What are the presenting features of neonatal and childhood herpes simplex encephalitis?

Herpes simplex encephalitis (HSE) is a devastating disease that can be difficult to diagnose in its early stages. By definition, neonatal herpes simplex (HSV) disease presents in the first 4 weeks of life and is almost always acquired by perinatal exposure to HSV. Illness symptoms often begin between the first 7–21 days of life. There is a spectrum of clinical syndromes; encephalitis is the most serious presentation, usually associated with lethargy, fever and convulsions. Identifying the source of HSE in neonatal disease can be difficult as a history of known maternal HSV disease (genital or occasionally oral) is not universal and maternal disease may be asymptomatic.

Childhood HSE presents with similar features: fever, altered mental state (encephalopathy), a deteriorating level of consciousness, focal seizures or focal neurological abnormalities. The infective source is usually elusive. Parents can describe encephalopathy as a change in behaviour, sleepiness or confusion. Children with normal behaviour at presentation may become confused later as the encephalitis progresses.

Does a child with HSE have to have external lesions for the diagnosis to be likely?

In neonates, skin lesions may be present. However, they may appear later in the clinical course than the presenting fever, lethargy or even seizures. In childhood HSE, only 10% have a prior history of mucosal symptoms such as cold sores or conjunctivitis.1 Therefore, diagnosis requires a high index of suspicion.

How common is HSE?

Neonatal disease is more common than childhood disease. The incidence of severe disease in infants is 1 in 64 000 infants per year. In children over 1 year, HSE is nearly four times less common, occurring in 1 in 230 000 children per year.2

How do I manage HSE?

Start antivirals urgently when HSE is suspected—earlier treatment is associated with a better outcome. Assess the child carefully for seizure activity, which may be subtle, and treat this promptly in order to avoid further increases in intracranial pressure. Involve the intensive care team early as infants and children with HSE can deteriorate quickly. Ensure adequate hydration as high-dose aciclovir can cause acute renal failure.

Should a lumbar puncture always be attempted in HSE?

CSF testing is an essential component of the diagnostic work-up; see box 1 for CSF investigations in children with suspected encephalitis. CSF should be tested as soon as it is safe to perform an LP in any child with suspected encephalitis. CSF can show lymphocytes or neutrophils.

It is common that insufficient CSF is obtained and it is important to take enough for local laboratory requirements. Children produce approximately 0.35 mL/kg of CSF per hour, and it is safe to take up to 0.2 mL/kg CSF, typically 1.5–2 mL (60 drops) from a 10 kg child and more from older children.3

Does it make a difference if the PCR is positive for HSV-1 or for HSV-2?

No, not really. HSV-1 is more common in childhood HSE. HSV-2 tends to be associated with genital herpes and is more common in neonatal HSE. Although neonatal disease is often more severe than childhood HSE, the HSV type does not dictate this and devastating HSE disease can occur in both age ranges.

What is the best neuroimaging modality?

Children presenting with an altered mental state and a fever may have a CT scan, preferably with contrast, to look for space-occupying lesions—tumours, abscesses or haematomas. However, MRI is better than CT for the diagnosis of encephalitis, so at least one brain MRI scan should be performed during the acute clinical course. A normal MRI does not rule out HSE, particularly early in the course of the disease, so it should be repeated after 4–7 days if suspicion remains. This information will contribute to diagnostic certainty and aid decision making about stopping or continuing the acute antiviral treatment course.

Is an EEG required?

Even after LP and MRI, there can be diagnostic uncertainty about HSE, and an EEG may provide additional diagnostic clues. The typical pattern is of periodic lateralising epileptiform discharges in the temporal lobe, with slow wave complexes occurring at intervals of 2–3 s. While these are strongly associated with HSE, they can be seen in other disorders including space-occupying lesions, so the triad of investigations—CSF analysis, MRI and EEG—are the diagnostic gold standard.

What therapy is recommended while waiting for the investigation results?

There is considerable clinical overlap between patients with encephalitis, meningitis and septic shock. Therefore, patients are usually prescribed broad-spectrum antibiotics and high-dose aciclovir until test results are available. Because of the severity and the non-specific presentation of neonatal disease, some clinicians start aciclovir in all neonates less than 21 days of age in whom antibiotic therapy is being given empirically for suspected sepsis,5 although others have cautioned that aciclovir is inappropriately or excessively used in children of all ages.6

What is adequate treatment?

High-dose intravenous aciclovir is most effective when started early. Following disease relapses in early aciclovir studies in neonates, the standard of care became high-dose intravenous aciclovir given for 21 days for neonatal HSE.7 However, there are no published randomised controlled trials (RCTs) on dosing or duration for HSE treatment of older children. Table 1 gives an overview of HSE treatment. Maintaining intravenous access for the required duration of the aciclovir course can be problematic, so early insertion of a PICC line once the diagnosis is strongly suspected or confirmed can be very helpful. Repeating an LP at the end of 21 days of treatment to ensure a negative CSF PCR result is associated with a better outcome,8 but this is not universal practice. Centres that advocate a ‘proof of cure’ LP recommend continuing intravenous antiviral therapy where the day 21 CSF remains HSV PCR positive, especially in neonatal disease.8 There is no place for oral aciclovir or valaciclovir in the treatment of acute HSE given the potential disease severity. Nor is there any evidence to support steroid use in childhood HSE.

Is aciclovir resistance an issue?

