Review for Disease of the Year: Treatment of Viral
Anterior Uveitis: A Perspective
Souska Zandi, MD1, Bahram Bodaghi, MD, PhD2, and Justus G. Garweg, MD1,3
1Clinic for Vitreoretinal Diseases, Swiss Eye Institute and Berner Augenklinik am Lindenhofspital, Bern, Switzerland, 2DHU ViewRestore, UPMC, Sorbonne Universities, APHP, Paris, France, and 3University of Bern, Bern, Switzerland
ABSTRACT
Purpose: To define a clinically tailored therapeutic strategy for the treatment of viral anterior uveitis (VAU). Methods: A PubMed search spanning the past 5 years was conducted using the MesH-terms “viral anterior uveitis” and “therapy.”
Results: The herpes simplex virus (HSV), the varicella zoster virus (VZV), and the cytomegalovirus (CMV) are the predominant pathogens in VAU. Other viruses, including rubella, chikungunya, and zika, have been linked with distinct forms of the disease. Depending on the causative agent and the host immunocompetence, the mainstay treatment for suspected VAU is a combination of topical or systemic antivirals and topical corticosteroids, supplemented with cycloplegics and intraocular-pressure-lowering medication.
Conclusions: Oral acyclovir, valacyclovir, and famciclovir are the mainstay of treatment for HSV- and VZV- induced infections. Brivudin serves as an alternative in insufficiently responsive cases. CMV-induced infections respond well to valganciclovir. A 3- to 12-month course of prophylactic treatment against recurrences is worth considering.
Keywords: Acyclovir, antivirals, treatment, valacyclovir, viral anterior uveitis
BACKGROUND
Anterior uveitis (AU) is the most common form of intraocular inflammation. If infectious, the broad dif- ferential diagnosis includes viral, bacterial, and fungal agencies. viral anterior uveitis (VAU) probably accounts for more than 10% of all cases of AU and is the most common form of the infectious disease. An early identification of the causative agent is the key to targeted therapy and to the prevention of secondary organ damage.
In the differential diagnosis of VAU, members of the herpes virus family (Herpesviridae), notably the herpes simplex virus (HSV) types 1 and 2, and the varicella zoster virus (VZV), have been most fre- quently reported as the causative agents.1,2 In immu- nocompetent individuals, the cytomegalovirus (CMV) figures prominently.3–7 Recently, this virus has been linked with the Posner–Schlossman and the Fuchs’ uveitis (FUS) syndromes8, which, heretofore, had been considered as rubella-induced pathologies.9–11 A relevant role in VAU of emerging viruses, such as chikungunya, zika, and the human parechovirus, has not been definitively established.
In adults, common clinical characteristics of the dif- ferent forms of VAU include a typically unilateral affection with either an acute or a recurrent course (HSV, VZV, and CMV), which may culminate in loss of vision due to secondary organ damage.15,16 CMV- and rubella-associated AU that present as either FUS or herpetic keratouveitis generally follow a chronic course, especially in younger patients.17,18 In cases of VAU-associated intraocular infl ammation, typical granulomatous precipitates may be observed on the corneal endothelium (Figure 1(a)) with uveovascular barrier disturbances of variable degrees; hypopyon is but a rare occurrence. The AU that is induced by a member of the herpes family is associated with an acute rise in intraocular pressure (IOP) and with char- acteristic sector iris hemorrhage (Figure 1(b)), which is followed by sector iris atrophy (Figure 1(c)).19–22 In cases of CNV- or rubella-induced VAU, iridal stromal atrophy is typically patchy or diffuse.5,23 Posterior synechiae are seldom observed. The acute rise in IOP that is characteristic of VAU is probably attributable to viral trabeculitis, which responds well to topical ster- oids. One-third of the cases with HSV- or VZV- induced AU manifest gonioscopically as an open angle with pigmentation.
Since there is a considerable overlap between clin- ical manifestations of the different infectious and non- infectious forms of AU, antivirals may be administered together with corticosteroids even if a viral etiology has not been verified.24 In more than 50% of cases, secondary complications, such as cataracts and glau- coma, are to be expected during the course of the disease.2,7 In this article, an attempt is made to defi ne a systematic and tailored course of treatment for the different forms of VAU.
METHODS
Articles appertaining to the treatment of VAU that have been published within the past 5 years were tracked by a PubMed search using the MeSH-terms “viral anterior uveitis” and “therapy”. The survey
identifi ed 115 publications under “viral anterior uvei- tis” and 50 under “therapy in viral anterior uveitis”. Our evaluation included prospective and retrospective comparative studies, cross-sectional studies, cohort studies, and case-control studies. Case reports and studies involving small case-series were not consid- ered. Cross references to earlier publications were taken into account if relevant.
