The purpose of this paper was to present a case series of self-limiting, peripheral acute retinal necrosis and to demonstrate efficacy of treatment with valacyclovir in patients resistant to acyclovir. The diagnosis was made on ophthalmoscopic examination and positive serum tests for herpes viruses.
Ten patients (6F and 4M) aged 19–55 years were diagnosed and treated for self-limiting acute retinal necrosis (ARN). The following endpoints were reported: visual outcomes, clinical features, disease progression, treatment, and complications. Patients received only symptomatic treatment because they did not consent to vitreous puncture.
Peripheral, mild retinitis was diagnosed in all eyes at baseline. Initially, all patients were treated with systemic acyclovir (800 mg, 5 times a day), prednisone (typically 40–60 mg/day), and aspirin in an outpatient setting. In 6 patients, treatment was discontinued at 6 months due to complete resolution of the inflammatory process. Four patients with immune deficiency showed signs and symptoms of chronic inflammation. Two patients did not respond to acyclovir (2 non-responders); however, those patients were successfully treated with valacyclovir. Complete resolution of inflammatory lesions was observed in 8 patients. In 2 patients, the disease progressed despite treatment – 1 female patient after kidney transplant who stopped the prescribed medications, and 1 male patient with SLE and antiphospholipid syndrome who experienced breakthrough symptoms on-treatment. He died due to cerebral venous sinus thrombosis. Neurological complications (encephalitis and meningitis) were observed in 2 female patients. Prophylactic laser photocoagulation was performed in 1 subject.
A series of cases of self-limiting acute retinal necrosis (ARN) is presented. This clinical form of ARN can resemble toxoplasmic retinitis in some cases. Oral antiviral medications provide an effective alternative to intravenous formulations in patients with self-limiting ARN. Retinitis is associated with the risk of encephalitis.
Acyclovir - analogs & derivatives; Acyclovir - standards; Acyclovir - therapeutic use; Central Nervous System Viral Diseases - cerebrospinal fluid; Central Nervous System Viral Diseases - etiology; Retinitis
To determine the incidence, methods of diagnosis, treatment strategies and outcomes for acute retinal necrosis (ARN) in the UK.
A 12‐month active case ascertainment study was carried out between March 2001 and March 2002 to record cases of ARN presenting to ophthalmologists via the British Ophthalmological Surveillance Unit (BOSU) reporting system. Questionnaires were sent to the reporting consultants, requesting data on patient characteristics, presentation, clinical findings, investigations and treatment. Diagnosis was made using the American Uveitis Society diagnostic criteria. Further questionnaires were sent at 2 weeks and 6 months to assess outcome and therapies.
74 cases of ARN were reported by 58 consultants between March 2001 and March 2002. Questionnaires were returned for 49 cases (66.2%), of which 18 (36.7%) were excluded. Of the 31 cases included, 22 (71.0%) were male and 9 (29.0%) were female. The age range was 13 to 85 years (mean 54.3 years). 28 cases (90.3%) were unilateral, with 3 patients (9.7%) presenting with bilateral ARN.
An aqueous or vitreous biopsy was performed in only 18 patients, with one patient having both. Herpes viral DNA analysis was performed on all 19 biopsies, with identification of the viral DNA in 16; results from 3 biopsies were not documented. Varicella zoster virus (VZV) was the commonest cause identified in 10 patients (56%).
Of the 31 subjects, 27 (87.1%) were treated for ARN with systemic antiviral treatment: with intravenous antiviral in 23 cases (85.2%) and oral antiviral in 4 cases (14.8%). 21 of these patients went on to receive oral antiviral maintenance therapy. In addition to antiviral treatment, systemic steroids were given to 16 subjects (51.6%). Surgical intervention for retinal detachment was performed on 5 patients.
During the 12‐month study period, 31 cases of ARN met the diagnostic criteria set by the American Uveitis Society. The incidence in the UK based on this study is approximately 1 case per 1.6 to 2.0 million population per year. We have ascertained that the management of ARN throughout the UK is variable, suggesting that national guidelines would be of benefit.
Valacyclovir, an orally administered pro-drug of acyclovir, is utilized in the therapy of herpes simplex and herpes zoster infections. Little data regarding the pharmacokinetics, safety and tolerability are available for pediatric patients. This report describes acyclovir pharmacokinetics following valacyclovir administration in immunocompromised pediatric patients, compares pharmacokinetic parameters following oral valacyclovir and IV acyclovir, and provides a limited assessment of efficacy in the setting of active herpes zoster infection.
A total of 37 immunocompromised children were enrolled on one of two studies. Pharmacokinetic data are available for 32 patients following valacyclovir (15 mg/kg) administration, 11 of whom also had pharmacokinetic sampling following IV acyclovir administration. Three patients received valacyclovir as treatment for herpes zoster infections.
Mean (± SD) Cmax values for acyclovir following oral valacyclovir were 18.8 ± 7 uM with a total exposure of 4106 ± 1519 uM•min. The mean bioavailability of acyclovir from valacyclovir was 64%. Grade 1 nausea and emesis, which occurred in 5 patients was the only valacyclovir-related toxicity. Two of the three patients treated for herpes zoster had complete scabbing of lesions by day 9.
Valacyclovir (15 mg/kg) was well tolerated in pediatric patients and demonstrated excellent bioavailablity. Consideration should be given to the use of oral valacyclovir for the treatment of herpes zoster in clinically stable pediatric oncology patients.
valacyclovir; acyclovir; pediatrics; pharmacokinetics
To compare the efficacy of prophylactic vitrectomy for acute retinal necrosis syndrome(ARN) with routine treatment in Chinese patients, thereby investigate the necessity of prophylactic vitrectomy for ARN.
