Continuing Education Activity

Posner-Schlossman syndrome (PSS), also known as glaucomatocyclitic crisis, is a rare cause of inflammatory ocular hypertension. Once thought to be benign, PSS is now known to be associated with significant ocular morbidity and loss of vision. The condition is characterized by recurrent episodes of uniocular rise in intraocular pressure (IOP) that are out of proportion with minimal intraocular inflammation. Cytomegalovirus infection of the anterior chamber may also be associated with this disease, which can lead to visual field loss and glaucomatous optic neuropathy. To avoid irreversible functional and morphological visual loss, PSS must be promptly diagnosed and treated.

This activity reviews the clinical presentation of PSS, characterized by sudden eye pain, redness, blurred vision, and halos around lights, typically affecting one eye at a time, as well as the interplay of cytomegalovirus infection with PSS and its association with ocular morbidity. The diagnostic approach to PSS is also covered, utilizing comprehensive eye examinations, IOP measurements, and specific tests like gonioscopy to confirm PSS and exclude other glaucomas. Moreover, this course discussion addresses PSS management strategies during acute episodes, focusing on IOP control and inflammation minimization through topical, systemic medications, laser therapy, or surgical interventions. The importance of continuous monitoring and follow-up care for preserving eye health in individuals affected by PSS is reviewed, as well as the role of the interprofessional team in evaluating and treating this condition and the need for further research to enhance diagnostic tools, understand underlying causes, and develop more specialized treatments.

Objectives:

• Assess the etiology of Posner-Schlossman syndrome (PSS).

• Evaluate the pathophysiology and histopathology of PSS.

• Apply the common physical exam and investigation findings associated with PSS.

• Implement interprofessional team strategies for improving diagnosis, management, care coordination, and communication for patients with PSS.

Introduction

In 1948, Posner and Schlossman published a series of 9 case reports of patients with the characteristic presentation of unique glaucoma, with open anterior angles of the anterior chamber, associated with unilateral acute elevations in intraocular pressure (IOP).[1][2] This combination of symptoms later became known as Posner-Schlossman syndrome (PSS), a rare disease also called the glaucomatocyclitic crisis.[3] 

PSS is a unilateral ocular disease characterized by recurrent episodes of acute nongranulomatous anterior uveitis and increased intraocular pressure (IOP).[3][4] This unique eye ailment manifests as a recurrent syndrome involving periodic rises in IOP. It differs from other glaucomas because it frequently involves mild-to-moderate anterior chamber inflammation; therefore, PSS is classified as inflammatory glaucoma.

These episodes of IOP can eventually result in secondary chronic glaucoma.[5] Initial attacks may go undetected because of the mild nature of the uveitis. PSS can be misdiagnosed as an acute angle-closure glaucoma (ACG) episode early in the disease because of the acute marked elevation in IOP and unnoticed inflammatory reaction in the anterior chamber.[6] 

During acute episodes, patients with PSS frequently report abrupt and intense eye pain, redness, blurred vision, and halos around lights. Between bouts, some people may also experience slight discomfort or a gritty sensation in their eyes. The majority of the time, these symptoms affect only one eye at a time.

The exact prevalence of PSS is unclear. Although it can affect anyone of any age or gender, PSS mainly affects people between the ages of 20 and 50. It can be difficult to correctly quantify the syndrome's true incidence because of its sporadic nature.

A thorough eye examination, which is primarily clinical, is necessary for diagnosing PSS. Ophthalmologists will measure the patient's IOP, look for inflammation in the anterior chamber, and rule out other possible causes of glaucoma. Diagnostic procedures like gonioscopy and imaging may be carried out to assess the angle of the eye's drainage system and rule out other types of glaucoma.

The outlook for PSS over the long term is usually positive. If the illness is treated quickly, vision loss is uncommon, and increased IOP episodes typically go away on their own or without medical intervention. Repeated episodes of elevated IOP, however, have the potential to harm the optic nerve and cause permanent vision loss if they are not well managed.[7] People with PSS must get continual monitoring and follow-up care to ensure their eye health is preserved.