RESULTS Therapeutic Strategy Diagnostics
In suspected cases of VAU, tapping of the anterior chamber and a PCR-analysis of the aqueous humor are helpful in typing the virus and in quantifying the viral load, based on a virus detection rate of about 33–48%.24–27
In more than 80% of the cases in which viral DNA is detected, the pathogen is the HSV. The sensitivity of the PCR-analysis varies considerably,28–30 depending upon the juncture at which the sample of aqueous humor is withdrawn and the status of the treatment at the time. Samples of aqueous humor that are with- drawn during the first days of an active disease are more likely to harbor viral DNA than are those that are taken at a later date. The chances of detecting the production of specific antibodies (using the Goldmann–Witmer coefficient) in samples that have
failed to reveal the presence of viral DNA by a PCR- analysis are higher if these have been withdrawn more than 2 weeks after the onset of the active disease.30 Due to a universally high seroprevalence, serological analysis alone is too unspecific to be of diagnostic value. Based upon an estimated detection sensitivity of 50% in a PCR-analysis, a negative result can never be assumed to exclude a viral etiology.
Antiviral therapyis generallyvirostatic; that is,itarrests viral replication without being able to eliminate the viral DNA from the infected cells and tissue. The clinical response to antiviral treatment can thus be delayed, and recurrences are to be expected throughout life.
In VAU, a systemic treatment strategy should be established with the aim of limiting secondary tissue damage and a further distribution of the virus. For this purpose, valacyclovir or famciclovir is preferable to acyclovir, since their serum and tissue concentrations are more reliably predictable. Prompt initiation of treatment immediately after the anterior chamber tap is advisable in order to bring the viral replication under control, which, in aggressive cases, is of utmost importance. Once a viral etiology has been established, the treatment strategy has to be tailored to the nature of the virus and to the clinical response that it triggers.- 25 As a general rule, however, most of the visible damage that is encountered is precipitated by the immune response to the viral infection, not to the viral infection per se.33 Hence, systemic antiviral ther- apy has to be combined with the local administration of anti-infl ammatory agents, namely corticosteroids. The therapeutic strategy that is instigated will depend upon the strength of the infl ammatory response and the immune status of the patient. In cases of VAU with stromal or endothelial keratitis, the administration of topical steroids is essential, since the infl ammatory response is immune mediated and not related to viral activity. Corticosteroids decrease recurrence rates, but do not eliminate the virus. In cases of HSV-induced epithelial keratitis, topical steroids should be avoided or used with caution to avoid the risk of serious complications.
An expeditious control of viral proliferation during the acute phase of infection will not only help to mini- mize the extent and the severity of tissue damage but also reduce the risk of chronic disease and secondary complications.
The most efficacious scheme of treatment for VAU involves a combination of systemic antivirals and topi- cal corticosteroids. Depending upon the clinical response, these drugs can be supplemented with either cycloplegics or topical IOP-lowering agents.
The choice between local and systemic therapy will be governed by the route of viral invasion. In cases of HSV and VZV infection, the virus is assumed to spread via the nerve fibers, which are not accessible to topical agents. The CMV, on the other hand, spreads via the bloodstream. Topical therapy may thus suffi ce to control the local disease until the virus has been cleared from the blood by the immune response that is mounted against it.
Antiviral Therapy
As aforementioned, systemic therapy with antiviral drugs should be initiated without delay to control viral replication. A number of antiviral agents are available to treat herpetic AU. The dosing schemes that are presented in Table 1 are the recommended ones for adult patients with a body weight of 75 kg, a normal hemogramme, and normal renal function. Following its oral administration, therapeutic levels of acyclovir are achieved in both the tears and the aqueous humor, thereby obviating the need for topical antiviral agents. The problem with acyclovir is the unpredictability of its resorption, which varies between 5% and 15% according to the pH of the gas- tric juices. The resorption of acyclovir is compromised if it encounters an empty stomach.38–40 The unab- sorbed fraction is excreted with the feces, which explains why some patients suffer from gastrointest- inal complaints. Individuals with a lactose intolerance are particularly prone to such side effects, since oral preparations of acyclovir contain lactose. These pro- blems can be circumvented by the use of valacyclovir, which is a prodrug of acyclovir. The bioactivity of this agent, which is available in a lactose-free form, is superior to that of acyclovir. It is absorbed at least twice as effectively from the gastrointestinal tract, thereby yielding three- to fourfold higher plasma drug levels than are achieved with oral acyclovir.41 However, both acyclovir and valacyclovir can induce thrombocytopenia, and, in individuals who are infected with the human immunodeficiency virus (HIV), high doses of these drugs have been reported to cause the purpura/hemolytic uremic syndrome (HUS). Since a case of HUS in an HIV-positive individual has been reported also when a low dose of valacyclovir has been administered, caution should be exercised in its use in this population of patients. However, the HIV is seldom responsible for isolated AU.45 High doses of acyclovir may worsen renal insuffi ciency in affected patients and precipitate the condition in those with other renal pathologies. Renal function should therefore be closely monitored during the course of treatment, which should be mod- ifi ed if necessary.46 Acute renal failure is induced at a dose exceeding1000 mg per day.47 As a general rule, however, oral acyclovir is usually well tolerated, even in patients with underlying nephropathies. Valacyclovir, on the other hand, can induce nephro- toxicity even in patients without a preexisting renal disease, especially in elderly ones.