Thirty patients (37 eyes) were retrospectively included in this study. The eyes were divided into 2 groups by treatment, including routine treatment, which consisted of antiviral medication and vitrectomy after retinal detachment (RD) (n=21), and prophylactic vitrectomy, which consisted of antiviral medication and vitrectomy for the prevention of RD performed during the active inflammatory phase (n=16). The extent of necrosis was determined by fundus photographs at the time of presentation (for eyes with mild vitreous opacity) or the drawings in the operation records. Necrosis of the 37 eyes was divided into 3 grades, including peripheral, middle-peripheral and extensive. The follow-up period ranged from 8 to 57 months. Differences in visual acuity and necrosis between groups were identified using independent samples t-test.
Necrosis was more extensive in the routine treatment group than in the prophylactic vitrectomy group (P<0.05). In the routine treatment group, conservative treatment improved necrosis and prevented RD in 6 eyes (29%). Seven eyes (33%) obtained anatomical success, but retinal redetachment occurred in 8 eyes (57%). There were also 5 eyes (24%) developed ocular hypotony or atrophy. Ten eyes (48%) achieved equal or increased visual acuity. In the prophylactic vitrectomy group, RD occurred in 2 eyes (13%). Twelve eyes (75%) were completely anatomically successful, and 10 eyes underwent silicone oil removal. Only one eye (6%) became ocular hypotony. Fourteen eyes (88%) achieved equal or increased visual acuity. The prophylactic vitrectomy group achieved better vision trends than the routine treatment group (P<0.05). Eyes with peripheral necrosis had better visual outcomes than those with mid-peripheral (P<0.05) or extensive (P<0.05) necrosis. However, there was no significant difference between eyes with mid-peripheral and extensive necrosis (P=0.3008)
Prophylactic vitrectomy can prevent RD and improve the prognosis of ARN, making it an option for cases with rapidly progressing necrosis despite antiviral treatment and cases with moderate to extensive necrosis and severe vitreous opacity.
acute retinal necrosis; prophylactic vitrectomy; retinal detachment; visual acuity
PURPOSE: A variety of factors have been reported as inducing the reactivation of latent herpes simplex virus (HSV), among them stress, trauma, and UV radiation. Excimer laser photorefractive keratectomy (PRK) is a surgical procedure utilizing a 193 nm ultraviolet light to alter the curvature of the cornea and hence correct vision. Reactivation of ocular herpes simplex keratitis following such excimer laser PRK has been reported. All published cases of HSV reactivation following excimer laser treatment in humans are reviewed. The present study evaluates whether stress, trauma of the corneal de-epithelialization prior to the laser, or the excimer laser treatment itself to the stromal bed induces this ocular reactivation of the latent HSV, and whether a systemic antiviral agent, valacyclovir, would prevent such laser PRK-induced reactivation of the HSV. METHODS: Forty-three normal 1.5- to 2.5-kg New Zealand white rabbits were infected on the surface of the cornea with HSV-1, strain RE. The animals were monitored until resolution, and then all animals were divided into 5 treatment groups: (1) de-epithelialization only, intraperitoneal (i.p.) saline for 14 days; (2) de-epithelialization plus laser, i.p. saline for 14 days; (3) de-epithelialization plus laser, valacyclovir 50 mg/kg per day i.p. for 14 days; (4) de-epithelialization plus laser, valacyclovir 100 mg/kg per day i.p. for 14 days; (5) de-epithelialization plus laser, valacyclovir 150 mg/kg per day i.p. for 14 days. Animals were evaluated in a masked fashion by clinical examination biweekly and viral cultures biweekly through day 28. RESULTS: The reactivation rates were as follows: group 1, 0%; group 2, 67%; group 3, 50%; group 4, 17%; and group 5, 0%. Viral titers were negative in animals that had no reactivation but persistently positive in those that had reactivation (day 6 through day 28). CONCLUSIONS: Excimer laser (193 nm) treatment can trigger reactivation of ocular herpes disease (67%) and viral shedding in the latently infected rabbit. De-epithelialization alone is not sufficient to cause reactivation or viral shedding. Prophylaxis with intraperitoneal valacyclovir decreases the recurrence rate in a dose-response fashion. At 150 mg/kg per day, there are no recurrences. The presence of persistent viral shedding in reactivated animals may correlate with cases of late HSV recurrence reported in humans undergoing excimer treatment. The data suggest that humans undergoing excimer laser procedures for correction of refractive errors or treatment of corneal scars with a history of herpetic keratitis are at increased risk for reactivation. Such patients, however, may appropriately be considered for prophylactic systemic antiviral medication at the time of the laser procedure in order to decrease the possibility of recurrence.
