks, then shows a tendency to recover within 5 weeks.
• Pain on eye movement: present in about 50% of cases. Usually absent in ischemic, compressive, or toxic causes.
• Typical age: 15–45 years (ischemic is usually over 50).
• MRI findings: typical contrast enhancement of the optic nerve (gadolinium-enhanced T1).
• Spontaneous recovery: in idiopathic or MS-related cases, over 90% recover to visual acuity of 0.5 or better after 1 year (ONTT study)⁴⁾.
• MS conversion risk: 15 years after first episode, 25% without brain MRI lesions and 78% with lesions progress to MS⁴⁾.

Situations where differentiation is difficult

Below, differentiation between optic neuritis and non-inflammatory optic neuropathy becomes difficult.

• Acute unilateral vision loss in women over 50: NAION vs. AQP4 antibody-positive optic neuritis (NMOSD)
• Acute bilateral vision loss in young adults: LHON vs. simultaneous bilateral optic neuritis vs. toxic optic neuropathy
• Unilateral vision loss with optic disc swelling: NAION vs. anterior optic neuritis vs. optic disc vasculitis

AQP4 antibody-positive optic neuritis is a steroid-resistant refractory disease accounting for about 10% of idiopathic optic neuritis, with a higher age of onset and a female predominance (female-to-male ratio 9:1) compared to typical optic neuritis ⁵⁾. The AQP4 antibody targets aquaporin-4 channels expressed on astrocytes in the optic nerve, causing complement-dependent cytotoxicity ⁵⁾. Since treatment strategies differ fundamentally between AQP4 antibody-positive and negative cases, antibody testing should be ordered before steroid pulse therapy. The cell-based assay (CBA) method has higher sensitivity and specificity than ELISA and is recommended ⁵⁾.

Before performing steroid pulse therapy for optic neuritis, infectious diseases (hepatitis B, syphilis, HIV, fungal infections) must be ruled out ²⁾. High-dose steroid administration in hepatitis B virus carriers can cause fulminant hepatitis. In syphilitic optic neuritis, antibiotics take priority over steroids.

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3. Disease types requiring high urgency

The table below shows the types of optic neuropathy that require particularly urgent management.

Disease type	Urgency	Consequences if missed
Arteritic anterior ischemic optic neuropathy (AAION/GCA)	Most urgent	Fellow eye blindness (65% develop within 10 days if untreated) 1)
Acute compressive optic neuropathy (tumor, cyst, hematoma)	Urgent	Progressive optic atrophy and irreversible vision loss
Nasal optic neuropathy (invasive aspergillosis)	Emergency	Reported mortality rate of 94%2)
Traumatic optic neuropathy (optic canal fracture)	Emergency	Early treatment may preserve visual function
Posterior ischemic optic neuropathy (PION)	Emergency	Occurs after surgery or massive blood loss; often irreversible

GCA Emergency Response Flow

Emergency Protocol for Suspected GCA

Age ≥50 and any of the following → same-day evaluation

1. Sudden unilateral vision loss (including amaurosis fugax)
2. Jaw claudication
3. Temporal headache, scalp tenderness, induration or loss of pulse of the temporal artery
4. Fever, weight loss, proximal muscle pain (PMR-like symptoms)
5. Diplopia (third, fourth, or sixth cranial nerve palsy)

Management steps

1. Immediate blood draw: check ESR, CRP, and platelets (CRP >10 mg/L or elevated ESR requires caution)
   • ESR reference range: male = [age/2], female = [(age+10)/2] mm/h
   • CRP is more specific than ESR¹⁾
2. Ophthalmic emergency evaluation (visual acuity, optic disc findings, RAPD)
3. Start steroids (do not wait for test results)
   • No visual symptoms: prednisolone 40–60 mg/day orally¹⁾
   • Visual symptoms present: Methylprednisolone 500–1,000 mg/day IV for 3 days¹⁾
4. Temporal artery biopsy (TAB) or head color Doppler ultrasound within 48–72 hours
   • TAB sensitivity and specificity both ≥95% (when performed properly)¹⁾
   • Color Doppler ultrasound halo sign: sensitivity 68%, specificity 91% (100% if bilateral positive)¹⁾
5. Biopsy possible within a few days after starting GC (pathological findings persist)
6. Multidisciplinary collaboration among ophthalmology, rheumatology, and neurology

Important: Start steroids without waiting for test results. Delaying administration directly increases the risk of blindness in the fellow eye.

Amaurosis fugax appears as a prodromal symptom in approximately 30% of cases of permanent vision loss, occurring on average 8.5 days prior ¹⁾. At this point, it is extremely important to suspect GCA and proactively initiate steroids as secondary prevention.

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4. Entry Point for Differential Diagnosis

Differential diagnosis of optic neuropathy is systematically organized along four axes: acute vs. chronic, unilateral vs. bilateral, presence or absence of pain, and optic disc findings.

