Clinical Characterization of Refractory Virus-Related Inflammation Inside Aqueous Outflow Pathways in Chinese Immunocompetent Patients
Posner-Schlossmann syndrome (PSS), also known as glaucomatocyclitic crisis, is a condition characterized by acute, unilateral, recurrent attacks of ocular hypertension, mild non-granulomatous anterior uveitis (AU), and spontaneous recovery. Despite its well-documented clinical features, the etiology of PSS remains unclear. Various mechanisms have been proposed, including viral infection, autoimmune responses, autonomic dysregulation, allergic conditions, and vascular endothelial dysfunction. Traditional treatment involves the use of topical anti-hypertensive and anti-inflammatory medications. However, repeated attacks can lead to long-term glaucomatous optic nerve damage over 5–10 years following the initial episode. The incomplete understanding of the pathophysiology of PSS has made the treatment and prevention of recurrences particularly challenging.
While PSS is generally considered a self-limiting disease, refractory cases have been observed at the Zhongshan Ophthalmic Center. These cases, characterized by multiple recurrences despite treatment with anti-inflammatory and anti-hypertensive medications, often develop progressive aqueous outflow dysfunction. Some patients require lifelong use of intraocular pressure (IOP)-lowering medications, while others necessitate filtration surgery to control IOP. The authors hypothesized that these refractory cases represent a distinct clinical entity with unique features and pathophysiology, differing from classic PSS. This study aimed to investigate this potential new clinical entity, referred to as “refractive PSS,” and to characterize its clinical features and treatment outcomes.
The study was conducted in two phases. The first phase involved a systematic review of medical records of 21 patients who underwent filtration surgery (trabeculectomy, Ex-PRESS implant surgery, or Ahmed tube implant surgery) due to uncontrolled IOP despite maximal anti-hypertensive medications. These patients did not respond to classic steroid treatment, suggesting that autoimmune inflammation was not the primary underlying pathology. The clinical features, disease course, and poor response to traditional treatment led the authors to propose a diagnosis of refractive viral infection within the trabecular meshwork (TM) and uveal scleral outflow pathway.
The common clinical features observed in these 21 patients included: (1) a prolonged disease course lasting at least one month or frequent relapses; (2) increasing refractoriness of inflammation and IOP to corticosteroids and IOP-lowering medications; and (3) the presence of one or more additional traits, such as non-mutton fat keratic precipitates (KPs), corneal endothelial cell lesions or loss, or iris atrophy/heterochromia. Based on these findings, the authors hypothesized that these patients exhibited refractory virus-related inflammation within the aqueous outflow pathways and should be treated with systemic anti-viral medications.
To evaluate this hypothesis, the authors conducted a retrospective study of a second group of 17 patients (18 eyes) treated between April 2016 and July 2017. The inclusion criteria for this group were: (1) a primary diagnosis of PSS revised to refractory virus-related inflammation inside aqueous outflow pathways; (2) a disease course prolonged for at least one month or at least three recurrences per six months or five recurrences per year; (3) increasing refractoriness of inflammation and IOP to corticosteroids and IOP-lowering medications; (4) the presence of one or more additional traits, including non-mutton fat KPs, corneal endothelial cell lesions or loss, or iris atrophy/heterochromia; and (5) resolution of the disease course without relapse after receiving oral ganciclovir in combination with anti-hypertensive and anti-inflammatory medications. Exclusion criteria included immunodeficient patients and those with systemic diseases such as diabetes or other eye diseases such as Harada syndrome, Behcet disease, eye trauma, or tumor.
The second group consisted of six females and 11 males with a mean age of 40.4±14.2 years (range: 24–75 years). The mean follow-up time was 10.8 months. All 17 patients experienced multiple acute IOP elevations prior to referral. In nine eyes, the mean presenting IOP was 32.4±12.8 mmHg (range: 22.7–68.0 mmHg), with high IOP (greater than 21.0 mmHg) despite maximal IOP-lowering and corticosteroid medications. KPs were observed in all patients, ranging from + to ++. Most KPs were round, thin, white, and non-mutton fat, with some exhibiting pseudopods or space gaps. Stellate KPs were also detected. KPs were predominantly located in the inferior cornea, with gonioscopic KPs occasionally observed. The ocular angle was open in all patients, with no neovascular membrane or inflammation detected. Anterior ocular inflammation was mild to moderate in all cases. Severe corneal endothelial cell lesions were observed in four eyes, leading to corneal edema. Endothelial cell morphology was distorted, with blurred cell margins. Iris atrophy was noted in six eyes, with heterochromia observed in two eyes. Cataract was detected in four eyes, but no patient underwent cataract surgery during the follow-up period. No posterior iris synechiae were detected in any patient.
