Glaucomatocyclitic Crisis (Posner-Schlossman Syndrome)
Posner-Schlossman Syndrome (PSS), also known as glaucomatocyclitic crisis, is a disease typified by acute, unilateral, recurrent attacks of elevated intraocular pressure (IOP) accompanied by mild anterior chamber inflammation. The pathophysiology is still unknown, although there are several theories proposed, ranging from autoimmune to infectious. Treatment management is focused on controlling the intraocular pressure and decreasing inflammation. While an attack usually resolves without sequelae, repeated attacks over time may lead to long-term glaucomatous damage (a secondary glaucoma).
Posner and Schlossman first reported a series of 9 cases and coined the term “glaucomatocyclitic crisis” in 1948. These patients suffered from recurrent unilateral attacks of ocular hypertension that shared the following characteristics:
- Mild discomfort or blurring of vision
- Increased IOP with open angles
- Mild anterior chamber reaction or fine white keratic precipitates (KP)
- Crises lasting from several hours to weeks
- Normal IOP and no signs of uveitis between attacks
- Normal visual fields and optic discs
PSS typically affects adults between the age of 20-50 years, although a case of an affected 13-year-old has been reported. The only study looking at population statistics came out of Finland, which found an incidence of 0.4 and prevalence of 1.9/100,000.
The exact pathophysiology of PSS is still unknown. However, one case of a patient with PSS who underwent trabeculectomy for uncontrolled IOP on medical therapy demonstrated presence of mononuclear cells in the trabecular meshwork of an intra-operative specimen. On electron microscopy, mononuclear cells were seen intercalated in the trabecular meshwork with long pseudopods, possibly impeding the outflow of aqueous (see Figure 1). The origin of these mononuclear cells is still unknown.
Figure 1: (a) Electron microscopy of trabecular meshwork in a PSS patient; (b) higher magnification view.
See Possible Etiologies for further discussion.
Patients usually present with unilateral blurred vision and mild eye discomfort or pain. There are rare cases reported of a bilateral presentation. In some cases, the patient may not experience any pain. Blurred vision or halos are usually associated with a mild corneal edema caused by elevated IOP. Patients may also endorse a history of prior episodes of blurred vision and eye discomfort that may be suggestive of prior attacks; these episodes may be months to years apart and last from several hours to weeks. The course is variable: some patients may only experience 1 or 2 episodes in their lifetime, whereas some have many recurrences. In general, the frequency of attacks decreases with increasing age. There is usually no inciting event or precursor to attacks.
On exam, the vision can vary from 20/20 to hand motion or light perception depending on the amount of corneal epithelial edema, although the amount of edema is usually mild. The pupil is often slightly dilated or sluggish. The conjunctiva is usually white and quiet, although a mild ciliary flush may be present. There may be small-to-medium, discrete, round, white keratic precipitates on the endothelium, usually in an inferior distribution (see Figure 2). The KPs usually resolve on their own or with anti-inflammatory treatment. The anterior chamber is deep with a mild iritis without significant cell or flare. In the past, iris atrophy or heterochromia has been noted in some cases, but it is not currently considered a characteristic finding for PSS.
Figure 2: Small, white, discrete keratic precipitates.
The IOP is often markedly elevated, usually 40-50 mmHg. It is important to note that the IOP is elevated out of proportion to the amount of anterior chamber inflammation. With prolonged elevation, significant corneal epithelial edema may develop. IOP elevation may last from several hours to weeks and may precede or follow the anterior chamber reaction.
An important criteria for diagnosis is an open angle on gonioscopy. Peripheral anterior synechiae are generally not present despite the presence of anterior chamber inflammation. Early case series have noted the presence of angle abnormalities such as an anteriorly displaced Schwalbe’s line, prominent iris processes, or a fine membrane covering the trabecular meshwork, but these are not considered typical diagnostic features.
The optic nerve can demonstrate glaucomatous cupping during an acute attack, as well as decreased perfusion due to the acute rise in IOP; however, many patients also present with normal nerves in an active episode. Cupping may reverse after an attack. In some cases of repeated attacks over a long period of time, glaucomatous cupping may fail to reverse thus indicating some degree of permanent damage to the optic nerve.
Iris angiograms performed during acute attacks demonstrate segmental iris ischemia, vascular congestion and vessel leakage. Interestingly in one case series, iris angiograms performed during the “prodromal phase” when IOP was not elevated also demonstrated focal iris ischemia.
Figure 3: Iris angiogram demonstrating focal iris ischemia during an attack.
Optic nerve topography and flowmetry demonstrate transient differences in morphology and blood flow during attacks compared to before/after attacks. Cup volume and area measured by Heidelberg Retinal Tomography increase during an attack, but pre- and post-attack measurements are comparable. Flowmetry may also demonstrate decreased optic nerve perfusion during an attack, particularly at the peripapillary temporal and nasal sectors, as well as at the level of the neuroretinal rim.
