Encephalitis

Introduction

Encephalitis should be suspected in any child with fever, seizures and decrease in consciousness or irritability.

Although this constellation of symptoms is a fairly common presentation in paediatrics, the most serious cause is HSV encephalitis, which untreated has a mortality rate of 70%. Treated, this is reduced to 20%, hence the high index of suspicion and low threshold to treat for this condition.

Other symptoms may include headaches, confusion, altered behaviour, vomiting and focal neurological deficits. There may be a history of fever and general malaise, or the onset may be quite sudden. It can be difficult to differentiate between encephalitis and other causes for the above symptoms, therefore all cases must be considered infectious and treated as such with antibiotics and aciclovir until proven otherwise.

The cause of encephalitis is only found in approximately one third of cases. This is a guideline to investigating encephalitis, which should be used in context with the clinical picture. Early discussion with the paediatric Infectious Diseases (ID) team is encouraged for immunocompromised children and those with particular travel/environmental exposure history.

History

Including:

• Recent infectious symptoms eg respiratory illnesses or chicken pox, rash, diarrhoea

• Travel and environmental exposures eg swimming in thermal pools, animal contact

• Family illness

• Previous neurological or psychiatric presentations

• Baseline developmental and behavioural status

• Immunisation history

• Consider risk of accidental or intentional drug ingestion (prescription and non-prescription)

Examination

• Thorough systems exam

• Full neurological exam including eye and fundal exam, mental state

• Don't forget careful skin exam for rash, lesions, neurocutaneous markers

Differential diagnosis

• Bacterial meningitis

• Viral meningo-encephalitis

• Tuberculous meningitis

• Parasitic

• Immune mediated encephalitis

• Demyelinating disorder

• Paraneoplastic disorder

• Epileptic encephalopathy

• Metabolic encephalopathy

• Vasculitis

• Poisoning or drug ingestion

• Psychiatric disorder

Initial investigations for all cases beyond neonatal period

• FBC

• U&E

• LFT

• Gas

• Glucose

• Lactate

• Ammonia (purple tube on ice)

• Blood cultures

• Serology

  • Take 2 red tubes (10mls blood - or as much as practicable for age) and request storage for serology if needed later

  • Serum is stored using the Neuronal Antibody request form available on the LabTest website

  • Mycoplasma and EBV and serology

  • Mumps and measles serology if community outbreak, or unimmunised

• Lumbar puncture (LP) - (if safe to do so - see below for Contraindications to Lumbar Puncture)

  • Take 4 tubes

  • MC&S, protein, glucose,

  • PCR for HSV, VZV enterovirus and parechovirus (pneumococcal and meningococcal PCRs are also typically included in laboratory CSF PCR panel)

  • Cryptococcal antigen if immune compromised

  • May show pleocytosis, raised protein or raised RBC count or may be normal.

• Nasopharyngeal swab for PCR panel (including adenovirus, enterovirus/rhinovirus, influenza A and B, mycoplasma)

• Throat and rectal swabs: enterovirus, adenovirus, parechovirus (infants) and rotavirus

• EEG - looking for generalised slowing and any epileptiform activity

• Neuroimaging - ideally MRI but CT if needed urgently to look for signs of raised intracranial pressure

• Consider urine for toxicology

Further Investigations

To investigate the underlying cause if not yet found - consider in clinical context

This is not a routine battery of tests but is a guide in the case of a diagnosis not being reached from initial screening. Suggest prior discussion with the Infectious Diseases team and Virology lab.

It is to be used in the immunocompetent child.

Immunosuppressed children should all be discussed with the Infectious Diseases team

Second line laboratory investigations

See Laboratory Guide for help with lab investigations

Other investigations

MRI/MRA - consider MRI spectroscopy if possible metabolic disorder

Management - older infants (>3 months) and children

Initial treatment

Start aciclovir and broad spectrum antibiotics intravenously for any child where there is a suspicion of encephalitis.

Where possible perform the above initial investigations including lumbar puncture (LP) prior to starting treatment. See below for contraindications to LP. If LP is not possible at the time it should be performed as soon as safely possible to allow informed decisions to be made about the duration of treatment.

A normal LP does not exclude encephalitis and HSV PCR can be negative on a first lumbar puncture even with HSV disease. If there is clinical suspicion aciclovir should be continued until further investigations including a second LP have been performed. Antibiotics should be continued until cultures are negative.

The child should be kept adequately hydrated but with judicious use of fluids, bearing in mind the risk of SIADH and cerebral edema. See Intravenous Fluids guideline.