Acute vs. Chronic

Acute (reaches maximum deficit within hours to days)

• NAION: Typically presents with sudden vision loss noticed upon waking
• AAION: Rapid unilateral vision loss, severe (vision <20/200 in >60%) ¹⁾
• Traumatic: Immediately to within hours after trauma

Subacute (days to weeks)

• Idiopathic optic neuritis: Progresses over 2 weeks, then recovery begins
• LHON: Unilateral painless subacute vision loss, becoming bilateral within weeks to months
• Compressive: May progress subacutely due to rapid tumor growth or hemorrhage

Chronic (slow progression over months to years)

• ADOA (autosomal dominant optic atrophy): Bilateral slow progression starting in school age
• Chronic compressive: Due to pituitary adenoma, orbital tumor, etc.
• Toxic/nutritional: Subacute to chronic progression with long-term exposure or malnutrition

One eye or both eyes

Diseases that tend to be unilateral

• NAION: Usually unilateral (simultaneous bilateral onset is extremely rare)
• AAION: Starts unilaterally; if untreated, 65% spread to the fellow eye within 10 days¹⁾
• Idiopathic optic neuritis / MS-related: Typically unilateral
• Compressive, traumatic, radiation-induced: Often unilateral

Diseases that tend to be bilateral

• LHON: Initially unilateral, becomes bilateral within weeks to months (eventually nearly 100% bilateral)
• ADOA: Bilateral symmetric onset
• Toxic/nutritional: Principally bilateral (if one eye is completely normal, consider excluding toxic causes) ²⁾
• NMOSD/AQP4-IgG positive: Severe, bilateral, relapsing. 60–69% have permanent vision loss of 20/200 or worse in at least one eye ⁵⁾
• MOGAD: Frequent bilateral onset (extremely rare in MS-related or idiopathic cases) ⁶⁾

Presence or absence of pain

Pain present	No pain (painless)
Idiopathic optic neuritis (eye movement pain ~50%)13)	NAION (no eye pain; headache, jaw claudication are GCA systemic symptoms)
MS-related optic neuritis	AAION (no eye pain; jaw claudication, headache present)
NMOSD-related (periorbital pain)	LHON/ADOA (painless) 14)
MOGAD (often with headache) 6)	Toxic/nutritional (no pain with eye movement)
Traumatic (pain from injury)	Compressive (usually painless but may have orbital pain)

Classification by Optic Disc Findings

Interpretation of Optic Disc Findings

Optic Disc Finding	Suspected Disease
Redness and swelling (hyperemic edema)	NAION (inferior sectoral), anterior optic neuritis
Pallid swelling	AAION (characteristic chalk-like pallid swelling) 1)
Severe swelling (marked hyperemia)	NMOSD/MOGAD-related optic neuritis (particularly severe disc swelling) 6)
Normal (retrobulbar lesion)	Toxic/nutritional/ADOA, MS-related optic neuritis (normal fundus in 65%)
Papillary redness and peripapillary telangiectasia (no fluorescein leakage)	LHON acute phase (distinction from optic neuritis by absence of fluorescein leakage) 14)
Pallor (atrophy)	Chronic/post-recovery optic neuropathies in general
Blurred margins without hyperemia	Pseudopapilledema (buried optic disc drusen)
White intra-papillary particles	Superficial optic disc drusen

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5. Examination and Testing

Essential Ophthalmic Evaluation

When optic neuropathy is suspected, perform the following evaluations systematically.

Visual acuity and color vision Corrected visual acuity is fundamental for assessing the degree of impairment and monitoring progression. Color vision (Ishihara, Farnsworth-Munsell 100 hue) is often affected early in optic neuropathy, and color vision abnormalities may precede visual acuity loss even when acuity is relatively preserved. In toxic and nutritional optic neuropathies, desaturation of red perception is an early sign ²⁾. In ADOA (autosomal dominant optic atrophy), acquired tritanopia (blue-yellow color vision defect) is characteristic, showing a tritan axis on the Farnsworth-Munsell 100 hue test ²⁾.

RAPD (relative afferent pupillary defect)

RAPD is assessed using the swinging flashlight test and serves as an objective indicator of optic nerve dysfunction. It is also useful for differentiating from malingering and functional visual disorders ²⁾.

Interpretation of RAPD

• Positive: Always positive in unilateral or asymmetric optic neuropathy. Reflects the difference in light input.
• Bilateral symmetric and negative: In symmetric disorders such as toxic, nutritional, and hereditary optic neuropathies, it is typically negative (pathological but easily overlooked).
• Note: This can also be positive in end-stage glaucoma and AZOOR (acute zonal occult outer retinopathy).
• Differentiation from glaucoma: RAPD occurs in end-stage glaucoma, but if RAPD is strong relative to the degree of visual field loss, suspect optic neuropathy.
• Use of a high-density filter: When the swinging light test is unclear, a neutral density filter can be placed over the affected eye to quantify the response.

OCT (Optical Coherence Tomography)

OCT is an essential test for staging and monitoring optic neuropathy.

