Herpetic keratouveitis: risk of glaucoma and treatment options

Herpetic keratouveitis is an inflammation of the cornea and vascular tract of the eye caused by the herpes simplex virus or the varicella-zoster virus. This inflammation often leads to increased intraocular pressure due to involvement of the trabecular meshwork, which can lead to secondary glaucoma and irreversible damage to the optic nerve. Clinical presentation ranges from severe pain, redness, and photophobia to asymptomatic symptoms with periodic pressure surges. [1]

Increased intraocular pressure in herpetic keratouveitis is caused by inflammation of the eye's drainage system, edema, and the deposition of cellular debris and inflammatory mediators in the anterior chamber angle. In some cases, the response to hormonal anti-inflammatory drugs also contributes, requiring particularly careful treatment selection. [2]

According to retrospective studies, patients with herpetic anterior uveitis frequently experience elevated intraocular pressure, and true glaucoma develops in a significant proportion of patients over the next few years of observation. In one study, elevated pressure was recorded in 75% of patients, and signs of glaucoma were recorded in 15% over a median of 7.9 years; the need for glaucoma surgery arose in approximately 19%. [3]

Recurrences of herpetic ocular infections are common, increasing the risk of further flare-ups of inflammation and pressure surges. High rates of long-term recurrence have been reported for herpes simplex, and the benefits of long-term antiviral prophylaxis have been demonstrated for ocular herpes zoster in some patients. [4]

Code according to ICD-10 and ICD-11

In the International Classification of Diseases, Tenth Revision, herpetic ocular pathology is coded in the herpesvirus infections section and the eye diseases section. Most often, codes reflecting the viral nature of the lesion and the specific ophthalmologic condition are combined: "herpesvirus ocular lesion" and "iridocyclitis" in uveitis, as well as "glaucoma due to ocular inflammation." Separate clarifying entries exist for herpes zoster. [5]

The International Classification of Diseases, Eleventh Revision, provides more precise nomenclature for "glaucoma due to ocular inflammation" and herpetic corneal lesions. In practice, both the viral cause and the ophthalmologic complication are coded, which is important for patient tracking and management. [6]

Table 1. Examples of codes for clinical use

Situation	ICD-10	ICD-11
Herpesvirus eye lesion, unspecified	B00.5	1F00.1x (eye lesion in herpes simplex virus infection)
Herpesvirus keratitis	B00.52	1F00.10 (herpesvirus keratitis)
Iridocyclitis, unspecified	H20.9	9B60.Y (uveitis, unspecified, with specification according to anatomy)
Iridocyclitis in herpes zoster	B02.32	1E91.1 (herpes zoster ophthalmicus)
Glaucoma due to inflammation of the eye	H40.4x	9C61.24 (glaucoma due to inflammation of the eye)
Source: systematization according to current versions of the ICD and clinical reference books. [7]

Epidemiology

Increased intraocular pressure is one of the most common complications of uveitis. In large case series, elevated pressure requiring treatment was observed in approximately 30% of patients with uveitis overall. In cohorts of herpetic anterior uveitis, elevated pressure at episode onset was recorded in the majority of cases. [8]

The proportion of patients who develop glaucoma with damage to the optic nerve and visual fields against the background of herpetic keratouveitis varies, according to data from different centers, from approximately 15% to 20%. The risk is higher with multiple pressure peaks and frequent relapses of inflammation. [9]

In herpes zoster of the eye, a significant proportion of patients experience ophthalmological manifestations, including keratitis and iridocyclitis, and some develop a chronic or recurrent scenario, which increases the likelihood of complications. [10]

With preventive measures, the incidence of ophthalmologic complications can be reduced. For herpes zoster, long-term low-dose antiviral prophylaxis has been shown to be effective in reducing recurrent episodes of keratitis or iritis, and there is also evidence of the effect of vaccination on the risk of ophthalmologic manifestations. [11]

Reasons

The main causative agents are herpes simplex virus types 1 and 2 and the varicella-zoster virus, which persist in sensory ganglia. Reactivation is facilitated by stress, ultraviolet light, fever, eye surgery, topical hormonal drugs, and certain prostaglandin analogs used to lower blood pressure. [12]