Visual fields performed during an attack may demonstrate non-specific changes, but in general, they remain normal following an attack. In patients whom repeated attacks occur, permanent glaucomatous optic nerve damage with accompanying visual field changes may occur and may be an indication for surgical intervention.
Figure 4: (a) initial visual field change; (b) visual field progression 2 years later.
If there is a strong suspicion for a uveitic glaucoma due to viral etiology, laboratory testing for HSV, VZV or CMV titers may be ordered. Viral PCR studies for the same viruses may also be performed on an aqueous tap sample.
Primary open-angle glaucoma (POAG): Up to a 45% concomitance between PSS and POAG has been reported. Kass et al. described a case series of 11 PSS patients, some of whom demonstrated persistent elevated IOP in the affected eye between episodes, as well as fellow eyes with an elevated IOP. Five patients demonstrated typical glaucomatous visual field loss, and four developed glaucoma optic nerve change on follow-up.
It has also been suggested, however, that persistent IOP elevation during frequent, recurrent attacks may lead to the same changes.
Non-arteritic ischemic optic neuropathy (NAION): 2 cases of NAION associated with PSS have been reported in the literature. Both patients had a history of hypertension, and one had a “crowded disc” optic nerve morphology. The presumed mechanism is decreased optic disc perfusion due to an acute rise in IOP. Some have suggested that use of prophylactic IOP-lowering drops may decrease the chance of an NAION in these patients, however rare it may be.
|Acute Angle Closure Glaucoma||Narrow/closed angles on gonioscopy|
Significant pain and red eye
May have significant PAS
Mature cataract if pupillary block
|Chronic Angle Closure Glaucoma||Significant PAS on gonioscopy|
|Primary Open Angle Glaucoma||Persistently elevated IOP without resolution|
Lack of anterior chamber inflammation
Family history of POAG
Glaucomatous-appearing optic nerves
|Ocular Hypertension||Persistently elevated IOP without resolution|
Lack of anterior chamber inflammation
|Uveitic Glaucoma||Often chronic or more fulminant anterior chamber inflammation|
|Herpetic Iridocyclitis (HSV, VZV)||IOP may not be significantly elevated|
Sectoral/diffuse iris atrophy
Stellate KPs, diffuse distribution
More robust anterior chamber reaction
|Fuchs Heterochromic Iridocyclitis||Iris heterochromia, diffuse atrophy|
Fine abnormal angle vessels on gonioscopy
Posterior subcapsular cataract
Initial treatment is directed towards controlling intraocular pressure and decreasing inflammation. Typical first-line therapeutics include topical beta-blockers such as timolol, alpha-agonists such as brimonidine, and carbonic anhydrase inhibitors such as dorzolamide. Apraclonidine has also been advocated as a first-line agent. Prostaglandin analogs may also be used for IOP control although there is a theoretical risk of exacerbating inflammation. Oral carbonic anhydrase inhibitors are sometimes used acutely to lower the IOP quickly.
For control of inflammation a topical steroid drop is the usually used, such as prednisolone acetate 1% QID, given the typically low level of inflammation. Topical NSAIDs may also be used. Oral NSAIDS such as indomethacin may also be used to avoid a possible steroid-induced glaucoma and for their anti-prostaglandin properties, as elevated prostaglandin levels in the aqueous have been associated with attacks.
Miotics and mydriatic agents are rarely used. In particular, pilocarpine should be avoided as this is thought to exacerbate a possible trabeculitis.
In cases where the IOP cannot be controlled using maximal medical therapy, surgical therapy may be considered, especially when signs of glaucomatous optic nerve damage or visual field changes appear. One case series reported 8 patients with PSS who underwent trabeculectomy with mitomycin-C for uncontrolled IOPs and visual field defects. At the end of follow-up, all patients did not require IOP-lowering drops, and although a recurrence of iritis was noted in 2 patients, the IOP remained stable during the episodes. Filtering surgery is thought to help not only in aqueous outflow, but also by increasing the egress of inflammatory cells.
Patients should be followed daily until their IOP comes down to an acceptable level, then weekly as anti-glaucoma drops and topical steroids are tapered. Well-educated and informed patients may also be able to self-treat with drops if they notice signs and symptoms of an impending or active attack, but should also be instructed to follow up immediately with an ophthalmologist.
Posner-Schlossman Syndrome has long thought to be a “benign” disease; most patients are treated for attacks and recover without long-term sequelae. However, a number of patients with repeated attacks, even if treated, may show long term glaucomatous changes in the optic nerve and on visual field testing  essentially becoming a secondary glaucoma. It is thought that it is the total duration of elevated IOP, not the frequency of attacks, that contributes to the damage. These patients may be candidates for surgical therapy as discussed earlier.
A number of theories have been proposed as causative and/or contributory factors to PSS. Some are no longer considered accurate, but much work remains in elucidating the causative factor.