Evaluation parameter	Acute phase findings	Chronic phase findings
pRNFL (peripapillary RNFL thickness)	Thickened in papilledema (caution for false positives)	Thinned in optic atrophy
GCL-IPL (ganglion cell + inner plexiform layer thickness)	Little change	Thinned reflecting retinal ganglion cell damage
Optic disc shape	Cupping disappears or decreases	Becomes fixed after atrophy

Pattern of pRNFL thinning and differential diagnosis

The pattern of pRNFL thinning on OCT is useful for differential diagnosis from several weeks to months after onset.

• Severe circumferential thinning: NMOSD (AQP4 antibody-positive type) is the most severe. Thinning is severe all around.
• Temporal thinning (papillomacular bundle): Toxic, nutritional, LHON, ADOA. Corresponds to central scotoma.
• Superior or inferior sectoral thinning: NAION. Corresponds to superior or inferior arcuate defect.
• MOGAD vs. MS-related: pRNFL thinning after MOG-ON is more severe than MS-related ⁶⁾.
• Differentiation from glaucoma: In glaucoma, optic disc changes (cupping enlargement) precede, and GCL thinning pattern differs.

Visual Field Testing (Humphrey Visual Field)

Visual field defect patterns directly relate to anatomical localization of the lesion.

Visual field defect pattern	Suspected disease	Anatomical correlation
Central scotoma, cecocentral scotoma	Toxic/nutritional, LHON, ADOA, idiopathic optic neuritis2)	Papillomacular bundle (PMB) damage
Horizontal defect (inferotemporal to inferior)	NAION (sectoral defect)3)	Ischemia of upper or lower half of optic disc
Bitemporal hemianopia	Optic chiasm compression (pituitary adenoma, craniopharyngioma)	Central crossing fibers of optic chiasm
Homonymous hemianopia (same side)	Post-chiasmal lesion (optic tract, optic radiation, occipital lobe)	Central visual pathway
Junctional scotoma	Anterior chiasmal lesion, a type of nasal optic neuropathy	Papillomacular bundle + contralateral superotemporal
Generalized sensitivity reduction	NMOSD-related / after severe optic neuritis5)	Extensive optic nerve fiber damage
Enlarged Mariotte blind spot (normal visual acuity)	Optic disc drusen, optic disc vasculitis, perioptic neuritis	Only around the optic disc

Clinical Use of Visual Field Testing

• Central scotoma differential diagnosis: can occur in macular disease. Distinguish by OCT macula (no GCL thinning → retinal disease) and pRNFL thinning (present → optic nerve disease).
• Horizontal defect strongly suggests NAION, but differentiation from inferior arcuate scotoma (glaucoma) is necessary.
• Bitemporal hemianopia confirmed requires head MRI for chiasmal lesion.
• Fluorescein angiography: In acute LHON, no leakage from the optic disc. This is the most important differentiating point from optic neuritis¹⁴⁾.

Cureus 2021;13(11):e19408, PMC8654114 – CC BY

Longitudinal changes in Humphrey visual field in a case of NAION. The right eye progresses from inferior altitudinal defect to concentric constriction, and the left eye shows an inferior altitudinal defect. This corresponds to the visual field defect patterns discussed in the section “Examination and Testing”.

Blood and Cerebrospinal Fluid Tests

Recommended tests for initial evaluation of acute optic neuropathy are shown.

Test Item	Purpose	Clinical Significance
ESR, CRP, platelets	Exclude GCA (AAION)	Highest priority. CRP has higher specificity than ESR1)
Anti-AQP4 antibody (cell-based assay)	Diagnosis of NMOSD	ELISA has lower sensitivity and specificity than CBA5)
Anti-MOG antibody (cell-based assay)	Diagnosis of MOGAD	CBA recognizing native MOG molecule is essential6)
Syphilis serology (TPHA/RPR) and HIV	Exclusion of infectious optic neuritis	Must be checked before steroids
Vitamin B12, B1, folic acid, copper	Evaluation of nutritional optic neuropathy	Especially important after bariatric surgery or on a vegan diet
Mitochondrial genes (mt11778, mt14484, mt3460)	Diagnosis of LHON	These three mutations cover over 95% of all cases14)
β-D-glucan and fungal culture	Suspected invasive aspergillosis	Tends to be elevated in invasive type2)
ACE, lysozyme, chest CT	Rule out sarcoidosis	—
ANA, dsDNA, ANCA	Systemic autoimmune diseases (SLE, vasculitis)	—

Indications for CSF examination Suspected infectious meningitis/encephalitis, diagnostic aid for NMOSD/MOGAD (CSF pleocytosis, elevated IgG index), diagnostic aid for MS (CSF oligoclonal bands). NMOSD may show marked pleocytosis of up to 50 cells/μL or more⁶⁾.

