Optic Neuritis
Aetiology, Clinical Features, Investigations & Management
Examination question · ~800 words
Describe the aetiology, clinical features, investigations, and management of optic neuritis.
Try to outline your answer mentally before expanding sections below.
Optic neuritis (ON) is an inflammatory optic neuropathy, classically demyelinating, presenting with acute or subacute unilateral visual loss, pain on eye movement, dyschromatopsia, and a relative afferent pupillary defect. It is a common cause of acute optic neuropathy in young adults, especially women aged 20-45 years. The Optic Neuritis Treatment Trial (ONTT) remains the landmark study defining its natural history, steroid response, visual prognosis, and risk of later multiple sclerosis (MS).
A. Classification by Anatomy
| Type | Location | Disc Appearance | Key Association |
|---|---|---|---|
| Retrobulbar optic neuritis | Behind the globe; most common anatomical pattern | Normal optic disc | MS, idiopathic demyelinating ON |
| Papillitis | Anterior optic nerve | Swollen, hyperaemic disc | Children, NMOSD, viral or parainfectious ON |
| Neuroretinitis | Optic disc plus outer retina | Disc oedema with macular star | Bartonella, Lyme disease, syphilis |
| Optic perineuritis | Optic nerve sheath inflammation | Mild disc oedema may be present | Sarcoidosis, IgG4-related disease |
B. Aetiology
| Category | Causes |
|---|---|
| Demyelinating | Multiple sclerosis, clinically isolated syndrome, NMOSD with AQP4-IgG, MOG-IgG associated disease (MOGAD) |
| Infectious | Bartonella henselae, Lyme disease, syphilis, tuberculosis, CMV, herpes zoster, post-COVID inflammatory optic neuropathy |
| Autoimmune / inflammatory | Sarcoidosis, SLE, antiphospholipid syndrome, Sjogren syndrome, vasculitis |
| Parainfectious | Post-viral optic neuritis, especially in children; may follow measles, mumps, EBV or other viral illnesses |
| Other | Radiation optic neuropathy, paraneoplastic optic neuropathy, idiopathic optic neuritis |
C. Pathophysiology
In typical MS-related ON, autoreactive T cells cross the blood-brain barrier and trigger inflammation within the optic nerve. CD4+ Th1/Th17 cells, macrophages and complement attack oligodendrocyte-derived myelin, producing conduction block and acute visual loss. With time, axonal degeneration produces persistent visual dysfunction. In AQP4-IgG positive NMOSD, complement-mediated astrocytic injury causes more destructive optic nerve damage and a worse prognosis than typical MS-ON.
- Uhthoff phenomenon: transient worsening of vision with fever, exercise or hot bath. It is a highly characteristic classic sign of demyelinating optic neuritis, but not strictly pathognomonic.
- Pulfrich phenomenon: misperception of moving objects in an arc due to asymmetric conduction delay between the two optic nerves.
A. Symptoms
| Symptom | Details | Exam Importance |
|---|---|---|
| Acute or subacute visual loss | Usually monocular; evolves over hours to days and reaches nadir over 1-2 weeks | Core presenting complaint |
| Pain on eye movement | Retrobulbar ache, often preceding visual loss by 1-2 days | Very typical of demyelinating ON |
| Dyschromatopsia | Red desaturation and washed-out colours | Often disproportionate to visual acuity loss |
| Reduced contrast sensitivity | Low-contrast vision remains impaired even when Snellen acuity recovers | Sensitive functional marker |
B. Signs
- RAPD is the most objective sign in unilateral or asymmetric optic neuritis and may persist after visual recovery.
- Visual acuity may range from near normal vision to no light perception; very severe loss is more concerning for NMOSD, MOGAD or another atypical cause.
- Visual field defects include central scotoma, centrocaecal scotoma, altitudinal defects and generalised depression; any pattern may occur.
- Colour vision is reduced; test with Ishihara plates and red-cap comparison.
- Fundus is normal in retrobulbar ON; disc oedema occurs in papillitis; macular star suggests neuroretinitis.
