Neonatal meningitis and encephalitis

Overview

• Neonatal meningitis and encephalitis represent life-threatening neurological emergencies requiring rapid recognition and empirical treatment.
• The neonatal period (birth to 28 days) carries uniquely high risks: an immature blood-brain barrier, impaired innate and adaptive immunity, and non-specific clinical presentations all contribute to diagnostic difficulty and delayed treatment.
• Mortality remains high even with appropriate therapy, and neurological morbidity is substantial among survivors.
• HSV encephalitis deserves particular emphasis given its treatability with aciclovir and the catastrophic consequences of delayed treatment.

Epidemiology and Aetiology

Bacterial Causes

• GBS accounts for the majority of early-onset bacterial meningitis in term neonates.
• Gram-negative organisms predominate in preterm infants in neonatal intensive care units.

Viral Causes

• HSV-1 and HSV-2: The most important viral cause of neonatal encephalitis. Neonatal infection occurs in approximately 1 in 5,000-10,000 births (UK incidence ~1 in 50,000 births; substantially higher in North America). Transmission is predominantly perinatal from the maternal genital tract (usually HSV-2); transplacental transmission is rare. Both HSV-1 and HSV-2 can cause neonatal encephalitis; neonates acquire HSV around delivery, with ~90% being HSV-2. Vertical transmission risk is up to 40% with primary maternal infection near delivery, falling to <5% with recurrent genital herpes.
• Enteroviruses (Coxsackievirus, Echovirus, EV71): Cause neonatal aseptic meningitis, often mild but occasionally severe; non-polio enteroviruses cause 80-90% of identifiable viral meningitis in children.
• Cytomegalovirus (CMV): Congenital infection causing encephalitis/meningoencephalitis.
• Parechovirus: Increasingly recognised cause of neonatal sepsis-like illness and CNS infection.
• Other: Varicella zoster virus, rubella (congenital), mumps (usually meningitis, less often encephalitis).

Pathophysiology

Bacterial Meningitis

• Bacterial invasion of the subarachnoid space triggers an intense inflammatory cascade.
• Cytokines (TNF-α, IL-1β, IL-6) increase blood-brain barrier permeability, causing cerebral oedema (vasogenic, cytotoxic, and interstitial types).
• Vasculitis leads to thrombosis and infarction.
• Hydrocephalus may develop from impaired CSF reabsorption or aqueduct obstruction.
• Elevated intracranial pressure and direct neuronal injury combine to cause the high rates of neurodevelopmental sequelae.

HSV Neonatal Encephalitis

Neonatal HSV acquired perinatally causes one of three distinct clinical syndromes:

1. Skin, eye, and mouth (SEM) disease: localised; lowest mortality; however, infants with apparently localised SEM disease may have neurological sequelae from unrecognised subclinical encephalitis
2. CNS disease (encephalitis): mortality ~50% if untreated; with aciclovir treatment mortality ~15%, but neurological sequelae in the majority of survivors
3. Disseminated disease: multiorgan involvement (liver, adrenals, lungs, brain); mortality ~80% if untreated; ~30% with treatment; can occur without visible skin lesions

• HSV-2 causes more severe disease, is more likely to recur, and causes more permanent sequelae than HSV-1.
• In neonates (predominantly HSV-2), CNS involvement tends to be diffuse rather than the focal temporal localisation characteristic of postneonatal HSV-1 encephalitis.

Viral Encephalitis (General)

• Acute viral encephalitis involves either direct invasion of neural tissue (predominantly grey matter) or postinfectious encephalomyelitis following viral or bacterial infection.
• Postinfectious encephalomyelitis is characterised by widespread asymmetric white matter demyelination without direct invasion, most often following a non-specific respiratory illness.

Clinical Features

Age-Specific Presentations

The classical triad of fever, neck stiffness, and altered consciousness is frequently absent in neonates.