Imaging tests

Test	Main evaluation items	Notes
Orbital MRI (fat-suppressed T2/contrast-enhanced T1)	Optic nerve inflammation, edema, mass, contrast enhancement	Contrast enhancement in optic neuritis. No enhancement in acute LHON14)
Head MRI (FLAIR)	Demyelinating lesions (MS, NMOSD), intracranial lesions	Used in McDonald criteria for MS diagnosis
CT (bone window)	Optic canal fracture (trauma), sinus lesions, calcification (drusen)	Essential for trauma and nasal diseases
Head ultrasound (color Doppler)	Halo sign for GCA diagnosis	Sensitivity 68%, specificity 91% (100% if bilateral positive)1)
PET-CT (FDG)	Evaluation of large-vessel involvement in GCA	Sensitivity 92%, specificity 85% (GAPS study)1)
Orbital ultrasound	Confirmation of calcification in optic disc drusen	—

Q Is MRI always necessary for optic neuropathy?

A

In acute optic neuropathy, orbital MRI is generally required. The priority is to rule out compressive lesions, and treatment strategy differs greatly depending on whether contrast enhancement (inflammatory) or compression/deformation (compressive) is observed in the optic nerve ²⁾. If contrast MRI shows no inflammatory findings in the optic nerve, toxic, hereditary, or nutritional causes should be considered. In the acute phase of LHON, there are no inflammatory findings, and fluorescein angiography shows no leakage from the optic disc, which is an important distinguishing point from inflammatory optic neuritis ¹⁴⁾. If MRI is contraindicated, CT is used to evaluate the sinuses, orbit, and optic canal.

Use of Visual Evoked Potentials (VEP)

Visual evoked potentials (VEP) are useful as a marker for demyelinating optic neuritis. Prolongation of P100 latency (normal within 130 ms) suggests demyelination, and in MS-related and idiopathic optic neuritis, the prolongation often persists even after recovery ¹³⁾. Reduction in amplitude is prominent in axonal damage (toxic, ischemic). In toxic optic neuropathy, there is no delay in P100 latency, and only amplitude is reduced, which helps differentiate it from demyelinating disease ¹³⁾. A decrease in critical flicker frequency (CFF) also reflects functional impairment in optic neuropathy, and is notably reduced in NMOSD-related optic neuritis ¹³⁾.

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6. Characteristics by Cause

Major optic neuropathies are classified by cause, and the characteristics of each type are summarized.

6-1. Ischemic Optic Neuropathy

Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

NAION is the most common type of acute optic neuropathy in adults, often occurring in those aged 50 and older ³⁾. Ischemic infarction of the optic disc occurs due to acute circulatory failure of the short posterior ciliary arteries (SPC arteries).

• Epidemiology: Annual incidence in the United States is 2.3–10.2 per 100,000 ³⁾. Most cases occur in people aged 50 and older, but incidence in those under 50 is also increasing.
• Risk factors: Hypertension, diabetes, hyperlipidemia, sleep apnea syndrome, and disc at risk (small optic disc with cup-to-disc ratio <0.2). Disc at risk is present in about 80% of fellow eyes ³⁾.
• Symptoms: Painless, acute unilateral vision loss, often noticed upon waking. RAPD positive on the affected side.
• Optic disc findings: Hyperemia and swelling (inferior sectoral pattern). May be accompanied by hemorrhages.
• Visual field: Altitudinal defect (inferior temporal defect is typical).
• Treatment: No established effective treatment in the acute phase. Management of vascular risk factors and treatment of sleep apnea are central to preventing recurrence.
• Recent attention: An observational study in 2024 reported an increased risk of NAION in users of semaglutide (GLP-1 receptor agonist). However, causality has not been established, and the benefits for diabetes and obesity treatment must be weighed when prescribing⁷⁾.

J Med Case Rep 2018;12:11, PMC5771151 – CC BY

Bilateral fundus findings (upper row) and Humphrey visual fields (lower row) after NAION onset. Both eyes show optic disc pallor centered on the temporal side and severe visual field defects. Corresponds to the optic disc findings and visual field patterns of ischemic optic neuropathy discussed in the section “Characteristics by Cause.”

Arteritic Anterior Ischemic Optic Neuropathy (AAION/GCA)

AAION accounts for 5–10% of all anterior ischemic optic neuropathies but is the most urgent optic neuropathy ¹⁾. It is caused by vasculitis of the short posterior ciliary arteries supplying the optic nerve head, and over 90% of cases are due to giant cell arteritis (GCA).

• Epidemiology: More common in elderly women aged 50 years or older (especially 75 years or older), with a female-to-male ratio of 3:1 ¹⁾. The incidence in Japan is 1.47 per 100,000 people, much lower than in Western countries.
• Symptoms: Acute severe unilateral vision loss (vision <20/200 in over 60%, no light perception in over 20%) ¹⁾. About 30% experience transient monocular vision loss (amaurosis fugax) beforehand.
• Systemic symptoms: Headache (65–90%), jaw claudication (11–45%), scalp tenderness, fever, and polymyalgia rheumatica-like symptoms.
• Optic disc findings: Chalky pale swelling (pallid swelling) is characteristic.
• Tests: Elevated ESR and CRP (elevated in >80% of cases)¹⁾. Temporal artery biopsy (sensitivity and specificity >95%)¹⁾.
• Treatment: High-dose steroids (mPSL 500–1,000 mg IV for 3 days, then oral prednisolone taper)¹⁾. Tocilizumab (IL-6 receptor antagonist) is effective for steroid sparing (GiACTA trial, RCT evidence)¹⁾.
• Prognosis: Visual recovery in the affected eye is rarely expected, but steroid treatment is effective in preventing onset in the fellow eye.

