Herpes Simplex Virus-Associated Anterior Uveitis: Clinical Characteristics, Diagnosis, and Current Aspects on Management

Abstract

Herpes simplex virus (HSV)-associated anterior uveitis accounts for 5–10% of patients with anterior uveitis and 3–10% of all uveitis patients, and is the most frequent etiology of infectious anterior uveitis. It is chiefly an acute unilateral iritis involving middle-aged individuals with preponderance in females. The clinical features of HSV anterior uveitis may mimic other non-infectious and infectious anterior uveitis entities, particularly at the early stage of the disease. Confirmed prior HSV infection and the presence of characteristic ocular findings such as keratitis, high intraocular pressure, and sectoral or patchy iris atrophy suggest the diagnosis and help to differentiate this condition from other etiologies of anterior uveitis. New diagnostic techniques, including evaluation of intraocular fluids applying polymerase chain reaction for viral DNA and the Goldmann–Witmer coefficient for antibodies against the virus can confirm the diagnosis in cases with no specific signs of HSV anterior uveitis. Oral antivirals and topical corticosteroids have become the main standards for treatment.

1. Introduction

The majority of acute iritis cases are either associated with HLA-B27 positivity or idiopathic. Herpes simplex virus (HSV) uveitis accounts for 5–10% of patients with anterior uveitis and 3–10% of all uveitis patients and is the most frequent etiology of infectious anterior uveitis [1]. This entity is an acute unilateral uveitis chiefly involving middle-aged immunocompetent individuals with preponderance in females. However, several bilateral HSV anterior uveitis cases have been described, often in immunocompromised patients [2].

HSV anterior uveitis can be easily diagnosed in the background of confirmed prior HSV ocular disease, typical herpetic dermatitis, dendritic keratitis, or iris atrophy, but these findings are often absent at first presentation [3]. In such situations, the diagnosis requires a high index of clinical suspicion and is based on clinical characteristics, including corneal opacity, decreased corneal sensation, and acutely increased intraocular pressure [3]. Other infectious agents of anterior uveitis including varicella zoster virus (VZV) and cytomegalovirus (CMV) can be associated with keratic precipitates (KPs), high intraocular pressure, and sectoral or patchy iris atrophy [4, 5]. Therefore, it is crucial to ask patients about previous diseases, general health, and the onset of the disease. In addition, they should be evaluated for non-infectious etiologies including sarcoidosis and HLA-B27 phenotype. Acute anterior uveitis caused by noninfectious etiologies tends to alternate between eyes. Recurrent episodes of anterior uveitis in the same eye should alert the ophthalmologist to consider herpetic etiology, even though most episodes of recurrent anterior uveitis confined to one eye are not caused by HSV in origin [3].

The gold standard diagnostic technique for HSV anterior uveitis is the detection of the viral genome or elevated concentrations of anti-viral antibodies in aqueous humor. However, these tests are not accessible to all ophthalmologists, and clinical diagnosis allows to start of appropriate treatment before the results of the molecular evaluation of aqueous humor are identified [6]. Oral antivirals and topical corticosteroids have become the main standards for treatment. In this chapter, we review the immunopathology, clinical findings, differential diagnoses, laboratory tests, and treatment modalities in HSV anterior uveitis. In addition, we describe the long-term prognosis and future directions for the management of the disease.

2. Immunopathology of HSV anterior uveitis

The majority of cases of ocular herpes infection are caused by HSV type 1 [7]. The primary infection which can be asymptomatic typically occurs during early childhood [7]. The virus establishes a ganglionic latency in the trigeminal nerve and lies dormant until triggered to proliferate, migrate down nerves, and establish recurrent infection in the area supplied by that nerve [7]. Despite the vast majority of the general population being latently infected with HSV type 1, only a few individuals develop anterior uveitis. Several factors influence the rate and type of ocular herpetic diseases, including age, genetic predisposition, immune status, virus strain, and route of infection [8, 9]. Both innate and adaptive immunity are essential to prevent HSV-1 reactivation [10]. Failure of this immune control results in the reactivation of the latent virus and may result in different ocular herpetic diseases such as anterior uveitis [7]. Left or right trigeminal ganglion is involved independently by latent HSV which explains the clinical observation that HSV anterior uveitis is usually unilateral [11, 12].

