Valacyclovir versus acyclovir for the treatment of herpes zoster ophthalmicus in immunocompetent patients.

BACKGROUND: Herpes zoster ophthalmicus affects the eye and vision, and is caused by the reactivation of the varicella zoster virus in the distribution of the first division of the trigeminal nerve. An aggressive management of acute herpes zoster ophthalmicus with systemic antiviral medication is generally recommended as the standard first-line treatment for herpes zoster ophthalmicus infections. Both acyclovir and its prodrug valacyclovir are medications that are approved for the systemic treatment of herpes zoster. Although it is known that valacyclovir has an improved bioavailability and steadier plasma concentration, it is currently unclear as to whether this leads to better treatment results and less ocular complications. OBJECTIVES: To assess the effects of valacyclovir versus acyclovir for the systemic antiviral treatment of herpes zoster ophthalmicus in immunocompetent patients. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2016, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2016), Embase (January 1980 to June 2016), Web of Science Conference Proceedings Citation Index-Science (CPCI-S; January 1990 to June 2016), BIOSIS Previews (January 1969 to June 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 June 2016. SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) in which systemic valacyclovir was compared to systemic acyclovir medication for treatment of herpes zoster ophthalmicus. There were no language restrictions. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, evaluated the risk of bias in included trials, and extracted and analysed data. We did not conduct a meta-analysis, as only one study was included. We assessed the certainty of the evidence for the selected outcomes using the GRADE approach. MAIN RESULTS: One study fulfilled the inclusion criteria. In this multicentre, randomised double-masked study carried out in France, 110 immunocompetent people with herpes zoster ophthalmicus, diagnosed within 72 hours of skin eruption, were treated, with 56 participants allocated to the valacyclovir group and 54 to the acyclovir group. The study was poorly reported and we judged it to be unclear risk of bias for most domains.Persistent ocular lesions after 6 months were observed in 2/56 people in the valacyclovir group compared with 1/54 people in the acyclovir group (risk ratio (RR) 1.93 (95% CI 0.18 to 20.65); very low certainty evidence. Dendritic ulcer appeared in 3/56 patients treated with valacyclovir, while 1/54 suffered in the acyclovir group (RR 2.89; 95% confidence interval (CI) 0.31 to 26.96); very low certainty evidence), uveitis in 7/56 people in the valacyclovir group compared with 9/54 in the acyclovir group (RR 0.96; 95% CI 0.36 to 2.57); very low certainty evidence). Similarly, there was uncertainty as to the comparative effects of these two treatments on post-herpetic pain, and side effects (vomiting, eyelid or facial edema, disseminated zoster). Due to concerns about imprecision (small number of events and large confidence intervals) and study limitations, the certainty of evidence using the GRADE approach was rated as low to very low for the use of valacyclovir compared to acyclovir. AUTHORS' CONCLUSIONS: This review included data from only one study, which had methodological limitations. As such, our results indicated uncertainty of the relative benefits and harms of valacyclovir over acyclovir in herpes zoster ophthalmicus, despite its widespread use for this condition. Further well-designed and adequately powered trials are needed. These trials should include outcomes important to patients, including compliance.

Immune Cell Status and Cytokines Profiles in Patients with Acute Retinal Necrosis.

Purpose: To assess the immune status of acute retinal necrosis (ARN) patients and to investigate the immune cell types involved in the immunopathogenesis.Methods: Peripheral blood and intraocular fluid were collected from 17 ARN patients and 9 control subjects. The Percentage of immune cells was measured using flow cytometry, levels of complement and antibodies were determined by rate nephelometry, and cytokine levels in the serum and aqueous humor (AH) were detected using cytokine quantitative chips. Data were analyzed using SPSS 23.0. p < .05 was considered statistically significant.Results: Proportion of T-helper 17 cells (p = .034) in serum and concentrations of multiple cytokines associated with Th17 cells (IL-6, IL-17, IL-17 F, IL-21, IL-22) in AH and serum were elevated of ARN patients.Conclusion: Th17 cells appeared to participate in the development of ARN. We found inflammatory cytokines and cells were elevated in the serum and AH of ARN patients.

Study of ocular manifestations in tuberculosis and its association with HIV AIDS in a tertiary care hospital.

