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Summary Table

Category	Details
Risk Factors	Primary maternal genital HSV infection near delivery (highest risk), prolonged rupture of membranes (>4-6 hours), use of fetal scalp electrodes, vaginal delivery with active lesions, maternal age <21 years
Etiology	HSV-2 (majority of neonatal cases) or HSV-1; transmitted intrapartum through direct contact with infected secretions in the birth canal
Patient Presentation	Neonate (typically days 1-28 of life) with vesicular skin lesions, seizures, lethargy, poor feeding, temperature instability, or fulminant sepsis-like picture unresponsive to antibiotics
Classic Physical Exam	Clustered vesicles on an erythematous base on the skin, scalp (especially at electrode sites), or mucous membranes; keratoconjunctivitis; hepatomegaly in disseminated disease; bulging fontanelle or focal neurologic signs in CNS disease
Key Diagnostic Results	HSV PCR of CSF (CNS disease), HSV PCR or viral culture of vesicle fluid/swabs (mucocutaneous), elevated CSF protein and pleocytosis, elevated liver transaminases and coagulopathy (disseminated), abnormal EEG with temporal lobe focus
Management	IV acyclovir 60 mg/kg/day divided every 8 hours for 14 days (SEM disease) or 21 days (CNS or disseminated disease), followed by oral acyclovir suppressive therapy 300 mg/m^2 TID for 6 months
Keywords	"Vesicles on erythematous base in a neonate," "sepsis-like picture not responding to antibiotics," "maternal history of genital herpes," "seizures in a neonate with CSF pleocytosis," "temporal lobe enhancement on MRI"

1. Pathophysiology

Neonatal HSV is caused by herpes simplex virus, a double-stranded DNA virus belonging to the Herpesviridae family. HSV-2 accounts for the majority of neonatal cases, though HSV-1 is increasingly recognized.

The primary route of transmission is intrapartum contact with infected maternal genital secretions during vaginal delivery. The critical determinant of transmission risk is whether the mother has a primary infection (no pre-existing antibodies) versus a recurrent outbreak at the time of delivery. A primary infection carries a transmission rate of approximately 30 to 50 percent because the mother lacks protective IgG antibodies that would otherwise cross the placenta and provide partial passive immunity to the fetus. In contrast, recurrent infection carries a transmission rate of only 2 to 5 percent, since pre-existing maternal antibodies offer partial protection.

Once the virus enters the neonate, the immature neonatal immune system is unable to contain viral replication effectively. T-cell mediated immunity, which is the primary defense against herpesvirus, is functionally immature in the newborn. This explains why neonatal HSV can rapidly become disseminated or neuroinvasive, unlike herpes infections in immunocompetent adults, which typically remain localized.

The virus exhibits neurotropism, traveling along peripheral sensory nerves to reach the central nervous system. In the brain, HSV has a predilection for the temporal lobes, producing hemorrhagic necrotizing encephalitis. This is why seizures and focal neurologic deficits are hallmarks of CNS disease.

In disseminated disease, hematogenous spread leads to viral involvement of the liver, lungs, adrenal glands, and other visceral organs, producing a clinical picture that closely mimics bacterial sepsis or disseminated intravascular coagulation (DIC). The liver is heavily targeted, resulting in fulminant hepatitis with markedly elevated transaminases and coagulopathy. This overlap with bacterial sepsis is the reason neonatal HSV is frequently missed on initial presentation, and is a favorite testing point.

True intrauterine (congenital) HSV is very rare, occurring from transplacental viremia during primary maternal infection in early pregnancy. When it does occur, the classic triad includes skin vesicles or scarring at birth, chorioretinitis, and microcephaly or hydranencephaly. This presentation is present at birth, distinguishing it from perinatally acquired disease which manifests days to weeks after delivery.

2. Classification and Clinical Manifestation

Neonatal HSV is classified into three distinct clinical categories based on the extent of disease involvement. This classification directly determines prognosis and treatment duration.

Classification	Onset	Clinical Features	Mortality (Untreated)	Mortality (Treated)
SEM Disease (Skin, Eye, Mouth)	Days 7-14 of life	Vesicular lesions on skin, oral mucosa, or conjunctivae; keratoconjunctivitis; no systemic or CNS involvement	Low, but progresses to CNS or disseminated disease in 70% if untreated	<2%
CNS Disease	Days 14-21 of life	Seizures (often focal), lethargy, irritability, poor feeding, bulging fontanelle, temperature instability; vesicles present in only ~60-70% of cases	~50%	~6%
Disseminated Disease	Days 1-7 of life (earliest onset)	Sepsis-like picture with hepatitis, pneumonitis, DIC, shock, multi-organ failure; vesicles may be absent in up to 40% of cases	~85%	~30% (highest mortality even with treatment)

The absence of vesicles does not exclude neonatal HSV. In disseminated disease, skin lesions are absent in nearly half of cases, and in CNS disease, about one-third of patients lack visible vesicles. Exam vignettes frequently test this concept by presenting a "septic neonate" without vesicles who is not improving on broad-spectrum antibiotics. The test-writer expects you to recognize that HSV must be considered in any critically ill neonate with negative bacterial cultures.