For the treatment of herpes infections, a third drug is available on the market, namely, famciclovir. Using the same dosing regimen that is employed for oral valacyclovir (500 mg twice daily or thrice daily in severe cases), the responses to the two drugs are similar.
HSV and VZV
As indicated above, systemic antiviral therapy is usually combined with the topical administration of corticoster- oids. In most cases, this treatment regimen is supplemen- ted with topical cycloplegics. For the treatment of ocular HSV and VZV infections, oral acyclovir and valacyclovir are the most frequently used medications. Zosteric uvei- tis typically arises in loose temporal association with zosteric dermatitis at any site, not only in association with an ocular Zoster (V1/2). Antiviral therapy for zos- teric dermatitis is maximally effective in averting meta- zosteric pain when it is initiated within 72 h of the appearance of dermal lesions. Zosteric uveitis, on the other hand, should be treated without delay, and the therapy should be continued as long as the condition remains active. Owing to the predictability of its resorp- tion, oral valacyclovir is generally preferred to oral acy- clovir. A thrice-daily dose of 0.5–1 g for 10–14 days is the standard protocol. However, our own experience with the drug, as well as that of several other ophthalmolo- gists, indicates that a thrice-weekly dose of 500 mg usually suffices to control the active disease.51–56 Thereafter, a prophylactic course of treatment against a recurrence should be initiated. In our experience, a thrice-weekly dose of 500 mg reliably maintains the sup- pression of viral activity. The prophylactic therapy should be continued for 3–12 months depending upon the topical demand for corticosteroids. Other authors adhere to the daily dose of 500 mg as a prophylactic measure for preventing recurrences.57 When oral acyclo- vir is used as an alternative to valacyclovir, a five-times daily dose of 400-800 mg is recommended. To control the active disease, the therapy should be continued for 10/14 days. Thereafter, a prophylactic course of treat- ment should be launched, the duration of which should be adapted to the need for topical steroids. To be effec- tive prophylactically, the drug should be administered more than once a day during the entire course of treat- ment (Table 1).
Cytomegalovirus
The human CMV responds well to ganciclovir or valgan- ciclovir. For CMV-induced AU, systemic therapy with valganciclovir is the preferred option. A twice-daily dose of 900 mg for the first 3 weeks and a likewise twice-daily one of 450 mg for minimally the next 6 weeks are the recommended treatment strategy.32 Valganciclovir can severely suppress the production of blood cells in the bone marrow. It can also induce renal and hepatotoxicity. Monitoring of the blood count as well as of renal and liver function is thus of paramount importance, and if signs of untoward effects are thereby revealed, the treatment regi- men should be modified. Therapeutic levels of most topi- cal antiviral agents are rarely achieved in the aqueous humor.58 It remains a matter of debate whether the topical application of ganciclovir in the form of a gel can effec- tively control CMV-induced AU at a proposed five-times daily dose of 0.15% for 3 months.58,59 Evidence in favor of this mode of therapy is, however, not lacking. At concen- trations ranging from 0.15%58,60,61 through 0.5%62 to 2% ,63,64 topical ganciclovir has been reported to effec- tively control disease activity in CMV-induced AU, with- out inducing untoward side effects.
The treatment of CMV-induced endotheliitis with either topical or systemic ganciclovir has been reported to be partially successful.
Some authors favor the administration of ganciclovir via an intravitreal route. An injection of 2 mg/0.1 ml or 2 mg/0.05 ml weekly for 3 months, either with or with- out adjunctive oral valganciclovir, is the recommended strategy.
Treatment of Complications
The main secondary complications of VAU are cat- aracts and glaucoma. Secondary glaucoma asso- ciated with uveitis is a diffi cult one to manage. In patients with elevated IOP, topical anti-glaucoma agents are the fi rst-line treatment. If the elevated IOP persists, even in the face of maximal topical therapy, then, during the acute phase of the disease, inhibitors of carbonic anhydrase can be delivered systemically.