With herpetic lesions, endotheliitis and stromal keratitis with an immune component, as well as isolated iridocyclitis, are possible. Damage to the trabecular meshwork and acute inflammation lead to a rapid increase in intraocular pressure. [13]

Herpes zoster localized in the area of the ophthalmic branch of the trigeminal nerve is more common in the elderly and immunocompromised individuals and carries a high risk of long-term ophthalmologic sequelae, including recurrent uveitis. [14]

Rarely, cytomegalovirus can mimic a similar picture in immunocompetent individuals, especially with endotheliitis. Laboratory testing of aqueous humor is required for accurate verification of the pathogen. [15]

Risk factors

Risk factors for herpes zoster include advanced age, immunodeficiency, frequent stress and phototrauma, previous ophthalmological surgery, and a history of repeated episodes of herpetic keratitis.[16]

The presence of multiple episodes of sharp increase in intraocular pressure during observation and severe inflammation are associated with a higher risk of developing glaucoma. [17]

The use of hormonal drugs, both locally and systemically, can provoke an increase in blood pressure and exacerbate the risk in those with a genetic predisposition to hormonal response. This requires individualized treatment and blood pressure monitoring. [18]

Certain antiglaucoma drugs may be associated with recurrence of herpetic keratitis in a small proportion of patients, which is taken into account when choosing lines of therapy. [19]

Table 2. Common risk factors and modifiable triggers

Factor	Comment
Old age	There is a higher risk of herpes zoster of the eye and complications
Immunodeficiency	Severe and protracted course
Ultraviolet radiation and stress	Triggers for herpes simplex reactivation
Eye surgery and trauma	Triggering a relapse in latent infection
Long-term hormonal therapy	Risk of increased blood pressure and steroid response
Source: reviews and clinical guidelines. [20]

Pathogenesis

The key mechanism for increased pressure is inflammation of the trabecular meshwork, the so-called trabeculitis reaction, which impairs the outflow of intraocular fluid. This is compounded by blockage of the angle by cellular material and inflammatory mediators, and swelling of the structures involved in hydrodynamics. [21]

The steroid response is another mechanism that increases blood pressure in some patients. It depends on the dose and duration of use of hormonal drops and individual predisposition. [22]

Prolonged inflammation leads to the formation of synechiae, trabecular tissue remodeling, and persistent outflow resistance, which perpetuates secondary glaucoma. In some patients, without timely elimination of triggers and inflammation control, the risk of irreversible vision loss increases. [23]

Herpes zoster is characterized by a pronounced neurotrophic component and endothelial damage to the cornea, which maintains chronic inflammation of the anterior segment. This increases the likelihood of recurrent flare-ups and prolonged hypertension. [24]

Table 3. Mechanisms and clinical consequences

Mechanism	Clinical investigation
Trabeculitis and cellular debris deposition	Rapid increase in pressure, pain, rainbow circles
Steroid response	Maintaining high blood pressure during treatment
Synechiae and remodeling	Persistent glaucoma, need for surgery
Endotheliitis and neurotrophic shifts	Recurrent course, corneal opacity
Source: modern reviews of the pathogenesis of uveitis glaucoma. [25]

Symptoms

Pain and a gritty sensation, redness, photophobia, decreased visual acuity, and halos around lights are common. Unilateral manifestations are more common, especially at first presentation. [26]

Herpes simplex is characterized by keratitis with disciform stromal edema, endothelial precipitates, decreased corneal sensitivity, and patchy iris atrophy. Symptoms can worsen rapidly with increased blood pressure. [27]

For herpes zoster of the eye, skin rashes in the eye and forehead area, severe pain, keratitis and iridocyclitis with the risk of a long-term course are typical. [28]

Periodic “crises” with sharp, disproportionately high pressure against a background of moderate inflammation require the exclusion of other viral causes and an assessment of developing glaucoma. [29]