6-2. Inflammatory Optic Neuritis

Idiopathic Optic Neuritis

An inflammatory disease of the optic nerve caused by an autoimmune mechanism, accounting for the majority of optic neuritis cases ¹³⁾. The typical age of onset is 15–45 years, with women comprising approximately 70% of cases. The annual incidence in Japan is 1.6 per 100,000 adults ¹³⁾.

• Symptoms: Acute unilateral vision loss and eye movement pain (approximately 50%). Progression occurs over several days to 2 weeks, with a tendency for spontaneous recovery within 5 weeks.
• Visual field: Central scotoma or cecocentral scotoma are common.
• MRI: Contrast enhancement (gadolinium) consistent with the optic nerve.
• Prognosis: More than 90% recover to visual acuity of 0.5 or better after 1 year (ONTT study) ⁴⁾.
• Treatment: Steroid pulse therapy with methylprednisolone 1,000 mg/day for 3 days accelerates recovery. Oral steroid monotherapy is not performed because it increases the recurrence rate (ONTT study) ⁴⁾.
• Risk of conversion to MS: Cumulative incidence 50% over 15 years after first attack. Without brain MRI lesions: 25%, with lesions: 78%⁴⁾.

MS-related optic neuritis

Optic neuritis occurs as the initial symptom in about 30% of MS cases, and up to 75% of MS patients experience at least one episode of optic neuritis during their lifetime⁸⁾. It is typically unilateral, with pain on eye movement, and often retrobulbar (normal fundus in 65%). Brain MRI showing demyelinating lesions (T2/FLAIR hyperintensity) is key for diagnosis. After diagnosis according to the McDonald criteria (2017 version, revised 2024), disease-modifying therapies (DMTs: interferon beta, natalizumab, fingolimod, anti-CD20 drugs, etc.) are used to prevent relapses.

NMOSD (neuromyelitis optica spectrum disorder)-related optic neuritis

AQP4-IgG positive. Predominantly affects women (female:male ratio 9:1), middle-aged, and Asian populations. It is more severe, bilateral, and recurrent than MS-related optic neuritis⁵⁾. Permanent visual impairment of 20/200 or worse in at least one eye occurs in 60–69% of cases⁵⁾. Orbital MRI shows long segment optic nerve lesions (often involving the chiasm). Treatment includes acute-phase steroid pulse therapy, followed by plasma exchange, and then relapse-prevention immunotherapy (eculizumab, rituximab, satralizumab)⁵⁾.

MOGAD (MOG antibody-associated disease)-related optic neuritis

MOG-IgG positive. Annual incidence is 1.6 to 4.8 per million people ⁶⁾. Bilateral onset is frequent with marked optic disc swelling and predominant anterior involvement. MRI shows characteristic optic disc swelling, long-segment optic nerve lesions, and optic perineuritis ⁶⁾. Sex ratio comparison among MS-ON, AQP4-ON, and MOG-ON shows male-to-female ratios of 3:1, 7-9:1, and 1:1, respectively ⁶⁾. Steroid-responsive but prone to relapse with early dose reduction; careful tapering is necessary ⁶⁾.

6-3. Compressive Optic Neuropathy

Caused by compression of the optic nerve by tumors, aneurysms, hematomas, abscesses, cysts, or enlarged extraocular muscles. Symptoms and visual field defect patterns vary greatly depending on the compression site.

• Orbital apex: Thyroid eye disease (thyroid optic neuropathy complicates 3-8.6% of thyroid eye disease, 70% bilateral), orbital tumors (benign: idiopathic orbital inflammation 20%, pleomorphic adenoma 13%, hemangioma 13%; malignant: malignant lymphoma most common) ⁹⁾.
• Optic chiasm: Pituitary adenoma (most common in adults, bitemporal hemianopia), craniopharyngioma (most common in children).
• Nasal optic neuropathy (special note): Invasive type of paranasal sinus mycosis (Aspergillus, Mucor) has a reported mortality rate of 94% ²⁾. It may be misdiagnosed as retrobulbar optic neuritis because steroids provide temporary improvement, and unknowingly continuing steroids can be fatal. CT/MRI findings of bone destruction are key to diagnosis, and urgent collaboration with an otolaryngologist is necessary.

The principle of treatment is surgical removal of the causative lesion. The earlier the decompression, the better the recovery of visual function; once optic atrophy is established, recovery is limited.

6-4. Toxic Optic Neuropathy

This is a group of diseases in which the anterior visual pathway is damaged by exposure to chemical substances²⁾. It is generally bilateral and painless; if one eye is completely normal, toxic optic neuropathy should be excluded²⁾.