If the IOP cannot be suffi ciently controlled or if the secondary glaucoma persists despite maximal treatment with anti-glaucomatous agents, then fi ltra- tion surgery, such as trabeculectomy, or the implan- tation of an Ahmed valve is required. The use of antimetabolites in conjunction with trabeculectomy requires careful consideration. In a series of patients who had undergone glaucoma fi ltering surgery, the administration of mitomycin C induced recurrent herpetic keratouveitis.67 Trabectome surgery (open- ing of Schlemm’s canal from the inside) may be more useful and a less atraumatic alternative to trabeculectomy.68 If both approaches fail, then cyclo- photocoagulation or cryotherapy may be considered as effective options.
Recurrent herpetic infection of the eye can lead to stromal keratitis with corneal scarring and even- tually to loss of vision and the need for penetrating keratoplasty. Although the utility of pre- and post- operative treatment strategies is a controversial issue, an antiviral and anti-infl ammatory approach is nevertheless highly recommended.54 Following corneal grafting for herpes keratitis or keratouveitis, the postoperative course may be complicated by a recurrence of the herpetic disease, which compro- mises the graft and increases its failure rate. In patients who had undergone corneal grafting for stromal keratitis or keratouveitis of herpetic or non- herpetic origin, the functional outcomes and the rejection rates were similar in the viral and non- viral groups if a minimally 1-year course of prophy- lactic treatment with antivirals against recurrences was established in the former category.
In suspected cases of rubella-associated AU, a con- firmation of the diagnosis is of great importance, since in this case, antiviral therapy is not useful. Rubella- induced VAU is thus not usually treated. Nevertheless,secondary complications such as cataracts and glau- coma still have to be dealt with.
Prophylaxis
Several viruses share in common a lifelong resi- dence in infected tissues. The risk of reactivation is thus ever present. The rate of recurrences and an involvement of the partner eye can be reduced if the active disease is suppressed with high doses of systemic antivirals during the acute phase and if the controlled situation is sustained by the systemic delivery of the same agents at low doses. Nevertheless, it is still a matter of debate whether prophylactic treatment with systemic antivirals does indeed infl uence the rate of recurrence of her- petic AU32,70,71, since a reactivation of the disease eventually occurs even after a prolonged course of therapy. With respect to herpetic keratitis, however, a minimally 3-month course of prophylactic treat- ment, which may be extended to 12 months in recurrence-prone cases, does appear to be benefi cial.71 The benefi ts may perhaps be paralleled in cases of herpetic AU.
VAU is most frequently induced by the HSV or the CMV, and the rates of recurrence are high. Although the risk of recurrence in VZV-induced AU is lower, chronic metaherpetic stromal keratitis occurs more frequently.32,72,73 The AU that is induced by emerging viruses such as zika and chi- kungunya usually follows a self-limiting course,74 which renders unnecessary the instigation of specifi c therapies. Chee and colleagues reported that in 80% of patients with acute CMV-induced AU and in 86% of those with a chronic condition, a relapse occurs after a 3-month course of successful recurrence prophylaxis.3 This may namely be of interest since 80% of acute AU and 86% of chronic AU cases tend to relapse. The rate of recurrence of CMV-induced AU can be reduced by treating the active disease with topical ganciclovir at a concentration of 0.15%60, which suggests that this regimen may be valuable also in a prophylactic context. The delinea- tion of an effective prophylactic strategy is a chal- lenge in most cases of herpetic keratouveitis and AU. In many instances, the prophylactic effect of the therapy endures only as long as it is continued. It should thus be sustained until the affected tissue has largely recovered and until the interval between the applications of the corticosteroid has been extended to minimally 24 h. In patients who are prone to frequent and early recurrences, the course of pro- phylactic treatment may need to be continued inde- fi nitely, frequently in conjunction with the administration of topical corticosteroids at low doses and of anti-glaucoma agents.
Corticosteroids
In most patients with active herpetic AU, antiviral therapy needs to be combined with the application of a topical corticosteroid to control the inflammatory response that is triggered by the virus. The administration of a cyclople- gic/mydriatic agent may also be required to prevent the formation of posterior synechiae and to reduce pain.
The topical route is the preferred one for the delivery of corticosteroids to control inflammation in cases of VAU. However, if the disease is severe, recurrent, and bilateral, then periocular and systemic routes may also be considered.16 The intensity of the treatment depends upon the degree and the duration of the inflammatory response, on the earlier episodes of uveitis, and on the previous response to treatment. Tapering of the applica- tions of a corticosteroid to accord with the clinical response can be challenging, and the process often takes months to effect in conjunction with systemic pro- phylactic treatment against recurrences.16,21
The severity of the uveitis serves as the basis for the choice of the topical corticosteroid. To control a severe inflammatory response in the anterior chamber, a potent steroid should be administered; for the control of a weaker one, betamethasone or dexamethasone can be used.