OBJECTIVE: To assess and understand the prevalence and clinical presentation of ocular morbidity in patients suffering from tuberculosis and compare it with ocular involvement in patients coinfected with tuberculosis and HIV AIDS. MATERIALS AND METHODS: This was a non-comparative, observational, cross sectional study done on 580 patients, who were diagnosed cases of tuberculosis, pulmonary or extrapulmonary, on or off treatment, visiting the Ophthalmology OPD, Tuberculosis OPD and ART Centre of the institute in the period from March 2015 to March 2018, screened for ocular morbidity. RESULTS: Out of 580, 408 patients had only tuberculosis and 172 had tuberculosis with HIV AIDS. 108 patients were found to have ocular involvement (18.6%) out of which 63 were males and 45 were females. The prevalence of ocular morbidity in patients with only tuberculosis was found to be 16.4% and in those having both tuberculosis and HIV AIDS was found to be 23.8%. CONCLUSION: Our study concludes that posterior uveitis, pan uveitis, periphlebitis and vitritis are the most common ocular manifestations in tuberculosis. In patients with both tuberculosis and HIV most common ocular findings included vitritis and herpes zoster ophthalmicus. Our study also concludes that lower CD4 counts (less than 200) in HIV AIDS patient is significantly associated with ocular involvement.

Headache and vision changes in an elderly man with rheumatoid arthritis.

We present a case of an elderly, immunosuppressed patient with rheumatoid arthritis who was not appropriately vaccinated, and subsequently developed herpes zoster ophthalmicus, which initially presented similar to giant cell arteritis. Evidence-based vaccinations are integral in decreasing the incidence of preventable diseases and promoting optimal health at the individual and population level. Although the patient ultimately did not suffer any long-term adverse sequelae, this case highlights the importance of vaccination in the rheumatology setting, and to consider both inflammatory and infectious causes of headache and vision changes in the elderly.

Ring corneal infiltrate and progressive ring thinning following primary varicella infection.

Unilateral stromal keratitis is a known rare sequela of primary varicella infection. The authors describe a unique case of immunological (Wessely) ring formation and progressive ring thinning following primary varicella infection in a 6-year-old girl.

Immunopathology of Virus-Induced Anterior Uveitis.

Herpes simplex virus, varicella zoster virus, human cytomegalovirus, and rubella virus are the most common causes of virus-induced anterior uveitis. They can present in a variety of entities not only with typical but also overlapping clinical characteristics. These viral infections are commonly associated with ocular infiltration of T cells and B/plasma cells, and expression of cytokines and chemokines typical of a proinflammatory immune response. The infections differ in that the herpes viruses cause an acute lytic infection and inflammation, whereas rubella virus is a chronic low-grade infection with slowly progressing immunopathological responses. The outcome of an intraocular viral infection may largely be guided by the characteristics of the virus, which subsequently dictates the severity and type of the immune response, and the host immune status.

Optic neuropathy and ophthalmoplegia in herpes zoster oticus.

A 55-year-old man with herpes zoster oticus and minimal cutaneous involvement developed reversible optic neuropathy, and ocular motor and cerebellar abnormalities. Serologic changes confirmed infection with herpes zoster. A demyelinating process seems likely to have been responsible for these lesions. It is suggested that herpes zoster antibody titers should be measured whenever the syndrome of polyneuritis cranialis of acute onset is being investigated.

Ocular inoculation of monkeys with simian varicella virus: clinical and histopathologic observations.

PURPOSE: To explore the possibility that inoculation of the eyes of African green monkeys with simian varicella virus (SVV) induces the symptoms of herpes zoster ophthalmicus (HZO), as seen in humans, and to develop a realistic and reproducible animal model of herpes zoster ophthalmicus for experimental studies. METHODS: In the first experiment, the right eyes of three African green monkeys were inoculated by intrastromal and subconjunctival injections with a suspension of SVV-infected Vero cells. In the second experiment, three additional monkeys were pretreated with intramuscular injections of methylprednisolone (41 mg/kg) for 7 days before ocular inoculation with SVV and for 3 weeks at 14 mg/kg after virus inoculation. The eyes were examined by slit-lamp biomicroscopy. Histologic, immunohistochemical, and electron microscopic studies were performed. RESULTS: In the first experiment, all three animals developed high titers of anti-SVV antibodies (IgG). Diffuse stromal opacity, with keratitic precipitates, stromal edema, and mild vascularization of the cornea, appeared 12 to 14 days after inoculation. The onset of ocular disease was correlated with the rise in serum antibody levels. There was no clinical evidence of a systemic viral infection resulting from the corneal inoculations in these monkeys. In the second experiment, all three animals treated with methylprednisolone developed severe ocular pathology within 1 week of inoculation. The clinical appearance of the diseased eyes strongly indicated that local viral infection had occurred. Dendritiform keratitis, corneal erosion, and stromal necrosis with vascularization of the cornea was seen in all the eyes. The disease resolved within 4 to 5 weeks of inoculation, leaving opaque, vascularized corneas. Histologic studies showed that inflammatory cells and viral antigens were widespread throughout the diseased corneas. A high titer of anti-SVV antibody (IgG) was detected in the immunosuppressed monkeys, but no evidence of systemic viral infection was observed. CONCLUSIONS: The authors propose that inoculation of the eyes of methylprednisolone-treated African green monkeys with simian varicella virus provides an appropriate animal model for studies of the virology and immunopathology of ocular varicella virus infection.