OBJECTIVE: To evaluate the frequency of ocular complications and the clinical outcomes of these complications in patients with various stages of HIV infection. METHODS: Retrospective review of all HIV-infected patients seen in an AIDS ophthalmology clinic from November 1983 through December 31, 1992. RESULTS: Eleven-hundred sixty-three patients were seen for ophthalmologic evaluation. Of these, 781 had the acquired immune deficiency syndrome (AIDS), 226 had symptomatic HIV infection (AIDs-related complex [ARC]), and 156 had asymptomatic HIV infection. Non-infectious HIV retinopathy was the most common ocular complication, affecting 50% of the patients with AIDS, 34% of the patients with ARC, and 3% of the patients with asymptomatic HIV infection. Cytomegalovirus (CMV) retinitis was the most common opportunistic ocular infection, affecting 37% of the patients with AIDS. Other opportunistic ocular infections, including ocular toxoplasmosis, varicella zoster virus retinitis, and Pneumocystis choroidopathy were all much less common, each occurring in < or = 1% of the patients with AIDS. Treatment of CMV retinitis with either foscarnet or ganciclovir was successful in initially controlling the retinitis. However, relapse represented a significant problem and required frequent re-inductions. As a consequence of the retinal damage associated with relapse, loss of visual acuity occurred. The median time to a visual acuity of 20/200 or worse for all eyes with CMV retinitis was 13.4 months, and the median time to a visual acuity of 20/200 or worse in the better eye was 21.1 months. At last follow-up, 75% of the patients had a final visual acuity of 20/40 or better in at least one eye. Retinal detachments were a frequent ophthalmologic complication of CMV retinitis with a cumulative probability of a retinal detachment in at least one eye of 57% at 12 months after the diagnosis of CMV retinitis. Herpes zoster ophthalmicus developed in 3% of the overall series and was seen in all stages of HIV infection. Fifty-six percent of the cases of ocular toxoplasmosis had simultaneous toxoplasmic cerebritis. Ocular toxoplasmosis responded to standard anti-microbial therapy. Varicella zoster virus retinitis, when manifested by the acute retinal necrosis (ARN) syndrome, responded to intravenous acyclovir therapy. Conversely, in a limited number of patients with the progressive outer retinal necrosis syndrome, the disease responded poorly to intravenous acyclovir therapy, but appeared to respond to combination foscarnet and acyclovir therapy. Neuro-ophthalmic lesions were present in 6% of the patients with AIDS. The most common cause of a neuro-ophthalmic lesion was cryptococcal meningitis, and 25% of the patients with cryptococcal meningitis developed a neuro-ophthalmic complication. CONCLUSIONS: Ocular manifestations are common in patients with AIDS. CMV retinitis represented a major vision-threatening problem in these patients. While available therapy was successful in initially controlling the retinitis, the phenomenon of relapse resulted in some degree of long-term visual loss. Preservation of the patient's visual acuity in at least one eye was generally successful. Other opportunistic ocular infections were substantially less common than CMV retinitis but require aggressive therapy.
Central serous chorioretinopathy (CSC) has been traditionally treated with laser photocoagulation. We thought that transpupillary thermotherapy (TTT) utilizing a lower temperature than that of conventional laser photocoagulation might minimize permanent retinal and choroidal damage. Studies suggest that undesirable effects on vision due to TTT are minimal even if it is applied to foveal and/or parafoveal lesions when TTT requires a larger irradiation spot. The aim of this study was to evaluate the efficacy of TTT in the management of atypical CSC.
We defined atypical CSC as bullous retinal detachment with diffuse or several leakages, severe leakage with fibrin formation under serous retinal detachment, or leakage within a pigment epithelium detachment. Eight consecutive patients with atypical CSC underwent visual acuity testing, ophthalmic examination, color photography, fluorescein angiography, and optical coherence tomography to evaluate the results of transpupillary thermotherapy. Retreatment of atypical CSC was based on ophthalmic examination, optical coherence tomography, and fluorescein angiography. TTT was performed on the leaking spots shown in fluorescein angiography, with a power of 50–250 mW, spot size of 500–1200 μm, and exposure time of 13–60 seconds to minimize retinal damage.
In five of eight affected eyes, serous detachments completely resolved within 1 month after the initial TTT. One eye had persistent subretinal fluid and required a second TTT treatment. Two eyes showed no resolution of CSC and were treated by conventional photocoagulation. Initial best-corrected visual acuity (BCVA) ranged from 20/600 to 20/20 (mean, 20/40; median, 20/30). Final BCVA ranged from 20/200 to 20/20 (mean, 20/25; median, 20/20). BCVA improved in all cases. Only two eyes with persistent subretinal fibrin and existing retinal pigment epithelial alternations in macular area showed limited improvement of BCVA despite the absence of subretinal exudation. The presence of retinal attachment was confirmed by optical coherence tomography in six eyes (75%).
TTT seems to be effective for the treatment of atypical CSC in the short term. Additional studies are necessary to evaluate the long-term effectiveness and safety.
transpupillary thermotherapy; central serous chorioretinopathy; optical coherence tomography; fluorescein angiography; serous detachment
Oral valacyclovir is better absorbed than oral acyclovir, increasing acyclovir bioavailability three- to fivefold. This provides the opportunity to explore whether high systemic acyclovir concentrations are effective in the treatment of cold sores (herpes labialis). Two randomized, double-blind, placebo-controlled studies were conducted. Subjects were provided with 2 g of valacyclovir twice daily for 1 day (1-day treatment), 2 g of valacyclovir twice daily for 1 day and then 1 g of valacyclovir twice daily for 1 day (2-day treatment), or a matching placebo and instructed to initiate treatment upon the first symptoms of a cold sore. In study 1, the median duration of the episode (primary endpoint) was reduced by 1.0 day (P = 0.001) with 1-day treatment and 0.5 days (P = 0.009) with 2-day treatment compared to placebo. Similarly, the mean duration of the episode was statistically significantly reduced by 1.1 days with 1-day treatment and 0.7 days with 2-day treatment compared to placebo. The proportion of subjects in whom cold sore lesion development was prevented and/or blocked was increased by 6.4% (P = 0.096) with 1-day treatment and 8.5% (P = 0.061) with 2-day treatment compared to placebo. The time to lesion healing and time to cessation of pain and/or discomfort were statistically significantly reduced with valacyclovir compared to placebo. In study 2, results similar to those in study 1 were obtained. AEs were similar across treatment groups. These studies provide evidence supporting a simple, 1-day valacyclovir treatment regimen for cold sores that is safe and effective. The 1-day valacyclovir regimen offers patients a unique and convenient dosing alternative compared to available topical therapies.