The pathogenesis of HSV anterior uveitis is believed to involve a cytopathic effect of the actively replicating pathogen on ocular tissue during the early phase and the host immune responses during the late phase of the disease [7]. The genetic makeup of patients, their immune status, and the characteristics of the virus determine the severity and outcome of the resulting uveitis. HSV causes an acute lytic infection which results in the release of different inflammatory chemokines and cytokines [7]. This innate immune response attracts immune cells, predominantly CD 8+ T cells. The aqueous humor of HSV anterior uveitis patients is typically devoid of neutrophils [7]. T cells secret more chemokines and cytokines, including interferon gamma and tumor necrosis factor alpha, and apply cytotoxicity toward the virus-infected cells which further exacerbates the inflammation [13]. High intraocular pressure encountered during the acute phase of HSV anterior uveitis is a local inflammatory response rather than the viral cytopathic effect on the trabecular meshwork. This hypothesis is confirmed by the beneficial effect of corticosteroid treatment on high intraocular pressure [5]. Chronic application of corticosteroid eye drops and trabecular meshwork damage owing to long-term and recurrent inflammation can result in a permanent elevation in intraocular pressure in a subset of affected individuals.

3. Clinical findings

Each episode of HSV anterior uveitis is characterized by decreased visual acuity, redness, pain, and photophobia. The episodes may last from several days to several months and tend to recur once per year, on average. Clinical findings include herpetic dermatoblepharitis (blisters), conjunctivitis, keratitis, iritis, and retinitis [5].

3.1 Corneal involvement

Corneal involvement which is present in 30–40% of patients with HSV anterior uveitis includes epithelial keratitis, disciform keratitis, active interstitial keratitis, endotheliitis, corneal edema, and old opacities (Figures 1–3) [5]. Dendritic keratitis is transient and generally presents less frequently during recurrent disease, especially at uveitis onset. Corneal edema can result from interstitial keratitis and endotheliitis but may also be secondary to episodes of increased intraocular pressure [5]. Many patients also have decreased corneal sensation [5].

Figure 1.

Diffuse slit-lamp photograph demonstrates epithelial keratitis in an eye with herpes simplex virus-associated anterior uveitis. The dendritic lesion has a branching pattern and terminal end bulbs.

Figure 2.

Diffuse slit-lamp photograph demonstrates herpes simplex virus disciform keratitis. The lesion is characterized by corneal stromal edema with folds in the Descemet membrane. There is no active infiltration in the corneal stroma.

Figure 3.

Corneal involvement in herpes simplex virus-associated anterior uveitis. Diffuse slit-lamp photograph demonstrates stromal infiltration and edema with small to medium size keratic precipitates under the area of active corneal involvement.

3.2 Anterior uveitis

The iritis can be nongranulomatous but is more frequently granulomatous with moderate size mutton fat KPs, usually in a triangular shape [4]. KPs can be situated inferiorly; however, they collect frequently under the area of active corneal involvement (Figure 3). Anterior chamber inflammation may vary from mild to severe and can be associated with hypopyon or hyphema.

3.3 High intraocular pressure

High intraocular pressure (>30 mmHg) is encountered in 46–90% of the cases; this highlights the importance of close observation of intraocular pressure in HSV anterior uveitis [4, 14, 15]. Elevated intraocular pressure usually rapidly decreases following the administration of topical corticosteroids and anti-glaucoma medication. However, a minority of these patients (18–31%) may progress to secondary glaucoma, necessitating long-term application of anti-glaucoma medication or a filtering procedure [4, 5, 14, 16, 17].

3.4 Iris abnormalities

Ischemic necrosis of the iris stroma leads to iris atrophy that is characterized by a well-defined defect involving iris stroma and pigment epithelium. Typical for HSV anterior uveitis is patchy or sectoral iris atrophy (Figure 4); however, diffuse iris atrophy may develop due to different pathological mechanisms such as inflammation [5, 14]. Iris atrophy is best seen on retroillumination and may distort the pupil. It is a very valuable sign for the diagnosis of HSV anterior uveitis [14]. This sign, however, is usually absent during the acute phase of the disease. Therefore, iris atrophy is only a helpful diagnostic criterion in chronic or recurrent forms of the disease [14]. Posterior synechiae are another iris abnormality which are seen in 50% of the affected patients [4].

