Herpes simplex uveitis is an anterior uveitis (corneal endotheliitis, iridocyclitis) caused by intraocular infection with herpes simplex virus (HSV). Posterior uveitis (retinitis such as acute retinal necrosis [ARN]) is described under a separate disease category; this section focuses on anterior uveitis.
The most common subtype associated with ocular infection is HSV-1, which remains latent in the trigeminal ganglion. Almost the entire population is asymptomatically infected with HSV-1 in early childhood, and the disease develops when the virus reactivates and spreads into the eye. It often presents as anterior uveitis, accounting for approximately 5–10% of all uveitis cases 1).
Classification by inflammation localization:
Epidemiology:
Contact lens use is not a specific risk factor for herpes simplex uveitis. The main trigger is reactivation of HSV from the trigeminal ganglion, which can be caused by fever, stress, immunosuppression, or ultraviolet exposure. There is no difference in risk between contact lens users and non-users.
Onset with redness, eye pain, blurred vision, and photophobia. When intraocular pressure is markedly elevated (can reach 50–60 mmHg 2)), headache and nausea may occur. If the trigeminal nerve has been severely damaged by previous HSV episodes, pain may be reduced or absent.
Unilateral mutton-fat keratic precipitates (KP) and anterior chamber inflammatory cells are the main features. Many cases are accompanied by elevated intraocular pressure. Sometimes dendritic keratitis is present, and corneal stromal edema (corneal endotheliitis) corresponding to the location of mutton-fat KP, as well as iris and angle nodules, may occur. Inflammatory cells may be seen in the anterior vitreous, but there are no fundus lesions.
Corneal and Anterior Chamber Findings
Keratic precipitates (KP): Can be granulomatous, non-granulomatous, or stellate. Focal corneal edema (corneal endotheliitis) corresponding to the location of mutton-fat KP is characteristic.
Dendritic keratitis: When present, clinical diagnosis becomes easier.
Anterior chamber cells and flare: Inflammatory reaction in the anterior chamber. Inflammatory cells may be seen in the anterior vitreous, but there are no fundus lesions.
Iris and intraocular pressure findings
Elevated intraocular pressure: May reach 50–60 mmHg. Caused by trabeculitis or clogging by inflammatory cells2).
Localized or sectoral iris atrophy: Observed in approximately 50–59% of cases1). Not present in early stages, appears with chronicity.
Posterior synechiae: Formed in recurrent or chronic cases.
Complications:
During an acute iritis episode, intraocular pressure may reach 50–60 mmHg. Usually, once inflammation is controlled, intraocular pressure normalizes and continuous antiglaucoma treatment is unnecessary. However, in chronic or recurrent cases, attention is needed as it may transition to chronic secondary glaucoma due to peripheral anterior synechiae2).
HSV is a double-stranded DNA virus that, after primary infection, establishes latency in the trigeminal ganglion (in ocular HSV, the V1 distribution). The disease is triggered by reactivation of HSV-1 latently infected in the eye.
Known triggers for reactivation include:
HSV-1 reduces MHC-I expression, has resistance to Fas-mediated apoptosis, and secretes TGF-β1 to reduce IFN-γ-induced MHC-II expression, thereby evading immune responses 2). This mechanism leads to insufficient immune clearance by CD4+ T cells in infected ocular tissues, perpetuating a chronic inflammatory cycle.
Cases of HSV reactivation after COVID-19 vaccination have been reported, suggesting that vaccine-induced immune modulation (CD8+ T cell activation) may alter the balance controlling latent virus 3).
If typical dendritic keratitis coexists, a clinical diagnosis is possible. In addition, HSV uveitis is strongly suspected with the following combination:
The diagnostic criteria from the Herpetic Eye Disease Study (HEDS) are referenced1).
| Examination | Features and points to note |
|---|---|
| Anterior chamber PCR (HSV DNA) | Sensitivity 91.3%, specificity 98.8%2). Useful for definitive diagnosis. Note false negatives in chronic phase or after treatment initiation1) |
| Goldmann-Witmer coefficient (Q value) | Q<1: no intraocular infection / 1≤Q<6: suspected intraocular infection / 6≤Q: intraocular infection present4). Note false negatives within 10 days of onset |
| Multiplex PCR (advanced medical care) | Indicated for suspected herpetic corneal endotheliitis/iritis, ARN, CMV retinitis, PORN4) |
| Serum HSV antibody | If negative, can exclude the cause. Positive only indicates past infection and does not directly support diagnosis |
| Intraocular pressure measurement | Essential for confirming and monitoring high intraocular pressure |
The Goldmann-Witmer coefficient (Q value) is an index that quantitatively evaluates intraocular infection by the ratio of antibody titers in intraocular fluid and serum, and is particularly useful in chronic cases or when PCR is negative. Calculation formula: Q = [pathogen antibody titer in intraocular fluid / IgG concentration in intraocular fluid] ÷ [pathogen antibody titer in serum / IgG concentration in serum]4).