C. MS-ON vs NMOSD-ON vs MOGAD-ON
| Feature | MS-ON | NMOSD (AQP4+) | MOGAD-ON |
|---|---|---|---|
| Laterality | Usually unilateral | Often bilateral or sequential | Often bilateral |
| Pain | Common | May be mild or absent | Common |
| Visual loss | Moderate in typical cases | Severe, often LP/NLP | Severe initially, but often recovers well |
| Optic disc | Usually normal | Disc oedema may occur | Disc oedema common |
| Visual recovery | Excellent in most patients | Poorer; attacks are destructive | Good to excellent |
| MRI optic nerve lesion | Short segment lesion | Long segment lesion, often posterior/chiasmal | Long, frequently bilateral anterior optic nerve involvement |
| Biomarker | CSF oligoclonal bands support MS | AQP4-IgG | MOG-IgG |
| Risk of conversion to MS | Depends strongly on brain MRI lesion burden | Does not convert to MS | Does not convert to MS |
| Treatment emphasis | IV steroids for faster recovery; MS disease-modifying therapy if criteria met | Aggressive acute treatment plus long-term immunosuppression | Steroids, IVIG in selected cases, relapse prevention if recurrent |
A. MRI Brain, Orbit and Spine
- MRI orbit with fat suppression / STIR and gadolinium: T2/STIR hyperintensity and contrast enhancement of the optic nerve confirm active inflammation.
- Brain MRI: periventricular, juxtacortical and infratentorial T2 lesions predict future MS risk.
- Spinal MRI: short cord lesions favour MS; longitudinally extensive transverse myelitis involving >3 vertebral segments strongly suggests NMOSD.
ONTT 15-Year MS Risk by Baseline Brain MRI Lesions
| Baseline Brain MRI Lesion Count | 15-Year MS Risk |
|---|---|
| 0 lesions | 25% |
| 1 lesion | 60% |
| 2 lesions | 68% |
| >=3 lesions | 78% |
| >=1 lesion combined | 72% |
B. Electrophysiology
- Visual evoked potential (VEP) shows delayed P100 latency, classically >115 ms, reflecting demyelination.
- Amplitude may be reduced when axonal loss is significant.
- VEP may remain abnormal after clinical visual recovery and is useful for detecting previous subclinical optic neuritis in MS workup.
C. OCT
- RNFL thickness may be normal or increased acutely because of disc oedema.
- After 3-6 months, RNFL thinning reflects retinal ganglion cell axonal loss, often most marked temporally.
- Macular GCL/IPL thickness is the best OCT predictor of permanent visual dysfunction and correlates with acuity and contrast sensitivity.
- RNFL thickness <75 microns suggests significant axonal loss and correlates with poor low-contrast letter acuity.
- OCT-A may show reduced peripapillary capillary density in the acute phase.
D. Laboratory Workup
| Test | Purpose |
|---|---|
| AQP4-IgG, preferably serum | Diagnose NMOSD; changes treatment completely |
| MOG-IgG, serum | Diagnose MOGAD, especially in bilateral, recurrent or disc-oedema-predominant ON |
| CSF oligoclonal bands and IgG index | Support MS diagnosis; oligoclonal bands are common in MS and typically absent in NMOSD |
| Bartonella IgG/IgM | Neuroretinitis, especially disc oedema with macular star |
| VDRL / FTA-ABS | Exclude syphilis |
| ACE, chest X-ray or HRCT chest | Sarcoidosis workup |
| ANA, ANCA, ESR, CRP, CBC | Screen for autoimmune, vasculitic or systemic inflammatory disease |
A. ONTT: Landmark Treatment Findings
| ONTT Finding | Conclusion |
|---|---|
| IV methylprednisolone 1 g/day for 3 days followed by oral prednisolone taper | Speeds visual recovery by about 2 weeks but does not improve final visual acuity at 6 months or 1 year |
| Oral prednisolone alone at 1 mg/kg/day | Increases recurrence of optic neuritis and is contraindicated as sole treatment in typical ON |
| Placebo | Final visual outcome similar to IV steroid group at 1 year |
| IV steroid arm | Reduced MS conversion at 2 years, but not sustained beyond 3 years |
| Baseline MRI risk | Normal MRI: 25% 15-year MS risk; >=1 T2 white matter lesion: 72% 15-year MS risk |
B. Acute Treatment Algorithm
| Scenario | Treatment |
|---|---|
