Study reference

Study characteristics

Patient characteristics

Intervention (I)

Control (C)

Follow-up

Outcome measures and effect size

Comments

Tibbetts, 2010

Type of study:

Retrospective cohort study

Country:

USA

Competing interests:

Jay S. Duker, MD, Consultant: Alcon, Genentech, Ophthotech; Research Support: Topcon

Medical Systems, Carl Zeiss Pharmaceuticals, Optivue; Scientific Advisory Board: Paloma Pharmaceuticals

Inclusion criteria:

Unilateral ARN with minimum follow-up time of 6 months. The diagnosis of ARN was established using criteria established by the American Uveitis Society. Before the publication of the American Uveitis Society guidelines in 1994, inclusion criteria consisted of clinical criteria, including a rapidly progressive necrotizing retinitis, and prominent intraocular inflammation, including vitritis and vasculitis.

Exclusion criteria:

follow-up less than 6 months and bilateral

ARN before initiation of treatment.

Group 1: acyclovir only era

N=36 patients treated during a time when acyclovir was the only available antiviral treatment (1981 to 1997).

Treatment regimen:

Patients were treated initially

with intravenous acyclovir (500 mg/m2 3 times per day) for a

period of 7 to 10 days. Half of the patients (18/36) were further

treated with oral acyclovir 800 mg 5 times per day for at least 6 weeks, whereas the other half were not treated with oral acyclovir. The decision of whether or not to treat with oral acyclovir was dependent on the particular practice pattern of the treating physician and was not influenced by the severity of the disease.

Group 2: newer antiviral era

N=22 patients treated during the era of new antivirals such as valacyclovir and famciclovir (1998 to 2008).

Treatment regimen:

Patients were all treated with systemic antiviral agents, including intravenous acyclovir, intravitreal

antiviral injections, oral antiviral therapy, or some combination

thereof. Systemic corticosteroids (initial dose of 30–80 mg daily) were initiated in 77% of patients (17/22) and typically tapered over 2 to 6 weeks. All eyes received topical

steroids (prednisolone acetate 1% every 1–6 hours) during the initial treatment period. Fifty-nine percent of patients (12/22) in the newer antiviral group underwent pars plana vitrectomy for diagnostic sampling, vitreous hemorrhage, or retinal detachment.

Length of follow-up:

6 months after start treatment

Lost to follow-up:

Not reported

Outcome measures:

- Visual acuity

- Retinal detachment

Results:

Visual acuity:

Mean logMAR at 6 months:

Group 1: 1.74

Group 2: 1.24

Mean logMAR significantly better in group 2 (p=0.042)

Change in logMAR at 6 months:

Group 1: from 1.24 to 1.74 (p=0.0015; n=25)

Group 2: from 0.946 to 1.24 (p=0.10; n=22)

Both groups had worsening in VA at 6 months

Retinal detachment

The rate for the newer antiviral era was 23% per person-year, compared with 15% per person-year in the acyclovir-only era (p=0.22).

Observational study (starts with low quality of evidence)

Different treatment regimens and co-medication in both groups.

Clinically relevant difference in outcome measures not defined.

No analysis to adjust for potential confounders.

GRADE: very low quality of evidence

Brydak-Godowska, 2014

Type of study:

Retrospective study

Country:

Poland

Competing interests:

Not stated

Inclusion criteria:

Patients who were diag­nosed with self-limiting ARN based on the clinical presentation, after exclu­sion of other potential causes of chorioretinitis.

Exclusion criteria:

Not stated

Intervention:

Acyclovir and prednisolon (N=10 patients)

Treatment regimen:

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 inflam­matory process.

Treatment with valacyclovir and prednisone was continued in 2 patients due to the incomplete healing of inflammatory le­sions.

Length of follow-up:

Variable (5 months to 11 years)

Lost to follow-up:

None

Outcome measures:

- Control of inflammation

Results:

Control of inflammation

Complete resolution of inflammatory lesions was observed in 8 patients (80%).

In 6 patients (60%), treatment was discontinued at 6 months due to complete resolution of the inflammatory process.

Four patients (40%) 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. In 2 patients, the disease pro­gressed despite treatment.

Complications

Neurological complications (encephalitis and men­ingitis) were observed in 2 patients.

Observational study (starts with low quality of evidence)

Variable follow-up

Very small sample size (N=10)

No analysis to adjust for potential confounders.

GRADE: very low quality of evidence

Aizman, 2007

Type of study:

Retrospective study

Country:

USA

Competing interests:

None declared

Inclusion criteria:

Patients with symptomatic ARN syndrome treated solely with oral antiviral medications (oral valacyclovir or famciclovir) at a university hospital vitreoretinal service.

Exclusion criteria:

Use of other systemic or intraocular antiherpetic medication as part of initial therapy.

Intervention:

oral valacyclovir (N=4) or famciclovir (N=4) (total N=8 patients with 10 eyes)

Treatment regimen:

Patients were treated with either oral valacyclovir 1 g 3 times daily

or oral famciclovir 500 mg 3 times daily until complete resolution of retinitis was observed. The dose was then slowly tapered over 2 to 6 months. Chronic maintenance therapy with oral acyclovir 400 mg twice daily was employed in 4 patients with presumed impaired immunity. All patients were started on oral prednisone therapy when unequivocal regression of areas of retinal necrosis was observed. Prophylactic laser retinopexy was applied immediately posterior to the necrotic retina in eyes with sufficiently clear

media, generally 1 to 3 weeks after the initiation of oral antiviral

therapy. No patient received aspirin unless it was part of their therapeutic regimen prior to onset of ARN.

