Neonatal Herpes Simplex Virus Type-1 Central Nervous System Disease With Acute Retinal Necrosis : The Pediatric Infectious Disease Journal

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Neonatal Herpes Simplex Virus Type-1 Central Nervous System Disease With Acute Retinal Necrosis

Fong, Choong Yi FRCPCH*†; Aye, Aye Mya Min MMedSc (Paeds)*; Peyman, Mohammadreza MD; Nor, Norazlin Kamal MRCPCH*; Visvaraja, Subrayan FRCOphth; Tajunisah, Iqbal MD; Ong, Lai Choo MRCP*†

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The Pediatric Infectious Disease Journal 33(4):p 424-426, April 2014. | DOI: 10.1097/INF.0000000000000137


Neonatal herpes simplex virus (HSV) infection is a potentially severe infection associated with high mortality and morbidity if left untreated.1 While infants with intrauterine infection have congenital brain malformations, micropthalmia, chorioretinitis and cutaneous lesions at birth,1 those with intra- or postpartum infection would present with localized disease confined to the skin-eye-mouth, disseminated disease or central nervous system (CNS)/encephalitis (with or without skin-eye-mouth involvement).1 Primary eye disease in HSV infection typically presents with herpetic keratitis or follicular conjunctivitis. On the other hand, HSV retinitis and acute retinal necrosis (ARN) may be due to viral spread from the brain via the suprachiasmatic or paraventricular nuclei.2

ARN is an uncommon pediatric eye disease, typically presenting as a progressive red eye and blurred vision with varying degrees of pain or irritability. The hallmark features are rapidly progressive peripheral retinal necrosis, retinal arteritis and prominent inflammatory reactions in the anterior chamber and vitreous.3 All cases of pediatric ARN reported in the literature presented with external ocular signs (red eye, decreased visual acuity or anisocoria). Compared with adult ARN, which is caused by varicella zoster virus and HSV-1, HSV-2 is the predominant cause in children.4–8 HSV-1 is rarely seen in pediatric ARN, with only 4 published cases to date and none has been reported in infants.6,9,10 We describe a case report of an infant with primary neonatal HSV-1 CNS disease and concomitant HSV-1 ARN without any external ocular or cutaneous features.


A 17-day-old term female infant was admitted to our institution with a 4-day history of intermittent periods of jerking of her right leg. The infant had been previously well with no significant antenatal history, neonatal history or recent periocular trauma. There was no maternal history of genital lesions or cold sores. On examination, the infant was clinically well with no cutaneous features of HSV or varicella zoster virus. She then had intermittent focal clonic upper limb seizures with ictal electroencephalography showing focal epileptiform discharges over the midline-vertex and right frontal-midline regions on hospital day 1.

Cerebrospinal fluid (CSF) analysis on hospital day 2 of illness revealed a pleocytosis (80 lymphocytes/μL), high protein (1.06 g/L), reduced CSF:serum glucose ratio of 40% and CSF HSV-1 polymerase chain reaction (PCR) positive. Intravenous (IV) acyclovir (20 mg/kg/dose 8 hourly) was then initiated. Ophthalmologist assessment on hospital day 3 of illness showed nonspecific exudates in the posterior segment of her left eye; the rest of the ophthalmology examination was normal.

The remainder of the investigations performed in the infant included CSF and vitreous fluid PCR for HSV-2 and cytomegalovirus; serum serology for HSV-2, varicella zoster virus, toxoplasma gondii, rubella, cytomegalovirus and human immunodeficiency virus and serum immune function assay which were all normal. Gynecological assessment of the mother showed no evidence of genital herpes. Maternal serum HSV serology detected HSV-1 IgM with a negative HSV-1 IgG and HSV-2 IgG/IgM.

Ophthalmological reassessment on hospital day 9 of illness revealed active vitritis, optic nerve swelling, arteriolar sheathing and circumferential peripheral retinal necrosis in her left eye with a normal right eye (see Figure, Supplemental Digital Content 1A, External ocular examination of both eyes remained normal. Left ocular vitreous tap sample was PCR positive for HSV-1. Based on the ophthalmology findings of ARN, intravitreal injections of foscarnet (1.2 mg in 0.1 mL) was administered weekly into the left eye for a total of 4 doses. Following the intravitreal injections, significant improvement in the necrotic areas of the left retina was seen (see Figure, Supplemental Digital Content 1B,

Brain magnetic resonance imaging performed on hospital day 10 showed regions of cerebritis with cortical gyral and leptomeningeal contrast enhancement in the superior frontal lobes particularly over the peri-rolandic regions bilaterally. There was no evidence of other systemic involvement. After 21 days of IV acyclovir therapy, repeat CSF PCR for HSV-1 was negative and serum HSV-1 IgM was now positive.

