Posner-Schlossman syndrome (PSS) is an iritis with unilateral, recurrent acute intraocular pressure elevation of unknown cause. It is also called glaucomatocyclitic crisis. In 1948, Posner and Schlossman first reported 9 cases and proposed the term “glaucomatocyclitic crisis”7).
It is a unilateral recurrent iridocyclitis with intraocular pressure elevation, causing repeated attacks of acute high intraocular pressure (40–60 mmHg). Onset is most common in the 20s to 50s. Inflammation and intraocular pressure elevation occur simultaneously, but attacks often resolve within a few days. The interval between attacks ranges from several months to 1–2 years, and during remission, neither anterior chamber inflammation nor intraocular pressure elevation is observed.
The most important clinical feature is that despite the mild degree of anterior chamber inflammation, intraocular pressure rises sharply to 40–60 mmHg or higher. This “imbalance between inflammation and intraocular pressure” is the most crucial clue for diagnosing PSS. Corneal edema is often very mild relative to the intraocular pressure elevation, and since it is not accompanied by corneal endothelial damage, it has traditionally been considered a “disease with good prognosis.” However, recent long-term follow-up studies have revealed secondary glaucoma due to repeated attacks and progressive loss of corneal endothelial cells, leading to a reevaluation of its benign nature.
In a nationwide epidemiological survey of uveitis (3060 cases), PSS accounted for 57 cases (1.9%) and 69 cases (1.8%), ranking among the top 10 most common uveitis entities1). It is slightly more common in men, and although racial differences and HLA associations are not clear, an association with HLA-Bw54 has been reported in 41% of a Japanese cohort6). A Finnish population study reported an incidence of 0.4 per 100,000 and a prevalence of 1.9 per 100,000. It typically occurs in adults aged 20–50 years, but cases as young as 13 years have been reported, indicating that juvenile onset is possible.
The coexistence of PSS and POAG (primary open-angle glaucoma) has been reported in up to 45% of cases. Even during interictal periods, intraocular pressure in the affected eye may remain slightly elevated, and some patients show elevated pressure in the contralateral eye, suggesting that POAG may be latent in the background of PSS.
In recent years, reports of cytomegalovirus (CMV) detection in the aqueous humor of patients have accumulated, and it is increasingly thought that PSS may be identical to or partially overlap with CMV iritis. Both conditions share many features, such as mild anterior chamber inflammation accompanied by elevated intraocular pressure. In regions with a high prevalence of CMV anterior uveitis, CMV accounts for up to 66% of viral anterior uveitis11), and approximately 50% of patients presenting with a PSS phenotype test positive for CMV.
Complete cure is difficult, and attacks often recur at intervals of several months to several years. However, the frequency of attacks tends to decrease with age. Each attack usually resolves spontaneously within a few days, and with appropriate treatment, most cases recover without sequelae. On the other hand, repeated attacks over a long period can lead to glaucomatous optic neuropathy, so regular follow-up is essential.
Subjective symptoms during an attack are often relatively mild.
The course is variable; some patients experience only one or two episodes in a lifetime, while others have repeated recurrences. Attack frequency often decreases with age. Preceding triggers or prodromes are usually absent.
As a representative case, a 40-year-old male was referred with suspected glaucoma, presenting only with blurred vision in the right eye, and was found to have marked ocular hypertension of 65 mmHg 1). There were no findings of ciliary injection or corneal endothelial edema, and mild anterior chamber cells were observed. The angle showed decreased pigmentation in the affected eye compared to the fellow eye, and no abnormal findings were noted in the fundus or vitreous. Treatment with steroid eye drops, intraocular pressure-lowering medications, and oral carbonic anhydrase inhibitors was initiated, and after 3 days, intraocular pressure normalized and intraocular inflammation almost resolved. However, a similar attack recurred 4 months later 1).
The most significant clinical feature is that the intraocular pressure elevation is disproportionately high relative to the degree of anterior chamber inflammation.
When attacks recur over a long period and inflammation and intraocular pressure elevation become chronic, optic disc cupping enlarges and glaucomatous visual field defects appear 1).
The exact cause of PSS is unknown. Cytomegalovirus (CMV), herpes simplex virus (HSV), and other infections have been reported as causes, but this has not been confirmed.
Proposed etiological hypotheses include the following:
Distinguishing idiopathic PSS from viral PSS is clinically important because it directly affects treatment strategy. In CMV-positive cases, antiviral therapy is necessary, and long-term prognosis may differ.