Disseminated disease presents the earliest (first week of life) and carries the worst prognosis, which is counterintuitive for many students who assume that CNS involvement would be the most lethal form.

SEM disease, while carrying the best prognosis, will progress to CNS or disseminated disease in the majority of cases without treatment. This is why even isolated vesicular lesions in a neonate demand urgent workup and empiric treatment.

3. Diagnostic Workup

Test	Role	Key Findings
HSV PCR of CSF	Best initial and most accurate test for CNS involvement	Positive HSV DNA; also shows CSF pleocytosis (lymphocyte predominant), elevated protein, normal or low glucose, possible RBCs (hemorrhagic component)
HSV PCR or viral culture of vesicle fluid	Best test for mucocutaneous disease; also useful for typing (HSV-1 vs HSV-2)	Positive viral isolation or PCR amplification from swab of vesicle base
Surface swabs for HSV PCR/culture	Part of initial workup even without visible lesions	Swab conjunctivae, nasopharynx, mouth, and rectum; positive results confirm neonatal HSV even if systemic disease is not yet apparent
Serum ALT/AST	Screening for hepatic involvement in disseminated disease	Markedly elevated transaminases (often >1000 U/L)
Coagulation studies (PT, PTT, fibrinogen, D-dimer)	Evaluate for DIC in disseminated disease	Prolonged PT/PTT, low fibrinogen, elevated D-dimer
MRI brain	Evaluate extent of CNS involvement	Temporal lobe edema, hemorrhage, or restricted diffusion; may show more widespread cortical involvement
EEG	Assess for subclinical seizures in CNS disease	Periodic lateralized epileptiform discharges (PLEDs), often with temporal lobe focus
Tzanck smear	Rapid but insensitive bedside test	Multinucleated giant cells; low sensitivity, largely replaced by PCR

When neonatal HSV is suspected, the workup should be initiated simultaneously with empiric IV acyclovir. Do not wait for results before starting treatment.

The cornerstone of diagnosis is HSV PCR, which has replaced viral culture as the preferred method due to its superior sensitivity and faster turnaround time. CSF HSV PCR is the single most important test when CNS disease is suspected. However, it is important to recognize that CSF PCR can be falsely negative in the first 24 to 72 hours of CNS disease. If clinical suspicion remains high despite a negative initial result, the lumbar puncture should be repeated in 3 to 5 days.

Surface cultures and PCR swabs from the conjunctivae, nasopharynx, mouth, rectum, and any skin vesicles should be obtained in all suspected cases, as these can be positive even before systemic disease declares itself.

In the disseminated form, the liver function tests and coagulation panel are critical. Markedly elevated ALT and AST (often exceeding 1000 U/L) with evidence of DIC should raise strong suspicion for disseminated HSV, especially in a neonate who looks septic but has sterile bacterial cultures.

MRI of the brain is indicated in all cases of suspected CNS disease. The classic finding is temporal lobe involvement with edema, hemorrhagic necrosis, or restricted diffusion. This temporal lobe predilection mirrors what is seen in adult HSV encephalitis and is a frequently tested imaging finding.

An important exam pearl: maternal HSV serologies are not useful for diagnosing neonatal HSV and should not delay the workup. The diagnosis in the neonate relies on direct viral detection from the infant.

4. Management and Treatment

Phase	Intervention	Details
Empiric initiation	Start IV acyclovir immediately upon clinical suspicion	Do not wait for confirmatory results
SEM Disease	IV acyclovir	60 mg/kg/day divided every 8 hours (20 mg/kg/dose) for 14 days
CNS Disease	IV acyclovir	60 mg/kg/day divided every 8 hours for 21 days; repeat CSF HSV PCR near end of therapy to confirm clearance before stopping
Disseminated Disease	IV acyclovir	60 mg/kg/day divided every 8 hours for 21 days + supportive care for multi-organ failure
Oral suppressive therapy	Oral acyclovir after completing IV course	300 mg/m^2 TID for 6 months (all forms of neonatal HSV)
Ophthalmologic involvement	Topical antiviral (trifluridine 1% or vidarabine)	In addition to systemic acyclovir if keratitis or conjunctivitis present
Monitoring during IV acyclovir	Renal function and absolute neutrophil count	Acyclovir can cause nephrotoxicity (crystal deposition) and neutropenia

The single most important management principle is early empiric treatment. IV acyclovir should be initiated as soon as neonatal HSV enters the differential, without waiting for PCR or culture results. Delays in treatment directly increase morbidity and mortality, and this is a commonly tested decision point.

The dose in neonates is 60 mg/kg/day, which is higher than the dose used for adult HSV encephalitis. This is divided into three doses given every 8 hours. Students frequently confuse the neonatal dose with the adult dose, which is a known exam trap.

Duration of therapy depends on the classification:

SEM disease: 14 days of IV acyclovir
CNS and disseminated disease: 21 days of IV acyclovir

For CNS disease, a repeat lumbar puncture with CSF HSV PCR must be performed near the end of the 21-day course. If the repeat PCR is still positive, IV acyclovir is continued for an additional 7 days, followed by another repeat LP. Treatment is not stopped until CSF PCR is confirmed negative.