Figure 4.

Sectoral iris atrophy in an eye with previous episodes of herpes simplex virus-associated anterior uveitis.

4. Differential diagnosis

The clinical presentations of HSV anterior uveitis can be seen in other infectious and non-infectious anterior uveitis cases particularly at the early stage [4, 5]. However, some subtle differences may be helpful in distinguishing anterior uveitis caused by HSV from other viral etiologies, including VZV and CMV, and non-infectious etiologies [18].

4.1 VZV anterior uveitis

Anterior uveitis caused by VZV occurs in older individuals (60 years) than HSV anterior uveitis (50 years), however, the age distributions overlap [5, 14, 18]. A history of ipsilateral zoster dermatitis is useful in the diagnosis of VZV-associated anterior uveitis, but dermatomal zoster is not always present [5]. Keratitis is less frequent in cases with VZV anterior uveitis (<3%) compared to cases with HSV anterior uveitis [5]. The pattern of dendritic epithelial lesions, when present, is helpful in differentiating HSV from VZV as the etiology of anterior uveitis. HSV dendrites demonstrate a branching pattern, with fluorescein staining in the ulcer base, rose bengal staining at the border, and terminal end bulbs (Figure 1). In contrast, VZV pseudodendrites are frequently broader, polymorphous, and slightly elevated, with few terminal dilatations, less regular branching, and no ulceration (Figure 5). Severe and diffuse reduction in corneal sensation favors the diagnosis of VZV uveitis, but corneal sensation can be profoundly decreased by HSV as well [5]. The intensity of anterior chamber reaction is higher in VZV than in HSV anterior uveitis, whereas fibrin formation in the anterior chamber has been reported less frequently in VZV (5%) than in HSV (13%) associated anterior uveitis [5]. The incidence of elevated intraocular pressure has been reported in 63% of cases with HSV anterior uveitis and 85% of cases with VZV anterior uveitis with a higher intraocular pressure level observed in VZV infection [5]. Sectoral or patchy iris atrophy and posterior iris synechiae are equally encountered in these two etiologies of anterior uveitis [5, 18].

Figure 5.

Diffuse slit-lamp photograph demonstrates a pseudodendrite in an eye with varicella zoster virus-associated anterior uveitis. The pseudodendrite is characterized by its broad, polymorphous, and slightly elevated appearance, with few terminal dilatations, less regular branching, and no ulceration.

4.2 CMV anterior uveitis

CMV has recently implicated in acute, recurrent, or chronic iritis in patients with the competent immune system. Several clues can differentiate this entity from HSV anterior uveitis. Endotheliitis is less common in CMV than HSV anterior uveitis, however, coin-shaped nodular KPs and reduced endothelial cell count reported in CMV anterior uveitis are not associated with HSV anterior uveitis [5]. Medium size KPs are more frequently seen in HSV anterior uveitis than CMV anterior uveitis which tends to have fine to small size KPs [4, 5]. Eyes with CMV anterior uveitis have no corneal opacities, and iris transillumination, when present, is patchy rather than sectoral as seen in HSV uveitis [5]. Moreover, anterior chamber reaction is less severe and fibrin formation has not been reported in CMV anterior uveitis [5]. Posterior iris synechiae is frequent in HSV uveitis but absent in CMV anterior uveitis, whereas peripheral anterior synechiae is more frequent in the latter [5]. Nodule formation at trabecular meshwork by gonioscopic examination is less frequently observed in CMV than in HSV anterior uveitis (6 vs. 13%, respectively) [5]. The incidence of elevated intraocular pressure has been reported in 78% of eyes with CMV anterior uveitis, and intractable glaucoma develops more frequently in CMV anterior uveitis compared to HSV uveitis [5, 19]. Finally, CMV should be considered in cases who are diagnosed with HSV anterior uveitis but fail to respond to acyclovir and corticosteroids.

