Cytomegalovirus anterior uveitis: how does it compare to the characteristics of other anterior uveitides to provide unique management opportunities

KEYWORDS:

• CMV
• anterior uveitis
• HLA-B27
• Fuchs uveitis Posner–Schlossman’s syndrome ganciclovir

1.

Anterior uveitis (AU) is the commonest type of uveitis [1,2]. Most cases (48–70%) are considered idiopathic. HLA-B27-associated spondyloarthritis is the most common systemic disease associated with adult AU. It was reported in 18–32% of patients with AU in Western countries and in 6–13% of patients with AU in Asia [3]. AU in children is also frequently associated with juvenile idiopathic arthritis. Several other causes of AU have been described in the literature including herpes family virus, syphilis, tuberculosis, sarcoidosis, tubulointerstitial nephritis and uveitis syndrome, and Adamantiades–Bechet’s disease (ABD) [4].

In terms of disease duration, AU has been divided into acute, recurrent, and chronic. A chronic course is defined as episode duration over 3 months or relapses within less than 3 months of treatment cessation [5].

Chronic AU has been linked to an increased risk for loss of vision from serious complications such as glaucoma, cataract, band keratopathy, cystoid macular edema, and phthisis bulbi [4]. Prompt identification of possible infectious causes or systemic associations may prevent complications and loss of vision and can positively affect the overall visual prognosis and the patient’s quality of life [6].

For example, in patients with juvenile idiopathic arthritis (JIA)-associated chronic AU, the use of immunosuppression reduces the risk of vision loss by ~ 40% [7] and an early identification of herpetic AU may significantly reduce the risk of glaucoma and cataract formation [8].

1. Clinical characteristics of CMV AU

Cytomegalovirus (CMV) has long been considered a cause of morbidity and mortality in immunocompromised patients, causing posterior uveitis with necrotizing retinitis, but has relatively recently been recognized as a cause of AU in immunocompetent adults [9]. Today, CMV AU is considered the commonest type of CMV-related uveitis.

CMV anterior uveitis is typically unilateral and may appear with two distinct clinical profiles: Most commonly may present as a recurrent hypertensive uveitis similar to Posner–Schlossman’s syndrome [10] or as a chronic uveitis that occasionally resembles Fuchs uveitis. This profile is more frequent in patients of European origin [11,12].

In CMV AU, young to middle-aged males are affected the most. Uveitis is typically associated with high intraocular pressure (IOP) at its active phase, along with a mild anterior chamber (AC) reaction. Few fine medium-sized keratic precipitates (KPs) located in middle or paracentral cornea are present [13], while posterior synechiae are typically absent. Unilateral diffuse iris atrophy and heterochromia may be present, which is why it occasionally resembles Fuchs uveitis. Corneal endotheliitis, a feature of herpetic keratouveitis, may more commonly be observed in CMV than the other herpesviruses [13].

Recently, the Standardization of Uveitis Nomenclature working group considered positive polymerase chain reaction (PCR) for CMV on aqueous specimen as a necessary criterion for the diagnosis of CMV uveitis and consequently the institution of specific treatment [14]. It has been suggested that early antiviral interventions reduce the risk of complications such as cataract formation, corneal decompensation, and glaucoma [11]. However, AC paracentesis is a costly procedure and unavailable in many settings. Therefore, a strong suspicion of diagnosis based on clinical characteristics is warranted in order for this intervention to be performed early in the disease course. Certain points from ocular history and clinical examination should raise suspicion of CMV iritis that will lead to AC paracentesis.

2. How CMV AU compares to the other AUs

CMV AU may easily be differentiated from HLA-B27-associated AU. Apart from the systemic manifestations of ankylosing spondylitis, patients with HLA-B27 are usually younger and will usually present with a recurrent unilateral, bilateral, or alternating non-granulomatous anterior uveitis. In HLA-B27 AU, a fibrinous AC reaction with a profound increase in AC flare may be present, synechiae may occur, and in severe cases hypopyon may form. The cornea is not affected. Spillover of AC cells to the anterior vitreous may be seen. Occasionally, cystoid macular edema and papillitis may occur [3,15]. No such changes are typically present in CMV AU.