Systemic anti-viral treatment was administered to all 17 patients in addition to IOP-lowering and anti-inflammatory medications. Oral ganciclovir was prescribed at a dosage of one gram three times daily for the first two to three weeks to control corneal endothelial cell lesions. The dosage was then tapered to 0.5 grams twice daily and maintained for at least three months. At the last follow-up, all patients had fully recovered without relapse.
The study highlighted the importance of distinguishing classic PSS from refractory virus-related inflammation inside the aqueous outflow pathways. The authors proposed that the pathogenesis of refractory cases involves chronic viral infection within the aqueous outflow pathways. In the initial 21 patients reviewed in the first group, the pathology likely involved trabecular cell damage progressing from cell edema and inflammatory debris blockage to trabecular cell death, cirrhosis, scarring, and complete loss of trabecular aqueous outflow function. Traditional anti-inflammatory treatment is beneficial only when trabecular damage is at the reversible edematous stage. If the viral infection is self-limiting, traditional treatment leads to complete recovery. However, in refractory cases, the outcome often results in complete loss of trabecular cells. Therefore, early identification and treatment of these patients during the reversible stage is crucial.
Corneal endothelial cells are also commonly affected by viral infection. Untreated viral endothelitis can lead to endothelial cell morphological changes and eventual endothelial decompensation. In the first group of 21 refractory PSS cases, two patients developed corneal endothelial decompensation requiring penetrating keratoplasty (PKP) surgery. Unfortunately, corneal edema recurred following transplantation, likely due to persistent viral infection. Aqueous humor paracentesis with PCR analysis confirmed the diagnosis of viral infection in these two patients. Systemic anti-viral treatment resolved the corneal edema without recurrence.
The mean age of the second group was 40.4±14.2 years, slightly older than the typical onset age of classic PSS. The authors noted that immunological inflammation is less common in patients over 50 years old, and a viral etiology should be considered in this subset. Older patients are also more prone to viral infections. A recent history of a cold was frequently reported in older PSS patients with self-limited or refractory disease. Close follow-up is advised for older patients, and refractory viral infections should be considered if the pathology persists for more than one month or if recurrences occur.
KPs were observed in all patients in the second group, ranging from + to ++. Most KPs were round and white, located in the inferior cornea. Pigmented KPs were observed in one patient with a disease course lasting over seven years. Stellate KPs were found in one patient. Cytomegalovirus (CMV)-positive patients exhibited small, round, white KPs with pseudopods, while herpes simplex virus (HSV)-positive patients had larger KPs. Classic mutton-fat KPs were uncommon in refractory virus-related cases, as viral infection primarily involves lymphocyte and monocyte infiltration, resulting in smaller KPs with pseudopods or space gaps. However, slightly larger mutton-like KPs were occasionally observed in patients with a long, protracted disease course, likely due to chronic inflammation and immune response.
Iris atrophy was observed in six out of 18 eyes in the second group. The authors suggested that viral infection infiltrates the iris, leading to ischemic necrosis of the iris stroma. Previous studies have identified CMV in the smooth muscle cells of the iris. The patients in this study exhibited diffuse, sectoral, or patchy iris atrophy patterns. Virus infection can also cause depigmentation of the iris, with heterochromia observed in two eyes. No posterior ocular segment involvement was detected in any of the cases, consistent with previous PSS-related studies.
In conclusion, clinicians should differentiate classic PSS from refractory virus-related inflammation inside the aqueous outflow pathways. For the 17 refractory patients reviewed in the second group, early administration of oral ganciclovir in addition to traditional ocular treatment resulted in complete recovery without recurrence. This outcome contrasted sharply with the poor outcomes observed in the 21 refractory cases in the first group, who required filtration surgery due to sustained uncontrolled IOP. This substantial difference in clinical outcomes supported the authors’ hypothesis that refractory virus-related inflammation of the aqueous outflow pathways represents a distinct clinical entity. The authors recommended diagnosing this condition based on specific clinical signs rather than laboratory results, given the technological challenges of virus pathogen testing in many Chinese ophthalmic practices. Future research should focus on developing a powerful eye-specific platform for aqueous humor analysis at the microliter level and conducting corresponding basic and animal experiments to further support this hypothesis.
doi.org/10.1097/CM9.0000000000000034
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