During the active phase of infl ammation, antiviral agents are needed to control viral replication to ward off recurrences. No benefi ts are to be gained by down- grading the treatment with these agents during the acute phase of the disease. The administration of an antiviral agent should be continued until the interval between the applications of the corticosteroid has been extended to minimally 12 h.
Emerging viral diseases
The clinical relevance of diseases that are induced by emerging viruses such as zika-, influenza A-, Ebola-, or parechovirus14,75–77 and appropriate treatment strate- gies have yet to be established. As aforementioned, these diseases may follow a self-limiting course, but this is not always the case. The Ebola virus has been reported to persist in the ocular fl uids and to reactivate AU in convalescent patients.
Currently, no specific therapeutic strategy or vaccine is available for arboviral diseases, the treatment of which is thus chiefly supportive.79 Arbovirus-induced inflam- matory activity in the anterior segment resolves after a period that spans several weeks to a few months. The inflammation can be dampened by treatment with topi- cal steroids and cycloplegics, and the associated rise in IOP can be controlled with anti-glaucoma agents.
CONCLUSION
Viruses, particularly those of the herpes family, are an important, frequent, and underdiagnosed cause of acute and chronic intraocular infl ammation. Prompt identifi cation of the infectious nature of the infl ammatory response is based on clinical experi- ence and a confi rmatory analysis of the intraocular specimen (i.e. aqueous humor). Considering that viruses can undergo rapid intraocular expansion, that the disease characteristics can vary according to the viral type, and that these pathogens persist in the ocular tissues, the treatment needs to be prompt, specifi c, and often long term. Given that viruses of the herpes family are highly prevalent and that a reactivation of the disease may ultimately lead to loss of vision, prophylactic treatment against recurrences should be considered as a matter of course in all cases.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
FINANCIAL DISCLOSURES
The authors have no financial conflicts of interest with the data that are presented in this article.
REFERENCES
1.Gaynor BD, Margolis TP, Cunningham ET Jr. Advances in the diagnosis and management of herpetic uveitis. Int Ophthalmol Clin. 2000;40:85–109.
2.Jap A, Chee SP. Viral anterior uveitis. Curr Opin Ophthalmol. Nov 2011;22(6):483–488.
3.Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. Br J Ophthalmol. 2010;94:1648–1652.
4.Kongyai N, Sirirungsi W, Pathanapitoon K, et al. Viral causes of unexplained anterior uveitis in Thailand. Eye (Lond). 2012;26:529–534.
5.Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical features of cytomegalovirus anterior uveitis in immu- nocompetent patients. Am J Ophthalmol. 2008;145:834–840.
6.Choi JA, Kim KS, Jung Y, Park HY, Park CK. Cytomegalovirus as a cause of hypertensive anterior uveitis in immunocompe- tent patients. J Ophthalmic Inflamm Infect. Dec 2016;6(1):32. doi:10.1186/s12348-016-0100-5. Epub 2016 Sep 9.
7.Accorinti M, Gilardi M, Pirraglia MP, et al. Cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients. Graefes Arch Clin Exp Ophthalmol. Nov 2014;252 (11):1817–1824.
8.Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and posner-schlossman syndrome: comparison of cytome- galovirus-positive and negative eyes. Am J Ophthalmol. Dec 2008;146(6):883–9.e1.
9.Suzuki J, Goto H, Komase K, et al. Rubella virus as a possible etiological agent of Fuchs heterochromic iridocycli- tis. Graefes Arch Clin Exp Ophthalmol. Oct 2010;248(10):1487– 1491. Epub 2010 Jun 29.
10.De Groot-Mijnes JD, De Visser L, Rothova A, Schuller M, van Loon AM, Weersink AJ. Rubella virus is associated with Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2006;141:212–214.
11.Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol. 2004;138:46–54.
12.Mahendradas P, Shetty R, Malathi J, Madhavan HN. Chikungunya virus iridocyclitis in Fuchs’ heterochromic irido- cyclitis. Indian J Ophthalmol. Nov-Dec 2010;58(6):545–547.
13.Takahashi H, Sugita S, Shimizu N, Mochizuki M. A high viral load of Epstein-Barr virus DNA in ocular fluids in an HLA-B27-negative acute anterior uveitis patient with psor- iasis. Jpn J Ophthalmol. 2008;52:136–138.
14.De Groot-Mijnes JD, De Visser L, Zuurveen S, et al. Identification of new pathogens in the intraocular fluid of patients with uveitis. Am J Ophthalmol. Nov 5, 2010;150:628– 636. Epub 2010 Aug 5.
15.Merayo-Lloves J, Power WJ, Rodriguez A, Pedroza-Seres M, Foster CS. Secondary glaucoma in patients with uveitis. Ophthalmologica. 1999;213:300–304.
16.Agrawal RV, Murthy S, Sangwan V, Biswas J. Current approach in diagnosis and management of anterior uveitis. Indian J Ophthalmol. Jan-Feb 2010;58(1):11–19.