A relationship between varicella-zoster virus-specific delayed hypersensitivity and varicella-zoster virus-induced anterior uveitis.

BACKGROUND: We recently reported that acute retinal necrosis in humans develops in a setting where delayed hypersensitivity (DH) to the varicella-zoster virus (VZV) antigen was absent, implying that virus-specific DH mitigates against acute retinal necrosis. OBJECTIVE: To determine whether a similar correlation exists for patients with anterior uveitis caused by VZV. DESIGN: Using VZV and purified protein derivative (PPD) antigens to evaluate DH, we skin tested patients with acute, VZV-induced anterior uveitis (herpes zoster ophthalmicus [ZO-AU]) (n = 12), those with uveitis caused by VZV in the absence of dermatitis (zoster sine herpete [ZSH-AU]) (n = 3), and age-matched patients whose ophthalmic herpes zoster was unassociated with uveitis as controls (n = 7). Varicella-zoster virus-induced anterior uveitis was diagnosed by polymerase chain reaction methods and serum antibody titration. Serum samples were collected and analyzed for anti-VZV antibody titers. Anterior uveitis activity was assessed clinically. Delayed hypersensitivity skin tests were repeated in patients with zoster sine herpete 3 months after onset, when ocular recovery had taken place. RESULTS: All patients with VZV-induced skin disease alone (control group) displayed intense DH when tested with VZV and PPD antigens. By contrast, only 4 (33%) of 12 patients with ZO-AU had a positive DH to VZV, whereas 11 (91.6%) of these patients displayed positive PPD skin reactions. The clinical intensity of anterior uveitis correlated negatively with VZV DH responses (P<.05). Serum anti-VZV and anti-herpes simplex virus antibody titers were comparable in DH-positive VZV cases and in DH-negative patients with uveitis. Patients with uveitis and ZSH-AU also displayed absent VZV-specific DH, although their PPD responses were normal. MAIN OUTCOME MEASURES: Varicella-zoster virus-specific DH, PPD-specific DH, VZV-specific antibody titration, and intraocular pressure in patients with ZO-AU. CONCLUSIONS: Absence (or loss) of DH reactivity to VZV antigens seems to be a concomitant feature of VZV uveitis of high intensity, implying that virus-specific DH may interfere with the emergence of VZV-induced anterior uveitis, as it does for acute retinal necrosis. CLINICAL RELEVANCE: In a clinical setting, absence of virus-specific DH to anterior uveitis caused by VZV may not only reveal a possible pathogenic mechanism, but a negative DH response may prove useful in diagnosing ZSH-AU in the acute stage.

Evidence for antigen-specific immune deviation in patients with acute retinal necrosis.