To compare the outcomes of combination systemic and intravitreal antiviral therapy vs systemic antiviral therapy alone for treating acute retinal necrosis syndrome (ARN). We hypothesize that combination therapy might result in superior visual acuity (VA) and retinal detachment (RD) outcomes vs traditional systemic antiviral therapy alone.
A retrospective, interventional, comparative single-center study of patients with ARN. We reviewed demographic data, herpesvirus diagnoses, polymerase chain reaction (PCR) results, VA, RD, and the use of systemic and intravitreal antiviral therapy. Outcome measures included VA improvement by 2 or more lines, severe visual loss, VA ≤20/200, and RD.
We studied 29 eyes of 24 patients, treated from 1987 through 2009. Mean age was 42.6 years and mean follow-up was 44.0 months. Twelve patients (14 eyes) were treated with combined systemic and intravitreal antiviral therapy and 12 patients (15 eyes) with systemic therapy alone. Kaplan-Meier survival analysis revealed that patients receiving combination intravitreal and systemic antiviral therapy were more likely to have VA improved by 2 lines or greater (P=.006). Patients receiving combination therapy also showed a decreased incidence of progression to severe visual loss (0.13/patient-years [PY]) compared to patients receiving systemic therapy alone (0.54/PY, P=.02) and had decreased incidence of RD (0.29/PY vs 0.74/PY, P=.03).
Combination oral and intravitreal antiviral therapy may improve visual and functional outcomes in patients with ARN. Clinicians should consider prompt administration of combination systemic and intravitreal antiviral therapy as first-line treatment for patients with clinical features of ARN.
Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken.
Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted.
Patients and Methods
Children 3–15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome.
We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course.
We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral loads that decreased over the course of their treatment, suggesting that phase II studies should investigate this correlation further. This study paves the way for a phase II efficacy trial of combined valacyclovir and CPM in the treatment of endemic Burkitt lymphoma.
Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O6-methylguanine–DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect.
Patients and Methods
Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 1010, 1 × 1011, or 3 × 1011 vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment.
Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3+ T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months.
AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.
To identify predictive factors for improvement of visual acuity and central retinal thickness by intravitreal bevacizumab for the treatment of macular edema (ME) due to branch retinal vein occlusion (BRVO).
Two hundred and five eyes from 204 patients with ME secondary to BRVO were retrospectively included at six sites. All eyes received intravitreal bevacizumab therapy (1.25 mg/0.05 ml). The mean follow-up was 36.8 ± 12.7 weeks (range, 18 to 54 weeks). Measurement of ETDRS best-corrected visual acuity (BCVA, in all eyes) and optical coherence tomography (OCT, in 87% of eyes) were performed at baseline and at follow-up examinations every 12 weeks. Using fluorescein angiography, the perfusion status of the macula at baseline could be assessed in 84% of the eyes. The main outcome measures were changes in BCVA and central retinal thickness (CRT). For analysis of predictive factors, the results at 24 weeks were used.
The median BCVA was 0.6 LogMAR at baseline and improved to 0.4 LogMAR at 24 and 48 weeks. This visual improvement was associated by a significant reduction in CRT, decreasing from a baseline of 454 μm to 267 μm and 248 μm after 24 and 48 weeks respectively. Eyes with ME and intact (perfused) or interrupted (ischemic) foveal capillary ring showed a 2-line increase of median BCVA [45 eyes (22%) and 128 eyes (62%) respectively]. However, the final median BCVA was significantly worse in eyes with ischemic ME (0.6 versus 0.3 logMAR in perfused ME). Other factors for visual improvement were absence of previous treatments of the ME, age younger than 60 years and low baseline BCVA (≥0.6 logMAR) (2, 3, and 2 median BCVA lines increase respectively). Furthermore, eyes with duration of the ME of less than 12 months responded with a 3-line increase of the median BCVA. Final CRT only showed minor differences between the subgroups. During the entire follow-up, retreatments were performed in 85% of the eyes, with a median number of injections of three (mean 3.2; range, 1 to 10) and a median time-interval between injections of 11.6 weeks (mean 14.6 weeks).
Intravitreal injection of bevacizumab resulted in a significant improvement of BCVA and reduction of ME in BRVO. Baseline BCVA, patient’s age, and duration of BRVO were found to be of prognostic relevance for visual improvement. A less favorable outcome of the bevacizumab therapy in eyes with longstanding BRVO would advocate initiation of treatment within 12 months after onset.
Macular edema; Bevacizumab; Branch retinal vein occlusion; Intravitreal therapy; Predictive factors; Prognostic facotrs for visual improvement
To report the optical coherence tomography (OCT) findings of 27 eyes treated with intravitreal bevacizumab for intraretinal and subretinal vascular activity associated with atypical choroidal nevi.
This was an Internal Review Board-approved retrospective review of 27 eyes of 27 patients with choroidal nevus treated for secondary vascular activity with intravitreal injections of bevacizumab, performed by a single surgeon (TGM) at the Bascom Palmer Eye Institute. All patients were rigorously evaluated before the procedure and followed thereafter with ophthalmic examinations, refractive analysis, fundus photos, optical coherence tomography (OCT), and ocular echography. Patient demographics, tumor characteristics, dates of bevacizumab injections, and spectral-domain (SD)-OCT findings at each injection were recorded. Macular edema was graded as per SD-OCT findings for the initial and final visit.
