Cystic Encephalomalacia in a Neonate With a Rash

A female infant born at 31 3/7 weeks of gestation presents at birth with a rash with a mixture of papules, vesicles, and pustules, concentrated on palms and soles (Figures 1–3).Born to a 21-year-old gravida 2 para 1 Caucasian womanConcern for fetal ventriculomegaly and small cerebellum at 31 1/7 weeksPregnancy complicated by gestational diabetes mellitus and preterm laborNotable maternal serologies: Group B Streptococcus unknown, Rubella non-immune, rapid plasma regain (RPR) nonreactive during 2nd trimester and day prior to deliveryDelivered via spontaneous vaginal delivery at 31 3/7 weeksApgar score: 4 and 7 at 1 and 5 minutes, respectivelyThe infant required 1 minute of positive pressure ventilation in the delivery room, then transitioned to continuous positive airway pressure (CPAP) and was admitted to the neonatal intensive care unit. Following birth, she was found to have several skin lesions, with a mixture of papules, vesicles, and pustules (Figures 1–3). Blood and wound cultures, along with herpes simplex virus (HSV) polymerase chain reaction (PCR) tests (serum, left foot wound, and skin swabs, including eye, nose, mouth, and rectum), parvovirus PCR (serum), varicella PCR (wound swab), and RPR testing were sent. Empirical intravenous (IV) penicillin, gentamicin, acyclovir, and fluconazole were initiated.Heart rate: 155 beats/minRespiratory rate: 40 breaths/minBlood pressure: 51/34 mm Hg (mean 39)Oxygen saturation: 94%, CPAP PEEP 5, FiO2 0.30Temperature: 98.5 °F (36.9 °C)Birthweight: 2.04 kg (91st percentile), Length: 42 cm (72nd percentile), Head circumference: 28 cm (42nd percentile)General: No acute distressHead: Normocephalic, anterior fontanelle open and flatPulmonary: Tachypneic, clear breath soundsCardiac: Normal rate and regular rhythm, normal pulsesNeurologic: HypotonicSkin: Bilateral palms and soles with confluent coalescing papules, vesicles, and pustules, some ruptured (Figures 1 and 2); right medial thigh with small cluster of pinpoint clear vesicles with surrounding erythema (Figure 3)White blood cell count: 9900 /μL, 33% neutrophils, 60% lymphocytesHemoglobin: 18.2 g/dL (182 g/L)Hematocrit: 52.6%Platelet count: 198 × 103 /μLLiver enzymes: AST 23 U/L, ALT 9 U/LCongenital cutaneous candidiasis (CCC)Congenital HSVCongenital syphilisEpidermolysis bullosaParvovirusVaricella zoster syndromeStaphylococcus scalded skin syndrome (SSSS)A head ultrasonogram done on day of birth demonstrated periventricular leukomalacia (Figures 4 and 5) with extensive periventricular and subcortical cysts. A lumbar puncture was performed on day of life 2. Rapid meningitis encephalitis panel and culture of the cerebral spinal fluid (CSF) were sent, in addition to CSF Venereal Disease Laboratory (VDRL) and toxoplasma PCR. The rapid meningitis encephalitis panel returned positive for HSV type 2. Soon after, HSV serum PCR, wound PCR, and skin swab PCR all returned positive for HSV type 2. The patient received IV acyclovir for 21 days, whereas all other antimicrobials were discontinued following negative culture results. At age 1 week, the patient exhibited abnormal movements, which were confirmed to be seizures on electroencephalography, and phenobarbital was initiated. An ophthalmologic examination showed bilateral chorioretinitis. Repeat lumbar puncture was negative for HSV PCR at age 3 weeks. The patient was then started on 6 months of suppressive acyclovir therapy. Brain magnetic resonance imaging was performed at age 4 weeks with findings compatible with sequelae of neonatal herpes encephalitis with near complete absence of brain parenchyma (Figure 6). Repeat ophthalmologic examination was concerning for bilateral retinal detachment; however, given presumed poor neurologic visual processing, a vitrectomy was deferred. An auditory brainstem response screen was concerning for bilateral sensorineural hearing loss. An oropharyngeal motility study demonstrated silent aspiration, and a gastrostomy tube was placed. The patient was subsequently discharged at 2 months.Congenital HSV type 2HSV is a devastating virus that can lead to significant morbidity and mortality. Timely diagnosis and treatment are vital to a neonate’s survival and long-term outcome. Current data estimates the incidence of neonatal HSV between 1 in 3000 and 1 in 20 000.1 The majority of neonates contract the infection in the peripartum period (85%), whereas 10% acquire HSV postnatally. Rarely, HSV can be acquired during the intrauterine period, known as congenital HSV.2 Factors increasing transmission include primary maternal infection, prolonged rupture of membranes, vaginal mode of delivery, and disruption of the mucocutaneous barrier.3Identifying an initial episode of genital HSV during pregnancy can be difficult. Approximately 80% of