17.Chan NS, Chee SP, Caspers L, Bodaghi B. Clinical features of CMV-Associated anterior uveitis. Ocul Immunol Infl amm. 2018;26:107–115.
18.Daas L, Seitz B, Pleyer U. Fuchs uveitis. Ophthalmologe. May 2017;114(5):481–492.
19.Pogorzalek N, De Monchy I, Gendron G, Labetoulle M. Hypertony and uveitis: 103 cases of uveitis. J Fr Ophtalmol. Mar 2011;34(3):157–163. Epub 2011 Mar 1.French.
20.Goldstein DA, Mis AA, Oh FS, Deschenes JG. Persistent pupillary dilation in herpes simplex uveitis. Can J Ophthalmol. Jun 2009;44(3):314–316.
21.Sungur GK, Hazirolan D, Yalvac IS, Ozer PA, Aslan BS, Duman S. Incidence and prognosis of ocular hypertension secondary to viral uveitis. Int Ophthalmol. Apr 2010;30 (2):191–194. Epub 2009 Apr 3.
22.Markomichelakis NN, Canakis C, Zafirakis P, Marakis T, Mallias I, Theodossiadis G. Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology. 2002;109:879–882.
23.Wensing B, Relvas LM, Caspers LE, et al. Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis. Ophthalmology. 2011;118:1905–1910.
24.Schacher S, Garweg JG, Russ C, Böhnke M. Diagnosis of herpetic uveitis and keratouveitis. Klin Monatsbl Augenheilkd. 1998;212:359–362.
25.Chronopoulos A, Roquelaure D, Souteyrand G, Seebach JD, Schutz JS, Thumann G. Aqueous humor polymerase chain reaction in uveitis – utility and safety. BMC Ophthalmol. Oct 28, 2016;16(1):189.
26.Laaks D, Smit DP, Harvey J. Polymerase chain reaction to search for Herpes viruses in uveitic and healthy eyes: a South African perspective. Afr Health Sci. Sep 2015;15 (3):748–754.
27.Shoughy SS, Alkatan HM, Al-Abdullah AA, El-Khani A, De Groot-Mijnes JD, Tabbara KF. Polymerase chain reaction in unilateral cases of presumed viral anterior uveitis. Clin Ophthalmol. Dec 2015;14(9):2325–2328.
28.Van der Lelij A, Ooijman FM, Kijlstra A, et al. Anterior uveitis with sectoral iris atrophy in the absence of keratitis. Distinct Clinical Entity among Herpetic Eye Dis Ophthalmol. 2000;107:1164–1170.
29.Yamamoto S, Pavan-Langston D, Kinoshita S. Detecting herpesvirus DNA in uveitis using the polymerase chain reaction. Br J Ophthalmol. 1996;80:465–468.
30.Westeneng AC, Rothova A, De Boer JH, De Groot-Mijnes JD. Infectious uveitis in immunocompromised patients and
the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis. Am J Ophthalmol. Nov 2007;144(5):781–785. Epub 2007 Aug 20.
31.Pebody RG, Andrews N, Brown D, et al. The seroepidemiol- ogy of herpes simplex virus type 1 and 2 in Europe. Sex Transm Infect. Jun 2004;80(3):185–191.
32.Pleyer U, Chee SP. Current aspects on the management of viral uveitis in immunocompetent individuals. Clin Ophthalmol. Jun 2015;5(9):1017–1028.
33.Atherton SS, Pesicka GA, Streilein JW. Retinitis and deviant immune responses following intravitreal inoculation of HSV-1. Invest Ophthalmol Vis Sci. 1987;28:859–866.
34.Azher TN, Yin X-T, Tajfi rouz D, Huang AJW, Stuart PM. Herpes simplex keratitis: challenges in diagnosis and clin- ical management. Clin Ophthalmol. 2017;11:185–191.
35.Bucher J, Koyfman A. What is the most effective treatment of herpes simplex keratitis? Ann Emerg Med. Jul 2016;68 (1):26–27.
36.Grinde B. Herpesviruses: latency and reactivation – viral strategies and host response. J Oral Microbiol. Oct 2013;25:5. doi:10.3402/jom.v5i0.22766.
37.Landais I, Nelson JA. Functional genomics approaches to understand cytomegalovirus replication, latency and patho- genesis. Curr Opin Virol. 2013;3:408–415.
38.Wilson CG, Washington N, Hardy JG, Bond SW. The influ- ence of food on the absorption of acyclovir: a pharmacoki- netic and scintigraphic assessment. Int J Pharm. August 1987;Volume 38(Issues 1–3):Pages221–225.
39.De Miranda P, Blum MR. Pharmacokinetics of acyclovir after intravenous and oral administration. J Antimicrob Chemother. 1983;12:29–37.
