Guideline for the Management of Herpes Simplex Virus Encephalitis in Infants and Children (1 month - 16 years)

• Summary
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• Background
• Clinical Diagnosis
• Investigation
• Treatment
• Non-Antimicrobial Treatment
• Empirical Antimicrobial Treatment
• Directed Antimicrobial Treatment (when microbiology results are known)
• Duration of Treatment
• Switch to oral agent(s)
• Referral Criteria

This guideline applies to infants and children with confirmed herpes simplex virus encephalitis (HSE).
Confirmed HSE = Clinical findings consistent with HSE (see below) PLUS typical findings on CT/MRI head AND/OR Herpes simplex virus (HSV) positive PCR on CSF.

History/Examination
HSE commonly presents with impaired consciousness (lethargy, decreased conscious level or coma) or seizures (focal or generalised) and a fever.
This may or may not be in combination with new focal signs and symptoms including:

• altered behaviour (especially abnormal irritability);
• disturbances of memory;
• signs of raised intra cranial pressure (these should be looked for and appropriate management instituted);
• cranial nerve palsies;
• hemiplegia;
• anosmia;
• olfactory hallucinations;
• dysphasia;
• ataxia;
• meningism.

These symptoms may fluctuate but generally have a deteriorating trend.

NB Children may be managed initially according to Guideline for the initial management of a child with a fever and seizure or suspected acute CNS infection.

Investigations required

• Lumbar puncture (if not already done) for CSF HSV PCR
• MRI
• EEG

Non-Antimicrobial Management
Monitor and manage any raised intra-cranial pressure.

Antimicrobial treatment
Continue/start high dose IV Aciclovir (see below).
Review/stop IV Cefotaxime / Ceftriaxone and IV Clarithromycin , if started empirically.

N.B Aciclovir should be continued if there is a high index of suspicion that this is HSE even if the CSF PCR is negative.

IV Aciclovir *

• Child 1-3 months 20mg/kg every 8 hours.
• Child 3 months- 12 years 500mg/m2 every 8 hours. (use body surface area nomogram at back of BNFc)
• Child 12-16 years 10 mg/kg every 8 hours.

*To avoid excessive dose in obese patients parenteral dose should be calculated on the basis of ideal weight for height (as per BNFc).
All IV doses need to be given as an infusion over 1 hour - see IV monographs on Trust website.

Duration of therapy
21 days of IV Aciclovir .

Aciclovir can be stopped if HSV PCR is negative (>72 hours after onset of illness) and low clinical suspicion.

Switch to oral agents
There is no place for using oral Aciclovir to treat HSV encephalitis

Referral criteria
Confirmed cases can be referred to virology or paediatric neurology.
There is a need to be alert to the possibility of Primary Immunodeficiency in patients. Consider discussing with immunology.

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Herpes simplex virus encephalitis (HSE) is an acute focal necrotizing encephalitis with inflammation and swelling of brain tissue. It represents about 10% of all severe viral CNS infections. Thirty one percent of cases occur in patients below 20 years of age and 12% in those between 6 months and 10 years ^{2, 3}. In children (and adults) the mortality in untreated HSE is 70%, 19% in treated HSE but greater than 50% of survivors have neurological sequelae⁴.

It is important to have a low threshold to consider HSE due to the potential severity of its outcome and because it is treatable.

For this guideline to apply, a confirmed case of HSE is defined as:

1) clinical findings consistent with HSE (see Clinical Diagnosis section)

AND

2) radiological evidence of HSE on CT or MRI scanning the head AND/OR a positive Herpes simplex virus PCR (see Investigations section)

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HSE can present with reduced consciousness (lethargy, decreased Glasgow Coma score or coma), abnormal behaviour, focal neurological signs or seizure and a fever and cases are likely to be initially managed according to Guideline for the initial management of a child with a fever and seizure or suspected acute CNS infection.

Recommendation: A child that does not recover from a “febrile seizure” within an hour should be investigated and treated for encephalitis⁶
[Evidence level C]

Focal signs and symptoms may also be present (one or more of the following)

• seizures (focal or generalised);
• altered behaviour (especially abnormal irritability);
• disturbances of memory;
• signs of raised intra cranial pressure (these should be looked for and appropriate management instituted);
• cranial nerve palsies;
• hemiplegia;
• anosmia
• olfactory hallucinations
• aphasia;
• ataxia;
• meningism.

The symptoms of encephalitis are preceded in 60%⁵ of cases by prodromal symptoms that may just be fever and malaise often lasting a few days.  Fever may develop after the onset of neurological symptoms¹.