After completing the IV course, all neonates with confirmed HSV (regardless of disease classification) should receive oral acyclovir suppressive therapy at 300 mg/m^2 three times daily for 6 months. This regimen has been shown to improve neurodevelopmental outcomes in CNS disease and reduce skin recurrences in SEM disease. The absolute neutrophil count must be monitored during suppressive therapy, as neutropenia is the primary dose-limiting side effect.

During IV acyclovir therapy, adequate hydration is essential to prevent acyclovir crystal nephropathy. Serum creatinine and urine output should be monitored regularly.

Obstetric prevention is equally high-yield for exam purposes. Pregnant women with a history of genital herpes should receive oral acyclovir or valacyclovir suppressive therapy starting at 36 weeks of gestation to reduce the likelihood of active lesions at delivery. If active genital lesions or prodromal symptoms are present at the time of labor, cesarean delivery is indicated. However, if membranes have already been ruptured for a prolonged period (>4-6 hours), the benefit of cesarean section diminishes.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Bacterial sepsis / meningitis	Disseminated HSV closely mimics neonatal sepsis with lethargy, temperature instability, shock, and DIC	Bacterial cultures are negative; transaminases are disproportionately elevated; poor response to antibiotics; consider HSV when a "septic" neonate does not improve after 48-72 hours on broad-spectrum coverage
Congenital syphilis	Both can present with skin lesions, hepatomegaly, and multi-organ involvement in a neonate	Syphilis produces maculopapular or bullous lesions (not grouped vesicles on erythematous base), and is associated with snuffles, osteochondritis, and positive maternal RPR/VDRL
Congenital varicella	Both are caused by Herpesviridae and can produce vesicular skin lesions in the neonate	Varicella lesions appear in different stages simultaneously ("crops") in a diffuse distribution, versus HSV vesicles which are clustered. Maternal varicella history is key
Congenital CMV	Both can cause CNS disease, chorioretinitis, and hepatitis in neonates	CMV classically presents with periventricular calcifications, petechiae, "blueberry muffin" rash (extramedullary hematopoiesis), and sensorineural hearing loss; CMV does not produce vesicular skin lesions
Congenital toxoplasmosis	Both can produce chorioretinitis, intracranial calcifications, and seizures in neonates	Toxoplasmosis produces diffuse (scattered) intracranial calcifications, while HSV shows temporal lobe predominance; toxoplasmosis also causes a classic triad of hydrocephalus, chorioretinitis, and diffuse calcifications
Enteroviral sepsis	Presents similarly to disseminated HSV with sepsis-like illness, hepatitis, and myocarditis in neonates	Enteroviral infection often has a seasonal predilection (summer/fall), and skin findings, when present, are maculopapular rather than vesicular; PCR differentiates
Incontinentia pigmenti	Can present with vesicular skin lesions in a neonate along linear (Blaschko) lines	Lesions follow Blaschko lines, there is peripheral eosinophilia, and the infant is otherwise well without systemic illness; occurs almost exclusively in females

6. Traps and High-Yield Pearls

The most common way students get neonatal HSV questions wrong is by ruling out the diagnosis when vesicles are absent. This is the single biggest trap. Up to 40% of disseminated HSV cases and roughly 30% of CNS cases present without any visible skin lesions. The vignette will describe a critically ill neonate with signs of sepsis and DIC whose bacterial cultures return negative, and the expected answer is to initiate IV acyclovir and send HSV PCR.

A second major trap involves confusing the treatment duration. SEM disease requires 14 days, while CNS and disseminated disease require 21 days. Students who generalize "21 days for all" will get SEM questions wrong, and those who choose 14 days for CNS disease will miss the correct answer.

The third testing focus is the importance of the repeat CSF PCR at the end of CNS disease treatment. This is a "next best step" question where the student has correctly identified the diagnosis and treatment, and the vignette describes day 21 of therapy asking what to do next. The answer is to repeat the LP before discontinuing IV acyclovir.

Another commonly tested concept is obstetric decision-making. A vignette describing a woman at 39 weeks in active labor with visible genital vesicles should trigger cesarean delivery as the answer. Conversely, if the question states she has a history of genital herpes but no active lesions and is on suppressive therapy, vaginal delivery is appropriate.

Finally, students sometimes confuse neonatal HSV with other TORCH infections. The key discriminators to commit to memory: grouped vesicles on an erythematous base are essentially pathognomonic for HSV among neonatal infections, temporal lobe predilection on brain MRI distinguishes HSV encephalitis from CMV (periventricular calcifications) and toxoplasmosis (diffuse calcifications), and the finding of a sepsis-like picture with sterile bacterial cultures and markedly elevated transaminases in a neonate should immediately place disseminated HSV at the top of the differential.

The core competency being tested is your ability to recognize neonatal HSV even in atypical or vesicle-free presentations, initiate empiric treatment without delay, and correctly sequence the diagnostic and therapeutic steps.

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