Classification, forms and stages

There are forms with predominantly corneal lesions, with leading iridocyclitis, and mixed variants. Depending on the pathogen, there are variants associated with the herpes simplex virus and the herpes zoster virus. [30]

The course of inflammation is classified as acute episodes, recurrent episodes with periods of remission, and chronic persistent inflammation. The risk of glaucoma increases with the number of episodes of increased pressure and the duration of inflammation. [31]

Based on the state of the anterior chamber angle, an open angle without synechiae, partial blockage by synechiae and pronounced synechial closure are distinguished, which determines the prognosis and treatment tactics. [32]

Glaucoma staging is based on the level of intraocular pressure, the state of the optic nerve head and visual fields, which dictates the goals of treatment and the frequency of monitoring. [33]

Complications and consequences

The main complications are secondary glaucoma with progressive visual field defects, corneal scarring and clouding, cataracts, adhesions, and chronic pain. Without control of inflammation and pressure, the risk of irreversible vision loss increases. [34]

In cohorts of herpetic uveitis, glaucoma surgery is required in a significant proportion of patients, particularly those with multiple pressure peaks. This reflects the aggressive nature of uveitis glaucoma. [35]

With ocular herpes zoster, complications are often protracted, including recurrent keratitis and uveitis and neuropathic pain. Long-term antiviral prophylaxis can reduce the frequency of exacerbations and the severity of pain in some patients. [36]

Progression of complications is more often observed with late diagnosis, non-compliance with treatment and concomitant steroid reaction, which emphasizes the importance of patient education and regular monitoring. [37]

When to see a doctor

You should seek immediate medical attention if you experience sudden eye pain, a sharp deterioration in vision, the appearance of rainbow circles, severe redness, and photophobia, especially if similar episodes have occurred previously. [38]

An urgent ophthalmologist consultation is necessary if a skin rash appears on the forehead and eyelid on the affected side of the eye, as this may indicate the onset of ocular herpes zoster. Early treatment improves the prognosis. [39]

If hormonal drops have already been prescribed and they increase discomfort or cause pressure surges, a quick revision of the treatment regimen is necessary. [40]

Patients with established uveitis glaucoma and any signs of visual field loss, headache, or halos around lights should have their follow-up visits scheduled more frequently rather than waiting for the next appointment. [41]

Table 4. Symptoms requiring urgent medical attention

Symptom	Why is this dangerous?
Sudden pain and rainbow circles	Possible sharp increase in pressure
Skin rash in the forehead and eyelid area	Risk of ocular shingles
Rapid decline in visual acuity	Risk of damage to the optic nerve and cornea
Increased discomfort with hormonal drops	Steroid response is likely
Source: clinical guidelines and reviews. [42]

Diagnostics

The initial examination includes visual acuity testing, intraocular pressure measurement, and slit-lamp examination. The cornea is assessed for dendritic defects, stromal edema, endothelial precipitates, and anterior chamber reaction. [43]

Gonioscopy is performed to assess the anterior chamber angle and the presence of adhesions, as well as examination of the optic disc and visual fields for the initial assessment of glaucomatous damage. This determines the initial target pressure values. [44]

Instrumental verification includes optical coherence tomography of the disc and nerve fiber layer, pachymetry to measure corneal thickness, and, if necessary, anterior segment tomography. These methods allow for recording the initial structure and dynamics during treatment. [45]

In cases of atypical presentation, frequent relapses, or doubt regarding the causative agent, polymerase chain reaction (PCR) analysis of aqueous humor is indicated, which detects DNA of herpes simplex, herpes zoster, and cytomegalovirus viruses. A number of series report high sensitivity and specificity of this testing; the Goldman-Witmer coefficient is additionally used to assess intra-articular antibody synthesis. [46]