4.3 Fuchs’ heterochromic iridocyclitis

It can be challenging to differentiate Fuchs’ heterochromic iridocyclitis from HSV anterior uveitis as both entities can demonstrate fine stellate KPs, high intraocular pressure, and iris atrophy. In Fuchs’ uveitis syndrome, however, KPs are fine, feathery, and diffuse, and diffuse stromal atrophy results in loss of the corrugated appearance of the iris. Moreover, transillumination defects are radial rather than patchy or sectoral. High intraocular pressure in Fuchs’ heterochromic iridocyclitis is unresponsive to topical corticosteroids and antiviral medication as it is caused by damage to the trabecular meshwork rather than a transient inflammation. In addition, posterior synechiae are not the feature. Other specific findings in Fuchs’ heterochromic iridocyclitis include heterochromia and small translucent nodules at the pupil border. Recently, some investigators have suggested that Fuchs’ uveitis syndrome may be caused by CMV and rubella virus.

4.4 Posner-Schlossman syndrome (glaucomatocyclitic crisis)

The Posner-Schlossman syndrome is characterized by fine and medium size KPs either in a linear or ring pattern, mild to moderate anterior chamber reaction, and an acute increase in intraocular pressure. Patchy or diffuse iris atrophy is common. It has been suggested that this syndrome may have an association with HSV infection; Van der Lelij et al. [14] found that approximately 20% of the cases with HSV anterior uveitis were initially diagnosed with Posner-Schlossman syndrome [14].

5. Laboratory test

The diagnosis of HSV anterior uveitis can be confirmed by analyzing aqueous humor for the virus genome and antibodies against virus antigens. Polymerase chain reaction (PCR) for viral DNA had a sensitivity and specificity of 91.3 and 98.8%, respectively [20]. A less commonly used technique is the Goldmann-Witmer coefficient (GWC), which measures the level of anti-herpes antibodies in aqueous humor. The GWC compares the ratio of antibodies directed against the virus in serum and aqueous humor with that of total immunoglobulin G in serum and aqueous humor; a ratio > 3 is considered positive. This test is less specific than PCR because anti-HSV antibodies can cross-react with antibodies directed against VZV [4, 14]. In addition, the results of the GWC may vary depending on the duration of the uveitis; the viral genome is readily detectable, and local antibody is absent at the onset of the disease, whereas the reverse result is more frequent when aqueous humor is sampled later [21]. Moreover, the GWC is more helpful when the patient’s immune system is normal, and false-negative result has been reported in severely immunocompromised patients [21, 22]. For these reasons, both PCR and GWC should preferably be performed simultaneously.

6. Treatment

Oral antivirals and topical corticosteroids have become the mainstays of treatment to reduce virus replication and T cell-mediated response against viral antigens, respectively. Other medications prescribed for the treatment of HSV anterior uveitis include cycloplegic and ocular antihypertensive agents [23].

6.1 Antiviral treatment

Several antiviral agents are currently available for the treatment of HSV anterior uveitis. Oral acyclovir, 400 mg five times a day, is reported to provide adequate concentrations in tears and aqueous humor, essentially eradicating the need for topical antiviral medication, even in eyes with active keratitis. Oral acyclovir can reduce the duration of HSV-induced inflammation as well as the chance of recurrent epithelial lesions with topical corticosteroids. Maintenance doses of oral acyclovir, 400 mg twice a day, when prescribed on a long-term basis (more than 6 months) have been demonstrated to reduce the recurrent episodes of HSV anterior uveitis.

Similar antiviral effects have been shown with oral valacyclovir, 1 g three times a day and famciclovir, 500 mg three times a day for 1 week, while providing the advantage of convenient dosing. Compared to oral acyclovir, oral valacyclovir, a pro-drug of acyclovir, is absorbed more efficiently and provides threefold to fourfold higher blood concentration. Valacyclovir should probably be avoided in patients infected by the human immunodeficiency virus as this drug can cause the thrombocytopenic purpura/hemolytic uremic syndrome in these cases [23].

The majority of topical antiviral agents do not reach therapeutic levels in the aqueous humor and can cause corneal epitheliopathy or allergic blepharoconjunctivitis in 5–10% of patients with long-term use [23]. The only exception is acyclovir ointment which is usually well tolerated, even with prolonged use, and has good ocular penetration providing adequate concentrations in aqueous humor. Therefore, acyclovir ointment 3% four times a day can be administered instead of oral acyclovir. Acyclovir ointment, however, may decrease visual acuity and does not prevent viral replication in trigeminal ganglia. For these reasons, the majority of ophthalmologist prescribe oral antivirals for HSV anterior uveitis cases [23].