Length of follow-up:

Mean follow-up of 36 weeks (range, 7–72 weeks)

Lost to follow-up:

None

Outcome measures:

Primary outcomes:

- Resolution of active retinitis as

determined by clinical ophthalmoscopic examinations and grading of serial wide-angle photographs where possible.

- Best-corrected visual acuity on final follow-up.

Secondary outcomes:

- Time to complete resolution was

defined as total disappearance of white patches of retinitis, with evidence of retinal and retinal pigment epithelial atrophy.

Results:

Resolution of active retinitis

Complete resolution of retinitis was observed in 10/10 (100%) eyes.

Median time to complete resolution was 14 days (average, 17.0 days)

Visual acuity

At the last examination, the visual acuity was improved (≥ 2 Snellen lines) in 6 (60%) eyes, stable in 2 (20%) eyes, and worse

in 2 (20%) eyes.

Involvement contralateral eye

No patient with initially unilateral involvement (N=6) developed disease in the contralateral eye.

Complications

3 patients developed rhegmatogenous retinal detachment that was successfully repaired with 1 vitrectomy. No patient developed clinical or laboratory systemic adverse effects associated with treatment.

Observational study (starts with low quality of evidence)

Variable follow-up

Very small sample size (N=8)

No analysis to adjust for potential confounders.

GRADE: very low quality of evidence

Yeh, 2014

Type of study:

Retrospective study

Country:

USA

Competing interests:

The authors have no financial or proprietary interest in the materials presented herein

Inclusion criteria:

Patients diagnosed with ARN based on based on char­acteristic clinical features defined by American Uveitis Society criteria, response to antiviral ther-

apy, and PCR diagnostics

Exclusion criteria:

ARN diagnosis was inconclusive or if fewer than 6 months of follow-up data were available

Group 1:

systemic antiviral alone (N=12 patients with 15 eyes)

Acyclovir/valacyclovir/prednison

Treatment regimen:

Patients received 1) intravenous acyclovir 10 mg/kg/dose three times daily for 2 weeks, followed by acyclovir 800 mg five times daily or valacyclovir 1,000 mg three times daily, or 2) oral antiviral monotherapy (prednisone).

Group 2:

combination systemic and intravitreal (N=12 patients with 14 eyes)

(Val)acyclovir plus foscarnet injections

Treatment regimen:

Patients received either intravenous acyclovir 10 mg/kg/dose three times daily or oral (PO) valacyclovir 1,000 mg three times daily in combination with serial foscarnet injections (2.4 mg/0.1 mL) every 3 to 4 days until disease quiescence was achieved (median of 3 injections, rang: 1-7). Famciclovir 500 mg three times daily was an alternative if acyclovir was

contraindicated due to renal dysfunction.

Length of follow-up:

24 months

The final endpoint for all analyses was set at 24 months,

because the mean follow-up of the combination therapy group (26 months) most closely approximated 24 months.

Lost to follow-up:

None

Outcome measures:

- Visual acuity. A two-line or greater VA improvement was considered a success.

- Retinal detachment.

Results

Visual acuity

Patients treated with combination an-

tiviral therapy were more likely to attain two lines or more of VA improvement compared to patients treated with systemic antiviral drugs alone (p=0.0056).

The incidence rate of a two-line or greater

VA gain was 0.51 per patient-year (PY) in the combination therapy group compared to 0/PY in the group treated with systemic antiviral alone (p=0.0004).

Retinal detachment

Four eyes (29%) detached in the combination group, and nine eyes (60%) detached in the systemic therapy group (HR = 0.44; 95% CI 0.12–1.43; p=0.16).

The incidence of RD was significantly lower in the combination antiviral therapy group at

0.29 events/PY when compared to 0.74 events/PY in the systemic antiviral group (p=0.03).

Of the 13 eyes with RDs, 12 underwent surgical repair. All eyes were attached at final follow-up.

Phthisis

Phthisis was observed in 3/15 eyes (20%) from the systemic therapy group and 0/ 14 eyes (0%) treated with combination therapy.

Observational study (starts with low quality of evidence)

Variable follow-up, differences in systemic treatment, limited

numbers of patients in both groups.

No analysis to adjust for potential confounders.

GRADE: low quality of evidence

Jeon, 2012

Type of study:

Retrospective study

Country:

Korea

Competing interests:

None declared

Inclusion criteria:

Patients with diagnosis ARN

Exclusion criteria:

HIV positive

Group 1 (N=27):

prolonged oral acyclovir (>14 weeks)

Group 2 (N=28):

shorter duration of oral acyclovir (<14 weeks)

Treatment regimen:

All patients were treated with iv acyclovir (500 mg/m² x 3 times daily) for 7-13 days, followed by oral acyclovir therapy (800 mg x 5 times daily) for the next 1-24 months. Oral corticosteroids were introduced when there was either an increase in inflammation or optic nerve involvement, such that vision continued to fall or an afferent pupillary defect. The dosage of oral corticosteroid was 1 mg/kg/day with gradual tapering by 10 mg every 5 days.

Length of follow-up:

Group 1: mean 60.2 months

Group 2: mean 63.1 months

Lost to follow-up:

Not reported

Outcome measures:

- Involvement of the contralateral eye

- Visual acuity

- Retinal detachment

Results

Involvement of the contralateral eye

Group 1: 1/27=3.7%

Group 2: 6/28=21%

P=0.036

Visual acuity

Score of 6/60 or worse in 28/55 (50.9%) patients (not specified by group).

Duration of acyclovir was not associated with visual outcome. Multivariate analysis failed to find any significant prognostic factors.

Retinal detachment

27/55=49% eyes (not specified by group)

Observational study (starts with low quality of evidence)

Wide range of duration of therapy (1-24 months).

GRADE: low quality of evidence