The clinical course of the disease tends to exhibit a variable pattern. Patients can have frequent attacks with shorter symptom-free intervals or less frequent attacks with more prolonged symptom-free intervals; in between episodes, patients tend to have a normal IOP. In either case, the symptoms are self-limiting, with spontaneous resolution occurring within days or weeks, even without treatment.[3][8] 

Management during an episode is aimed at controlling the IOP and minimizing intraocular inflammation.[3] The main objective of PSS therapy is to control the acute increase in IOP and inflammation that occurs during episodes.[9] Topical and systemic drugs, like oral glaucoma medications and anti-inflammatory eye drops, are frequently used as part of treatment.[10] IOP management may occasionally require more intrusive techniques, such as laser therapy or surgery.[11][12]

Even though PSS is a well-known illness, further research is needed to grasp its underlying causes and risk factors fully. Prospects could involve the creation of more specialized treatments and enhanced diagnostic equipment to help with the early identification and treatment of PSS. Researching the genetic [13] and immunological causes [14][13] of the disease may also provide potential preventative measures.[15]

This review aims to summarize information on the diagnosis and treatment of PSS.

Etiology

Though the exact cause of PSS is debatable, different etiologies have been proposed, including autoimmune and allergy (as proposed by Theodore and Kraupa, who described this entity before Posner and Schlossman).[16][17] There is mention in previous literature, dating back to about 1935, of similar clinical signs to PSS in patients with "glaucoma allergicum."[16] Posner and Schlossman proposed autonomic dysregulation as the mechanism of the disease, whereas Skolic, Raitta, and Vannas proposed vascular and developmental abnormalities.[18][19] 

The infectious theory appears to have gained widespread acceptance because of well-documented evidence. The more likely infectious theory of PSS etiology implicates cytomegalovirus (CMV), varicella-zoster virus (VZV), and herpes simplex virus (HSV).[20][21] Another possible cause is Helicobacter pylori.[22]

The most robust evidence for a causal association between PSS and CMV is the report by some researchers on the successful treatment of PSS using antiviral agents targeting CMV. Bloch-Michel et al first proposed CMV as the infective agent, and other researchers have corroborated this finding.[23] The evidence for this is the detection of CMV antibodies and CMV DNA in the aqueous humor using a polymerase chain reaction (PCR). The CMV DNA has been detected in the aqueous humor during periods of acute flares of PSS and weeks after an attack.[21]  

It has been reported that anterior uveitic patients who respond suboptimally to conventional topical steroid therapy have a higher probability of having a viral infection.[24][25] In a study, 67% of anterior uveitis patients who underwent aqueous sampling tested positive for CMV, HSV, VSV, or rubella.[24] It was also observed that patients with elevated IOP were more likely to test positive for CMV (75%).[26] Furthermore, oral ganciclovir and valganciclovir targeting the infecting virus have been effectively used.[27] Intravitreal ganciclovir has also been used with a favorable response, confirming the viral etiology of PSS. Most of these patients experienced a relapse after cessation of antiviral therapy.[25][28]

Epidemiology

Males are more at risk of developing PSS. In one study, females were reported to have a greater incidence of PSS (56.6%); however, most studies have shown a male predilection.[29][30] PSS has been reported in a 13-year-old, but it is a disease of adulthood.[31] Most patients are diagnosed within the age range of 20 to 50 years.[32][33] However, affected age groups from various studies show significant regional variation. For instance, a European study reported that the incidence of PSS was highest in the 20- to 29-year age group.[34] Reports from Asia suggest a later onset (ie, the third to the fifth decade).[21][35]Studies have reported a mean age of diagnosis that ranges from 32.6 to 58.9 years.[2][36][37]

Rates of PSS in Japan and Singapore have been documented to be within 1.7% to 4.3% of all uveitis diagnoses.[2][38][39] According to a Japanese study, the rate of glaucoma varies from 6.5% to 11.4% of all uveitic glaucoma.[40] Another study on PSS from Finland reported an incidence of 0.4 and a prevalence of 1.9 in 100,000 people.[34] A hospital-based study from Wenzhou, China, reported a 10-year cumulative incidence of 39.5 in 100,000 people and a mean annual incidence of 3.91 in 100,000 people. This study reported a male predominance and an age range of 20 to 59 years to be most affected. The same study reported a significantly higher rate of new cases in spring, suggesting a possible seasonal variation of PSS.[41]

