Guideline for the initial management of a child with fever and seizure or suspected acute CNS infection (not NICU)

• Summary
• 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)
  • Treatment Failure
• Meningitis prophylaxis

Summary

Pathway document

1. Presentation

Seizure / altered conscious state AND temperature >37.8, OR examination evidence of febrile illness.
OR,
Suspected CNS infection.

• Record weight
• Record observations/ PAWS
• Provide antipyretics as appropriate
• Then enter pathway corresponding to History & Examination

WARNING - infants and children with an open fontanelle are unlikely to have classic symptoms and signs of meningitis

Overview of pathways

Final Common Pathway

1. Repeat set of observations satisfactory
2. Patient advice leaflet given to parents and information for self-help groups
3. Discharge letter:
   • given to parents
   • faxed to GP
4. Contact number to CAT given Explain parents to use this over next 48hrs
5. Follow-up. All Children with proven or suspected bacterial meningitis should have a hearing check within 4 weeks arranged and follow-up with the results with Children’s Medicine. Consider additional follow-up with appropriate specialities based on co-morbidities. HV and or school nurse should be informed.
6. Children with a second episode of meningitis, meningococcal non-group-B serotypes, or who have a history of recurrent bacterial infection should be considered by the consultant for immune testing. In addition, those with meningococcal disease with a FH of meningococcal disease or complement deficiency

Back to top

Background

Infants and children with CNS infection may present acutely with a variety of symptoms and signs of CNS disease. There may be overlap in the presenting features of meningitis, acute infectious encephalitis and brain abscesses and it may not be possible to distinguish the cause of infection, or non-infective causes on clinical grounds. Headache is the most frequent symptom in children with brain abscesses, followed by fever and seizures. Importantly, the classical triad of fever, headache and neurological deficit are insensitive
for the diagnosis of brain abscesses.

Meningitis

The infectious causes of meningitis may be bacterial, viral or fungal. The most common causes of viral meningitis include non-polio enterovirus, lymphocytic choriomeningitis
virus, mumps virus and polio virus.

Table 1 illustrates the common causes of bacterial meningitis, which vary with age.

Encephalitis

Viruses cause the majority of acute infectious encephalitis episodes and Enteroviruses and Herpes simplex virus being the most common aetiological agents. Bacteria can occasionally cause encephalitis, Mycoplasma pneumoniae, for example and some bacteria can cause a mixed clinical picture sometimes referred to as meningoencephalitis (e.g.Listeria monocytogenes).

Herpes simplex encephalitis (HSE) is acute focal necrotizing encephalitis with inflammation and swelling of brain tissue. It represents about 10% of all severe viral CNS infections. 31% of cases occur in patients below 20 years of age and 12% in those between 6 months and 10 years ^{1, 2}. The mortality is 50% in neonates treated with disseminated disease. In children and adults, the mortality in untreated HSE is 70%, 19% in treated HSE but greater than 50% of survivors have neurological sequelae³.

Brain abscesses

Brain abscess is a focal, intracerebral infection, which usually begins as an area of cerebritis and develops into a collection of pus surrounded by a well-vascularised capsule. A brain abscess is initiated when microorganisms are introduced into the brain tissue following trauma, contiguous pericranial infection (e.g., ear or sinus infection), and meningitis or haematogenous dissemination from a distant infective focus (e.g. endocarditis). A wide variety of pathogens can cause brain abscesses (LTHT children’s brain abscess guidelines) and there may be overlap in terms of clinical presentation, with other causes of CNS infection.

Back to top

Clinical Diagnosis

Recommendation: Because the signs and symptoms of CNS infection may be subtle and are often not classical in infants and young children careful clinicalassessment and often a period of observation is required to establish a diagnosis.
[Evidence level D]

Recommendation: Red flag (or alert) symptoms and signs in suspected CNS infection should include:

• Definite neck stiffness or Kernigs sign
• Multiple seizures same illness
• Seizure with focal features
• Prolonged seizure > 15 minutes
• Does not wake or if roused does not stay awake 30 minutes after seizure (infant)
• Conscious level depressed (GCS<15), V or less (AVPU) 30min after seizure (1-16 years) non-blanching rash
• new onset of focal neurological signs irritability
• high pitched cry
  [Evidence level C/B]

Recommendation: Other elements in the history or examination that should alert one to the possibility of CNS infection include: vomiting, poor feeding, headache, ill appearance
[Evidence level C] #

Recommendation: Over 1 year of age, if there are no red flag symptoms, then directed investigation and observation are important to allow a diagnosis to be made.
[Evidence level C]

In older children, more classical features are often seen:

• neck stiffness
• headache
• photophobia

Specific signs of Kernig and Brudzinski are not reliable in children.