CMV AU also has different characteristics from herpes simplex virus (HSV) AU and varicella-zoster virus (VZV) AU, which belong in the same family and may also cause recurrent AU with iris atrophy and increased IOP. HSV and VZV AUs were shown to have similar clinical features consisted in pain, ciliary hyperemia, and a more severe AC inflammation than in CMV AU. HSV and VSV AU are characterized by the presence mutton-fat KPs with diffuse distribution and posterior synechiae, in contrast to the CMV AU, which is characterized by focally distributed fine non-granulomatous KPs or ring-shaped KPs and the absence of posterior synechiae. ‘Pigmented KPs are observed significantly more often in VZV AU’ [16,17]. Moreover, patients with CMV AU very frequently develop corneal endotheliitis and reduction in endothelial cell count [16,18].

Acute and recurrent AU is a common ocular presentation in ABD. There is no marked inflammation of the ciliary body and the eye is relatively white, while AC reaction may be moderate to severe. Non-granulomatous, non-fibrinous AC inflammation typically occurs and hypopyon may form (typically named as ‘cold’ hypopyon). A dilated fundus examination may reveal small areas or retinitis [19].

In the context of chronic AU, CMV AU differs from granulomatous AU such as sarcoidosis or tuberculosis as it is always unilateral and there are no posterior synechiae. Sarcoidosis AU represents more than half of the sarcoid uveitis cases, affecting usually females in their early 50s [20].

It is usually bilateral and chronic, with granulomatous KPs following the distribution of Arlts triangle. Koeppe and Busacca iris nodules may be present. Posterior synechiae are commonly seen and gonioscopy may reveal anterior synechiae as well [20].

Syphilitic AU is a chronic uveitis, often associated with increased intraocular pressure as CMV AU. Eye involvement is usually unilateral but it can also be bilateral. Inflammation may be either granulomatous or non-granulomatous [21]. Based on the above, there are no specific features typical for syphilitic AU except iris roseolae. They are relatively specific for syphilis but are infrequently seen. They consist of vascular tufts in the middle third of the iris surface and are identified on slit-lamp biomicroscopy.

Finally, in cases of Fuchs phenotype, the presence of abnormal vessels in the anterior chamber angle and vitritis point toward rubella AU. Conversely, intraocular pressure greater than 26 mmHg was more commonly encountered in CMV AU than in rubella AU and large keratic precipitates characterize CMV-associated AU [12].

3. Management of CMV anterior uveitis

Ganciclovir (GCV) is the antiviral of choice for CMV AU. Topical GCV and oral valganciclovir (VGCV) are the mainstay of antiviral therapy for CMV AU in immunocompetent hosts.

It has been suggested that early initiation of antivirals reduce complication rates and improve visual prognosis. Reports show a lower incidence of glaucoma by reducing the long-term inflammatory damage to trabecular meshwork [11]. However, there has been no unanimity in the literature regarding the route of administration, dosage, and duration of treatment. ‘A recent survey of uveitis experts indicated that the majority of experts will commence with a topical antiviral, with ganciclovir gel 0.15% being the most preferred treatment choice’ [22]. According to a recent meta-analysis, combination of systemic VGCV and topical application of GCV achieved marginally better success in terms of inflammation resolution, but offered no greater benefit in terms of preventing recurrence when compared to topical therapy alone [13]. Oral VGCV should be used with caution as it has been linked to severe adverse effects, including hematological disturbance creatinine/electrolyte imbalance, elevated liver enzymes, and even stroke [23]. Most patients will experience recurrences and therefore long-term treatment (up to 1 year) was recommended for patients with chronic course inflammation and those with at least two episodes of CMV AU within 1 year [22].

4. Conclusion

CMV AU is a rare AU with distinct features. It carries the risk of loss of vision due to glaucoma and requires specific management strategies. Early detection and prompt intervention are keys in preventing long-term consequences of the disease. The markedly raised intraocular pressure along with the low grade of inflammation, the presence of diffuse iris atrophy, and location and morphology of KPs may provide useful clues for the differential diagnosis. Aqueous PCR should be performed to confirm the diagnosis. Early treatment with oral VGCV and/or topical GCV should be used in order to prevent complications.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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Additional information

Funding

This paper was not funded.