The mean age was 66.6 years (range, 40–86 years), with ten males and 17 females. Mean, median, and range baseline best corrected visual acuity (BCVA) were 20/53, 20/40, and 20/20–4/200, respectively. After a mean follow up of 29 months, the final BCVA mean, median, and range were 20/50, 20/40, and 20/20–20/400, respectively. The final BCVA ranged from 20/20 to 20/25 in nine eyes, while only six eyes had an initial BCVA within the same range. All patients demonstrated OCT findings of vascular activity suggestive of choroidal neovascularization (CNV). Initial SD-OCT findings included intraretinal cysts in eleven eyes, intraretinal fluid in six eyes, subretinal fluid in 14 eyes, pigment epithelial detachment in six eyes, epiretinal membrane in five eyes, and subretinal neovascularization in 14 eyes. On fundus photos, four eyes presented retinal hemorrhage. A mean of eight (range of 1–31) intravitreal bevacizumab (1.25 mg/0.05 cc) injections were given in all cases. A total of 37% (10/27) of eyes had complete or partial regression of vascular activity. The mean initial OCT classification for macular edema was 3 and a mean grade of 3 was maintained at the final follow-up OCT. All 27 choroidal nevi remained stable, and there were no adverse effects from the bevacizumab injections.
To our knowledge, this is the largest published case series of eyes treated with intravitreal bevacizumab for vascular activity associated with choroidal nevus. Intravitreal bevacizumab seems to be effective in the treatment of CNV secondary to choroidal nevus, and OCT can be a useful tool in the follow up of these patients, to assess the regression of CNV and to monitor macular edema.
macular edema; choroidal neovascularization; subretinal fluid; optical coherence tomography
Aim: To determine an aetiological diagnosis in patients presenting with necrotising retinopathies that simulate acute retinal necrosis (ARN).
Methods: Retrospective non-comparative case series. The charts of 16 patients presenting with a clinical impression of ARN at Pitié-Salpêtrière Hospital, Paris, France, between 1994 and 1999, who required initial antiviral therapy were reviewed. All of the patients had extensive laboratory tests. Anterior chamber paracentesis was performed on 14 patients and evaluated by polymerase chain reaction (PCR) and/or the Witmer-Goldmann coefficient to determine the cause of retinitis. Three of the 14 cases also had diagnostic vitrectomy. Responses to specific treatment, initiated based on laboratory results, and the final outcome were evaluated.
Results: Seven of the 16 patients were female and nine were male. The retinitis was bilateral in five patients and unilateral in 11 patients. The average age of the patients at presentation was 53.6 years. 13 patients were immune deficient for various reasons. Upon initial presentation, the patients’ visual acuities were less than 20/200 in 68% of the affected eyes. The final diagnoses, based on laboratory data and therapeutic response were toxoplasmic retinochoroiditis (62.5%), syphilitic retinitis (12.5%), aspergillus endophthalmitis (12.5%), Behçet’s disease (6.2%), and intraocular lymphoma (6.2%). Visual acuity was stabilised or improved in 12 patients (75%). Two patients with aspergillosis died despite antifungal therapy.
Conclusions: Toxoplasmic retinochoroiditis is the major cause of retinal necrosis that simulates ARN, and PCR analysis of the aqueous humour is helpful in establishing the diagnosis. Such atypical toxoplasma retinochoroiditis may be associated with poor visual outcome.
necrotising retinopathies; retinal necrosis syndrome; Behçet’s disease; syphilis; toxoplasmosis
Episodic therapy of genital herpes is usually recommended for patients with infrequent symptomatic recurrences and where transmission is not a concern. While shorter courses are as effective as standard 5-day regimens, it is unknown whether abbreviated therapy has detrimental effects on natural history and the development of antiviral resistance.
To assess time to next recurrence and development of antiviral resistance in patients with recurrent genital herpes treated with either single-day famciclovir (1 g twice-daily) or 3-day valacyclovir (500 mg twice-daily).
Longer-term, follow-up data on the time to next recurrence and antiviral sensitivity were collected from a previously reported multicenter, multinational, double-blind, parallel group study in which 1179 immunocompetent adults were randomized 1:1 to receive either single-day famciclovir or 3-day valacyclovir. Treatment was self-initiated within 6 hours of a recurrence. Swabs for viral culture and sensitivity testing were collected for two sequential recurrences.
The median time to next recurrence from treatment initiation was 33.5 days for famciclovir and 38.0 days for valacyclovir. No drug resistance to penciclovir, the active metabolite of famciclovir, was observed at baseline nor did any develop by the time of the next recurrence.
The study had no placebo arm, typing of viral isolates was not performed and viral resistance testing was restricted to penciclovir only.
Treatment with single-day famciclovir for recurrent genital herpes did not shorten the time to the next recurrence. Drug resistance to penciclovir continues to be a rare event in immunocompetent patients.
Drug resistance; Famciclovir; Genital herpes; Single-day therapy; Time to next recurrence
Poor oral absorption is one of the limiting factors in utilizing the full potential of polar antiviral agents. The neuraminidase target site requires a polar chemical structure for high affinity binding, thus limiting oral efficacy of many high affinity ligands. The aim of this study was to overcome this poor oral absorption barrier, utilizing prodrug to target the apical brush border peptide transporter 1 (PEPT1). Guanidine oseltamivir carboxylate (GOCarb) is a highly active polar antiviral agent (prodrug) with insufficient oral bioavailability (4%) to be an effective therapeutic agent. In this report we utilize a carrier-mediated targeted prodrug approach to improve the oral absorption of GOCarb.