| Typical MS-ON, mild to moderate | Observation or IV methylprednisolone 1 g/day for 3-5 days followed by oral taper, depending on severity and patient needs |
| Severe visual loss, bilateral disease or fellow-eye involvement | IV methylprednisolone 1 g/day for 3-5 days and urgent neurology referral |
| AQP4+ NMOSD optic neuritis | High-dose IV steroids; early plasma exchange if poor response; long-term relapse-prevention immunosuppression |
| MOGAD optic neuritis | IV steroids; consider IVIG in selected or recurrent cases; maintenance therapy for relapsing disease |
| Infectious neuroretinitis due to Bartonella | Doxycycline 100 mg twice daily for 4-6 weeks with or without rifampicin; steroids only after infection control and specialist review |
| Sarcoid optic neuropathy | High-dose oral or IV steroids; steroid-sparing agents such as methotrexate or azathioprine when required |
C. MS and NMOSD Relapse Prevention
| Category | Examples | Use |
|---|---|---|
| First-line injectable MS therapy | Interferon-beta-1a/1b, glatiramer acetate | Low to moderate risk CIS or relapsing-remitting MS |
| First-line oral MS therapy | Dimethyl fumarate, teriflunomide | Moderate-risk relapsing-remitting MS |
| High-efficacy MS therapy | Natalizumab, alemtuzumab, ocrelizumab, cladribine | High-risk or active MS under neurology supervision |
| AQP4+ NMOSD prevention | Rituximab, eculizumab, inebilizumab, satralizumab; azathioprine or mycophenolate in selected settings | Relapse prevention in NMOSD; MS DMTs such as interferon-beta may worsen NMOSD |
D. Emerging and Failed Neurorepair Therapies
- MD1003 high-dose biotin failed Phase 3 evaluation in progressive MS and is not established for optic neuritis recovery.
- Opicinumab / anti-LINGO-1: Phase 2 RENEW in acute ON showed partial VEP latency improvement, but later SYNERGY and AFFINITY trials failed to meet primary endpoints. Development was discontinued in 2020; no Phase 3 optic neuritis trial is planned or ongoing.
- Autologous haematopoietic stem cell transplantation (AHSCT) may be considered only for highly active refractory relapsing-remitting MS in specialist centres.
E. Visual Prognosis
- Visual recovery usually begins within 2-4 weeks.
- Most typical MS-ON patients recover good high-contrast visual acuity by 6 months.
- Persistent deficits in contrast sensitivity, colour vision and low-contrast acuity are common despite apparent Snellen recovery.
- Poor prognostic features include severe initial loss, no light perception, AQP4+ NMOSD, painless presentation, poor VEP recovery and severe RNFL/GCL thinning on OCT.
Trap 1 — TRUE
“A normal fundus in acute visual loss with pain on eye movement can still be optic neuritis.”
This is classic retrobulbar optic neuritis: the patient sees nothing and the doctor sees nothing.
Trap 2 — FALSE
“Oral prednisolone alone is appropriate treatment for typical optic neuritis.”
ONTT showed oral prednisolone alone increases recurrence of optic neuritis. IV methylprednisolone followed by an oral taper is acceptable when steroids are indicated.
Trap 3 — FALSE
“IV steroids improve final visual acuity in typical optic neuritis.”
IV steroids speed recovery but do not improve final visual outcome at 6 months or 1 year.
Trap 4 — FALSE
“Baseline abnormal brain MRI in ONTT means about 50% 15-year MS risk.”
The overall ONTT cohort risk was about 50%. Patients with >=1 baseline T2 white matter lesion had 72% 15-year MS risk; patients with 0 lesions had 25% risk.
Trap 5 — FALSE
“Neuroretinitis with macular star should be diagnosed as typical MS-related optic neuritis.”
Neuroretinitis has essentially no MS conversion risk; Bartonella and other infectious causes must be excluded first.
Trap 6 — FALSE
“Uhthoff phenomenon is pathognomonic of demyelinating optic neuritis.”
It is highly characteristic of demyelinating optic neuritis, but not strictly pathognomonic because it can rarely occur in other optic neuropathies.
Q: Why is oral steroid alone contraindicated in typical optic neuritis?