One third of cases will have skin, eye or mouth manifestations of HSV.  Signs and symptoms that may be present are:

• vesicular rash
• irritability
• lethargy
• poor feeding
• seizures
• temperature instability
• bulging fontanelle
• pyramidal tract signs
• sepsis like syndrome (hypothermia, respiratory distress  and very elevated hepatic enzymes)
• jaundice

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Recommendation:  If there are no contraindications, lumbar puncture (LP) should be performed in all cases of suspected HSE and cerebrospinal fluid (CSF) sent for microscopy, bacterial culture, protein, glucose (paired with blood), HSV polymerase chain reaction (PCR)
[Evidence level B]

Recommendation: If a LP was initially contraindicated, it can be done later in the course of the illness (and sent for tests above) if the contraindications are resolved.
[Evidence level B]

Recommendation: If the CSF HSV PCR result is negative (early in the course of the illness) and the diagnosis of HSE is considered likely, a LP should be repeated and CSF sent for HSV PCR.
[Evidence level D]

Recommendation: If the CSF HSV PCR result is negative (≤72 hours after onset of symptoms) and the diagnosis of HSE is considered likely, and a repeat LP is contraindicated, a blood sample should be sent for HSV IgM and IgG testing.
[Evidence level D]

Recommendation:  If symptoms persist at the end of a treatment course a repeat CSF PCR analysis should be considered prior to therapy being altered (see also, duration section)
[Evidence level B]

Recommendation: If skin vesicles are present, vesicle fluid should be sent for viral PCR.
[Evidence level D]

Recommendation: MRI (including diffusion weighted imaging), should be performed as soon as possible on all patients with suspected encephalitis in whom the diagnosis is uncertain; ideally this should be within 24 hours of hospital admission, but certainly within 48 hours.
[Evidence level B]

Where the patient’s clinical condition precludes an MRI, urgent CT scanning may reveal an alternative diagnosis.  
[Evidence level A]

Recommendation: An Electroencephalogram (EEG) should not be performed routinely in all patients with suspected encephalitis; however, in patients with mildly altered behaviour, if it is uncertain whether there is a psychiatric or organic cause an EEG should be performed to establish whether there are encephalopathic changes. EEG should also be performed if subtle motor or subclinical seizures are suspected. An EEG should be performed in children with suspected chronic viral encephalitis for example sub-acute sclerosing panencephalitis (SSPE).
[Evidence level B]

Evidence

• Establishing HSV as the cause of encephalitis is important because it justifies a prolonged course of a potentially toxic therapy and has prognostic implications.
• Every effort should therefore be made to investigate appropriately.
• PCR for HSV has been shown in studies to have a sensitivity of 96% and specificity of 97 % ⁷. False negative results may be obtained in the following circumstances:
  • Early testing (in first few days of onset of symptoms),
  • After the first 5-7 days of treatment (although studies have shown that 50% of patients are PCR positive after 1 week of treatment)
  • Presence of PCR inhibitors (e.g. haemoglobin; blood contaminated CSF)
  • External quality assurance programmes indicate overall false positive HSV PCR rates of 1-3%. To improve specificity LTHT virology department confirms positives by repeat testing. Where insufficient CSF remains this repeat is performed on the original extracted material. Initial positive results may be telephoned to ensure appropriate patient management.
• Intrathecal antibody detection is no longer provided as a service.
• In detecting the early cerebral changes of viral encephalitis, MRI is reported to be significantly more sensitive than CT. In HSV encephalitis a CT obtained early may be normal, or have only subtle abnormalities. One small series reported only a quarter of patients with HSV encephalitis had an abnormality on initial CT scanning compared to MRI obtained within 48 h of hospital admission which showed abnormality  in approximately 90% of patients⁸.
• It has been shown that EEG is abnormal in most patients with encephalopathy, including more than 80% of those with acute viral encephalitis. It can be used in finding out whether abnormal behaviour is due to psychiatric causes or is an early feature of encephalopathies when patients have a more subtle presentation. It is also useful in determining whether a patient has non-convulsive or subtle clinical seizures, which occur in both HSV encephalitis and other encephalopathies⁸.

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Look for evidence of raised intracranial pressure and manage this.

Recommendation: Aciclovir can be nephrotoxic and it is important to ensure that the patient is well hydrated.
[Evidence level B]

Recommendation: When a diagnosis of HSE is confirmed, consider early insertion of a long line for administration of IV Aciclovir .

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See Guideline for the initial management of a child with a fever and seizure or suspected acute CNS infection.

Recommendation: Empirical Aciclovir therapy should be reviewed with the results of investigations.
[Evidence level C]

Recommendation: Aciclovir may be discontinued if a negative CSF HSV PCR test is obtained at >72 hours following onset of neurological symptoms in a patient with a low probability of having HSE.
[Evidence level D]

If a child has HSE, referral to the paediatric neurology team for advice regarding investigation, management and treatment is appropriate.

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Recommendation: Aciclovir (dosed as below) is the treatment of choice for children with confirmed HSE.
[Evidence level A]

Children*

• Child 1-3 months IV Aciclovir 20mg/kg every 8 hours
• Child 3 months- 12 years IV Aciclovir 500mg/m² every 8 hours (use body surface area nomogram at back of BNFc)
• Child 12-16 years IV Aciclovir 10 mg/kg every 8 hours

*To avoid excessive dose in obese patients parental dose should be calculated on the basis of ideal weight for height.  (as per BNFc)

Recommendation: A full course of Aciclovir therapy should be given to children with confirmed HSE (dose and route as above). [Evidence level B]

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Recommendation: 21 days of IV Aciclovir is recommended.

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Recommendation: Oral Aciclovir is not appropriate for treatment of HSE. [Evidence level C]

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Confirmed cases can be referred to virology or paediatric neurology to discuss the risk of recurrence/reactivation and if prolonged oral therapy is required.

There is a need to be alert to the possibility of Primary Immunodeficiency in patients. Consider discussing with immunology.

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