Differentiation is made by collecting aqueous humor and testing for CMV-DNA using PCR 1). A positive CMV result provides a basis for adding antiviral drugs (ganciclovir or valganciclovir) to the treatment. Even if PCR is negative, there is a possibility of false negatives, so a comprehensive judgment including the clinical course is necessary. The test requires anterior chamber paracentesis (collection of aqueous humor).
Clear diagnostic criteria for PSS have not been established. The definition from the first report by Posner and Schlossman in 1948 is often referenced 7).
This condition is considered when there is unilateral, paroxysmal high intraocular pressure, scattered white non-pigmented keratic precipitates, open angle, angle depigmentation, and mild anterior chamber cells 1).
The clinically important triad is as follows:
It is important to differentiate from the following diseases that present with unilateral iritis with high intraocular pressure 1).
| Differential Disease | Key Points for Differentiation |
|---|---|
| Primary Open-Angle Glaucoma (POAG) | No keratic precipitates or anterior chamber cells. Paroxysmal high intraocular pressure above 40 mmHg is rare. |
| VZV Iridocyclitis | Focal iris atrophy and paralytic mydriasis are observed. |
| CMV Iridocyclitis | Difficult to distinguish from PSS based on findings. Differentiation is made by detecting CMV DNA via PCR. |
| Sarcoidosis | Often bilateral. Systemic findings, characteristic vitreous opacities and fundus findings. |
| Fuchs Heterochromic Iridocyclitis | Iris heterochromia, diffuse atrophy, angle neovascularization. |
| Steroid responder | History of steroid use. No keratic precipitates or anterior chamber cells |
Differentiation from primary open-angle glaucoma can be clinically difficult, but in PSS, corneal endothelial deposits and anterior chamber cells are observed, and in POAG, paroxysmal ocular hypertension of 40 mmHg or higher is rare, which provides clues for differentiation 1). Coexistence of PSS and POAG has been reported in up to 45% of cases, so attention should also be paid to the possibility of both diseases coexisting.
The principle of treatment is to control inflammation and intraocular pressure. Since there is a tendency for spontaneous remission, unnecessary treatment should be avoided 1).
Anti-inflammatory Drugs
Corticosteroid eye drops: 1% prednisolone acetate four times daily is standard. High-frequency administration is unnecessary because the level of inflammation is low.
Mydriatics: Usually unnecessary. This disease does not form posterior synechiae.
Intraocular Pressure-Lowering Drugs
Beta-blockers (e.g., timolol): First-line treatment 4).
Carbonic anhydrase inhibitors: Eye drops (e.g., dorzolamide) or oral (acetazolamide). Oral administration is used for a short period when intraocular pressure elevation is significant.
Alpha-2 agonists (brimonidine): Can be used in combination.
Drugs to Avoid
Pilocarpine: Should be avoided because it may worsen trabeculitis 4).
Prostaglandin preparations: Use with caution during active inflammation due to concerns about exacerbation of inflammation and induction of CMV anterior uveitis 4).
Control of inflammation and intraocular pressure is important. Treatment includes topical corticosteroids, beta-blockers, and carbonic anhydrase inhibitors (topical or oral). If high intraocular pressure persists and does not respond to medication, surgical treatment is performed. No treatment is needed during remission.
There is no need to continue topical steroids during remission 1). Since the course is often transient, long-term treatment is usually not required.
If CMV-DNA is detected in aqueous humor PCR, consider adding antiviral drugs.
The international Delphi survey (TITAN Report 2) reached the following consensus 4).
Topical steroids (1% prednisolone acetate, 4 times daily, 1–2 weeks) are used under antiviral coverage and tapered over up to 12 months according to clinical response 4). Systemic or periocular steroids should be avoided (88% agreement) 4).
A systematic review suggests a treatment regimen of 0.15% ganciclovir ophthalmic gel ≥5 times daily for ≥2 weeks for acute hypertensive CMV anterior uveitis 10).
Su et al. (2014) investigated the efficacy of topical ganciclovir treatment in CMV-positive PSS patients and reported clinical improvement 9).
Beta-blocker eye drops (e.g., timolol) are first-line, combined with carbonic anhydrase inhibitors (dorzolamide eye drops or oral acetazolamide). Corticosteroid eye drops (1% prednisolone acetate 4 times daily) are used to calm anterior chamber inflammation. Pilocarpine should be avoided as it may worsen trabeculitis. In most cases, intraocular pressure normalizes within a few days.