• Causative substances: Tobacco, alcohol, paint thinner (drugs: ethambutol [most famous], amiodarone, linezolid, cisplatin, immunosuppressants, etc.).
• Visual field: Characteristically, a centrocecal scotoma or central scotoma (due to predominant damage to P cells)²⁾.
• Color vision: Dulling of red color perception is an early sign.
• Fundus: Initially normal or mild redness → chronic phase: temporal pallor of the optic disc and loss of papillomacular bundle fibers.
• RAPD: Usually negative due to bilateral symmetry.
• VEP: Decreased amplitude without delay in P100 latency (latency delay is characteristic of demyelinating optic neuritis) ¹³⁾.
• Ethambutol: Dose-dependent (risk increases above 15 mg/kg). Baseline visual function testing before administration and regular monitoring are essential.
• Treatment: Discontinuation of the causative agent is fundamental. No specific antidote exists.

6-5. Nutritional optic neuropathy

Bilateral, symmetric, progressive optic neuropathy caused by deficiency of B vitamins (B12, B1, B2, B9) and copper. It lies on the same spectrum as toxic optic neuropathy but is distinguished by nutritional deficiency as the cause. Modern risk factors include post-bariatric surgery (lifelong monitoring required), vegan diet, and alcohol dependence. Symptoms, visual field, and fundus findings are similar to toxic optic neuropathy (central scotoma, painless, temporal pallor of the optic disc). Early nutritional supplementation can lead to recovery, but chronic cases may result in irreversible damage.

6-6. Hereditary Optic Neuropathy

LHON (Leber Hereditary Optic Neuropathy)

An acute or subacute optic neuropathy caused by point mutations in mitochondrial DNA (mtDNA) with maternal inheritance ¹⁴⁾. Three major mutations (mt3460, mt11778, mt14484) account for over 95% of all cases, with mt11778 accounting for approximately 90% of all cases in Asia ¹⁴⁾.

• Epidemiology: Prevalence 1/31,000 to 1/68,000. Penetrance 2.5–17.5%, with most carriers not developing the disease ¹⁴⁾. In Japan, approximately 117 new cases per year (2014 survey). Designated as an intractable disease.
• Symptoms: Predominantly affects young males (male-to-female ratio approximately 93:7). Subacute, painless bilateral central scotoma (one eye affected first, then both eyes within weeks to months).
• Acute fundus: Optic disc hyperemia and swelling, with dilation and tortuosity of peripapillary capillaries. Fluorescein angiography shows no leakage from the optic disc (important distinction from inflammatory optic neuritis) ¹⁴⁾.
• Pupillary light reflex: Relatively preserved compared to other optic nerve diseases, or only mildly impaired ¹⁴⁾.

Cureus 2024;16(10):e71210, PMC11550097 – CC BY

Humphrey 10-2 visual fields at onset of LHON (m.14484T>C mutation). Both right eye (A) and left eye (B) show severe central scotomas, with marked sensitivity loss in Total Deviation and Pattern Deviation. Corresponds to the central scotoma pattern of hereditary optic neuropathy discussed in the section “Characteristics by Cause.”

• Final visual acuity: Around 0.01 or less in mt11778. mt14484 has the highest rate of spontaneous recovery ¹⁴⁾.
• Treatment: Idebenone 900 mg/day (approved by EMA). In the LEROS trial, CRR (clinically relevant recovery) was 46.0% (vs placebo) ¹⁰⁾. In the Wales cohort study, CRR reached 86% at 27 months ¹⁰⁾. Gene therapy has also shown efficacy in phase III trials ¹¹⁾. Smoking cessation guidance is important for preventing onset and progression.

ADOA (Autosomal Dominant Optic Atrophy)

The most frequent hereditary optic neuropathy, primarily caused by OPA1 gene mutations. It is discovered during school age as bilateral unexplained visual developmental impairment. Acquired third color vision deficiency (blue-yellow color blindness) is characteristic. OCT shows RNFL thinning predominantly in the temporal to inferior quadrants ²⁾. Currently, there is no effective treatment, and management mainly consists of low vision care and genetic counseling.

6-7. Traumatic Optic Neuropathy

Optic nerve damage occurring after blunt trauma to the head or orbit, often due to indirect force within the optic canal. Acute vision loss occurs immediately after injury. CT bone window confirms optic canal fracture. High-dose steroids or optic canal decompression surgery may be considered, but evidence for both is limited.

6-8. Radiation Optic Neuropathy

A delayed ischemic disorder following radiotherapy for head and neck or orbital tumors. Visual function is lost through mechanisms primarily involving endothelial damage. Onset occurs 3 months to 9 years after irradiation, most commonly at 10–20 months, with an average of about 18 months ¹²⁾. Risk increases with total dose >50 Gy or single fraction >10 Gy. It is usually painless and has a poor prognosis. No established treatment exists; systemic steroids, anticoagulation, and hyperbaric oxygen therapy have limited efficacy ¹²⁾. MRI shows contrast enhancement corresponding to the optic nerve.

