Neonatal HSV, like neonatal sepsis, can have nonspecific symptoms ( Table 96.7 ) Neonatal HSV classically produces three presentations (skin, eyes, mouth [SEM] [45%], CNS disease [30%], or disseminated HSV [25%]) Fever occurs in 30% of neonates with HSV, whereas 20% present with hypothermia While HSV is uncommon, the overall incidence of HSV in febrile neonates is approximately 1% Neonates presenting with fever, irritability, and CSF pleocytosis should be worked up for HSV disease, particularly if seizures occur SEM disease presents with vesicular eruptions usually 10 to 12 days after birth Clusters of vesicles appear on the skin and mucous membranes without involvement of any other organ system, particularly the scalp for neonates born with cephalic presentations Herpetic keratitis can lead to corneal scarring CNS disease presents with mucocutaneous lesions that appear around 17 to 19 days, as well as neurologic manifestations (seizures, bulging anterior fontanelle, and lethargy) Absence of skin lesions does not rule out CNS disease; 30% to 60% of infants with CNS disease not have mucocutaneous lesions Neonates with disseminated disease typically present at about 10 to 12 days with septic shock These infants have the worst prognosis Multiple organ systems involvement produces acute hepatitis, respiratory distress, pneumonia, pleural effusions, adrenal disease, neurologic manifestations, pneumatosis intestinalis, and disseminated intravascular coagulopathy Again, absence of skin lesions (up to 40%) does not exclude disseminated disease Neonates suspected of having HSV disease should undergo a full sepsis workup including CBC, urinalysis and urine culture, blood culture, liver functions, lumbar puncture, and HSV cultures Isolation of HSV by culture (blood, CSF, and surface cultures) (swabbing the conjunctiva, mouth, nasopharynx, and ending with the rectum then placing swabs in one viral media containing tube) remains the definitive diagnostic method HSV cultures can be obtained from skin lesions Diagnosis of HSV can also be confirmed by PCR from CSF samples CSF PCR for HSV should be accompanied by surface cultures CSF will show mild pleocytosis with abundant mononuclear cells, elevated protein level, normal glucose concentration, and a negative Gram stain Infants suspected of having any form of HSV disease, even SEM, should have a lumbar puncture performed Blood HSV PCR can also be obtained but not enough data are available to recommend its routine use Liver functions may show elevated alanine aminotransferase (ALT) Electroencephalogram (EEG) may show nonspecific findings but occasionally temporal lobe seizures may be seen Transfer of maternal antibodies makes serologic tests in neonates difficult to interpret and therefore not useful