Despite a negative CSF HSV-1 PCR, a repeat ophthalmological assessment on hospital day 21 showed early features of focal retinitis and vasculitis in the previously healthy right eye (see Figure, Supplemental Digital Content 1C, Intravitreal foscarnet was then initiated into the right eye and IV acyclovir was also continued for another 2 weeks, resulting in complete resolution of the ocular inflammation. After 5 weeks of IV acyclovir therapy, antiviral treatment was then converted to oral acyclovir 6 months to prevent relapse of HSV infection. Oral corticosteroid (1 mg/kg/d) was also then given for 1 month to treat the residual inflammation in the left eye. The infant subsequently developed tractional retinal detachment in the left eye (see Figure, Supplemental Digital Content 1C, requiring a vitrectomy at 50 days of age. A repeat vitreous fluid PCR for HSV was obtained intraoperatively, which was negative for HSV-1 and HSV-2. The right fundus remained normal. At the latest follow up at 6 months of age, the visual prognosis remains poor on the left eye with a burnt-out retina appearance and significant afferent pupillary defect. The right eye examination was normal and she was able to fix and follow fully.


To our knowledge, this is the first case report of neonatal ARN secondary to HSV-1 infection (previous reported pediatric HSV-1 ARN cases aged 3.5–16 years),6,9,10 and the first pediatric case of ARN presenting without external ocular or cutaneous features. Neonatal ARN is rare with only 7 published cases to date.8,11–13 All these cases were secondary to HSV-2 with 4 occurring concurrently with HSV-2 CNS disease, 1 as part of a disseminated infection and 2 as part of a skin-eye-mouth involvement. All these patients also had cutaneous or external ocular signs. A poor ocular outcome was seen in these patients with either retinal detachment or proliferative vitreoretinopathy.

Neonatal HSV CNS disease accounts for 30% of all neonatal HSV infections and 60–75% of disseminated disease.1 HSV encephalitis with extensive CNS involvement may also increase the risk of developing co-concomitant ocular involvement. HSV-associated bilateral ARN, as seen in our case, is uncommon in children accounting for approximately 15% of published pediatric ARN cases.5,8,10,13–15 Studies have postulated that the virus accesses the retina from the brain by a trans-axonal route, and bilateral involvement may be determined by early recognition and treatment of the first eye to limit further virus spread to other CNS sites including the other eye.2,16,17

Our patient clearly illustrates the rapid progression and virulent course of HSV-1 ARN when treated with IV acyclovir alone. The ocular involvement evident in the left eye at day 7 of illness rapidly progressed to ARN within a week necessitating intravitreal foscarnet treatment for stabilization and improvement in the disease. Previous studies suggested good efficacy of intravitreal foscarnet in treating HSV retinitis with no retinal toxicity.18 Close surveillance and early detection of involvement of the previously unaffected right eye, with immediate commencement of intravitreal foscarnet, was associated with complete resolution of the disease in that eye. This case report demonstrates that timely initiation of intravitreal antiviral treatment can result in resolution of an otherwise devastating ocular disease.

In neonatal HSV, the majority (85%) of cases are acquired during the peripartum period, mainly due to direct contact with the infected mother’s blood and body secretions while passing through the birth canal. The remainder of cases are acquired either intrauterine (5%) or postpartum (10%) as contact from an environmental source of HSV.1 Based on the virology results with concurrent maternal IgM HSV-1 seropositivity and absence of clinical features indicating intrauterine HSV-1 infection, our infant is likely to have acquired the HSV-1 from mother during the peripartum period (at the time of delivery). There remains a possibility of horizontal infection from father to child during the neonatal period as HSV serological testing was not performed in the father.

The published pediatric HSV ARN case series postulate that HSV-mediated ARN is due to a latent viral reactivation of a primary HSV infection.5,7,8 Findings to support this hypothesis would include prior evidence of primary HSV infection, stigmata of previous chorioretinal disease accompanying the acute retinitis, preceding triggering event like ocular trauma/neurosurgery or ARN occurring after commencement of systemic corticosteroids. The absence of such findings, absence of features indicating in utero neonatal HSV disease, age of onset, CSF and vitreous fluid PCR positivity with subsequent elevated serum IgM, in the absence of simultaneous high levels of IgG in our patient indicate a primary infection rather than a viral reactivation.

Our case report expands the clinical spectrum of neonatal HSV CNS disease and neonatal ARN. It emphasizes the importance of having a high index of suspicion of possible ARN in infants with neonatal HSV CNS disease, who do not have any external ocular or cutaneous manifestation. All infants with neonatal HSV CNS disease should undergo a thorough ophthalmological evaluation to facilitate prompt diagnosis and immediate treatment of this rapidly progressive sight-threatening disease.


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herpes simplex virus; central nervous system; acute retinal necrosis; neonate

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