BACKGROUND: Because experimental acute retinal necrosis (ARN) induced by herpes simplex virus in mice develops only if mice fail to acquire virus-specific delayed hypersensitivity (DH), although they produce antiviral antibodies (ie, anterior chamber-associated immune deviation), we sought to determine whether a similar inverse correlation exists for patients with varicella-zoster virus (VZV)-induced ARN. DESIGN: Patients with acute, VZV-induced ARN and age-matched control subjects were skin tested with VZV and purified protein derivative antigens to evaluate DH. Varicella-zoster virus-induced ARN was diagnosed using polymerase chain reaction and intraocular antibody quotient. Serum samples were collected and analyzed for anti-VZV and anti-herpes simplex virus antibody titers. Acute retinal necrosis activity was assessed clinically, and DH skin tests were repeated 3 months after onset when ocular recovery had taken place. RESULTS: Whereas controls displayed intense DH when tested with VZV and purified protein derivative antigens, a subset of patients with ARN displayed absent VZV-specific DH (although their purified protein derivative responses were normal). Patients with the most severe ARN had the lowest DH responses to VZV antigens. Serum anti-VZV antibody titers were higher in patients with ARN than in controls, and antiviral titer correlated inversely with the intensity of anti-VZV DH responses. Varicella-zoster virus-specific DH responses were restored in patients who recovered from ARN. CONCLUSION: Varicella-zoster virus-ARN develops in a setting where DH reactivity to viral antigens is absent, implying that virus-specific DH might ameliorate the severity of ARN. CLINICAL RELEVANCE: Linking virus-specific DH to vulnerability to ARN in individuals infected with VZV might reveal an underappreciated pathogenic mechanism.

Ophthalmic herpes zoster with contralateral hemiparesis: a case report.

Herpes zoster of the ophthalmic division of the left fifth cranial nerve with contralateral hemiparesis was observed in a 30-year-old man. Left carotid angiography showed segmental constrictions consistent with cerebral arteritis, possibly provoked by direct viral infection along the intracranial part of the ophthalmic nerve. An ischaemic lesion revealed by computed tomographic scan was considered secondary to arteritis and responsible for the hemiparesis. The presence of an immune response within the blood-CSF barrier was suggested by an increase of oligoclonal CSF IgG and IgA.

Skin test with varicella-zoster virus antigen for ophthalmic herpes zoster.

We assessed delayed dermal hypersensitivity to varicella-zoster virus by a varicella skin test in 12 patients (nine women and three men ranging in age from 27 to 85 years) with ophthalmic herpes zoster during the acute stage and in a group of 27 healthy controls (15 women and 12 men ranging in age from 18 to 58 years). Of the 27 healthy individuals, 25 had positive skin test reactions whereas only one of the 12 patients with ophthalmic herpes zoster had a positive skin test reaction within two weeks after the onset of the eruption, suggesting that cellular immunity to varicella-zoster virus antigens is impaired in the development of ophthalmic herpes zoster. Our study also showed that the varicella skin test is a convenient way to diagnose ophthalmic herpes zoster during the acute stage of the disease.

The enigma of herpes stromal disease.

Herpes stromal disease is due to direct damage as a result of viral replication, virally induced immune mechanisms, or a combination of the two. Viral replication may have a major initiating role in the production of herpes simplex and herpes zoster induced stromal disease, and steroids may initially be harmful in their treatment. On topical antiviral drugs alone, in patients who never previously had had topical steroids, 14 of 15 cases of herpes simplex induced disciform keratitis responded favourably in an average of 44 days of treatment. This compared with one out of 14 responding if steroids had previously been used, 13 of 14 requiring topical steroids and an average 112 days' treatment. In herpes zoster stromal disease cases 78% had epithelial involvement, 54 of 57 responded to topical antivirals alone without the use of steroids, 2% recurred, and treatment averaged a total of 62 days. If steroids were used alone or in combination with antivirals, there was a 50% recurrence rate and 200 day total treatment duration.

Severe herpes zoster ophthalmicus in young African adults: a marker for HTLV-III seropositivity.

This report proves the relationship between herpes zoster ophthalmicus and seropositivity for HTLV-III in young and often apparently healthy African patients. The ophthalmologist should screen patients with herpes zoster ophthalmicus for antibodies against HTLV-III in areas where this virus is endemic or if the patient belongs to a known risk group. If the test is positive, the patient should be instructed about the infectious nature of his condition to prevent spread of this sexually transmitted disease. As the rate of corneal involvement and postherpetic neuralgia are very high in these patients, it would be worthwhile to ascertain whether routine use of acyclovir treatment in HTLV-III seropositive patients with herpes zoster has a beneficial effect on these complications.

Immune deviation and ocular infections with varicella zoster virus.