Posner and Schlossman first postulated that glaucomatocyclitic crisis was a result of autonomic dysregulation; they noted that 4 patients in their original 1948 case series also had a history of migraines. In 1977, Raita and Vannas performed iris angiograms on a series of PSS patients and found that not only was there focal iris ischemia during attacks, but during the prodromal, normotensive, phase, ischemia was also present.
In early case series of PSS patients, associations with allergic conditions have been noted. The term “glaucoma allergicum” was first coined by Kraupa in 1935 when he described 4 cases of recurrent unilateral inflammation and glaucoma. In Posner and Schlossman’s original case series, 2 patients had hay fever, 2 had asthma, and 2 had concurrent urticaria on the same side of the face as the glaucoma, although the authors made a point that their findings did not corroborate or disprove Kraupa’s theory. Subsequent case series also noted pre- or co-existing allergic conditions in patients and one reported case where the frequency and severity of attacks decrease with “injections” for ragweed and grass allergies. In general, allergy is not currently considered a leading theory.
Variation of developmental glaucoma
Another theory that has fallen by the wayside is that PSS is a variant of developmental glaucoma. In early case series in the 1950s/60s, this theory was based on the observation of bilateral angle abnormalities on gonioscopy during attacks. Features such as abnormal iris processes, anteriorized Schwalbe’s line, and a “grey membrane” covering the trabecular meshwork have been described. It is now generally agreed that the angle morphology is normal, without obvious abnormalities, and this theory has not been given much credence.
Vascular endothelial dysfunction
Similar to the theory of autonomic dysregulation, vascular endothelial dysfunction has also been proposed. This has been supported by evidence suggesting ciliary vascular abnormalities, such as focal iris ischemia and leakage from iris/ciliary blood vessels on angiogram during attacks. This is also based on the fact that other studies have shown abnormal flow-mediated vasodilation in other types of glaucoma. A recent case series of 12 PSS patients by Shen et al. demonstrated significant peripheral vascular endothelial dysfunction compared to an age-matched control group. This underlying vascular endothelial abnormality may explain the propensity for glaucomatous optic nerve damage in the long run. While more work is currently being done in this area, possible future treatments, if this theory holds true, may seek to address endothelial dysfunction with cardiovascular therapies such aspirin, etc.
Prostaglandins are thought to play a role in glaucomatocyclitic crises. The mechanism of IOP elevation has been thought to be due to a decrease in outflow facility as well as an increase in aqueous production . In animal models, prostaglandins can achieve both effects, the former by breakdown of the blood-aqueous barrier, allowing inflammatory cells into the anterior chamber and thus leading to clogging of the trabecular meshwork. Furthermore, elevated prostaglandin levels, particularly PGE2, have been found in the aqueous during attacks and levels positively correlate with IOP. The same study also demonstrated an IOP-lowering effect with indomethacin treatment, a prostaglandin inhibitor.
One study of a Japanese cohort of 22 PSS patients found that 41% had HLA-Bw54 haplotype vs. 8% of controls. HLA-Bw54 has also been implicated in Voyt-Koyanagi-Harada syndrome and while it may not necessarily a causative gene, it may be linked through linkage dysequilibrium to a causative gene or indicate an underlying susceptibility to the syndrome. Interestingly, in this same study, HLA-Bw52 was found in 21% of controls, whereas none of the PSS cohort demonstrated HLA-Bw52 positivity, suggesting a protective effect of the haplotype.
An association between H. pylori antibodies and anterior uveitis has been proposed in the past. The two diseases also affect a similar age distribution. Knox first noted an association between PSS and peptic ulcer disease (PUD) in a case series of 32 patients, where 38% of females and 68% of males also had PUD vs. a normal incidence of 5% and 10-20%, respectively. A prospective study also confirmed an association between the presence of anti-H. pylori serum IgG and PSS. It has been suggested that there may be some cross-reactivity or -antigenicity between intestinal mucosa and the contents of the anterior chamber or trabecular meshwork that may predispose PUD patients to PSS.
Both HSV and VZV have been proposed in the past as possible infectious culprits underlying PSS. VZV was the first infectious agent proposed in 1985, with one study demonstrating an association between the level of varicella immunity and frequency of PSS attacks. However, subsequent case series have failed to demonstrate this association in other tests, such as VZV PCR. One case series demonstrated HSV PCR positivity in aqueous samples collected during attacks, but subsequent case series have failed to replicate these findings. Furthermore, acyclovir has been found to be ineffective in treating or preventing PSS.
Several studies have been published examining the possible role of CMV in PSS. Studies have found active CMV-antibody production occurring in a significant number of PSS patients, and small case series/reports have suggested an association. Larger-scale studies in Singaporean cohorts have supported an association between CMV and PSS, and there have been some reports of response to and questionable prophylactic benefit of anti-viral therapy specific to CMV such as cidofovir, foscarnet and valganciclovir. It remains to be seen whether the response or prophylaxis achieved by these antivirals represents a true treatment response or the normal history of PSS, which by definition is self-resolving.
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