Papillophlebitis (Optic Disc Vasculitis)

Key Points at a Glance

Key Points of This Disease

• Papillophlebitis is a clinical subtype of central retinal vein occlusion (CRVO) and is a rare disease that occurs in young healthy individuals aged 20–35 years (more common in women).
• Acute unilateral vision loss or blurred vision is the main complaint, but visual acuity is often normal or near normal, in contrast to ischemic CRVO.
• Characteristic findings include optic disc edema, marked dilation and tortuosity of retinal veins, and peripapillary retinal hemorrhages; RAPD is usually negative.
• The cause is often idiopathic, but associations with coagulation abnormalities such as Factor V Leiden mutation and post-COVID-19 infection have been reported.
• Corticosteroids are the main treatment, but since the disease can improve spontaneously, the superiority of treatment has not been established.
• The prognosis is generally good, with spontaneous resolution often occurring within 6 to 12 months, but up to 30% may progress to ischemic venous occlusion, so regular follow-up is essential.
• If coagulation abnormalities are confirmed, collaboration with a hematologist is important.

1. What is papillophlebitis?

Papillophlebitis is a clinical subtype (incomplete type) of central retinal vein occlusion (CRVO) and is a rare disease that occurs in young healthy individuals under 45 years of age ^{1, 2)}. It is also called “optic disc vasculitis.”

While CRVO in middle-aged and elderly individuals is associated with aging, hypertension, and arteriosclerosis, papillophlebitis is characterized by its occurrence in healthy young people aged 20–35, especially women. Hayreh (1972) classified this disease into the following two types.

Type I (Papilledema type)

Lesion: Vessels in the prelaminar region

Mechanism: Venous stasis due to nonspecific inflammation

Features: Predominantly papilledema. Steroids have been reported to be effective.

Type II (Central retinal vein occlusion type)

Lesion: Optic disc or retrolaminar region

Mechanism: Inflammation of the central retinal vein

Features: Accompanied by venous dilation, tortuosity, and retinal hemorrhage. Some reports indicate no response to steroids

Q What is the difference between CRVO and papillophlebitis?

A

CRVO is more common in middle-aged and elderly individuals with risk factors such as hypertension, diabetes, and arteriosclerosis, and ischemic type often leads to severe visual impairment. In contrast, papillophlebitis occurs in young healthy individuals, vision is often relatively preserved, and it is a disease with a good prognosis that resolves spontaneously within 6 to 12 months. However, in young patients with CRVO, differentiation from papillophlebitis is important, and systemic steroid administration may be necessary.

2. Main symptoms and clinical findings

papillophlebitis fundus macular oct

Central retinal vein occlusion in a young healthy COVID-19 patient: A case report. Am J Ophthalmol Case Rep. 2020 Nov 16; 20:100992. Figure 1. PMCID: PMC7668173. License: CC BY.

A- Fundus photography of the left eye showing tortuosity and dilatation of all branches of the central retinal vein, dot, blot and flame-shaped hemorrhages throughout all four quadrants, and optic disc edema. B- Optical Coherence Tomography (OCT) of the macula was within normal limits.

Subjective Symptoms

• Unilateral vision loss or blurred vision: Acute onset, painless. Visual acuity is usually normal or near normal, in contrast to ischemic CRVO.
• Floaters: Due to vitreous cells or hemorrhage ²⁾.
• Enlargement of the Mariotte blind spot: A characteristic finding confirmed by visual field testing.

Clinical Findings

• Optic disc edema: marked redness, swelling, and blurred disc margins.
• Retinal vein dilation and tortuosity: marked venous engorgement in all quadrants.
• Intraretinal hemorrhages: various degrees of hemorrhage concentrated around the optic disc^{1, 2)}.
• Cotton-wool spots: focal nerve fiber layer infarcts due to capillary occlusion¹⁾.
• Vitreous cells: findings suggestive of inflammation.
• RAPD negative: Relative afferent pupillary defect is usually negative, an important distinguishing point from ischemic CRVO. The pupillary light reflex is often normal.
• Macular edema: Rare compared to CRVO but can occur ^{1, 2)}.

3. Causes and Risk Factors

The etiology is often presumed to be idiopathic, but an association with hypercoagulable states has been reported.

The following table shows the main risk factors and rates of systemic disease complications.