Since experimental, herpes simplex virus-induced acute retinal necrosis (ARN) develops in mice only if the mice fail to acquire virus-specific delayed hypersensitivity (DH) and despite their production of anti-viral antibodies (i.e. ACAID), I investigated whether a similar situation exists for patients with either varicella zoster virus (VZV)-induced ARN or anterior uveitis caused by VZV. Patients with either acute VZV-induced ARN, anterior uveitis with dermatitis (herpes zoster ophthalmicus, ZO-AU), or anterior uveitis without dermatitis (zoster sine herpete, ZSH-AU) were skin-tested with VZV to evaluate DH. The formal diagnoses of ARN associated with VZV, ZO-AU, and ZSH-AU were established by PCR analysis of the ocular samples and/or by the Goldmann-Witmer coefficient to determine levels of local antibody production. ARN, ZO-AU, and ZSH-AU activity were assessed clinically, and DH skin tests were repeated three months after onset when ocular recovery had taken place. All patients with VZV-induced skin disease alone (control group) displayed intense DH when tested with VZV antigen. In contrast, subsets of patients with ARN or ZO-AU displayed loss of VZV-specific DH. Patients with the most severe ARN or ZO-AU had the lowest DH responses to VZV antigens. Serum anti-VZV antibody titers were higher in ARN patients than in normal controls, and the anti-viral titer correlated inversely with the intensity of anti-VZV DH responses. VZV-specific DH responses were restored in patients who recovered from ARN. Patients with ZSH-AU also failed to display VZV-specific DH. The absence of DH reactivity to VZV antigens (i.e. immune deviation) appears to be a concomitant feature of VZV uveitis of high intensity, implying that virus-specific DH may interfere with the emergence of VZV-induced ARN or anterior uveitis.

The diagnostic significance of enzyme linked immuno-sorbent assay for herpes simplex, varicella zoster and cytomegalovirus retinitis.

PURPOSE: To evaluate the diagnostic usefulness of enzyme linked immuno-sorbent assay (ELISA) in single serum samples to associate herpes simplex virus (HSV), varicella zoster virus (VZV) or cytomegalovirus (CMV) with viral retinitis as against polymerase chain reaction (PCR) on intraocular specimens. It was also designed to study the seroprevalence in normal healthy individuals, and the genomic prevalence of HSV, VZV and CMV in patients without an active viral inflammatory process. METHODS: PCR for the detection of HSV, VZV and CMV genomes was done on 33 and 90 intraocular fluids from viral retinal patients and non-viral controls respectively. ELISA was done on 30 and 100 serum samples from viral retinitis patients and normal healthy controls respectively. RESULTS: PCR did not detect HSV, VZV and CMV genomes except one, in which VZV-DNA was detected. ELISA showed prevalence rates of 28%, 83% and 90% for antibodies against HSV, VZV and CMV respectively in the normal population. In the 30 viral retinitis patients, PCR detected HSV-DNA in 2 (6.7%), VZV-DNA in 7 (23.3%) and CMV-DNA in 6 (20.0%) patients, while ELISA detected antibodies against HSV, VZV and CMV in 13 (43.3%), 24 (80.0%) and 23 (76.7%) patients respectively. ELISA was of value in indirect diagnosis only in 6 (20.0%) as compared to 15 (50.0%) of 30 patients by PCR, this difference was statistically significant (McNemar test, P value = 0.005). CONCLUSION: Serology by ELISA is no longer a useful diagnostic tool to associate HSV, VZV and CMV viruses with viral retinitis.

Ophthalmic manifestations of herpes zoster virus in patients with multiple myeloma following bone marrow transplantation.

We report three patients with ophthalmic herpes zoster (HZ) manifestations on the background diagnosis of multiple myeloma (MM). It seems that immunocompromised status has caused reactivation of the varicella zoster virus (VZV) producing a well-characterised neurological syndrome and subsequent postherpetic neuralgia in two patients. One patient experienced lymphocytic leptomeningitis resulting in unilateral optic neuritis. All patients received similar myeloma disease-specific treatment prior to HZ reactivation. All patients were treated with thalidomide and steroids, and they thereafter underwent autologous stem cell transplantation. Prior to HZ reactivation they received new immunomodulatory drugs in the form of thalidomide in addition to bortezomib (2 patients) and lenalidomide (1 patient). Immediate specific antiviral therapy was successfully applied with intravenous acyclovir for 10 days, followed by long-term oral famciclovir maintenance. Two patients progressed to have chronic HZ ophthalmicus and postherpetic neuralgia requiring ongoing antiviral therapy and neuroepileptic medications for the neuropathic pain.