Table 5. Diagnostic route for suspected herpetic keratouveitis and glaucoma

Step	What are we doing?	For what
Basic examination	Visual acuity, intraocular pressure, slit lamp	Confirm inflammation and increased pressure
Gonioscopy	Examination of the angle, synechia	Selecting pressure reduction tactics
Disc and field assessment	Fundoscopy and perimetry	Glaucoma control base
Tomography	Optical coherence tomography of the disc and nerve fiber layer	Objective recording of structural changes
Laboratory	Aqueous humor polymerase chain reaction, Goldman-Witmer coefficient	Virus identification and targeted therapy
Source: modern diagnostic algorithms. [47]

Differential diagnosis

It must be distinguished from cytomegalovirus anterior uveitis, which is characterized by coin-shaped precipitates on the endothelium, often high pressure, and a good response to specific antiviral therapy. Aqueous humor polymerase chain reaction helps confirm this. [48]

Fuchs's syndrome of heterochromic iridocyclitis results in chronic, asymptomatic inflammation with small stellate precipitates, iris atrophy, and a tendency toward cataracts; hormonal drops are often ineffective. [49]

Posner-Schlossman syndrome is characterized by acute unilateral "crises" of very high pressure against a background of moderate inflammation and normalization between episodes; a viral cause must be excluded. [50]

Other causes of uveitis with elevated pressure should be excluded, including association with the HLA-B27 antigen, sarcoidosis and toxoplasmosis; when in doubt, a comprehensive clinical and laboratory evaluation is decisive. [51]

Table 6. Signs that help to distinguish similar conditions

State	Distinguishing features
Herpetic keratouveitis	Dendritic defects or discoid stromal edema, large precipitates, segmental iris atrophy, decreased corneal sensitivity
Cytomegalovirus uveitis	Coin-shaped precipitates, frequent pressure peaks, confirmed by polymerase chain reaction
Fuchs syndrome	Long-term asymptomatic picture, small stellate precipitates, weak response to hormonal drops
Posner-Schlossman syndrome	Sharp, single pressure peaks with moderate inflammation, normalization between episodes
Source: modern reviews and guides. [52]

Treatment

Basic principles include simultaneous suppression of viral replication and gentle control of inflammation, as well as safe reduction of pressure to an individualized target, taking into account the condition of the optic nerve and visual fields. In active epithelial herpetic keratitis, hormonal drops are not used without adequate antiviral coverage. [53]

In the acute period, systemic antiviral drugs are prescribed. For herpes simplex and herpes zoster, acyclovir is used at a daily dose of 400 mg five times a day or 800 mg five times a day, valacyclovir 1000 mg three times a day, or famciclovir 500 mg three times a day for a course of at least 7-10 days; for endotheliitis and stromal keratitis, systemic forms are preferred. Topical ganciclovir 0.15% can be used as an adjunct. [54]

Hormonal drops of prednisolone or dexamethasone are used in a tapering regimen for stromal and endothelial lesions and iridocyclitis, but only in conjunction with active antiviral therapy to reduce the immune component and the risk of scarring. Cycloplegics are prescribed for pain relief and the prevention of posterior adhesions. [55]

Intraocular pressure reduction begins with beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors in eye drops; if necessary, oral carbonic anhydrase inhibitors are briefly added. Prostaglandin analogues are used with caution after active inflammation has subsided, taking into account the individual risk of relapse. [56]

If medications are ineffective, laser and surgical methods are considered. Selective laser trabeculoplasty may be an option in patients with an open angle and controlled inflammation; small case series show sustained pressure reduction in some patients. The decision is made on an individual basis. [57]

Mitomycin C filtration surgery remains an effective option for uveitis glaucoma, but requires strict inflammation control before and after the procedure, as well as a well-thought-out anti-scarring strategy. [58]

Implantation of drainage devices, such as valved and valveless systems, has shown significant pressure reduction in patients with uveitis glaucoma; device choice depends on the anatomy, inflammatory activity, and surgeon experience. In some series, valveless systems provided greater pressure reduction at the expense of a higher risk of hypotony. [59]

Minimally invasive intraocular tract procedures may be considered in carefully selected patients with controlled inflammation. Series with goniotomy and transluminal trabeculotomy have been published demonstrating significant reductions in pressure and eye drop requirements with adequate inflammation control. [60]