Pathophysiology

The pathophysiology of PSS remains unclear. Some authors have suggested a possible abnormal vascular process in which patients with PSS were reported to have significantly lower endothelium-dependent flow-mediated vasodilation levels compared to controls.[29] Vascular endothelium cell dysfunction is a known risk factor for primary open-angle glaucoma (POAG) and normal tension glaucoma.[42]

The episodic increased IOP in these patients during acute phases could be due to the impairment of aqueous outflow from inflammation in the anterior segment, particularly of the trabecular meshwork. Prostaglandins, most likely prostaglandin E, could mediate this proinflammatory process, which has been reported to be higher in aqueous humor during acute phases of elevated IOP in patients with PSS.[43]

Studies have reported altered cytokine profiles in the aqueous of patients with PSS, which include higher levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF), and vascular endothelium growth factors (VEGF).[40] Elevated IOP in acute phases can give rise to temporarily reduced blood flow to the optic nerve head and retina, which tends to return to normal without leaving permanent damage in most cases.[44] 

PSS appears to fall into the spectrum of acute uveitic conditions with possible involvement of the trabecular meshwork. With CMV infection of the anterior chamber, possible mechanisms of elevated IOP include:

• Trabeculitis, which gives rise to an edematous and thick trabecular meshwork
• Trabecular outflow obstruction by chronic inflammatory cells and pigments
• Eventual peripheral anterior synechiae (PAS) with evolution to secondary angle closure [2] 

Around 26% to 52% of PSS patients may show the presence of CMV DNA in the aqueous humor.[24][36][45] The location of the initial infection is unknown. Possible locations include the iris, trabecular meshwork, and corneal endothelial cells. Genetics, vascular endothelial dysfunction, and aqueous humor cytokine profile may also contribute to the pathophysiology of PSS.[29] Furthermore, human leukocyte antigen (HLA) polymorphism is associated with PSS in the Chinese population.[46] Polymorphism of both classical and nonclassical HLA types has been observed with PSS.[46][47] 

Hirose, Ohno, and Matsuda noted the presence of HLA-Bw54 in 9 (41%) of 22 Japanese patients with PSS.[48] This association with HLA suggests a genetic basis for PSS. However, the contribution of HLA to the entire PSS spectrum is unknown.

Histopathology

Mononuclear cells having long pseudopods have been identified in the trabecular meshwork using electron microscopy.[49] These mononuclear cells were seen in the intraoperative specimen of PSS patients who underwent trabeculectomy due to uncontrolled IOP. The significance and origin of these mononuclear cells are unknown, but they may increase resistance to aqueous outflow.

History and Physical

The history given by the patient may vary from being asymptomatic to having unilateral ocular pain or discomfort and dimness of vision. If symptomatic, recurrent episodes may be experienced. Haloes that may be seen around a light reflect the presence of corneal epithelial edema, which can be associated with a severe increase in IOP. It is typical for the patient to have repeated episodes in the same eye, but bilateral presentations have also been reported.[50] The frequency of episodes could vary considerably. Some patients have more frequent episodes within a month, whereas others have fewer episodes (eg,1 to 2 attacks within a year). In between attacks, the patient is symptom-free.

An ocular examination is critical to making the diagnosis of PSS. Findings during an attack vary considerably. In some cases, vision may be normal, whereas extremely poor vision when counting fingers or light perception may be the presentation if IOP significantly increases with corneal epithelial edema. During an attack, the IOP will be elevated to as high as 40 mmHg or above.[51] Goldmann applanation tonometry is the preferred method for measuring IOP.[52] A gonioscopy should be done and will show an open angle. However, Liu et al reported a series of case reports of patients with narrow or closed angles diagnosed as PSS. This clinical scenario may be more commonly observed in patients of Asian descent.[53] 

PAS are not seen in PSS despite the intraocular inflammation. There are reports of angle abnormalities such as anteriorly displaced Schwalbe's line and prominent iris process.[54][55] PSS has been reported in a 20-year-old patient with Axenfeld anomaly.[56] However, these are not taken as typical findings in PSS or as diagnostic criteria.

