Glaucoma associated with infection is secondary glaucoma caused by infection with pathogenic microorganisms (viruses, bacteria, parasites, prions). In many cases, infection-related uveitis impairs the aqueous humor outflow pathway, leading to elevated intraocular pressure and progression to glaucoma.
Inflammatory glaucoma (uveitic glaucoma) is a condition in which persistent or recurrent intraocular inflammation causes elevated intraocular pressure, leading to progressive optic disc cupping and loss of the retinal nerve fiber layer1). Approximately 20% of uveitis patients have concurrent glaucoma1).
In patients with virus-related anterior uveitis, 10–40% are reported to develop secondary glaucoma. Acute intraocular pressure elevation is characteristic of Posner-Schlossman syndrome and HSV, VZV, and CMV infections, while chronic intraocular pressure elevation is characteristic of Fuchs heterochromic iridocyclitis, sarcoidosis, and syphilis 2)3).
QHow often does glaucoma associated with infection occur?
A
Approximately 20% of all uveitis patients have concurrent glaucoma. In virus-related anterior uveitis alone, 10–40% develop secondary glaucoma. Particularly in herpetic keratouveitis, 28% show elevated intraocular pressure and 10% show glaucomatous damage.
Acute elevation of intraocular pressure causes eye pain, blurred vision, rainbow-colored halos around lights, and conjunctival injection 4). In glaucoma associated with chronic uveitis, subjective symptoms are often absent, and patients may not notice until visual field defects progress. Herpetic keratouveitis also causes photophobia.
Keratic precipitates (KP): Herpes virus infection shows characteristic KP with projections. In Fuchs heterochromic iridocyclitis, white stellate KP scattered over the entire corneal endothelium are observed.
Anterior chamber inflammation: Flare and cells are present. CMV infection may cause a rapid rise in intraocular pressure exceeding 30 mmHg.
Iris findings: Iris atrophy, nodules, and posterior synechiae may be observed. In Posner-Schlossman syndrome, posterior synechiae do not form.
Angle findings: The angle is often open, but angle closure due to peripheral anterior synechiae or posterior synechiae can also occur 1).
Ocular Findings in Bacterial and Parasitic Infection
Syphilitic interstitial keratitis: Neovascularization and opacification of the deep corneal stroma are observed. The angle is open with uneven pigmentation and a “dirty” appearance 1).
Tuberculous uveitis: Presents as granulomatous anterior uveitis with mutton-fat KP and angle nodules. May be accompanied by synechial angle closure.
Listeria endophthalmitis: Characterized by dark hypopyon. Intraocular pressure elevation results from inflammation, iris necrosis, and pigment dispersion.
Acanthamoeba keratitis: Chronic inflammation of the trabecular meshwork leads to synechiae and angle closure.
In herpetic keratouveitis, intraocular pressure elevation is observed in 28% of cases, and glaucomatous damage has been reported in 10% 1). The average duration of intraocular pressure elevation is 2 months 1).
HSV, CMV, and VZV are DNA viruses belonging to the Herpesviridae family, causing secondary glaucoma following anterior uveitis. CMV is established as a cause of intraocular pressure elevation exceeding 30 mmHg, and the number of pressure spikes is an important indicator of progression to chronic glaucoma. CMV and HSV have been reported as causes of Posner-Schlossman syndrome.
Adenovirus causes epidemic keratoconjunctivitis, but its association with glaucoma is rare. Animal models have shown reduced aqueous humor outflow facility.
In syphilis, 15% develop interstitial keratitis, of which 20% develop secondary glaucoma1). Open-angle type is common, the angle appears “dirty,” and response to antiglaucoma medications is poor 1).
H. pylori infection has been suggested to be associated with open-angle glaucoma, including normal-tension glaucoma, through inflammation, release of vasoactive factors, and trabecular meshwork dysfunction via oxidative stress.
Mycobacterium tuberculosis causes chronic anterior uveitis leading to synechial angle closure and pupillary block. Mycobacterium leprae is also associated with secondary angle-closure glaucoma due to intraocular inflammation.
In Acanthamoeba keratitis, chronic inflammation of the trabecular meshwork leads to adhesion and angle closure. Gnathostoma invades the anterior chamber, causing acute anterior uveitis.
In prion diseases, structural changes in the normal protein PrPC destabilize the extracellular matrix, increasing trabecular meshwork resistance and leading to open-angle glaucoma.
QWhich virus is most likely to cause glaucoma?
A
CMV is the most established cause of secondary glaucoma, causing rapid intraocular pressure elevation exceeding 30 mmHg. HSV and VZV also cause acute intraocular pressure elevation. In herpetic keratouveitis, intraocular pressure elevation is observed in 28% of cases.