A: ONTT showed it increases the recurrence rate of optic neuritis; IV methylprednisolone followed by oral taper is acceptable, but oral prednisolone alone is not.
Q: Normal disc with acute painful visual loss: what is the diagnosis?
A: Retrobulbar optic neuritis.
Q: When should optic neuritis not be treated as typical MS-ON?
A: Atypical features include bilateral severe disease, no pain, age <12 or >45 years, progressive course, poor recovery, macular star, severe disc oedema, recurrent attacks, AQP4-IgG or MOG-IgG positivity.
Q: Best objective clinical sign of unilateral optic neuritis?
A: Relative afferent pupillary defect.
Q: Earliest or classic visual field defect in optic neuritis?
A: Central scotoma is classic, but any field pattern can occur.
Q: What happens to VEP after recovered optic neuritis?
A: P100 latency often remains prolonged despite visual acuity recovery, reflecting persistent demyelination.
Q: How does AQP4-IgG positive optic neuritis change management?
A: It suggests NMOSD, requiring aggressive IV steroids, early plasma exchange if poor response, and long-term immunosuppression rather than standard MS disease-modifying therapy.
Q: How does MOGAD optic neuritis differ from NMOSD?
A: MOGAD targets myelin oligodendrocyte glycoprotein, often causes bilateral disc oedema, usually recovers well, responds to steroids or IVIG, and does not convert to MS.
A 28-year-old woman presents with bilateral simultaneous optic neuritis, VA 1/60 in both eyes, severe disc oedema, no pain, previous transverse myelitis, long-segment optic nerve lesions and LETM on MRI. AQP4-IgG is positive and she was started on interferon-beta. How would you manage her differently from typical MS-ON?
Answer
This is AQP4-IgG positive NMOSD, not typical MS-ON. Stop interferon-beta because some MS disease-modifying therapies can worsen NMOSD. Treat the acute attack with IV methylprednisolone 1 g/day for 5 days. If there is inadequate response within 5-7 days, start plasma exchange, usually 5-7 sessions, to remove pathogenic AQP4-IgG. Long-term management aims to prevent attacks using immunosuppression such as rituximab, eculizumab, inebilizumab, satralizumab, mycophenolate mofetil or azathioprine depending on setting and availability. Eculizumab evidence comes from the PREVENT trial, which showed about 94.2% relapse reduction versus placebo in AQP4+ NMOSD. The rationale is that NMOSD is primarily antibody/complement-mediated astrocytic injury, so B-cell, antibody and complement-targeted therapy is required. Visual prognosis is guarded because each attack causes cumulative axonal loss; monitor with OCT RNFL/GCL, VEP and MRI.
References
- Optic Neuritis Study Group. Visual function 15 years after optic neuritis. Ophthalmology. 2008;115(6):1079-1082. (0 lesions: 25%; ≥1 lesion: 72%)
- Pittock SJ et al. Eculizumab in AQP4-IgG-positive NMOSD. NEJM. 2019;381:614-625.
- PMC5152601 (Uhthoff's phenomenon 125 years later, 2016): uses 'strongly suggestive of MS', not pathognomonic.
- StatPearls NBK470244: 'Exercise- or heat-induced transient visual loss (Uhthoff's phenomenon) frequently is seen with optic neuritis and rarely with…Leber's hereditary optic neuropathy (LHON).' PubMed 9323955: Prolonged Uhthoff phenomenon documented in sarcoidosis of the optic nerve.
- Beck RW et al., 'Multiple Sclerosis Risk after Optic Neuritis: Final Optic Neuritis Treatment Trial Follow-Up,' Arch Neurol 2008; PMC2440583. Per-stratum 15-year MS risks: 0 lesions = 25%, 1 lesion = 60%, 2 lesions = 68%, ≥3 lesions = 78%, ≥1 lesion combined = 72%.
- Beck RW et al., Arch Neurol 2008; PMC2440583. Per-stratum 15-year MS risks: ≥1 lesion combined = 72%; ≥3 lesions specifically = 78%.
- Beck RW et al., Arch Ophthalmol 1992;110:1045–1054
- Thompson AJ et al., Lancet Neurol 2018;17(2):162–173