6-9. Other Specific Optic Neuropathies

Posterior Ischemic Optic Neuropathy (PION) Ischemia of the posterior intraorbital or intracanalicular optic nerve. Postoperative PION is typical, occurring after massive hemorrhage, hypotension, spinal surgery, or cardiac surgery. Fundus findings are normal (no optic disc changes), but there is acute vision loss. The pupillary light reflex shows a relative afferent pupillary defect (RAPD). No effective treatment has been established.

Neuroretinitis A syndrome characterized by optic disc edema and a macular star figure. Causes include Bartonella henselae (cat scratch disease), syphilis, and Leber idiopathic stellate neuroretinitis. The star figure results from exudate deposition along the Henle fiber layer in the macula, appearing several weeks after disc edema resolves. It tends to resolve spontaneously, but specific treatment is given for infectious causes.

Papillophlebitis A syndrome occurring in young to middle-aged adults, characterized by unilateral optic disc edema without visual dysfunction and retinal venous dilation and tortuosity. Enlargement of the Mariotte blind spot is observed, but corrected visual acuity is normal. Orbital MRI is normal. Prognosis is good and treatment is not required, but differentiation from papilledema, optic neuritis, and ischemic optic neuropathy is important²⁾.

Immune checkpoint inhibitor-related optic neuropathy Optic neuropathy rarely occurs as an immune-related adverse event (irAE) of cancer immunotherapy (e.g., nivolumab, pembrolizumab). It is treated with steroid pulse therapy, and the continuation of cancer treatment should be discussed with an oncologist.

Summary Table of Optic Neuropathy One-Liners

Disease	Laterality	Pain	Optic disc findings	Visual field	Key points
NAION	Unilateral	None	Redness and swelling (inferior)	Horizontal sectoranopia	Onset upon waking, disc at risk3)
AAION/GCA	Unilateral → bilateral	None (headache, jaw claudication)	Pale swelling	Variable (severe)	Most urgent, elevated ESR/CRP1)
Idiopathic optic neuritis	Unilateral	Present (50%)	Swollen or normal	Central scotoma	Young women, risk of MS conversion 13)
NMOSD-related	Tends to become bilateral	Yes	Swollen or normal	Variable (severe)	AQP4 antibody positive, refractory5)
MOGAD-related	Often bilateral	Present (headache)	Severe swelling	Variable	MOG antibody, perineuritis6)
Compressive	Unilateral/Bilateral	None	Normal or atrophic	Variable	MRI required9)
Toxic	Both eyes	None	Normal → temporal pallor	Centrocecal scotoma	Ask about causative substance 2)
Nutritional	Both eyes	None	Normal → temporal pallor	Central scotoma	B12/copper deficiency
LHON	Both eyes (one eye first)	None	Redness/telangiectasia	Central scotoma	Young male, no fluorescein leakage14)
ADOA	Both eyes	None	Pale	Central scotoma	School age, blue-yellow color vision deficiency2)
Traumatic	Unilateral	Yes (trauma)	Normal	Variable	CT confirms optic canal fracture
Radiation-induced	Unilateral/bilateral	None	Normal → atrophy	Various	Average 18 months12)

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7. Treatment Principles

Treatment of optic neuropathy depends on the cause and differs fundamentally by disease type. Common principles are shown below.

Situations Requiring Emergency Treatment

1. GCA/AAION: High-dose systemic steroids (start on the same day). Do not wait for test results ¹⁾.
2. Acute compressive optic neuropathy: Surgical decompression (urgent collaboration with otolaryngology and neurosurgery). In invasive aspergillosis, discontinue steroids and switch to antifungal agents ²⁾.
3. Traumatic: Consideration of optic nerve decompression surgery.

Treatment of inflammatory (optic neuritis)

Steroid pulse therapy (mPSL 1,000 mg/day for 3 days) accelerates recovery speed in the acute phase ⁴⁾. Oral steroids alone are not administered because they increase the risk of relapse in idiopathic optic neuritis (ONTT study) ⁴⁾. In the acute phase of NMOSD, stepwise treatment is performed: steroid pulse → plasma exchange for insufficient response → relapse prevention immunotherapy ⁵⁾. MOGAD optic neuritis is steroid-responsive but relapses with early tapering, so careful gradual reduction is necessary ⁶⁾.

Treatment of ischemic (NAION)

No effective treatment has been established for the acute phase. Management of vascular risk factors (hypertension, diabetes, hyperlipidemia, sleep apnea syndrome) is the mainstay, and prevention of onset in the fellow eye is the treatment goal. Regarding semaglutide (GLP-1 receptor agonist), observational studies suggest an association with NAION, so careful explanation and follow-up are desirable in patients with a history or risk ⁷⁾.