Intraocular pressure measurement, anterior segment examination, and gonioscopy are fundamental. In glaucoma due to uveitis, evaluation of peripheral anterior synechiae by gonioscopy and assessment of the degree of angle closure are essential for determining treatment strategy1).
Differentiating the cause based on the characteristics of keratic precipitates (KP) is important. Mutton-fat KP suggests granulomatous uveitis (sarcoidosis, tuberculosis, herpes infection), while fine KP suggests non-granulomatous uveitis. KP with projections are findings suggestive of infectious uveitis such as herpetic iritis.
When viral infection is suspected, aqueous humor analysis is recommended2). PCR testing and antibody testing are performed via anterior chamber paracentesis to identify causative viruses such as HSV, CMV, and VZV. Confirming or ruling out viruses is necessary to initiate appropriate antiviral therapy2).
If intraocular pressure elevation is present at the time of diagnosis, inflammation is likely contributing to the pressure elevation1). Careful follow-up and confirmation of treatment history are important for differentiation from steroid-induced glaucoma1).
The treatment of glaucoma associated with infectious diseases is based on the principle of treating both the underlying disease and controlling intraocular pressure.
If viral infection is suspected or confirmed by aqueous humor analysis, systemic antiviral therapy is administered 2). For bacterial infection, appropriate antibiotics are used. As anti-inflammatory treatment, steroid eye drops and mydriatics are used concomitantly, with priority given to controlling inflammation 1).
Beta-blockers and carbonic anhydrase inhibitors are first-line choices as ocular hypotensive eye drops 2). Prostaglandin-related drugs can be used in eyes with controlled inflammation, but caution is needed because they may induce inflammation 2).
If intraocular pressure cannot be controlled with eye drops or oral medications, surgery is considered 4).
Laser trabeculoplasty is avoided during the acute inflammatory phase 2)3). In secondary glaucoma associated with uveitis, trabeculotomy is effective, especially for steroid-induced glaucoma. If trabeculotomy does not sufficiently lower intraocular pressure, filtering surgery is performed. Tube shunt surgery is also an option 1).
QDoes treatment differ between infection-associated glaucoma and ordinary glaucoma?
A
The biggest difference is that treatment of the underlying disease (infection) must be performed simultaneously. Infection control with antiviral or antibacterial drugs and suppression of inflammation with steroids are prioritized. In the selection of intraocular pressure-lowering drugs, beta-blockers and carbonic anhydrase inhibitors are first-line, and prostaglandin-related drugs are used after inflammation is controlled. Laser trabeculoplasty is avoided in the acute phase, which is also a difference.
The main mechanisms by which intraocular inflammation associated with infection causes open-angle glaucoma are as follows 1).
Trabecular meshwork obstruction is the most common mechanism, where disruption of the blood-aqueous barrier (BAB) allows inflammatory cells to enter the aqueous humor and become trapped in the aqueous outflow pathway 1). Edema of the trabecular lamellae and changes in endothelial cells physically narrow the intertrabecular spaces, ultimately leading to permanent damage and scar formation 1).
The increase in aqueous humor protein concentration due to BAB disruption raises aqueous viscosity, increasing outflow resistance 1).
Trabeculitis has been proposed in Posner-Schlossman syndrome and viral keratouveitis, and is a mechanism that explains the disproportionately high intraocular pressure elevation relative to anterior segment inflammatory findings 2).
Inflammatory cells and proteins in the aqueous humor form adhesions between the iris and lens (posterior synechiae), leading to pupillary block, iris bombé, and eventually peripheral anterior synechiae formation 1). Subsequently, angle neovascularization and fibrovascular occlusion may occur 1).
In tuberculosis and leprosy infections, synechial angle closure due to granulomatous inflammation is the main mechanism.
Prions (PrPSc) cause structural changes in normal PrPC protein. This structural change destabilizes the extracellular matrix and increases outflow resistance in the trabecular meshwork. As a result, aqueous humor drainage decreases, leading to intraocular pressure elevation and optic nerve degeneration.
Mechanism of intraocular pressure elevation in CMV infection
CMV directly damages the trabecular meshwork, and fibrin and inflammatory cells produced during infection increase aqueous humor viscosity. The number of intraocular pressure spikes during infection reflects the degree of cumulative trabecular damage and the risk of progression to chronic glaucoma.
Recent studies have shown that bacteria (such as Staphylococcus aureus and Candida albicans) increase adhesion to retinal vascular endothelial cells, reach the neural retina via transcytosis, and impair the outer blood-retinal barrier. Research using three-dimensional models (integrating RPE, Bruch’s membrane, and choroid) is a future challenge.
Disruption of the blood-retinal barrier has been shown to be closely associated with the development of autoimmune uveitis. Uncontrolled immune responses to intraocular self-antigens lead to persistent chronic inflammation, and the pathway leading to secondary glaucoma is being elucidated.