Evidence of intraocular inflammation usually appears after the IOP has been elevated for days to weeks. If examined using a slit-lamp biomicroscope, one will notice an anterior chamber reaction with fine, nongranulomatous keratic precipitates (KPs). In cases with CMV infection, there could be associated endotheliitis, which is seen as a coin-like opacities appreciated on the cornea.[25] This area of endotheliitis consists of circumferential KPs with stromal edema.[49] This clinical presentation is highly predictive of aqueous humor infection with CMV,[10] which can be confirmed by PCR testing of aqueous humor tap.[25] Features suggesting a diagnosis of PSS include a history of recurrent acute attacks, high IOP with disproportionately few anterior chamber cells, and 1 or 2 sentinel keratic precipitates over the inferior endothelium.

Recent studies have shown that corneal endothelium cell density (ECD) can be reduced in patients with PSS.[57] Risk factors of reduced ECD include a longer disease duration, elevated aqueous levels of IL-10, a higher degree of retinal nerve fiber layer thinning and glaucomatous damage, and elevated levels of cytomegalovirus DNA in the anterior segment. 

Optic disc findings are significant in PSS. In several cases, the optic disc appears normal during an acute attack. Also, the optic disc may show decreased perfusion during the episode of elevated intraocular pressure.[58][59] Over an extended period and with the protracted rise in IOP, permanent glaucomatous damage may occur. In some cases, open-angle glaucoma eventually ensues. Another clinical sign observed after recurrent or prolonged episodes of PSS is iris atrophy.[19][45] Posterior synechiae are, however, not a clinical feature of PSS. A uveitic cataract may occur after prolonged intraocular inflammation.

Evaluation

An essential investigation in characterizing PSS is PCR analysis of aqueous humor tap to assess viral DNA.[35][60] The common viruses assessed are CMV, HSV, and VZV.[49][61] Also, laboratory serum titers for the same viruses can be checked. Confirmation of the presence of the virus may play a vital role in treatment planning.

It is essential to perform central visual field testing (Humphrey visual field, 24-2 or 30-2) to assess a glaucomatous pattern of visual field loss suggestive of optic nerve damage. Also, stereoscopic optic disc photography is helpful for glaucoma assessment and monitoring. The finding of progressive optic disc cupping and disc hemorrhage after an acute attack of severely elevated IOP may suggest permanent damage to the optic disc.

Iris angiography during an acute episode may demonstrate areas of segmental iris ischemia, vascular congestion, and leakage.[19] Scanning laser Doppler flowmetry of the optic nerve also demonstrates decreased optic nerve perfusion during an acute attack.[59]

Optical coherence tomography (OCT) and OCT angiography (OCTA) of the optic disc provide useful information about optic nerve structure, retinal nerve fiber layer, and peripapillary vessel density. A decrease in these parameters may suggest permanent glaucomatous damage.[62] 

Consider the OCT image taken from a 45-year-old male patient diagnosed with left eye PSS (see Image. OCT Evaluation). His clinical presentation was characterized by recurrent episodes of left eye anterior uveitis (iritis), elevated IOP, and open anterior chamber angle. His vision was normal in both eyes, and he was asymptomatic between attacks. This OCT was obtained 9 years after presentation.

The image shows a significant loss of ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL) in the left eye. There is evidence of progression to glaucomatous damage, characterized by optic nerve cupping of the left eye. The optic nerve is normal in the right eye.

A second OCT image examines the change analysis in the same patient over the 9-year follow-up period (see Image. Change Analysis). It reveals a rate of GCC loss of -0.97 µm per year and RNFL of -1.14 µm per year, both having significant P values. He has been managed with topical steroid and nonsteroid medications (Nepafenac) during periods of acute inflammatory flair and maintained on topical hypotensive to manage ocular hypertension.