Encephalitis: General Clinical Features (All Ages)

• Fever
• Behavioural disturbance
• Altered consciousness
• Seizures
• Ataxia or other movement disorders
• Focal neurological deficits
• Meningism is frequently absent

HSV-Specific Features in Neonates

• Vesicular rash on skin, oral mucosa, or conjunctivae, important but not universal; disseminated disease can occur without skin lesions
• Disseminated HSV mimics neonatal sepsis: fever/hypothermia, DIC, hepatitis, shock, pneumonia
• CNS HSV presents with seizures (often focal), irritability, encephalopathy, or bulging fontanelle
• Neonatal viral meningitis is usually mild, if CSF suggests viral infection but the baby is seriously ill, herpes is the most likely diagnosis

HSV Encephalitis in Older Children (Postneonatal, Predominantly HSV-1)

• Prodromal fever, headache, behavioural change, intermittent delirium, progressive lethargy
• Progressive encephalopathy, focal seizures (often temporal lobe onset)
• Focal neurological deficits (hemiparesis, dysphasia)
• Meningism may be present
• Frontal and temporal lobe localisation is characteristic, but PCR and MRI testing have shown the disease can be more diffuse, particularly in young children

Encephalitis, Diagnostic Clues from History

The aetiology may be suggested by:

• Season (enterovirus peaks in late summer/autumn in temperate climates)
• Recent travel history
• Animal exposures (arbovirus)
• Drug and immunisation history
• Family illness
• Presence of lymphadenopathy, parotitis, rash, or pneumonia

Investigations

Lumbar Puncture and CSF Analysis

• CSF examination is the cornerstone of diagnosis.
• Lumbar puncture should not be delayed if meningitis/encephalitis is suspected, unless contraindicated (raised ICP with focal signs, coagulopathy, haemodynamic instability).
• Up to 50% of patients with encephalitis have normal CSF parameters.

Important caveats:

• Neonatal CSF has higher normal protein and cell counts than older children, age-appropriate reference ranges are essential
• Occasionally babies with meningitis have falsely reassuring CSF white cell counts; viral encephalitis can be present with no CSF pleocytosis
• CSF obtained very early after meningeal invasion may not yet reflect the inflammatory response
• In herpetic meningoencephalitis in neonates, CSF may show findings similar to bacterial meningitis
• A repeat LP at 12-24 hours may help clarify an ambiguous initial result

Microbiological Investigations

• CSF PCR for HSV-1/HSV-2, enterovirus, CMV, parechovirus, the diagnostic test of choice for viral CNS infection; provides rapid and accurate diagnosis across a wide range of pathogens
• Blood culture: mandatory before antibiotics
• CSF Gram stain and culture: for bacterial aetiology; throat and stool cultures/PCR may also detect enteroviruses
• HSV cultures/PCR from vesicle fluid, conjunctival swabs, nasopharyngeal swab, blood, urine, saliva, and CSF, rapid diagnosis by immunofluorescence of vesicle fluid or PCR is preferred to culture or serology
• Serology: limited value in neonates (cannot distinguish passively acquired maternal antibody from endogenously produced antibody); intrathecal HSV antibody synthesis supports ongoing infection; rising IgG titres may be useful in older infants
• Throat and stool PCR/cultures for enterovirus

Neuroimaging

MRI is preferred over CT for superior sensitivity; MRI changes in HSV encephalitis may appear earlier than CT changes.

• CT is used emergently when MRI is unavailable or herniation is an immediate concern
• Corticosteroids should be considered when MRI shows striking enhancement of multifocal white matter lesions consistent with postinfectious encephalomyelitis
• Cranial ultrasound can serve as an interim bedside tool in unstable preterm neonates

Electroencephalography (EEG)

• EEG abnormalities are seldom specific but are particularly helpful in HSV encephalitis
• In postneonatal HSV encephalitis: periodic lateralised epileptiform discharges (PLEDs) localised to the temporal region are characteristic (though not pathognomonic)
• In neonatal HSV encephalitis: temporoparietal high-voltage, low-frequency activity may be seen
• EEG is essential for detecting subclinical seizures in neonates (where clinical manifestations are often subtle) and for characterising seizure type