Acyloxy(alkyl) ester based amino acid linked prodrugs were synthesized and evaluated as potential substrates of mucosal transporters e.g. PEPT1. Prodrugs were also evaluated for their chemical and enzymatic stability. PEPT1 transport studies included [3H]Gly-Sar uptake inhibition and cellular uptake experiments using HeLa cells over-expressing PEPT1. The intestinal membrane permeability of the selected prodrugs and the parent drug were then evaluated for epithelial cell transport across Caco-2 monolayers, and in the in-situ rat intestinal jejunal perfusion model.
Prodrugs exhibited a pH dependent stability with higher stability at acidic pHs. Significant inhibition of uptake (IC50 <1mM) was observed for L-valyl and L-isoleucyl amino acid prodrugs in competition experiments with [3H]Gly-Sar, indicating a 3–6 times higher affinity for PEPT1 compared to valacyclovir; a well-known PEPT1 substrate and >30 fold increase in affinity compared to GOCarb. The L-valyl prodrug exhibited significant enhancement of uptake in PEPT1/HeLa cells, and compared favorably with the well absorbed valacyclovir. Transepithelial permeability across Caco-2 monolayers showed that these amino acid prodrugs have a 2–5 fold increase in permeability as compared to the parent drug and showed that the L-valyl prodrug (Papp = 1.7×10−6 cm/sec) has the potential to be a rapidly transported across the epithelial cell apical membrane. Significantly, only the parent drug (GOCarb) appeared in the basolateral compartment, indicating complete activation (hydrolysis) during transport. Intestinal rat jejunal permeability studies showed that L-valyl and L-isoleucyl prodrugs are highly permeable compared to the orally well absorbed metoprolol, while the parent drug had essentially zero permeability in the jejunum, consistent with its known poor low absorption.
Prodrugs were rapidly converted to parent in cell homogenates suggesting their ability to be activated endogenously in the epithelial cell, consistent with the transport studies. Additionally, L-valyl prodrug was found to be a substrate for valacyclovirase (Km=2.37 mM) suggesting a potential cell activation mechanism.
Finally we determined the oral bioavailability of our most promising candidate, GOC-L-Val, in mice to be 23% under fed conditions and 48% under fasted conditions.
In conclusion, GOC-L-Val prodrug was found to be a very promising antiviral agent for oral delivery. These findings indicate that the carrier-mediated prodrug approach is an excellent strategy for improving oral absorption of polar neuraminidase inhibitors. These promising results demonstrates that the oral peptide transporter-mediated prodrug strategy has enormous promise for improving the oral mucosal cell membrane permeability of polar, poorly absorbed antiviral agents and treating influenza via the oral route of administration.
Prodrugs; valacyclovirase; PEPT1; influenza; neuraminidase; oral absorption; intestinal permeability; antiviral; oseltamivir; transporter; stability; caco-2 permeability; glysar; rat perfusion
This study aims to report a case of traumatic maculopathy in a 12-year-old male following blunt trauma in his left eye (LE) who presented 6 months after injury.
Retrospective and descriptive case report based on data from clinical records, patient observation and analysis of diagnostic tests.
A previously healthy, 12-year-old male presented for a routine visit with complaints of a 2-month history of decreased visual acuity in his LE. Six months before the initial visit, he suffered blunt trauma to the LE during a struggle and had no medical observation. At the visit, best-corrected visual acuity (BCVA) in the LE was counting fingers and in the right eye, it was 20/20. Fundus examination of the LE showed a central macular lesion of 1 disc diameter with fibrosis, increased retinal thickness and intraretinal hemorrhage. Optical coherence tomography showed disruption of the inner/outer segment (IS/OS) photoreceptor junction, increased reflectivity, cell infiltration of the retinal wall and retinal pigment epithelium detachment. Retinal thickness was 289 μm at the site of the lesion. A fluorescein angiogram revealed early impregnation and late diffusion. High-dose steroid pulse therapy (intravenous methylprednisolone 500 mg for 3 days and oral prednisolone 30 mg, tapering for 10 days) was done. LE BCVA increased to 20/200, and retinal thickness decreased by 71 μm 1 week after treatment. Off-label intravitreal triamcinolone (IVTA; 0.05 ml/2 mg) was administered 2 weeks after oral treatment in an attempt to achieve additional improvement. Three weeks after IVTA, LE BCVA improved to 20/150 and retinal thickness decreased by 10 μm. Three months after the initial visit, LE BCVA was 20/125 and retinal thickness 208 μm.
We present a case of commotio retinae caused by an ocular blunt trauma 6 months before, with loss of BCVA. BCVA improved after oral steroids and IVTA. Nevertheless, fibrosis and disruption of the IS/OS junction in the macula limited the gain of BCVA.
Traumatic maculopathy; Commotio retinae; Intravitreal triamcinolone acetonide
To determine the incidence of acute retinal necrosis (ARN) in the United Kingdom and to describe the demographics, management, and visual outcome in these patients.
This was a prospective study carried out by the British Ophthalmological Surveillance Unit (BOSU) between September 2007 and October 2008. Initial and 6-month questionnaires were sent to UK ophthalmologists who reported cases of ARN via the monthly BOSU report card system.
In all, 45 confirmed cases (52 eyes) of ARN were reported in the 14-month study period, giving a minimum incidence of 0.63 cases per million population per year. There were 20 females and 25 males. Age ranged from 10 to 94 years. Eight patients had a history of herpetic CNS disease. Aqueous sampling was carried out in 13 patients, vitreous in 27, and cerebrospinal fluid (CSF) in 4. Varicella-zoster virus followed by herpes simplex were the most common causative agents. Treatment in 76% of the cases was with intravenous antivirals; however, 24% received only oral antivirals. In all, 47% of patients had intravitreal antiviral therapy. Visual outcome at 6 months was <6/60 in 48% of the affected eyes.