Surgery is indicated when intraocular pressure cannot be controlled with maximum medical therapy, or when signs of glaucomatous optic neuropathy or visual field changes appear. Surgical options include trabeculectomy (with antimetabolites) and tube shunt surgery 2). Laser trabeculoplasty is often ineffective 2).
Surgery is indicated when recurrent attacks cause glaucomatous visual field changes, or when intraocular pressure is inadequately controlled with medication.
The pathophysiology of PSS remains largely unknown. Two direct mechanisms for intraocular pressure elevation have been proposed.
Intraoperative specimens from PSS patients who underwent trabeculectomy showed mononuclear cells with long pseudopodia interposed in the trabecular meshwork, potentially physically obstructing aqueous outflow 3). Obstruction of the trabecular meshwork by inflammatory cells (trabeculitis) is considered the main mechanism of intraocular pressure elevation in PSS.
High concentrations of prostaglandin E2 (PGE2) are detected in the aqueous humor during attacks, and PGE2 levels show a positive correlation with intraocular pressure 3). It is thought that PGE2-induced increase in aqueous humor secretion from the ciliary epithelium, combined with increased outflow resistance, causes a rapid rise in intraocular pressure.
CMV can present as anterior uveitis in a form similar to PSS with acute ocular hypertension, or as a chronic form similar to Fuchs heterochromic iridocyclitis 4). It is presumed that viral activation in the anterior segment, or local immune responses such as macrophages against the virus, trigger inflammation of the iris and trabecular meshwork. Evidence of CMV involvement has been accumulating through quantitative PCR 8).
The prevalence of CMV anterior uveitis varies by region, with CMV accounting for up to 66% of viral anterior uveitis in some areas 11). Even in immunocompetent individuals, CMV can latently infect the anterior segment and cause inflammation upon reactivation 4).
Research is also progressing on the morphology and blood flow of the optic nerve head. Measurements using the Heidelberg Retina Tomograph (HRT) show that cup volume and area transiently increase during an attack, but measurements before and after the attack are comparable. Blood flow measurements sometimes show decreased optic nerve perfusion during an attack, particularly in the temporal and nasal sectors of the peripapillary region.
Schulte et al. (2023) reported a case of a 26-year-old female who developed NAION secondary to a PSS attack 5). It was presumed that a rapid increase in intraocular pressure (38 mmHg) led to decreased optic disc perfusion, causing ischemia, swelling, and infarction. A small cup-to-disc ratio (“disc at risk”) was identified as a risk factor. The use of prophylactic intraocular pressure-lowering medications in PSS has been suggested to reduce the incidence of NAION.
The Standardization of Uveitis Nomenclature (SUN) Working Group published classification criteria for CMV anterior uveitis in 2021, requiring positive aqueous humor PCR for research purposes. For clinical diagnostic criteria, a more sensitivity-focused approach is being considered 4).
In CMV-positive PSS patients, the efficacy of long-term maintenance antiviral therapy (up to 12 months) is being evaluated. According to the international consensus (TITAN Report 2), 88% of experts support the use of long-term maintenance antiviral therapy for patients with two or more recurrences per year 4). However, since ganciclovir is virostatic (suppresses viral replication but does not eliminate the virus), recurrence after discontinuation is a problem. The emergence of drug-resistant CMV strains is also a concern.
PSS has long been recognized as a “benign” disease, but recent long-term follow-up studies have reported that approximately one-quarter of patients with recurrent attacks develop glaucomatous optic neuropathy, and progressive corneal endothelial cell loss is also reported as a significant structural complication. Corneal endothelial damage may correlate with the number of attacks and disease duration. Periodic evaluation of corneal endothelial cell density by specular microscopy is increasingly recommended.
It has been pointed out that corneal endothelial damage may be more pronounced in CMV-positive cases, and coin lesion-type keratic precipitates in CMV anterior uveitis are associated with endothelial damage. In the TITAN Report 2 survey, 42.7% of experts responded that “if corneal edema persists, treatment should be continued even if intraocular inflammation and intraocular pressure have normalized,” and it has been noted that corneal endothelial decompensation can occur even after a single attack 4). Normalization of intraocular pressure (77%) and resolution of anterior chamber inflammation (96%) are the main criteria for treatment efficacy, but long-term monitoring of the corneal endothelium also plays an important role in prognosis management 4).