Diagnostic Pathway

Approach to Suspected Neonatal Meningitis/Encephalitis

1. Clinical assessment: fever/hypothermia, altered tone, seizures, bulging fontanelle, skin/mucocutaneous lesions, signs of shock or hepatitis
2. Blood investigations: FBC, CRP, blood culture, blood glucose, LFTs, coagulation studies (DIC screen), blood HSV PCR
3. Lumbar puncture: CSF cell count, protein, glucose, Gram stain, culture, PCR panel (HSV, enterovirus, parechovirus, CMV)
4. Neuroimaging: MRI brain (or cranial ultrasound as interim in preterm/unstable neonates); CT if MRI unavailable acutely
5. EEG: particularly if seizures suspected, if subclinical seizures possible, or if HSV encephalitis is a consideration
6. Empirical treatment: commence aciclovir AND antibiotics simultaneously, do not delay for results

If herpes is suspected, begin treatment before a definitive diagnosis is established; some fulminant cases only come to light at postmortem.

Autoimmune Encephalitis (Anti-NMDA Receptor Encephalitis)

• Anti-NMDA receptor (anti-NMDAR) encephalitis is increasingly recognised in children.
• It should be considered when encephalitis is not explained by infectious or metabolic causes, particularly with prominent movement disorder, psychiatric features, and autonomic instability.

• Diagnosis requires clinical syndrome + positive anti-NMDAR antibodies.
• Both serum and CSF should be sent; CSF is the more sensitive specimen.

Management

Initial Empirical Therapy

Never delay antimicrobial treatment in a sick neonate or child with suspected meningitis/encephalitis.

Aciclovir Dosing for HSV Encephalitis

• Aciclovir is administered intravenously and is the treatment of choice at all ages.
• Treatment reduces postneonatal mortality to below 20%; neonatal mortality from untreated encephalitis is ~50%.

Key principles:

• Commence aciclovir empirically as soon as HSV encephalitis is suspected, do not wait for PCR results
• Continue until HSV encephalitis is definitively excluded by negative PCR AND clinical/radiological criteria
• If CSF PCR remains positive at end of planned treatment course, extend therapy (as per the clinical principle of persisting HSV DNA requiring continued treatment)
• Following IV therapy for neonatal HSV CNS disease, administer oral aciclovir suppressive therapy for 6 months, this reduces neurodevelopmental morbidity and frequency of cutaneous recurrences
• Apply topical aciclovir to eye and skin lesions
• Monitor renal function during IV aciclovir; ensure adequate hydration to prevent crystalline nephropathy

Management of Autoimmune Encephalitis

First-line immunotherapy (used concurrently or sequentially):

• High-dose IV methylprednisolone (typically 20-30 mg/kg/day for 3-5 days)
• IV immunoglobulin (IVIG; typically 2 g/kg over 2-5 days)
• Plasma exchange (plasmapheresis), particularly in severe or refractory cases

Second-line therapy (if inadequate response within ~10 days):

• Rituximab (anti-CD20 monoclonal antibody)
• Cyclophosphamide

Tumour search (ovarian teratoma) is mandatory in adolescent females; surgical resection of the teratoma is itself therapeutic.

Supportive Care

• Seizure management: Phenobarbitone (first-line in neonates); benzodiazepines for acute seizures; levetiracetam increasingly used
• Fluid management: Careful fluid management; avoid fluid overload; monitor for SIADH (hyponatraemia)
• Intracranial pressure: Elevate head of bed; controlled ventilation if needed; avoid hypotonic fluids
• Nutrition: Enteral or parenteral nutrition as appropriate
• Respiratory support: Assisted ventilation for apnoea or respiratory failure
• Corticosteroids: Consider when MRI shows multifocal white matter enhancement consistent with postinfectious encephalomyelitis

Complications

• In HSV encephalitis, even with aciclovir treatment, many survivors have severe neurological or behavioural sequelae.
• HSV-2 is associated with more severe, recurrent disease and greater likelihood of permanent sequelae than HSV-1.