Baseline renal function should be measured and this should be monitored for the duration of aciclovir treatment. See below for safe usage of aciclovir.

Duration of treatment

HSV PCR positive cases should be given a minimum of 14 days of IV acyclovir (minimum 21 days under 3 months of age or if immunocompromised), with LP at end of treatment course for repeat HSV PCR prior to stopping acyclovir.

Oral aciclovir or valaciclovir are not valid alternatives.

In the case of suspected encephalitis where the cause has not been identified, LP should then be repeated after 3-4 days for second line investigations including repeat PCR for HSV, and consider repeating EEG and neuroimaging.

If these are again normal, and there are no abnormalities on EEG or neuroimaging consistent with HSE, and the child has clinically completely recovered, the aciclovir could be stopped.

In any child who clinically has had an encephalopathy, where there is either:

• Abnormal EEG

• Abnormalities on neuroimaging

• Incomplete recovery

then aciclovir should be continued for 21 days (even if the CSF was normal).

Convalescent serology should be taken 2-3 weeks after the initial serology was taken in any child where the cause has not been identified.

Any cases that are not straightforward should be discussed with the Neurology team and the ID team.

It is important to document carefully any decisions made to stop or start treatment and the reasons behind them.

Investigation and management of neonatal encephalitis (<3 months)

Neonatal encephalitis can be even more difficult to diagnose clinically as the symptoms can be even more non-specific. There may or may not be a history of genital herpes in mother or father, or of cold sores. Many genital infections will be asymptomatic and up to 60% of HSV meningitis there is no parental history of herpes.

A very low threshold for treating with aciclovir in an infant with fever without focus should be maintained if no other cause can be found. If aciclovir is commenced ensure that HSV PCRs have been requested on CSF and blood. Any infant with skin lesions suggestive of HSV should have a lumbar puncture to look for CNS disease as well as viral skin swabs for HSV. Elevated liver transaminases are an important clue for disseminated herpes simplex in neonate with fever without focus.

A positive result should prompt discreet and sensitive counselling of parents and investigations as warranted.

CSF in infants is more likely to be normal or only mildly abnormal, and PCR has been shown to be only 70% sensitive early in infection. Therefore LP should be repeated in the first week if initial results are normal.

Duration of treatment should be minimum 21 days. LP should be repeated just prior to 21 days to ensure clearance (negative HSV PCR). If the virus is not cleared treatment should be continued. Discuss these cases with the ID team.

Once the virus has been shown to be cleared the treatment can be stopped. However neonatal HSV CNS disease has a high relapse rate. Any recurrence of skin rash should prompt a repeat LP, as should any presentations suspicious for encephalitis, and further IV aciclovir.

Cases of HSV encephalitis, disseminated HSV or skin-eye-mouth disease are all recommended to receive aciclovir 300mg/m²/dose orally TID for 6 months as suppressive therapy (Kimberlin et al. 2011).

Investigations for infectious causes of encephalitis in the neonatal period

CSF:

• Culture to include Listeria monocytogenes

• HSV1 and 2, toxoplasmosis, CMV, enterovirus and parechovirus PCR

• VDRL if congenital syphilis suspected.

Blood:

• Culture

• Syphilis, HIV, toxoplasmosis, CMV serology

• HIV and HSV PCR

Contraindications to Lumbar Puncture

(see also Meningitis guideline)

• Deteriorating level of consciousness or GCS < 13 or fluctuating level of consciousness

• Focal neurological deficits e.g. Pupillary dilatation, ocular palsy, asymmetry

• A recent fit within 30 minutes, focal or prolonged fit > 30 minutes duration

• Abnormal posture of movement (decerebrate, decorticate, cycling)

• Inappropriately low HR, elevated BP, irregular respirations (ie. signs of impending brain herniation)

• Papilloedema

• Impaired oculocephalic reflexes (Doll’s eyes reflexes)

• Abnormal coagulation tests – INR >1.5 or platelets < 50

• Septic shock or haemodynamic instability

• A bleeding diathesis or widespread purpura

• Skin sepsis at the LP site

Note that a normal head CT scan does not exclude the presence of raised intracranial pressure and should not influence your decision to perform a lumbar puncture; this is a clinical decision.

Dosing regimen for intravenous aciclovir

See also the New Zealand Formulary for Children

Note:

Toxic to veins so a central venous catheter is advised for long courses.

Check baseline renal function and monitor frequently.

Avoid using in conjunction with ceftriaxone as this can increase the chance of renotoxicity.