Diseases to differentiate:
In the chronic phase or after starting antiviral therapy, the amount of viral DNA may fall below the detection limit, leading to false negatives. When PCR is negative, calculating the intraocular antibody ratio using the Goldmann-Witmer coefficient (Q value) can improve diagnostic accuracy. Note that within 10 days of onset, intraocular antibody production is insufficient, so the Q value may also be falsely negative.
The principle is to combine topical or systemic antiviral drugs with steroid eye drops.
| Drug | Dosage and administration |
|---|---|
| Acyclovir ophthalmic ointment (Sovirax ophthalmic ointment 3%) | 5 times daily application (topical; usually start with ophthalmic ointment) |
| Acyclovir (oral) | 400 mg 5 times daily |
| Valacyclovir (oral) | 1,000 mg 3 times daily |
| Famciclovir (oral) | 250 mg 3 times daily |
Usually start with ophthalmic ointment. Note that concurrent insurance claims for ophthalmic ointment and oral medication are not allowed. Switching to oral medication is considered when the effect is insufficient.
Prescription example (acute phase):
Betamethasone 0.1% or prednisolone acetate 1% is administered 4 to 8 times daily (adjusted according to the degree of inflammation). Systemic steroids carry a risk of HSV reactivation and are generally not recommended for anterior uveitis alone. After inflammation subsides, steroid tapering should be gradual, and long-term low-dose maintenance may be necessary in chronic cases.
Beta-blockers and carbonic anhydrase inhibitor eye drops are used. Prostaglandin-related drugs carry a risk of HSV reactivation, and careful monitoring is necessary in cases with corneal epithelialitis. If intraocular pressure elevation is significant, oral carbonic anhydrase inhibitors may also be considered.
The HEDS trial reported that prophylactic oral acyclovir reduced the recurrence rate of HSV ocular disease by nearly half over 12 months 1). Recommended doses:
Some reports recommend prophylactic oral therapy for at least 2 years after a uveitis episode, and possibly lifelong 1). Continuation of prophylactic therapy is particularly important in cases with recurrent episodes.
For cases with irreversible intraocular pressure elevation after long-term steroid use, trabeculectomy is performed after adequate antiviral and steroid therapy.
Mild cases can sometimes be managed with topical steroids and mydriatics, but for moderate to severe cases with elevated intraocular pressure, the addition of systemic antiviral agents is recommended. Systemic steroids carry a risk of reactivating HSV, so their use for isolated anterior uveitis should be carefully considered.
It results from reactivation of HSV-1 latently infected in the eye. HSV-1 establishes latency in the trigeminal ganglion and travels along sensory nerve branches (first division of the trigeminal nerve) to ocular tissues.
Upon reactivation, the virus reduces MHC-I expression, exhibits resistance to Fas-mediated apoptosis, and secretes TGF-β1 to suppress IFN-γ-induced MHC-II expression. This reduces CD4+ T cell activation and promotes immune evasion 2).
Classification of inflammatory mechanisms:
Mechanism of intraocular pressure elevation:
Trabeculitis and clogging of the trabecular meshwork by inflammatory cells are the main mechanisms. The virus may also directly infect trabecular meshwork cells, causing dysfunction of the aqueous humor outflow pathway. Acute elevated intraocular pressure usually improves with resolution of inflammation.
Cytokine and chemokine profile in aqueous humor:
In the chronic phase (active inflammation) of hypertensive anterior uveitis, IL-1RA (IL-1 receptor antagonist) shows the highest level in aqueous humor (approximately 1,000 pg/mL), and MCP-1 and IP-10 remain persistently elevated 2). MCP-1 is a monocyte chemoattractant protein that plays an important role in the pathogenesis of inflammatory diseases, and its level is also associated with the risk of secondary complications such as proliferative vitreoretinopathy 2). Elevations of IL-8 and IL-18 are also observed, indicating that multiple cytokines are involved in the persistence of inflammation.
Prognosis:
Most cases respond well to treatment with antiviral agents and steroids. However, a certain number of cases recur or become persistent, requiring long-term management. In cases where long-term steroid use leads to irreversible intraocular pressure elevation, trabeculectomy may be necessary.
Nguyen et al. (2024) performed aqueous humor cytokine analysis in hypertensive anterior uveitis and reported elevated levels of IL-1RA, MCP-1, IP-10, IL-8, and IL-18 2). Research is progressing on the application of machine learning models combined with cytokine analysis for etiological diagnosis of intraocular inflammation, with expected improvements in diagnostic accuracy for differentiating HSV, VZV, and CMV.
Ortiz-Egea et al. (2022) reported two cases of HSV-induced keratouveitis occurring within 72 hours after Pfizer-BioNTech COVID-19 vaccination 3). The mechanism by which vaccine-induced CD8+ T cell activation reaches ocular tissue and triggers inflammation, as well as herpes reactivation due to “distraction” of normal immune surveillance, is discussed. With the future spread of mRNA vaccines, attention to ocular symptoms after vaccination is necessary.