The minimum incidence of ARN in the UK is 0.63 cases per million. Patients with a history of herpetic CNS disease should be warned to immediately report any visual symptoms. There is increased use of oral and intravitreal antivirals in initial treatment.
acute retinal necrosis; retinitis; uveitis; epidemiology; herpes viridae
To report the outcomes of chorioretinectomy in severe ocular injuries where a foreign body penetrated the choroid or perforated the globe.
The study sample consisted of a retrospective, non-comparative, consecutive interventional case series of 13 perforating or severe intraocular foreign body ocular injuries that were treated at a single institution from March 2008 to March 2010. All the patients were operated with 20-gauge three-port pars plana vitrectomy (PPV) by removing the choroid and/or retina with scar tissue at the perforation site of the foreign body. The reports of patients were examined for best-corrected visual acuity, globe survival, retinal detachment status, and proliferative vitreoretinopathy.
A total of 13 eyes of 13 patients with a mean age of 25.8±9.0 years (range, 11–38 years) were followed for a median of 13.8±5.4 months (range, 8–29 months). The mean time period between injury and the vitreoretinal surgery was 13.6±9.3 days. All had an exit/impact site wound, eight of which were located in the posterior pole, which caused choroidal and retinal incarceration in the macular area. PPV together with chorioretinectomy, endolaser applications, silicone oil tamponade, with/without encircling band, and lensectomy surgery was applied to all of them. Final best-corrected visual acuity (BCVA) ≥20/200 occurred in 4 of 13 (30.76%) patients. Globe survival rates were 100% (13 of 13), and final retinal attachment rate was 84.6% (11 of 13). The proliferative vitreoretinopathy rate was 2 of 13 (15.3%).
Chorioretinectomy is a surgical option that may decrease post-traumatic proliferative vitreoretinopathy and tractional retinal detachment rates, thus improving final BCVA and increasing globe survival rates when a foreign body penetrates the choroid and perforates the globe.
ocular trauma; open-globe injury; intraocular foreign body; globe perforation; chorioretinectomy; perforating eye injury
The possible involvement of herpesviruses in the pathogenesis of multiple sclerosis (MS) was recently investigated in a clinical trial of valacyclovir in patients with MS. As an important part of that survey we performed an independent pharmacokinetic study in order to determine the concentration of acyclovir in cerebrospinal fluid (CSF). The concentrations of acyclovir in serum and CSF were measured at steady state after 6 days of oral treatment with 1,000 mg of valacyclovir three times a day. Samples were obtained from 10 patients with MS. All patients had normal renal function, and none had signs of a damaged blood-CSF barrier. The maximum concentration of acyclovir in serum was reached after 1 to 3 h (mean ± standard deviation [SD], 27.1 ± 5.6 μM), and the minimum concentration in serum was 3.1 ± 1.1 μM (mean ± SD). The acyclovir concentrations in CSF at 2 and 8 h were essentially stable, with the mean ± SD levels being 2.5 ± 0.9 and 2.3 ± 0.7 μM, respectively. Similar levels were recorded in serum and CSF samples from five other MS patients after 6 months of oral treatment with valacyclovir at identical dosages. The area under the concentration-time curve (AUC) for acyclovir in CSF to the AUC for acyclovir in serum (CSF/serum AUC ratio) was approximately 20%. We conclude that the improved bioavailability previously reported for valacyclovir in plasma results in higher concentrations in CSF, while the CSF/serum AUC ratio remains constant.
Background: Central serous chorioretinopathy is an idiopathic disorder that leads to serous neurosensory retinal detachment. The disorder is usually self-limited and resolves spontaneously; however, sometimes neurosensory retinal detachment persists. This form of the disorder is called chronic central serous chorioretinopathy (CCSC).
Objective: The aim of this study was to assess the effects of photodynamic therapy (PDT) on visual acuity with full-dose verteporfin for CCSC.
Methods: The eyes of patients with CCSC were included in the study. Ophthalmic examination including best-corrected visual acuity (BCVA), fundus examination, fluorescein angiography, and optical coherence tomography was performed before treatment and at 1, 3, 6, 9, and 12 months. PDT with full-dose verteporfin (6 μ/m2 of body surface area) was applied only to areas of active leakage. BCVA was converted to a log of the minimum angle of resolution (logMAR) equivalent for statistical analysis. Central foveal thickness and BCVA between baseline and follow-up were compared.
Results: Seventeen eyes of 16 patients (13 males, 3 females; mean [SD] age, 39.75 [7.51] years; mean duration of follow-up, 13.06 [1.82] months) were used in the study. The mean (SEM) logMAR BCVA was 0.26 (0.07) at baseline and 0.04 (0.02) at 12 months. Mean logMAR BCVA values at baseline (0.259) and after treatment (0.112, 0.053, 0.047, 0.041, and 0.041 at 1, 3, 6, 9, and 12 months, respectively) differed significantly (P = 0.006, P = 0.005, P = 0.005, P = 0.005, and P = 0.005). There was a significant difference in the mean central foveal thickness at the final visit (169 μm) compared with the baseline value (383 μm; P < 0.001). BCVA decreased in one eye (20/20 vs 20/25) and persisted during follow-up; in the other 16 eyes, BCVA either increased (n = 10) or remained stable (n = 6).