40.Han H, De Vrueh RL, Rhie JK, et al. 5ʹ-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. Aug 1998;15(8):1154–1159.
41.Cunningham ET Jr. Diagnosing and treating herpetic ante- rior uveitis. Ophthalmology. Dec 2000;107(12):2129–2130.
42.Bell WR, Chulay JD, Feinberg JE. Manifestations resembling thrombotic microangiopathy in patients with advanced human immunodeficiency virus (HIV) disease in a cytome- galovirus prophylaxis trial (ACTG 204). Medicine (Baltimore). Sep 1997;76(5):369–380.
43.Feinberg JE, Hurwitz S, Cooper D, et al. A randomized, double-blind trial of valaciclovir prophylaxis for cytomega- lovirus disease in patients with advanced human immuno- deficiency virus infection. AIDS clinical trials group protocol 204/Glaxo Wellcome 123-014 International CMV prophylaxis study group. J Infect Dis. Jan 1998;177(1):48–56.
44.Rivaud E, Massiani MA, Vincent F, Azoulay E, Coudrec LJ. Valacyclovir hydrochloride therapy and thrombotic throm- bocytopenic purpura in an HIV-infected patient. Arch Intern Med. Jun 12, 2000;160(11):1705–1706.
45.Kunavisarut P, Sirirungsi W, Pathanapitoon K, Rothova A. Clinical manifestations of human immunodeficiency virus- induced uveitis. Ophthalmology. Jul 2012;119(7):1455–1459. Epub 2012 Apr 27.
46.Eck P, Silver SM, Clark EC. Acute renal failure and coma after a high dose of oral acyclovir. N Engl J Med. 1991;325:1178.
47.Meng JB, Zheng X, Zhang G, Fang Q. Oral acyclovir induced acute renal failure. World J Emerg Med. 2011;2 (4):310–313. doi:10.5847/wjem.j.1920-8642.2011.04.013.
48.Carlon R, Possamai C, Corbanese U. Acute renal failure and severe neurotoxicity following valacyclovir. Intensive Care Med. Nov 2005;31(11):1593. Epub 2005 Sep 20.
49.Izzedine H, Launay-Vacher V, Deray G. Antiviral drug- induced nephrotoxicity. Am J Kidney Dis. May 2005;45 (5):804–817.
50.Degreef H1. Famciclovir Herpes Zoster Clinical Study Group. Famciclovir, a new oral antiherpes drug: results of the fi rst controlled clinical study demonstrating its efficacy and safety in the treatment of uncomplicated herpes zoster in immunocompetent patients. Int J Antimicrob Agents. 1994;4(4): 241–246.
51.Oshima K, Takahashi T, Mori T, et al. One-year low-dose valacyclovir as prophylaxis for varicella zoster virus disease after allogeneic hematopoietic stem cell transplantation. A pro- spective study of the Japan hematology and oncology clinical study group. Transpl Infect Dis. Oct 2010;12(5):421–427.
52.Bhatt UK, Abdul Karim MN, Prydal JI, Maharajan SV, Fares U. Oral antivirals for preventing recurrent herpes simplex keratitis in people with corneal grafts. Cochrane Database Syst Rev. 2016;11:CD007824.
53.Goldblum D, Bachmann C, Tappeiner C, Garweg J, Frueh BE. Comparison of oral antiviral therapy with valacyclovir or acyclovir after penetrating keratoplasty for herpetic ker- atitis. Br J Ophthalmol. Sep 2008;92(9):1201–1205.
54.Halberstadt M, Machens M, Gahlenbek KA, Böhnke M, Garweg JG. The outcome of corneal grafting in patients with stromal keratitis of herpetic and non-herpetic origin. Br J Ophthalmol. Jun 2002;86(6):646–652.
55.Tambasco FP, Cohen EJ, Nguyen LH, Rapuano CJ, Laibson PR. Oral acyclovir after penetrating keratoplasty for herpes simplex keratitis. Arch Ophthalmol. 1999;117:445–449.
56.Wilhelmus KR, Falcon MG, Jones BR. Herpetic iridocyclitis. Int Ophthalmol. 1981;4:143–150.
57.Miserocchi E, Modorati G, Galli L, Rama P. Efficacy of valacyclovir vs acyclovir for the prevention of recurrent herpes simplex virus eye disease: a pilot study. Am J Ophthalmol. 2007;144(4):547–551.
58.Chou TY, Hong BY, Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: background, effec- tiveness, tolerability, safety, and future applications. Ther Clin Risk Manag. Aug 20, 2014;10:665–681. doi:10.2147/TCRM.S58242. eCollection 2014.
59.Pavan-Langston D, Welch CL, Zegans ME. Ganciclovir gel for cytomegalovirus keratouveitis. Ophthalmology. Nov 2012;119(11):2411.