The diagnosis of "simple febrile convulsion" is a diagnosis of exclusion:

1. the seizure must have been an epileptic seizure ie. clonic or tonic-clonic
2. duration short i.e., less than 5 minutes.
3. the child must be between 6 months and 5 years
4. the conscious level must have returned to normal within 30 minutes of the end of the seizure unless benzodiazepines have already been given in which case recovery of consciousness may be delayed considerably - up to several hours. In this context the child should be in the RED PATHWAY until clinical improvement occurs (see Allen et al 2008)
5. there must be no focal neurological signs after the seizure has ended (see note 1 below)
6. there is no other obvious diagnosis e.g., meningococcal rash
7. a past history of a febrile seizure is weakly supportive but must not lead to the assumption the current episode cannot be a CNS infection

Note 1. If a child has had a short febrile seizure that nonetheless had some focal features -e.g., eye deviation or a unilateral clonic seizure AND they have no other risk factors as listed in the RED PATHWAY, then it may be reasonable to put them in the Yellow pathway. This is of course dependent on regular clinical review i.e., they should not be discharged at this point.

Back to top

Investigation

1. Lumbar puncture:

Recommendation: Cerebrospinal fluid (CSF) analysis and culture remain the gold standard for diagnosing meningitis ^(3,4) and lumbar puncture (LP) should be performed as soon as possible, unless there are clinical reasons to defer (see below).
[Evidence level A]

Recommendation: Because clinical assessment of acute CNS infection in younger infants is unreliable, CSF examination is considered mandatory in all children <1 year of age with no other focus to account for any of the above.
[Evidence level C]

Recommendation: Antibiotic administration should NOT be delayed if LP is deferred.
[Evidence level C]

Recommendation: LP should always be deferred and discussed with a consultant paediatrician in the presence of:

• shock
• suspicion of meningococcal bloodstream infection/disease (e.g., purpura or petechial rash in this context) raised intracranial pressure (ICP) (see non-antimicrobial management)
• Glasgow Coma Score <13 or deteriorating level of consciousness (eg a drop in GCS from 15 to 13); if GCS <13 but stable
• Other signs of raised intracranial pressure - altered pupillary responses, absent Doll's eye reflexes, decerebrate or decorticate posturing, abnormal respiratory pattern, papilloedema, hypertension, bradycardia.
• Within 30 minutes of a convulsive seizure (after 30 minutes, take GCS into consideration before LP).
• Focal seizures (may potentially indicate a structural abnormality including a tumour or an abscess).
• Tonic seizures BEWARE extensor posturing (syn. decerebrate posturing) is a sign of brain herniation until proved otherwise.
• New focal neurological signs - hemi/monoparesis, extensor plantar responses, ocular palsies.
• Local infection over the LP site.
• Coagulation disorder/patients treated with anticoagulants/low platelets.

suspect raised ICP if any: -
Please refer to the trust guideline “Performing a lumbar Puncture in Children under Paediatric medicine” for details of the procedure.

Table 1. Interpretation of CSF analysis results.

Lumbar puncture (LP) is an important diagnostic tool and is generally a safe procedure. However, in the presence of raised intracranial pressure it can be associated with herniation of the brain structures.
Clinical or LP findings in keeping with TB should be discussed with the Consultant or Infectious Disease specialist.
Repeat LP is sometimes indicated and should be discussed with the Consultant

2. Neuroimaging - Cranial computed tomography (CT).

Recommendation: CT should be undertaken in all children on RED pathway or when the clinical diagnosis is uncertain or space occupying lesion (e.g. cerebral abscess) is suspected. [Evidence level D]

Recommendation: CT must not delay antibiotic treatment to children on red pathway.
[Evidence level D]

Recommendation: CT cannot be relied upon to exclude raised intracranial pressure.
[Evidence level B]

3. Other Investigations: [Evidence level D]

Recommendation: The following investigations should be carried out in all children on red or yellow pathway:

• Blood Culture, Blood gas including blood glucose
• FBC
• U&Es, Bone profile, CRP (can be normal in the early stages of disease)
• Meningococcal & Pneumococcal PCR (EDTAA blood specimens)
• Clotting
• LFT
• Blood sample for Mycoplasma IgM (if encephalitis suspected)
• Urine (consider catheter)
• Throat swab

WARNING - a normal CRP and or FBC does not exclude bacterial meningitis. A negative blood PCR does not exclude N meningitidis

Back to top

Treatment

Non-Antimicrobial Treatment

General

Recommendation: Manage all children with suspected CNS infection in line with APLS guidelines/protocols, pay particular attention to:

• Airway security & adequacy of ventilation
• Fluid resuscitation & need for ionotropic support
• Seizure management (LHP guideline)
• Hypoglycaemia, recognition, and management
• Electrolyte disturbance, recognition, and management
  [Evidence level A]

Liaise with PICU/ Consultant if any doubt

Fluid Management

Recommendation: There is no evidence to restrict fluid in children without obvious signs of raised intracranial pressure. Recommended maintenance fluid is 5%
Glucose & 0.9% sodium chloride. See Guidelines for Fluid Management in Infants and Children on PICU.