In eyes with PSS associated with endothelins, the anterior segment OCT of the cornea  depicts an irregular and highly reflective endothelial cell layer.[63] Additionally, confocal scanning microscopy of the cornea endothelial layer shows large endothelial cells containing nuclei with a high reflection area and surrounded by a halo of low reflection, like the eye of an owl.[64] These "owl eye" cells are deemed to be CMV-infected corneal endothelial cells with an intranuclear inclusion body.[65]

Treatment / Management

Treatment of PSS is aimed at reducing IOP intraocular inflammation. Recently, therapy using antiviral treatment has been used to target the infecting virus. Treatment goals for PSS can be achieved using medical and surgical methods.

Medical Therapy

First-line treatment for reduction of IOP during acute attacks includes topical beta-blockers, alpha agonists, and carbonic anhydrase inhibitors, which are commonly used in the management of glaucoma.[66] These classes of topical medications or a combination of drugs can be used with a good response. In some cases, systemic medications such as oral carbonic anhydrase inhibitors are warranted to control the acute rise in IOP. It is best to avoid topical prostaglandin analogs because of the risk of exacerbating inflammation.[67] If the IOP is reduced to normal, topical ocular hypotensives could be withdrawn between attacks, especially if the patient is at low risk of developing glaucomatous optic neuropathy (GON) or other ocular complications. Topical pilocarpine should be discouraged as this is thought to exacerbate trabeculitis.[68]

Intraocular inflammation, often mild, can be controlled using topical steroids such as prednisolone or dexamethasone. Topical fluorometholone has also been used with good effect to control low-level intraocular inflammation. Cortisone topical therapy can be applied four times a day if needed, then quickly tapered. Topical and oral nonsteroidal anti-inflammatory drugs (NSAIDs) can suppress inflammation. Possible steroid-induced glaucoma can be avoided by using NSAIDs, which can also have a desirable antiprostaglandin effect since an aqueous prostaglandin level increase has been associated with attacks.[69]

Patient follow-ups should be conducted daily to monitor IOP during an acute episode and ensure the lowering of IOP to a safe level. Less frequent visits (weekly or monthly as appropriate) can be adopted when steroid and ocular hypotensive are tapered. Instructions to consult with an ophthalmologist as soon as an attack is noted should be given. When treatment is initiated, documentation of baseline optic nerve parameters (as noted previously) is required in the absence of apparently significant corneal edema. Topical ocular hypotensives and steroids should be commenced appropriately and tapered if the response is favorable. If the response to maximum therapy is unfavorable (ie, the patient shows no signs of improvement) or if multiple recurrences occur, a search should be done for the presence of anterior chamber CMV infection using an aqueous tap. Treatment with an antiviral agent should be considered if evidence of CMV DNA is found.

There is evidence of benefit for treating CMV infection of the anterior chamber.[61][70] Treatment of this CMV infection has been shown to improve PSS control. Valganciclovir and ganciclovir have been used for the treatment of CMV infection. Different formulations and combinations have been researched, and good effects have been reported. Also, various routes of administration of antiviral agents have been studied, including topical, oral, and intravitreal routes for treating hypotensive uveitis.

A combination of topical and oral ganciclovir has been used in previous research. The use of topical ganciclovir has resulted in the resolution of inflammation with cessation of topical steroids and reduction in pressure-lowering drops in several cases. However, this treatment did not completely stop the recurrence of future episodes.[61][71] Different concentrations of topical ganciclovir have been used (2% and 0.15%). The 2% preparation of ganciclovir appears to be associated with a higher concentration of the drug in the anterior chamber. It results in less recurrence, less endothelial cell loss, and better control of IOP.[33][70]Topical ganciclovir has been used as a 2% gel with good effect.[70] The 0.15% ganciclovir gel, which had more recurrence in an earlier study, showed a good effect but with a longer duration of use in a more recent study.[72]

Although oral valganiclovir was found to be superior to ganciclovir gel in terms of failure rate, the recurrence rate was significantly higher: 80% compared with 57%.[71] Oral valganciclovir has been administered at an oral loading dose of 900 mg twice daily for at least 2 weeks, followed by an additional 450 mg valganciclovir twice-daily maintenance therapy.[73] In this study, a good treatment effect was noted at this dose.[73] However, recurrence occurred after valganciclovir was stopped. Recurrence following cessation of valganciclovir has been reported to be high. This high recurrence rate can be attributed to valganciclovir being virostatic instead of virucidal. Also, the eye's immune privilege prevents the total eradication of the CMV infection.[71] 