women who deliver an infant with HSV have no known history of genital lesions.4 The expectant woman in our case was asymptomatic with no known history and no previous HSV testing to suggest infection. However, the infant exhibited prominent signs at birth, suggesting an intrauterine infection, such as congenital HSV. Regarding the other diagnoses in the differential, parvovirus and varicella have distinctive patterns when acquired through vertical transmission. Congenital parvovirus may present with hydrops fetalis and anemia, whereas congenital varicella may present cerebral atrophy, hydrocephalus, and hypertrophic scar tissue with reduction deformities of the upper extremities. Additionally, the infant’s mother was varicella immune, making congenital varicella syndrome less likely. Although congenital syphilis was high on the differential with the rash localized to the palms and soles, the multiple nonreactive RPR tests made it less likely. CCC is rare, typically presents in neonates weighing less than 1000 g, and has a generalized rash with the back, extensor surfaces of extremities, and skin folds having greatest involvement.5 SSSS very rarely presents at birth, and the rash is more diffuse with generalized erythema and fragile bullous lesions. Similarly, epidermolysis bullosa was not strongly considered due to the rash being localized to the palms and soles.Neonatal HSV infection is categorized by systems involved. These categories include skin, eyes, and mouth infection (SEM) (45%), disseminated disease (20%), and CNS infection (30%).6 In exclusive SEM disease, only these areas are affected.7 Disseminated disease affects multiple organs;2 however, patients with disseminated disease typically do not develop the characteristic vesicular rash, which can delay diagnosis. CNS disease is characterized by seizures, irritability, temperature instability, and bulging fontanelle. It may present with or without a vesicular rash and may not cause other organ dysfunction. Long-term sequelae of CNS disease include breakdown and atrophy of brain parenchyma, leading to profound neurodevelopmental impairment.7Several tests are needed to diagnose neonatal HSV. Testing includes surface PCR swabs of mucocutaneous sites, PCR of skin vesicles, CSF PCR, serum PCR, and liver enzymes to assess for liver disease.1 Specialists will need to follow affected infants, including infectious disease, neurology, and ophthalmology. An ophthalmologic examination is essential to assess eye disease, including chorioretinitis, corneal ulceration, and optic atrophy.8Along with CSF studies, brain imaging is vital in establishing the CNS involvement in neonatal HSV. Early in the course, a head ultrasonogram may be used to characterize brain anatomy, but magnetic resonance imaging is needed to evaluate for brain sequelae.1 Severe sequelae seen with disease progression include brain abscess and cystic encephalomalacia.1 Although rare, intrauterine infection can lead to severe cystic encephalomalacia, such as seen in our patient.9,10Gold standard treatment is high dose IV acyclovir for 21 days. Patients with CNS involvement require a repeat lumbar puncture at the end of their treatment course. If the CSF PCR remains positive, IV acyclovir should be continued for another week and serial lumbar punctures performed until the CSF PCR returns negative.7,11 Treatment reduces 1-year mortality and neurologic morbidity.7In severe HSV encephalitis, prognosis is poor. Although overall mortality has decreased significantly with the use of high dose IV acyclovir with current rates of approximately 5%, mortality remains highest for disseminated disease at approximately 40%.12 Long-term sequelae include intellectual disability, cerebral palsy, and epilepsy in 30% to 70% of infants.12,13 Patients require early intervention with speech, occupational, and physical therapy. There is minimal data regarding in-utero infection, treatment, and long-term outcomes. Treatment will not reverse organ injury sustained in-utero, but it may prevent disease progression in those that do not have CNS and systemic involvement at birth.14SummaryNeonatal HSV can be a devastating disease with variable presentation.Most transmission occurs during the peripartum period (85%), whereas a small subset of transmission occurs postnatally. Very rarely, intrauterine acquisition occurs, leading to congenital HSV.Three distinct infection categories exist (SEM, disseminated, and CNS) with some overlap.Early recognition and treatment (IV acyclovir) improves outcomes; however, there remains high morbidity associated with the disease including significant long-term neurologic complications.American Board of Pediatrics Neonatal-Perinatal Content SpecificationRecognize cutaneous infections.Understand infections of the central nervous system.