[Evidence level A]

Failure to administer sufficient fluids in children with meningococcal disease and septic shock is associated with a higher risk of mortality (NICE).

Dexamethasone

Children OVER 3 months of age.

Recommendation: give IV Dexamethasone base (0.15mg/kg -maximum 10mg, every 6 hours for 4 days) should be administered when there is a strong suspicion of meningitis (consultant decision) and LP result is likely to be delayed (>4 hours) OR if LP confirms diagnosis of meningitis (purulent CSF, or CSF WCC.1000/ x106/ l,
protein >1g/L, bacteria seen on Gram).

[Evidence level A]

UNDER 3 months of age:
Recommendation: DO NOT GIVE CORTICOSTEROIDS IN CHILDREN UNDER 3 MONTHS WITH SUSPECTED OR CONFIRMED BACTERIAL MENINGITIS.

[Evidence level A]

Any age.
Recommendation: Do not give steroids to Infants or children with clinical evidence of meningococcal septicaemia (i.e. typical non blanching purpuric rash) unless catecholamine resistant shock is present or in children with possible TB meningitis.

[Evidence level C]

Recommendation: If corticosteroids have been started, they can be stopped if the diagnosis turns out not to be meningitis (on clinical or CSF examination findings)

[Evidence level D]

Evidence from a systematic review suggests that corticosteroids significantly reduce mortality in acute bacterial meningitis, but the effect was not seen in a the subgroup of children (Van de Beek, D, 2007). Hearing loss was reduced in children with meningitis, mostly caused by H. influenzae type B (Van de Beek, D, 2007). Corticosteroids are not recommended for children under three months (NICE CG 102). NICE CG 102 recommends starting steroids early with the first dose of antibiotics, based on LP findings. If steroid administration is delayed NICE advise starting within 4 hours of commencing antimicrobial therapy, therefore, if a LP procedure (or result) is likely to be delayed more than 4 hours and there is a strong clinical suspicion of acute bacterial meningitis then we advise empirical steroid administration.

DO NOT GIVE CORTICOSTEROIDS GREATER THAN 12 HOURS FTER ANTIBIOTICS HAVE BEEN STARTED.

Management of raised intracranial pressure

• airway stabilisation,
• urgent discussion with Consultant on call
• Mannitol infusion Child <11 years 0.25-1.5g/Kg, Child 12-17 years 0.25-2g/Kg IV infusion, following discussion with Consultant. Intensive care management

Back to top

Empirical Antimicrobial Treatment

Recommendation: Commence empirical antimicrobial therapy in all children on red pathway as indicated below:

OVER 3 months of age

Ceftriaxone  80-100mg/kg once daily IV infusion over 30 minutes (first dose can be given as a bolus in emergency) [maximum dose 4g daily]
OR, If true penicillin/ cephalosporin allergy
Chloramphenicol  25 mg/kg) IV every 6 hours (reduce dose as soon as is clinically indicated)

Monitor chloramphenicol concentrations (all < 4 years of age and if doubling dose)

1- 3 months of age (& not on NICU)

IV Cefotaxime 

Child 1-3 months- 50mg/kg every 6 hours
OR, If true penicillin/ cephalosporin allergy
IV Chloramphenicol  12.5 mg/kg every 6 hours (may double dose)

Check dose carefully overdosage can be fatal

Monitor chloramphenicol concentrations Neonate (not on NICU)

IV Amoxicillin  50mg/kg every 8 hours
AND
IV gentamicin (see Gentamicin Prescribing Guideline for Neonates)

Recommendation: In children with focal seizures, focal neurological signs, status epilepticus or altered conscious level (V or less on AVPU) >30 minutes after a seizure add antimicrobial agents to cover encephalitis, pending further investigation.

[Evidence level D]

Aciclovir  IV infusion

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

PLUS

Clarithromycin 

Neonate up to 28 days: PO 7.5mg/kg every 12 hours
Bodyweight under 8kg: PO 7.5mg/kg every 12 hours
Bodyweight 8-11kg: PO 62.5mg every 12hours
Bodyweight 12 - 19kg: PO 125mg every 12 hours
Bodyweight 20-29kg: PO 187.5mg every 12 hours
Bodyweight 30-40kg: PO 250mg every 12 hours
Child 12-18 years: PO 250mg every 12 hours, increased in severe infections to 500mg every 12 hours

OR if unable to tolerate oral

Clarithromycin  IV infusion into large proximal vein

Child 1 month- 12years 7.5mg/kg IV infusion every 12 hours (max dose 500mg)
Child 12 -18 years 500mg IV infusion every 12 hours

N.B. The practise of adding a macrolide is controversial. The incidence of Mycoplasma encephalitis and the effectiveness of macrolide therapy are unknown. This practise will be reviewed, and a further risk benefit analysis undertaken.