In a reasonable number of patients, long-term valganciclovir treatment has resulted in long-term disease control when dosed as indicated above. Intravitreal injection of ganciclovir 2.0 mg in 0.05 cc, with or without oral antiviral, has also been studied.[74] Though intravitreal valganciclovir given at a dose of 2 mg/0.05 mL has been shown to reduce aqueous CMV to undetected levels, the rationale for intravitreal injections in an infection limited to the anterior chamber has been questioned. Further, oral valganciclovir can achieve similar aqueous CMV reduction, albeit with a risk of leukopenia.[75] Therefore, white cell count should be monitored in those patients on oral valganciclovir.[25][28]

Surgical Therapy

If medical treatment is unsuccessful, surgery is used to lower IOP in patients with PSS.[76] Surgery may also be needed for the management of corneal endothelial insufficiency.[76] A surgical technique that has been used for IOP control is trabeculectomy.[77] However, due to preoperative conjunctival inflammation, with mobilization of fibroblasts and macrophages, there is an increased tendency for conjunctival scarring and consequent failure of the conjunctival filtering bleb.[78] 

A practical technique to manage IOP is the augmentation of the trabeculectomy with antimetabolite, such as mitomycin C (MMC). Trabeculectomy with MMC reduces IOP spikes and improves inflammation and PSS.[79][80] One explanation for this postoperative improvement in inflammation is the draining out of the aqueous chamber inflammatory cells through the filtering bleb, reducing anterior chamber activity and trabeculitis.[2]

Other IOP-lowering surgical techniques used in PSS include trabectome surgery, trabeculectomy, canaloplasty, and Ahmed glaucoma drainage device insertion.[12][81][12][82] If cataracts form, cataract surgery is required.[83] As a general theme, preoperative control of inflammation is essential before any surgical procedure is undertaken.

As in postuveitic corneal endothelial insufficiency, penetrating keratoplasty (PK) or Descemet's stripping automated endothelial keratoplasty (DSAEK) can be employed to treat a similar complication in PSS. Also, after corneal surgery in PSS eyes, graft failure rates will mirror the situation in postuveitic cornea grafts (50%), which is higher than other causes of corneal endothelial insufficiency (13%).[84]

Differential Diagnosis

It is essential to recognize the differential diagnoses of PSS since this can affect the therapy and prognosis. The most familiar differential diagnoses include commoner glaucomas:[85]

• Acute and chronic ACG [86][87]
• Ocular hypertension [88]
• POAG [89]
• Uveitic glaucoma [90]
• Fuchs heterochromic iridocyclitis [91]
• Herpetic iridocyclitis [92]
• Other viral uveitis [93][94]  

Efforts must be made to differentiate PSS from other common causes of increased IOP. ACG ranks high on the list because of the acuteness of symptoms, unilateral nature, a marked rise in IOP, and the presence of ocular inflammation.[95] Per a case report of misdiagnosing PSS as ACG, peripheral iridectomy was performed.[6] However, ACG can be differentiated from PSS by the following features: narrow or closed angles, a more severe painful red eye, fixed dilated pupil, nausea and vomiting, and PAS. In chronic ACG, the occurrence of PAS will be a distinguishing factor.[96]

Patients with POAG tend to be older; there may be a known family history of the condition, and acute signs of intraocular inflammation are absent.[97] Pigmentary glaucoma and pseudoexfoliation glaucoma can give rise to IOP peaks; however, the clinical presentation of these types of open-angle glaucoma includes key diagnostic signs and symptoms. Pigmentary glaucoma usually presents with iris transillumination defects, pigmentation of the trabecular meshwork, and pigment deposits of the corneal endothelium (Krukenberg spindle).[98][99] Pseudoexfoliation glaucoma is normally diagnosed in the presence of white, flaky material on the lens anterior surface and around the iris pupillary border, in addition to a loss of iris pigment that can give rise to iris transillumination defects.[100]

The uveitic glaucomas are an essential group of conditions that are similar to PSS. In uveitic glaucoma, the intraocular inflammation is often more fulminant.[101] Fuchs heterochromic iridocyclitis can be differentiated from PSS by the presence of iris heterochromia (which occurs late in the course of the disease), fine abnormal anterior chamber angle vessels, fine diffuse keratic precipitates, and posterior subcapsular cataracts.[102] Uveitic glaucoma can be viral in etiology, such as herpetic iridocyclitis due to HSV and VZV. The following features may be observed to differentiate uveitic glaucoma from PSS: sectorial or diffuse iris atrophy, more severe anterior chamber reaction, and less markedly elevated IOP versus that seen in PSS.