Long-term antiviral prophylaxis reduces the risk of recurrence. For herpes simplex, a year-long course of acyclovir 400 mg twice daily has been shown to be beneficial, reducing the frequency of recurrences of keratitis and uveitis. For ocular herpes zoster, a recent randomized trial found that year-long prophylaxis with valacyclovir 1000 mg daily reduced the risk of recurrent episodes and pain. [61]

Management includes patient training in trigger control, adherence to treatment regimens, and regular monitoring of optic nerve pressure and structures. Treatment goals are revised based on visual field dynamics and nerve fiber layer tomography. [62]

Table 7. Main therapy groups and examples of regimens

Task	Funds	Comments
Antiviral induction	Acyclovir, valacyclovir, famciclovir; topical ganciclovir	The course is at least 7-10 days, preferably systemic forms for stroma and endothelium
Anti-inflammatory therapy	Hormonal drops with gradual dose reduction; cycloplegics	Only against the background of antiviral drugs
Reducing pressure	Beta blockers, alpha agonists, carbonic anhydrase inhibitors	Individual selection, taking into account the steroid response
Laser and surgery	Selective laser trabeculoplasty, filtration surgery, drainage devices, minimally invasive techniques	Conducted in cases of controlled inflammation and drug ineffectiveness
Relapse prevention	Acyclovir 400 mg 2 times a day, valacyclovir 1000 mg 1 time per day long-term	Reduction in the frequency of exacerbations in selected patients
Source: Clinical guidelines and research. [63]

Prevention

Vaccination with the recombinant herpes zoster vaccine in adults significantly reduces the risk of the disease and its ophthalmic forms. The vaccine's effectiveness in preventing ocular herpes zoster is confirmed by data from multi-thousand-person cohorts. [64]

In patients with recurrent herpetic keratouveitis, long-term antiviral prophylaxis should be considered, particularly in those with frequent episodes and a high risk to the cornea and optic nerve. The choice of drug and duration are discussed individually. [65]

Reducing exposure to triggers includes protection from intense ultraviolet radiation, stress management, and caution when planning eye procedures. Any hormonal eye drops should be used only as directed and with blood pressure monitoring. [66]

Regular follow-up visits with pressure measurements, optic disc and visual field assessment are key to preventing glaucoma progression and timely correction of treatment goals. [67]

Forecast

With early diagnosis, adequate antiviral and anti-inflammatory therapy, and targeted blood pressure control, the prognosis is more favorable and the risk of irreversible changes is lower. Repeated episodes and multiple blood pressure peaks worsen the prognosis. [68]

On average, a significant proportion of patients develop a persistent need for antihypertensive medications, and some require surgical reduction of blood pressure. Long-term outcomes depend on the activity of inflammation and adherence to therapy. [69]

For the ocular form of herpes zoster, the use of long-term low-dose antiviral prophylaxis can reduce the frequency of relapses and the severity of pain, which improves the quality of life and visual prognosis. [70]

Herpes zoster vaccination and patient education programs have the potential to reduce the burden of disease at the population level by decreasing the incidence of severe ophthalmic complications.[71]

Answers to frequently asked questions

Is it possible to treat herpetic keratouveitis with hormonal drops alone, without antiviral medications? No. For herpetic keratouveitis, hormonal drops are used only in conjunction with antiviral therapy; otherwise, the risk of increased viral replication and complications increases. [72]

Should blood pressure reduction be initiated immediately at the first visit? Yes. If a blood pressure increase is confirmed, treatment begins the same day, selecting medications with a favorable safety profile and taking into account inflammation and a possible steroid response. [73]

Do laser treatments help with uveitis glaucoma? In selected patients with open angles and controlled inflammation, selective laser trabeculoplasty may reduce pressure, but the decision is individualized given the limited data. [74]

Does antiviral prophylaxis work long-term? For herpes simplex, a year of acyclovir prophylaxis has been shown to reduce recurrences. For shingles, a year of low-dose valacyclovir reduces the frequency of exacerbations and pain in some patients. Tactics are discussed individually. [75]