Conclusions: In this small, open-label study, patients with CCSC treated with a single course of PDT with full-dose verteporfin had significant improvement from baseline in BCVA and resolution of subretinal fluid accumulation and active leakage. Treatment was generally well tolerated, but one patient had worsening in BCVA.
central serous chorioretinopathy; photodynamic therapy; optical coherence tomography; verteporfin
A 52-year-old male presented with acute retinal necrosis in his left eye. Slit lamp examination revealed stellate keratic precipitates and cells in the anterior chamber and vitreous. Funduscopy of his left eye revealed multiple yellow deposits. Pathological examination of the vitreous showed both small, reactive lymphocytes and a few macrophages. IL-6 and IFN-γ were elevated in the vitreous. Microdissected macrophages from the vitreous revealed DNAs from multiple viruses. The patient responded to oral valacyclovir. We conclude that multiple viral infections can be involved in the pathogenesis of acute retinal necrosis and that adequate anti-viral therapy has a beneficial effect on disease progression. However, retinal detachment can be a consequence for a poor visual outcome.
Acute retinal necrosis; Viral infection; Anti-viral treatment
To evaluate short term safety of an enhanced photodynamic therapy (PDT) protocol with half dose verteporfin for treating chronic central serous chorioretinopathy (CSC).
20 eyes of 18 patients with symptomatic chronic CSC underwent PDT using 3 mg/m2 verteporfin. Verteporfin was infused over 8 minutes followed by indocyanine green angiography guided laser application 2 minutes later. Serial optical coherence tomography (OCT) and multifocal electroretinography (mfERG) recordings were performed before PDT, at 4 days, 2 weeks, and 1 month after PDT. The best corrected visual acuity (BCVA), OCT central retinal thickness, and mean mfERG response amplitudes and peak latencies were compared longitudinally. Subgroup analysis was further performed for eyes with or without pigment epithelial detachment (PED).
At 1 month after PDT, the median BCVA improved from 20/40 to 20/30 (p = 0.001). The mean central retinal thickness also reduced from 276 μm to 158 μm (p<0.001) and 17 (85%) eyes had complete resolution of serous retinal detachment and/or PED. MfERG showed no significant changes in the mean N1 and P1 response amplitude and latency for all eyes. Subgroup analysis demonstrated that eyes without PED had a significant increase in the mean central mfERG P1 response amplitude with reduction in P1 peak latency at 1 month post‐PDT. For eyes with PED, transient reduction in the mean central P1 response amplitude was observed at 4 days post‐PDT.
The modified safety enhanced PDT protocol with half dose verteporfin appeared to be a beneficial treatment option for patients with chronic CSC, especially in eyes without serous PED. Further controlled study is warranted to demonstrate the long term safety and efficacy of this treatment option.
central serous chorioretinopathy; photodynamic therapy; verteporfin; multifocal electroretinography; optical coherence tomography
Suppressive HSV therapy can decrease plasma, cervical, and rectal HIV-1 levels in HSV-2/HIV-1 co-infected persons. We evaluated the effect of HSV-2 suppression on seminal HIV-1 levels.
Twenty antiretroviral therapy (ART)–naive HIV-1/HSV-2–MSM in Lima, Peru, with CD4 cell counts >200 cells/µL randomly received valacyclovir 500 mg twice daily or placebo for 8 weeks, then the alternative regimen for 8 weeks after a 2 week washout. Peripheral blood and semen specimens were collected weekly. Anogenital swab specimens for HSV DNA were self-collected daily and during clinic visits.
HIV-1 RNA was quantified in seminal and blood plasma by TaqMan real-time polymerase chain reaction (rt-PCR) or Roche Amplicor Monitor assays. HSV and seminal cytomegalovirus (CMV) were quantified by rt-PCR. Linear mixed models examined differences within subjects by treatment arm.
Median CD4 count of participants was 424 cells/µL. HIV-1 was detected in 71% of 231 semen specimens. HSV was detected from 29% and 4.4% of swabs on placebo and valacyclovir, respectively (P<0.001). Valacyclovir significantly reduced the proportion of days with detectable seminal HIV-1 (63% during valacyclovir vs. 78% during placebo, p=0.04). The quantity of HIV-1 in semen was 0.25 log10 copies/mL lower (95%CI −0.40 to −0.10, p=0.001) during the valacyclovir arm compared with placebo, a 44% reduction. CD4 count (p=0.32) and seminal cellular CMV quantity (p=0.68) did not predict seminal plasma HIV-1 level.
Suppressive valacyclovir reduced seminal HIV-1 levels in HIV-1/HSV-2 co-infected MSM not receiving ART. The significance of this finding will be evaluated in a trial with HIV-1 transmission as the outcome.
seminal plasma; HIV-1; viral load; HSV-2; valacyclovir; herpes; blood plasma
A case report of a 68-year-old male who developed acute retinal necrosis (ARN) after Boston type I keratoprosthesis is presented. The procedure was performed for multiple graft failure secondary to herpetic keratitis. Clinical data including visual acuity, color fundus photography, fluorescein angiography, laboratory tests findings, and management are presented. After exclusion of other causes by laboratory workup, the patient was diagnosed with ARN most likely secondary to herpetic infection. Intravenous acyclovir and oral prednisolone were administered to the patient resulting in marked improvement in visual acuity and regression in the size of the retinitis. The patient eventually developed a soft eye and choroidal detachment with light perception vision. In patients with a history of herpetic keratitis or keratouveitis, it is highly advisable to maintain prophylactic systemic antiviral treatment before and after any ocular procedure such as the Boston keratoprosthesis.
Acute Retinal Necrosis; Boston Type I Keratoprosthesis; Herpetic Keratitis; Visual Loss