In immunocompetent patients, viral resistance to aciclovir occurs rarely and is not clinically significant, the reported prevalence being less than 1%.12 However, in immunocompromised patients, this figure rises to 6%. The degree of immunosuppression, duration and frequency of exposure to aciclovir appear to be the most important risk factors for resistance. Resistance testing should be requested from a reference laboratory when suspected. Second-line drugs include foscarnet or cidofovir.

If HSE is unlikely, when is it safe to stop aciclovir?

This is a notoriously difficult decision. If doubt exists, a full course of aciclovir should be given risking overtreatment rather than undertreatment. Where clinical suspicion of HSE is low, it is usually appropriate to stop aciclovir if

• there is a negative CSF HSV PCR and cell count (<5 cells/mm³) and

• normal MRI neuroimaging and

• normal EEG and

• a full and rapid clinical recovery with normal level of consciousness or

• an alternative diagnosis becomes apparent.

Does a negative LP rule-out HSE?

Aciclovir should not be stopped if the CSF is negative on PCR for HSV when other features are consistent with HSE, particularly CSF cell count, MRI findings or EEG. Note that HSV PCR is a highly sensitive and specific test (94 and 96%, respectively), except during the first 24 h of the disease, when as many as 10% of HSE CSF samples can be falsely negative.13 If suspicion of HSE remains after an initial negative CSF PCR, a second LP and HSV PCR should be performed before day 4 of treatment.6 In addition, if aciclovir treatment is started some days before CSF is obtained for analysis, the PCR result may be falsely negative; HSV PCR results are unlikely to be affected by <48 h of aciclovir therapy and may still be informative up to a week after therapy is started.14

Can neonatal and childhood HSE recur?

Since the introduction of high-dose, prolonged therapy for neonates and children with proven or suspected HSE, early relapses are less common. Children presenting with features suggestive of HSV relapse need repeat cultures of blood and CSF, including CSF PCR for HSV and autoantibody quantification (see box 1).

After neonatal HSE, HSV can reactivate months to years after the initial infection, mostly presenting as dermal flares, or as an encephalitis as devastating as the initial illness.15 It is thought that early-life infection impairs the development of an effective adaptive immune response,1 but prolonged antiviral prophylaxis can prevent recurrence (see below).

Outside the neonatal period, HSE can signify the presence of underlying immunodeficiencies in the innate immune system associated with defective virus recognition, particularly in the TLR3 pathway.16 These children can develop protective adaptive immune responses. Though there are little data, older children are not routinely given antiviral prophylaxis beyond the first 3 months.

Both neonatal and childhood HSE predispose to subsequent autoimmune encephalitis, with new neurological symptoms, including aphasia, behavioural change, choreoathetoid movements and opercular syndrome.15 This may require immunomodulatory treatment with neurology advice.

What about prophylaxis after HSE?

Prophylaxis with aciclovir has been shown to reduce HSV relapse.15 While 12 months of antiviral prophylaxis is adequate for some children following neonatal HSE, late central or dermal flares may indicate that longer-term or even lifelong prophylaxis may be required. Findings from a small patient series proposed doses of 1340 mg/m² aciclovir given twice daily (total daily dose 2680 mg/m²),11 based on CSF penetration data, but a more recent larger placebo-controlled RCT validated oral aciclovir given at 300 mg/m² three times daily (900 mg/m²) as adequate at improving neurodevelopmental outcome.7

Valaciclovir is the prodrug of aciclovir and has better enteral absorption compared with aciclovir, producing higher plasma and, most importantly, CSF concentrations9 and permits a more manageable dosing regimen. Oral aciclovir is recommended for neonates and valaciclovir for older children requiring long-term prophylaxis (table 1).

What advice should we give to pregnant women who have genital HSV in the final weeks of pregnancy?

HSV primary infection in the third trimester presents a significant neonatal risk, and delivery by caesarean section is advised followed by neonatal screening for HSV (see below). Babies born vaginally should be started on intravenous aciclovir at birth.17 Women with primary HSV infection in the first or second trimester should be prescribed oral or intravenous aciclovir, followed by daily suppression with oral aciclovir from 36 weeks of gestation to reduce the chances of lesions being present at delivery.

In recurrent HSV infection, the risks are less, but if active lesions are present at delivery then delivery by caesarean section may be considered. For vaginally delivered babies, there are little data to guide initiation of aciclovir, and there is variable practice. We would recommend minimising the risk of a devastating illness by treating all infants born to mothers with active lesions.17

All babies born to mothers with suspected or proven active HSV should be screened for HSV by mucosal (conjunctiva, pharynx, rectum) and skin swabs taken between 12 and 24 h of age, even after caesarean section delivery. If HSV is detected, intravenous aciclovir treatment should be continued/initiated.

What onward referral is needed?

Where there is a family history of invasive HSV disease and/or consanguinity, children should be referred to an immunology centre. Identification of defects permits family testing, and consideration of antiviral prophylaxis in HSV-seronegative family members. Even where this is not the case, childhood HSE should be discussed with a local tertiary paediatric infectious diseases specialist with access to specialist paediatric neurologists.

Children with HSE will require long-term multidisciplinary neurodevelopmental follow-up and possibly also psychological and educational rehabilitation following what is often a long hospital stay and convalescence. They also may require treatment for longer-term complications, including epilepsy, spasticity and dystonia. Useful contacts for parents and children include charities that offer support to those who have suffered an acute brain injury, such as the Encephalitis Society (http://www.encephalitis.info), Headway and the Child Brain Injury Trust (http://www.headway.org.uk).