Treatment of hereditary (LHON)

Idebenone 900 mg/day is approved by the European Medicines Agency (EMA) and achieved a CRR of 46% in the LEROS trial (placebo-controlled) ¹⁰⁾. The Welsh cohort reported a CRR of 86% at 27 months, indicating favorable real-world outcomes ¹⁰⁾. Gene therapy (lenadogene nolparvovec) has shown efficacy in a Phase III trial, and further expansion of indications is expected ¹¹⁾. Smoking cessation counseling (smoking is a risk factor for onset) and appropriate low vision care are essential ¹⁴⁾.

Treatment of Toxic and Nutritional Optic Neuropathy

The basic approach is discontinuation of the causative substance or supplementation of deficient nutrients. Early intervention can lead to visual function recovery, but chronic cases may result in irreversible damage. Ethambutol optic neuropathy is dose-dependent, so baseline visual function testing before administration and regular monitoring (visual acuity, color vision, visual field) are essential.

Treatment of Compressive Optic Neuropathy

Surgical removal of the causative lesion is the principle. For thyroid optic neuropathy, urgent or elective orbital decompression is performed. Since visual recovery after surgical removal is limited once optic atrophy has progressed, early diagnosis and treatment are important.

Prognosis Overview

Disease type	Visual prognosis	Recovery potential
Idiopathic optic neuritis	Over 90% achieve 0.5 or better at 1 year4)	Good recovery
NAION	1/3 improve, 1/3 unchanged, 1/3 worsen	Partial recovery
AAION/GCA	Recovery of the affected eye is almost never expected	Goal is prevention in the fellow eye1)
NMOSD-related	Severe. At least one eye with 20/200 or worse in 60–69%5)	Relapse prevention is important
LHON (mt11778)	Final visual acuity often around 0.01	Spontaneous recovery only in some cases14)
LHON (mt14484)	Mutation type with highest spontaneous recovery rate	Recovery cases exist14)
ADOA	Slowly progressive, often does not lead to severe blindness	No progression suppression
Compressive	Recoverable with early removal	Before atrophy progresses is critical
Toxic/nutritional	Recoverable with early cessation/supplementation	Irreversible in chronic cases
Radiation-induced	Acute, severe, often irreversible vision loss 12)	No established treatment

Q What is the most important aspect of treating optic neuropathy?

A

Rapid identification of the underlying cause. If GCA is suspected, start steroids on the same day without waiting for test results to prevent vision loss in the fellow eye ¹⁾. For compressive causes, surgical removal of the causative lesion is the only way to preserve visual function, and delay in diagnosis leads to irreversible optic atrophy. In inflammatory cases (optic neuritis), steroid pulse therapy accelerates recovery, but additional treatment strategies vary greatly depending on the subtype. In particular, for anti-AQP4 antibody-positive cases, steroid monotherapy leads to repeated relapses, so early introduction of relapse-preventive immunotherapy is key to preserving visual function ⁵⁾.

Q Why is it important to differentiate between LHON and optic neuritis?

A

Both conditions present with similar initial symptoms of “acute to subacute painless vision loss,” and are easily confused, especially during the acute phase of LHON when optic disc swelling occurs. The most important distinguishing feature is the presence or absence of fluorescein leakage from the optic disc on fluorescein angiography. Inflammatory optic neuritis shows contrast enhancement and fluorescein leakage, but there is no fluorescein leakage in the acute phase of LHON ¹⁴⁾. Additionally, about 50% of optic neuritis cases present with eye movement pain, whereas LHON is painless. A definitive diagnosis can be made by mitochondrial genetic testing (mt11778, mt14484, mt3460), which can be performed as a send-out test ¹⁴⁾. Steroid administration is not only ineffective in LHON patients but also delays definitive diagnosis; therefore, it is essential to include LHON in the differential diagnosis for acute bilateral vision loss in young men.

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8. Related Articles (Optic Neuropathy)

Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

Details on NAION

Arteritic Anterior Ischemic Optic Neuropathy (AAION)

Details on AAION/GCA

Compressive Optic Neuropathy

Details on Compressive Optic Neuropathy

Toxic Optic Neuropathy

Details on Toxic Optic Neuropathy

Nutritional Deficiency Optic Neuropathy

Details on nutritional optic neuropathy

Leber Hereditary Optic Neuropathy (LHON)

Details on LHON

Autosomal Dominant Optic Atrophy (ADOA)

Details on ADOA

Radiation Optic Neuropathy

Details on radiation optic neuropathy

視神経乳頭ドルーゼン 偽乳頭浮腫の代表的原因。埋没型はうっ血乳頭との鑑別が重要。

外傷性視神経症 視神経管内の視神経損傷。頭部鈍的外傷後の急性視力低下で疑う。

Optic nerve diseases and tumors to differentiate

Idiopathic optic neuritis

Details on idiopathic optic neuritis

MS-related optic neuritis

Go to details of MS-related optic neuritis

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Go to details of NMOSD

MOG Antibody-Associated Disease (MOGAD)

Go to details of MOGAD

視神経鞘髄膜腫 眼窩内視神経を取り囲む髄膜腫。緩徐進行性視力低下と眼底所見が特徴。

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