Sectorial iris atrophy suggests HSV or VZV; vesicular rash and dendritic ulcers may also suggest HSV. In the clinical setting of high IOP and uveitis, other possible causes of ocular inflammation should be considered, including HLA B27 uveitis, sarcoidosis, HSV, Vogt Koyanagi Harada (VKH) disease, and human T lymphotropic virus type 1.[103] The finding of a severely elevated IOP out of proportion with mild iridocyclitis, absence of PAS, and posterior synechiae should raise suspicion of PSS.

If the diagnosis is in doubt, performing aqueous humor sampling and qualitative PCR analysis may become necessary.[104] More than one virus can coexist in a patient.[105] There have been reports of concurrent occurrences of CMV-positive PSS in one eye and HSV-positive keratouveitis in the other.

Additional differentiating signs of HSV include keratitis with corneal stromal opacities and edema resulting in scarring, neovascularization, and hypoaesthesia. VZV manifests with maculopapular rash and vesicles, which may occur at the tip, side, or root of the nose and sometimes on the forehead.[106] This presence of rashes at the tip of the nose is known as the "Hutchinson's sign" and is a strong predictor of intraocular involvement by VZV. It is also seen in immunodeficiency states.

Pertinent Studies and Ongoing Trials

A study used enhanced-depth imaging OCT (EDI-OCT) to measure the macular choroidal thickness (CT) in PSS eyes during acute episodes and compared this measurement with the CT when PSS was in remission, as well as with the fellow eyes and controls.[107] This study reported a significantly thinner mean CT in affected eyes in acute attacks compared with fellow eyes. The mean CT was significantly thicker in healthy normal than the affected eye during an acute attack and similar to the contralateral unaffected eye. Also, mean CT was significantly increased in the affected eye in remission compared with during an acute attack.

Prognosis

Over the years, several patients have been noted to progress to significant optic nerve damage with changes in the visual field and ganglion cell loss. The total duration of elevated IOP is responsible for this damage to the optic nerve, which assumes typical characteristics of a glaucomatous optic nerve head and is assumed to be secondary glaucoma. This association with GON has been explored extensively.[108]

In one study, as much as 45% of patients presented with concomitant GON at the initial visit.[5] Because flares of inflammation occur with mild symptoms, patients are unaware of the significant protracted rise in IOP and consequent damage to the optic nerve. For this reason, in eyes with evidence of significant OCT RNFL damage, it is rational to continue using topical ocular hypotensives between acute attacks.[2] 

This category of patients should be treated prophylactically. In one study, up to 26.5% of PSS patients developed GON. Factors that could predict progression to GON have been researched. Among those factors examined, the total duration of disease was predictive of glaucoma progression, but the age of onset and number of attacks were not.[79]

A recent meta-analysis based on 19 studies with a total of 1173 PSS eyes showed a pooled incidence of GON in 20% of eyes.[109] The risk factors reported in these cohorts of patients included older age, longer disease duration, and the presence of the condition in both eyes. Gender and IOP during acute phases were not shown to be significantly associated with GON development. Although IOP peaks in PSS patients tend to be transient, GON could be favored in the presence of numerous recurrent acute IOP peaks, high levels of inflammation, long-lasting elevated IOP, trabecular function impairment, and long-term use of steroids.[110] 

Complications

PSS was once considered to be a benign disease; however, it can result in significant ocular complications. One of these complications is progression to GON. Patients at risk of developing subsequent optic nerve damage, such as patients with a large cup-to-disc ratio, RNFL damage, and focal thinning of the neuroretinal rim, should be treated prophylactically with topical hypotensives. If IOP remains uncontrolled with evidence of progressive optic nerve damage, they can proceed to filtration surgery.[2][111]

PSS can also cause nonarteritic anterior ischemic optic neuropathy (NAION) and optic atrophy.[112][113][114] Eyes diagnosed with PSS with risk factors for NAION and ischemic optic atrophy (eg, a small cup-to-disc ratio) should also receive topical hypotensives prophylactically.