Risk factors / Associated diseases	Frequency / Notes
Diabetes	3–9%
Hypertension	23–42%
Inflammatory bowel disease, psoriasis	Associated
Pregnancy, oral contraceptives	Associated
High altitude, dehydration	Associated

The association with hereditary coagulation abnormalities is also important. Factor V Leiden (FVL) mutation, the most common hereditary hypercoagulable disorder in Europe, has a high heterozygous prevalence of 15% in Greece (the highest in Europe), and cases of retinal vein inflammation due to combined FVL and MTHFR-C677T heterozygous mutations have been reported ²⁾.

The association with COVID-19 is also noteworthy. SARS-CoV-2 causes vascular endothelial damage via ACE2 receptors and activates the coagulation system. More than 30% of COVID-19 patients develop venous or arterial thromboembolic events, and cases of retinal vein inflammation occurring 6 weeks after infection have been reported ¹⁾.

Prevention and Daily Care

If you experience unexplained vision loss or floaters at a young age, please see an ophthalmologist as soon as possible. If a coagulation abnormality is found, it is important to continue follow-up in collaboration with a hematologist. There are reports that a Mediterranean diet (rich in anti-inflammatory nutrients and antioxidants) may have a positive effect on the coagulation process ²⁾.

Q What are the characteristics of people prone to papillophlebitis?

A

It is more common in young women aged 20–35. Coagulation abnormalities (such as Factor V Leiden mutation), post-COVID-19 infection, and use of oral contraceptives have been reported as risk factors. Some cases also involve systemic diseases (hypertension, diabetes).

4. Diagnosis and Examination Methods

Papillophlebitis is a diagnosis of exclusion, and it is important to differentiate it from more common conditions in the same age group, such as papilledema and optic neuritis.

Imaging Tests

• OCT (Optical Coherence Tomography): The macula is often normal (a distinguishing feature from CRVO), showing retinal nerve fiber layer (RNFL) edema. However, cases of macular edema have also been reported ²⁾. OCT-angiography can detect optic disc edema and venous stasis ²⁾.
• Fluorescein Angiography (FA): Characteristic findings include blocked fluorescence due to intraretinal hemorrhage, and staining and leakage of the optic disc and retinal veins. In cases involving optic disc vasculitis, marked hyperfluorescence of the disc is observed. Confirm venous staining and leakage, as well as leakage and late staining from the optic disc ¹⁾.
• Head MRI/CT: Performed to rule out other causes of optic disc edema. Usually normal.

Blood Tests

The following tests are performed to confirm the diagnosis and investigate the cause.

• Complete blood count (CBC), serum electrolytes
• Coagulation: PT/INR, PTT, protein C/S, antithrombin III
• Hereditary thrombophilia: Factor V Leiden mutation, prothrombin gene mutation (G20210A)
• Homocysteine level, vitamin B6, folate
• Autoimmune markers (ANA, ANCA, etc.)
• COVID-19 testing (during epidemic or with history of infection)

Differential Diagnosis

The following diseases should be considered in the differential diagnosis.

• Central retinal vein occlusion (CRVO): Middle-aged or older adults with risk factors. Positive RAPD, ischemic findings present.
• Impending nonarteritic anterior ischemic optic neuropathy (NAION): Differentiated by age of onset, RAPD, and FA findings.
• Hypertensive retinopathy: Presence of systemic hypertension.
• Diabetic papillopathy: History of diabetes.
• Infectious papillitis: infection markers
• Unilateral papilledema secondary to idiopathic intracranial hypertension (IIH)
• Optic nerve sheath meningioma, orbital space-occupying lesions

5. Standard treatment

No universally accepted evidence-based treatment has been established at present.

Corticosteroids are the main treatment, used because vasculitis is presumed to be involved. They are reported to be effective in Type I but ineffective in Type II. Since the disease can improve spontaneously without treatment, there is no clear evidence of a definitive advantage of steroids. Systemic steroid therapy is often considered only for clinically severe cases.

Ntora et al. (2021) reported a 22-year-old woman (heterozygous FVL + heterozygous MTHFR-C677T mutation) who started oral methylprednisolone 50 mg/day with gradual tapering, showing improvement in findings within 1 week and complete resolution at 1 month. Visual acuity and visual field remained normal at 6 months ²⁾.

Other treatments such as antiplatelet therapy and anticoagulation have been proposed but their efficacy is not proven.

For severe macular edema, intravitreal anti-VEGF injection may be considered (not FDA-approved).

Insausti-García et al. (2022) treated a 40-year-old man who developed papillophlebitis after COVID-19 infection, initially with oral aspirin 100 mg/day and bromfenac 0.9 mg/mL eye drops twice daily. Subsequently, due to vision loss (20/200) from macular edema, an intravitreal dexamethasone sustained-release implant (Ozurdex) was injected, improving vision to 20/40 after 2 weeks ¹⁾.