60.Antoun J, Willermain F, Makhoul D, Motulsky E, Caspers L, Relvas LJ. Topical ganciclovir in cytomegalovirus anterior uveitis. J Ocul Pharmacol Ther. May 2017;33(4):313–318.
61.Wong JX, Agrawal R, Wong EP, Teoh SC. Efficacy and safety of topical ganciclovir in the management of cytome- galovirus (CMV)-related anterior uveitis. J Ophthalmic Inflamm Infect. 2016;6:10.
62.Fan NW, Chung YC, Liu YC, Liu CJ, Kuo YS, Lin PY. Long- term topical ganciclovir and corticosteroids preserve cor- neal endothelial function in cytomegalovirus corneal endotheliitis. Cornea. May 2016;35(5):596–601.
63.Su CC, Hu FR, Wang TH, et al. Clinical outcomes in cytome- galovirus-positive Posner-Schlossman syndrome patients trea- ted with topical ganciclovir therapy. Am J Ophthalmol. Nov 2014;158(5):1024–1031.e2.
64.Keorochana N, Choontanom R. Efficacy and safety of an extemporaneous preparation of 2% ganciclovir eye drops in
CMV anterior uveitis. BMJ Open Ophthalmol. Sep 7, 2017;2 (1):e000061.
65.Chee SP, Jap A. Immune ring formation associated with cyto- megalovirus endotheliitis. Am J Ophthalmol. Sep 2011;152 (3):449–453.e1.
66.Hwang YS, Lin KK, Lee JS, et al. Intravitreal loading injec- tion of ganciclovir with or without adjunctive oral valgan- ciclovir for cytomegalovirus anterior uveitis. Graefes Arch Clin Exp Ophthalmol. Feb 2010;248(2):263–269. Epub 2009 Sep 27.
67.Rao A, Tandon R, Sharma N, Sihota R, Gupta V, Dada T. Herpetic keratitis and keratouveitis after mitomycin-C use in glaucoma filtering surgery: a short case series. Eur J Ophthalmol. Nov-Dec 2009;19(6):1088–1090.
68.Pahlitzsch M, Torun N, Gonnermann J, et al. Trabeculectomy ab interno (trabectome): yet another possi- bility in the treatment of uncontrolled glaucomatocyclitic crisis under systemic valganciclovir therapy? Eye (Lond). Oct 2015;29(10):1335–1339.
69.Dastiridou AI1, Androudi S, Praidou A, Brazitikos P, Cg B, Ee T. Transscleral diode laser cyclophotocoagulation for refractory glaucoma secondary to juvenile idiopathic arthri- tis: a short term follow-up. Int Ophthalmol. Aug 2013;33 (4):409–413.
70.Rodriguez A, Power WJ, Neves RA, Foster CS. Recurrence rate of herpetic uveitis in patients on long-term oral acyclo- vir. Doc Ophthalmol. 1995;90:331–340.
71.Herpetic Eye Disease Study Group. Acyclovir for the pre- vention of recurrent herpes simplex virus eye disease. N Engl J Med. 1998;339:300–306.
72.Miserocchi E, Fogliato G, Bianchi I, Bandello F, Modorati G. Clinical features of ocular herpetic infection in an Italian referral center. Cornea. Jun 2014;33(6):565–570.
73.De Schryver I, Rozenberg F, Cassoux N, et al. Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol. Jul 2006;90(7):852–855. Epub 2006 Apr 5.
74.Mahendradas P, Avadhani K, Shetty R. Chikungunya and the eye: a review. J Ophthalmic Infl amm Infect. 2013;3:35.
75.Merle H, Najioullah F, Chassery M, Césaire R, Hage R. Zika-Related bilateral hypertensive anterior acute uveitis. JAMA Ophthalmol. Mar 1, 2017;135(3):284–285.
76.Nakagawa H, Noma H, Kotake O, Motohashi R, Yasuda K, Shimura M. Optic neuritis and acute anterior uveitis asso- ciated with influenza A infection: a case report. Int Med Case Rep J. Jan 4, 2017;10:1–5.55.
77.Hereth-Hebert E, Bah MO, Etard JF, et al. Postebogui Study Group. Ocular complications in survivors of the Ebola out- break in Guinea. Am J Ophthalmol. Mar 2017;175:114–121.
78.Varkey JB, Shantha JG, Crozier I, et al. Persistence of Ebola virus in ocular fluid during convalescence. N Engl J Med. Jun 18, 2015;372(25):2423–2427.
79.Khairallah M, Kahloun R, Ben Yahia S, Jelliti B, Messaoud R. New infectious etiologies for posterior uveitis. Ophthalmic Res. 2013;49:66–72.Brivudine