Prognosis

Approximately 10% of children with encephalitis die, and nearly half of survivors have neurological or educational disabilities.

Patients can make excellent recoveries even after prolonged coma, but this should not reduce urgency of treatment.

Follow-up

• Neurodevelopmental assessment: Multidisciplinary (paediatric neurology, developmental paediatrics, neuropsychology) at 3, 6, 12 months and annually
• Audiology: BERA/formal hearing assessment at discharge and 3-6 months post-illness, critically important after bacterial meningitis
• Ophthalmology: For neonatal HSV eye involvement and suspected cortical visual impairment
• Neuroimaging: Repeat MRI at 3-6 months to assess structural injury and guide prognosis
• EEG: For surveillance of post-encephalitic epilepsy
• Oral aciclovir suppression: 6-month course after neonatal HSV CNS disease; monitor compliance

Indications for Admission and Escalation

Immediate Admission

• Any neonate with suspected infection and altered neurological status, seizures, or fever
• Suspected HSV encephalitis at any age, urgent IV aciclovir and inpatient management
• Encephalopathy with behavioural change, seizures, or focal neurological signs in any child
• Signs of raised intracranial pressure

NICU/PICU Referral

• Coma or rapidly deteriorating consciousness
• Respiratory compromise or apnoea
• Haemodynamic instability (especially disseminated neonatal HSV)
• Refractory seizures requiring continuous anticonvulsant infusion
• Need for continuous EEG monitoring

Specialist Referral

• Paediatric neurology: All encephalitis cases; seizure management; autoimmune encephalitis workup
• Infectious diseases: Suspected HSV, resistant organisms, immunocompromised host, unusual pathogens
• Paediatric intensive care: Airway/respiratory compromise, haemodynamic instability
• Ophthalmology: Neonatal HSV eye involvement
• Neurosurgery: Hydrocephalus, brain abscess, subdural empyema
• Retrieval services (e.g. NSW NETS): Stabilisation and transport of critically unwell neonates to a tertiary centre

Key Clinical Pearls

• Empirical aciclovir should be started immediately whenever HSV encephalitis is suspected, do not wait for PCR results; treatment should continue until HSV is definitively excluded by clinical, radiological, and PCR criteria
• CSF PCR is the diagnostic gold standard for viral CNS infection but may be falsely negative very early in disease; consider repeat LP if clinical suspicion remains high
• Normal CSF does not exclude encephalitis: up to 50% of cases have normal CSF parameters
• Neonatal HSV can present without skin lesions, maintain a high index of suspicion in any unwell neonate, especially with hepatitis, coagulopathy, seizures, or sepsis-like illness not responding to antibiotics
• Neonatal HSV meningoencephalitis tends to be diffuse (unlike the focal temporal pattern of postneonatal HSV-1); CSF in neonatal herpetic encephalitis may mimic bacterial meningitis
• In neonatal HSV, if the baby is seriously ill but CSF findings suggest viral infection only, herpes is the most likely diagnosis
• MRI is superior to CT for detecting early encephalitic changes; EEG showing PLEDs in the temporal region strongly supports postneonatal HSV encephalitis; temporoparietal high-voltage, low-frequency activity is the characteristic EEG pattern in neonates
• Oral aciclovir suppression for 6 months following neonatal HSV CNS disease significantly reduces neurodevelopmental morbidity
• Anti-NMDAR encephalitis should be considered in children with unexplained encephalopathy, prominent psychiatric features, orofacial dyskinesias, and autonomic instability, send both serum and CSF antibodies, as CSF is more sensitive
• HSV-2 causes more severe neonatal disease with greater risk of recurrence and permanent sequelae than HSV-1
• Transplacental HSV is rare but results in profound injury (microcephaly, hydranencephaly, chorioretinitis, skin lesions); no treatment is available for congenitally infected infants