6.2 Corticosteroids

Topical corticosteroids control anterior chamber inflammation and also acutely reduce intraocular pressure due to the control of inflammation in the trabecular meshwork. A typical treatment regimen is topical prednisolone acetate 1%, four to eight times a day. Systemic corticosteroids are administered in cases with HSV anterior uveitis and concomitant epithelial keratitis; topical corticosteroids are started after dendritic keratitis heals. Corticosteroids should be tapered off slowly after the control of inflammation because rapid withdrawal of the medication may result in a rebound effect. A low dose of topical corticosteroids should be used indefinitely in some patients to maintain long-term control of their inflammation [23].

6.3 Other medications

A topical cycloplegic agent is typically required to avoid posterior synechiae formation and diminish ocular pain and photophobia. Topical and oral anti-glaucoma agents are often required to control high intraocular pressure, especially during the acute phase of the disease. These ocular antihypertensive medications include topical alpha-adrenergic agonists, topical beta-blockers, and topical or oral carbonic anhydrase inhibitors. Latanoprost should probably be avoided as this drug may potentiate HSV reactivation [23].

7. Long-term outcomes

The visual prognosis of HSV anterior uveitis is favorable when diagnosed promptly and if managed correctly. When the infection involves other ocular structures, however, the potential for profound visual loss is enormous. The most serious visual complications of HSV include neurotrophic keratitis, progressive outer retinal necrosis syndrome, and acute retinal necrosis. It is advisable to perform a dilated retinal examination for every case with HSV anterior uveitis to exclude any posterior segment involvement. Long-term use of topical corticosteroids may result in serious complications, including cataracts and glaucoma [4].

8. Future direction

New methods of HSV detection have been introduced recently. Specific circulating microRNAs (miRNAs) can be identified for herpesviruses, without a need for invasive intraocular sampling [24]. In addition, miRNA expression profiles are capable of differentiating latent infection from the active stage of the disease [25]. Artificial intelligence can be part of the future of uveitis diagnosis and management; through combining all data, including clinical signs, ocular imaging, circulating miRNA, and molecular analysis of aqueous humor, machine learning can play an important role in the diagnosis and management algorithms of HSV uveitis.

Novel treatment strategies should target key parameters within the inflammatory pathway that control the initiation and resolution phase of HSV infection. The current therapeutic agents cannot eradicate HSV when it establishes a ganglionic latency in the trigeminal nerve. In theory, immunization against the virus should reduce the incidence of HSV-related eye diseases. Although several candidate HSV vaccines have been tested in humans, currently there are no licensed vaccines against either HSV type.

Treatment for HSV anterior uveitis often requires systemic antiviral agents despite being confined to the eye. This results in issues regarding compliance and systemic adverse reactions, especially in a group of cases that need maintenance treatment to prevent disease recurrence. Local drug delivery systems may be a complementing method to enhance patients’ compliance, safety profiles, and cost-effectiveness. Two important issues should be addressed in local therapeutics development, including new delivery systems for the release of drugs in the form of a slow-release insert and drug formulation that enables anti-viral activity without inducing ocular side effects.

9. Conclusion

HSV anterior uveitis usually occurs as a result of recurrent infection rather than primary infection. Viral replication and T cell-mediated response both play a role in the pathogenesis of HSV anterior uveitis, which is an acute, recurrent, and typically unilateral ocular inflammation. Each episode of recurrence is associated with blurred vision, ocular pain, photophobia, and redness. In the absence of active keratitis, the diagnosis of HSV anterior uveitis is based on clinical features, including recurrent episodes of inflammation in the same eye, high intraocular pressure during the inflammatory attacks, localized or diffuse granulomatous KPs, and patchy or sectoral iris atrophy. Confirmation of the diagnosis relies on molecular analyses of aqueous humor, but characteristic clinical findings and high index of suspicion are crucial for early diagnosis and management in routine practice. Oral antivirals and topical corticosteroids have become the main standards for treatment. The visual prognosis of HSV anterior uveitis is favorable when diagnosed promptly and if managed correctly. Long-term oral acyclovir treatment and close follow-up are essential to reduce the burden of the disease and its complications.

Conflict of interest

The authors declare no conflict of interest.