Precautions in Treatment

Up to 30% of patients may progress to ischemic venous occlusion, so regular ophthalmic examinations are essential even during observation without treatment. Prompt intervention is required if macular edema or ischemia appears. Long-term steroid use requires attention to elevated intraocular pressure, cataracts, and systemic complications.

Q Can it heal naturally without treatment?

A

This disease shows natural improvement even without treatment, and the prognosis is generally good, with spontaneous resolution expected within 6 to 12 months. However, up to 30% have a risk of progressing to ischemic venous occlusion, so regular ophthalmological follow-up is essential. For details, see the section on “Standard Treatment”.

6. Pathophysiology and Detailed Mechanism

The pathophysiology of papillophlebitis is not clear, and it is thought that the mechanism of onset is not singular.

A main hypothesis is that idiopathic inflammation of the optic disc compresses the central retinal vein, leading to secondary venous insufficiency and intraretinal hemorrhage. In Hayreh classification Type I, nonspecific inflammation of the prelaminar vessels is presumed, while in Type II, inflammation of the central retinal vein at the optic disc or retrolaminar region is estimated as the mechanism.

Regarding the COVID-19-related mechanism, the following cascade has been proposed¹⁾.

1. SARS-CoV-2 binds to ACE2 receptor
2. Vascular endothelial injury → endothelial dysfunction
3. Vasoconstriction, ischemia, tissue edema, hypercoagulable state
4. Cytokine storm (CRP, IL-2, IL-6, IL-7, TNF, etc.)
5. Systemic inflammatory response syndrome → coagulation cascade activation → hypercoagulable state

As a pattern of COVID-19-associated coagulopathy (CAC), elevated D-dimer and fibrinogen occur in parallel with inflammatory markers¹⁾.

Involvement of hereditary coagulation abnormalities has also been reported. It is estimated that the combination of FVL heterozygosity and MTHFR-C677T heterozygosity can cause coagulation imbalance and contribute to the development of papillophlebitis²⁾. MTHFR-C677T mutation in homozygous form can cause hyperhomocysteinemia and contribute to a hypercoagulable state, but heterozygosity alone may not always lead to hyperhomocysteinemia.

Q Why does it occur in young people?

A

The pathogenesis is not singular, but a mechanism in which inflammation of the optic disc compresses the central retinal vein is hypothesized. Since young people lack the risk factors for CRVO in middle-aged and older adults, such as hypertension and arteriosclerosis, coagulation abnormalities (hereditary factors) and post-infectious inflammation (e.g., COVID-19) become relatively important triggers.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please be sure to read

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Papillophlebitis after COVID-19 infection

Insausti-García et al. (2022) reported a case of a 40-year-old man who developed papillophlebitis 6 weeks after COVID-19 infection ¹⁾. Laboratory tests showed elevated coagulation and inflammatory markers: D-dimer 672 μg/L (normal <460), fibrinogen 451 mg/dL (normal 200–400), CRP 0.898 mg/dL (normal <0.500). All hereditary thrombophilia tests were normal. Visual acuity improved from 20/200 to 20/40 two weeks after intravitreal dexamethasone implant (Ozurdex) injection. The rapid improvement with dexamethasone may support the inflammation hypothesis.

Cases with hereditary coagulation abnormalities

Ntora et al. (2021) reported the world’s first case of papillophlebitis in a 22-year-old woman with combined FVL heterozygous and MTHFR-C677T heterozygous mutations ²⁾. Complete remission was achieved with oral methylprednisolone alone. Genetic screening was shown to be an important search item in the diagnosis of papillophlebitis. Hematology consultation is essential for preventing future complications.

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8. References

1. Insausti-García A, Reche-Sainz JA, Ruiz-Arranz C, et al. Papillophlebitis in a COVID-19 patient: inflammation and hypercoagulable state. Eur J Ophthalmol. 2022;32(1):NP168-NP172.

2. Ntora E, Dalianis G, Terzidou C. Papillophlebitis associated with coexisting heterozygous mutations of Factor V Leiden and methylenetetrahydrofolate reductase enzyme (C677T). Cureus. 2021;13(5):e15081.

3. Abdel Jalil S, Amer R. The Spectrum of Papillophlebitis. Ocul Immunol Inflamm. 2024;32(10):2515-2520. PMID: 38842197.