Are there concerns of multi-resistant pneumococcal infection history of recent (<6month) travel to France, Spain, Portugal? if so use additional IV Vancomycin  see relevant neonatal/paediatric vancomycin guideline

Chloramphenicol  Monitoring

Monitor FBC daily on Chloramphenicol .

Check PRE-DOSE (“trough”) level before the 3rd dose and should not exceed 15mg/ litre

Check PEAK (1hour after 3rd IV infusion) 15-25mg/litre

NB levels are sent away so monitor daily FBC result.

Reduce high doses immediately. Overdosage can be fatal

Please refer to https://www.nbt.nhs.uk/severn-pathology/requesting/test-information/chloramphenicol Bristol Antimicrobial Reference Laboratory.

Vancomycin Monitoring

PRE-DOSE (“trough”) concentration should be 10-20mg/litre

Back to top

Directed Antimicrobial Treatment (when microbiology results are known)

Recommendation: Choice of antimicrobial therapy should be reviewed following confirmation of the clinical diagnosis, microbiology results and investigations. The relevant LTHT children's infection guidelines should be followed for subsequent management.

[Evidence level C]

Recommendation: Antimicrobial therapy should be “de-escalated” to the agent with the narrowest effective spectrum of activity, e.g. Benzyl penicillin  should be used
in preference to cephalosporins for treatment of susceptible isolates.

[Evidence level C]

Ambulatory Management

Recommendation: If considered appropriate, following discussion with the consultant, a child may be discharged home to complete their treatment course through once daily administration of Ceftriaxone .

[Evidence level B]

Back to top

Duration of Treatment

Recommendation: Duration of therapy should be determined by the final clinical diagnosis and results of microbiology.

[Evidence level C]

Children and young people aged 3 months or older

Current treatment guidelines recommend a 7-day course of antibiotic therapy for Neisseria meningitidis, 10 days for H. influenzae and 14 days for S. pneumoniae. A recent meta-analysis has shown no significant difference in terms of clinical effectiveness and safety of shortened (7 days or less) duration of treatment for community acquired bacterial meningitis.

Children younger than 3 months

Treat Group B streptococcal meningitis with intravenous Cefotaxime  for at least 14 days. Treat bacterial meningitis due to L monocytogenes with intravenous Amoxicillin  or ampicillin for 21 days in total, plus gentamicin for at least the first 7 days.Treat bacterial meningitis due to Gram-negative bacilli with intravenous Cefotaxime  for at least 21 days unless directed otherwise by the results of antibiotic sensitivities.

Over 3 months with an unconfirmed but clinically suspected bacterial meningitis treat with IV Ceftriaxone  for at least 10 days, depending on symptoms, signs, and course of the illness. This should be under guidance of the Consultant +/- microbiology.

Under 3 months with an unconfirmed but clinically suspected bacterial meningitis treat with Cefotaxime  plus Amoxicillin  for at least 14 days depending on symptoms, signs and course of the illness. This should be under guidance of the Consultant +/- microbiology and Consultant for infectious diseases.

Back to top

Switch to oral agent(s)

See relevant LTHT guidelines for recommendations.

Back to top

Treatment Failure

If the child is not responding to therapy as expected, then obtain:
Urgent review by Consultant.
Neuroimaging to exclude effusion/ abscess.
Discuss with Microbiology as appropriate.

Back to top

Meningitis prophylaxis

Recommendation: Prophylaxis is not required for the index case if they have been given a third-generation cephalosporin.

[Evidence level C]

Recommendation: Prophylaxis may be indicated for close contacts of the index case following discussion with Consultant in Communicable Diseases/ Public Health. Tel (0113) 3059798 (within hours) (0113) 2063283 (out of hours).

[Evidence level B]

Use the Meningococcal Prophylaxis Prescription (depicted below table) for prescribing meningococcal prophylaxis

Vaccinations recommendations for close contacts from the Green Book (last updated May 2022):

Confirmed or probable serogroup C disease, non-immunised, partially immunised & previously immunised (>1 year previously) - MenC conjugate vaccine single dose

Confirmed capsular group A, W or Y infections, non-immunised & previously immunised (>1 year previously) - Men ACWY conjugate vaccine single dose (aged <1 year requires 2 doses, >1 month apart)

Un-immunised index case - follow routine immunisation schedule

Notification

Inform Public health: Tel (0113) 3059798 (within hours) (0113) 2063283 (out of hours)