Corneal complications can occur in PSS patients. Reduced endothelial cell count has been demonstrated in eyes with CMV-associated PSS.[2] Corneal endothelial insufficiency ensues with significant endothelial cell loss following recurrent disease. Additionally, persistent elevation in IOP results in cornea epithelial edema and predisposes to corneal endothelial cell loss.[115] Endotheliitis is another finding in CMV-associated PSS.[116] Endotheliitis is a clinical presentation of CMV infection of the anterior chamber in the immunocompetent patient.[117] Other complications of PSS include iris atrophy and cataracts.[45]

Deterrence and Patient Education

A high index of suspicion is required to make a prompt diagnosis of PSS. The finding of a unilateral markedly elevated IOP out of proportion with the level of intraocular inflammation with an open anterior chamber angle should raise the suspicion of PSS. Patient education is critical to prevent long periods of elevated IOP during attacks, which can result in earlier complications if not treated.

Patients should be informed of the recurrent nature of the disease and advised to seek ophthalmologic consultation if symptoms of relapse (eg,  mild ocular discomfort, pain, or blurry vision) occur between periods of remission. Because some acute episodes may go unnoticed due to the mild nature of the uveitis, clinic appointments should be kept, and delays should be avoided in seeing PSS patients, especially those at risk of developing complications such as GON, NAION, and ischemic optic atrophy. Prophylactic treatment should be discussed with at-risk patients, and escalation to surgical treatment should be provided if needed.

Enhancing Healthcare Team Outcomes

PSS can result in significant ocular hypertension. With recurrent episodes of elevated IOP over a protracted period, significant permanent optic nerve damage occurs. Other complications of this disease have been described. Patients suffering from PSS may be misdiagnosed. In some cases, they may not seek treatment because of the absence of distressing symptoms. Early identification and management of patients with PSS are imperative in reducing irreversible visual loss.

The optometrist, often the primary eye care provider, could be the first member of the healthcare team to see patients with PSS and should be aware of the diagnosis. The optometrist should appropriately refer to the ophthalmologist to control IOP and intraocular inflammation. During disease-free intervals, the optometrist may monitor patients, with IOP being a regularly monitored parameter.

Patients with PSS require careful monitoring to detect optic nerve damage, and imaging of the optic nerve and other ancillary investigations may need to be performed by the ophthalmic technician. Cases of frequent recurrence and inflammation not responsive to topical steroids require aqueous biopsy and PCR analysis to screen for CMV and other viral DNA. Performing this essential investigation will require the help of a laboratory scientist. Since PSS can result in known complications, the services of different ophthalmic subspecialists, such as uveitis, glaucoma, cataract, and cornea specialists, will be necessary.

This team must collaborate effectively to improve outcomes for patients with PSS. Medication compliance is also essential to control IOP and inflammation. The pharmacist should emphasize to patients this need for compliance at the point of dispensing medications. Patients should also be counseled on the appropriate technique for using topical medications by the pharmacist and ophthalmic nurse and informed of the consequences of not using eye drops.

Healthcare professionals involved in the care of these patients should possess the essential clinical skills and knowledge to diagnose and manage PSS. The care of patients with PSS necessitates a collaborative approach among healthcare professionals to ensure patient-centered care and to improve overall management and outcomes. Care coordination plays a pivotal role in ensuring that a patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient outcomes.

Considering that some PSS patients have more frequent acute attacks than others, this group of patients will require closer monitoring. Eye drops for such patients may be tapered off slowly, and communication on when to schedule follow-up appointments should be unambiguous. Providers should ensure that PSS patients can be seen between appointments if they experience an attack before the next appointment. A strategic approach involving evidence-based strategies to optimize treatment plans and minimize adverse effects is equally crucial. Optimum patient outcomes occur when ophthalmic healthcare professionals and pharmacists work together to provide continual support and education to patients with PSS.