Bilateral Acute Retinal Necrosis with Concurrent Retinopathy of Prematurity in Two Neonates

Acute retinal necrosis (ARN) is a syndrome characterized by one or more areas of necrotizing retinitis with adjacent occlusive retinal vasculitis involving both arteries and veins. Additional signs often include vitritis and optic neuropathy.1 Since acute retinal necrosis is predominantly seen in the adult population, literature on neonatal cases is exceedingly rare. We present two cases of premature neonates who developed ARN with concurrent retinopathy of prematurity (ROP.)

A 985-g male was born at 27 weeks gestational age via vaginal delivery secondary to preterm labor to a mother with an unremarkable past medical history with no evidence of herpetic infection. The neonate was in respiratory distress at birth with later radiographic support of respiratory distress syndrome. He was intubated and given surfactant at birth; he was extubated to continuous positive airway pressure (CPAP) at approximately 9 hours of life.

The infant was evaluated in the neonatal intensive care unit (NICU) for ROP at 32 weeks gestational age. At that time, he was found to have peripheral cataracts and chorioretinitis bilaterally. He did not have ROP on initial evaluation. A TORCH workup (toxoplasmosis, “other” infections, rubella, cytomegalovirus, and herpes simplex virus) was initiated. Polymerase chain reaction (PCR) of his cerebral spinal fluid (CSF) was positive for herpes simplex virus (HSV) type 2, and negative for cytomegalovirus (CMV), toxoplasmosis, syphilis, human immunodeficiency virus (HIV), varicella zoster virus (VZV), and rubella. Despite treatment with intravenous acyclovir (20 mg/kg daily), chorioretinitis progressed to bilateral acute retinal necrosis and he developed stage 2 zone II ROP. No treatment for ROP was required, but laser demarcation of the necrotic retina was performed. Weekly follow-up exams were done while the patient was in the NICU until after the laser demarcation was done and retinal findings were stable. Intravenous acyclovir was increased to 20 mg/kg TID. After 3 weeks at this higher dosage, the ARN was stable and a repeat CSF PCR was negative for HSV type 2 and treatment was changed to oral acyclovir (20 mg/kg BID) on which he remains to date. Although his initial cranial ultrasound during the first week of life was normal, a repeat study performed 1 month later showed bilateral germinal matrix hemorrhages. His last eye exam at 4 years old following laser treatment revealed both retinas to be fully vascularized and attached with no active retinitis. His optic nerves showed mild pallor, and he had a 60-prism diopter exotropia and blinked to light OU. He did not fixate. His refraction measured −1.50 + 2.00 × 100 OD and plano +2.75 × 080 OS.

An 880-g female was born at 26 weeks gestational age via vaginal delivery secondary to preterm rupture of membranes to a mother with an unremarkable past medical history and no evidence of herpetic infection. At birth, the neonate had respiratory difficulty consistent with respiratory distress syndrome and was treated with surfactant and intubated for a period of 2 days. In the first week of life, she developed lesions on her neck, which were cultured and positive for HSV type 2. A lumbar puncture was then performed, and a CSF PCR was also positive for HSV type 2. An MRI was consistent with HSV encephalitis. She was started on a 3-week course of 20 mg/kg TID intravenous acyclovir. At the completion of this course, her HSV PCR was repeated and was negative. She was then switched to oral acyclovir at 20 mg/kg BID indefinitely.

The infant was evaluated at 29 weeks gestational age for ROP and found to have extensive bilateral acute retinal necrosis. The necrotic area did not progress even as the acyclovir dose was decreased. No laser photocoagulation was performed as treatment would have involved a large area of posterior retina in close proximity to the optic nerve. Retinopathy of prematurity at this time was stage 2 in zone II bilaterally. Weekly exams were done until 37 weeks when ROP had resolved without full vascularization of her retinas. At her last exam at 4 years of age, the patient briefly fixated with the left eye. There was horizontal nystagmus bilaterally with superotemporal retinal traction in her left eye and optic atrophy bilaterally. There was also marked anisometropia with a refraction of −6.00 + 0.50 × 095 in the right eye and +1.25 + 3.75 × 080 in the left eye. Both patients are now followed every 6 months.

Urayama and colleagues first described ARN in 1971.2 ARN is predominantly caused by herpesviridae; VZV is the most common cause in patients greater than 25 years old, and HSV types 1 and 2 are the most common causes in patients under 25 years of age.3--5 Several case studies of adolescent and young adult patients with ARN secondary to HSV suggest that it is a reactivation of a previous infection.5 In one such report, ARN developed 17 years after neonatal HSV encephalitis.6

In older children, ARN can present with symptoms such as irritability, red and painful eyes, or blurring or loss of vision.5^,7 In a case report of a 25-day-old infant, the initial symptoms were poor feeding, lethargy, and cough. On exam, he had an injected and blistered pharynx with blistering of the left proximal arm. It was only after HSV type 2 was diagnosed that an ophthalmologic exam identified bilateral ARN.8 Another case report described premature twins born at 33 weeks gestation who were both diagnosed with ARN after twin 1 presented with right eye redness and haziness, as well as a herpetic facial rash. His serology showed evidence of HSV type 2, which led to examination and diagnosis of twin 2, who had not been discharged from the NICU due to frequent apneic episodes. Neither infant had concurrent ROP.9 Our first case is significant for the development of ARN in the absence of encephalitic or systemic HSV symptoms.

There are a variety of treatment options available for ARN, with the most common being a brief initial course of intravenous antivirals followed by an extended course of oral antivirals. Several studies also support the use of systemic steroids for cases where there is severe inflammation or optic nerve involvement.10 The use of prophylactic laser photocoagulation is controversial in its use to prevent retinal detachment due to lack of a sufficiently large, randomized, controlled study. Such prophylaxis is also limited in its use due to vitritis, which may prevent the adequate visualization of the retina that is necessary to perform laser treatment.11 In the case of the 25-day-old neonate, the right eye underwent prophylactic laser demarcation, and the left eye developed severe subretinal hemorrhages in the macula necessitating pars plana vitrectomy with silicone oil tamponade.8 Adjunctive injections of foscarnet and ganciclovir have also been utilized in the treatment of ARN, but again there is a lack of randomized, controlled trials in the current literature to support that the addition of these treatments improves outcomes over intravenous and oral antivirals alone.12

Our two cases display the unique problem of evaluating and treating bilateral ARN in the presence of active ROP. Specifically, it is unclear if ARN influences ROP progression, and unknown whether the risk of retinal detachment from ARN is elevated in the presence of active ROP. One could theorize that the large areas of ischemic retina in ARN lower the risk for ROP progression due to a decreased amount of viable, angiogenic-factor-producing retina. Interestingly, our second case with large areas of bilateral retinal necrosis never did fully vascularize her peripheral retinas and she eventually developed traction. It is unclear whether this traction was due to ARN or ROP. We are unable to comment on any increased risk of retinal detachment from ARN in the presence of ROP.

Despite the different treatments pursued and the anatomic success of our first case, both patients have subnormal vision with poor visual potential due to the extent of ophthalmic and cortical involvement from neonatal, with possible in utero, herpetic infection. Based on our limited experience, we would recommend close follow-up for complete vascularization of the retina for an extended period of time in these cases, beyond the usual recommendation of 45 weeks. In addition, laser treatment of longstanding avascular retina in conjunction with laser demarcation of necrotic retina may be considered to prevent the retinal changes associated with ROP and ARN that can lead to retinal detachment.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.