Nottingham Children s Hospital

Meningitis and Encephalitis Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author) Directorate & Speciality Guideline for the assessment and management of meningitis and encephalitis in children and young people Dr Ruth Radcliffe, Paediatric SpR Dr Lucy Cliffe, Paediatric Consultant Date of submission December 2016 Date when guideline reviewed December 2019 Guideline Number 1991 Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Abstract Key Words Directorate: Family Health Children Speciality: Infection and Immunity Patients under 18 years of age with suspected meningitis or encephalitis This guideline describes the assessment and management of children and young people presenting with meningitis and encephalitis Paediatrics. Children. Meningitis, meningococcal disease, encephalitis, herpes simplex virus Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? 1a meta analysis of randomised controlled X trials 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasi-experimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer Consultation Process Staff at Nottingham Children s Hospital via the Guidelines E-mail process. Target audience Staff at the Nottingham Children s Hospital This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date. Dr Lucy Cliffe Page 1 of 14 December 2016

Document Control Document Amendment Record Version Issue Date Author V1 Aug 2010 Ruth Radcliffe Lucy Cliffe V2 Nov 2013 Lucy Cliffe V3 December 2016 Martin Hewitt General Notes: Summary of changes for new version: Clarification and highlighting of dexamethasone indications and dosing. Statement of Compliance with Child Health Guidelines SOP This guideline has had only minor changes made and therefore this version has not been circulated to all for review. A previous version had been approved by circulation to senior team members. Martin Hewitt Clinical Guideline Lead 14 August 2015 Dr Lucy Cliffe Page 2 of 14 December 2016

Related Paediatric Clinical Guidelines Fever in the pre-school child Sepsis Petechial Rash Lumbar Puncture Acute Encephalopathy Gentamicin Introduction Meningitis remains relatively a common and potentially fatal condition. Whilst encephalitis is rarer, it also has potentially devastating consequences. Optimal management requires early consideration of the diagnosis, investigation and initiation of appropriate treatment. Symptoms and Signs These can be non-specific, especially in a young child, but include: Infant Irritability Poor feeding Vomiting Seizures Temperature Instability Rash Shock Full fontanelle Drowsiness Older Child Vomiting Headache Photophobia Neck Stiffness Temperature Instability Rash Seizures Papilloedema Cranial Nerve Palsies Confusion or altered GCS THINK - Neonatal sepsis may be Disseminated HSV Key history points include contacts with people with meningitis or cold sores and a travel history. In infants it is important to ask about a maternal history of genital herpes, the timings of primary or recurrent infection with delivery, the mode of delivery and the use of invasive fetal monitoring (e.g. scalp electrode). In 60-80% of infants with neonatal HSV there is no maternal or birth history of herpes. The differentiation of meningitis and encephalitis can be clinically difficult, but it is important to try and distinguish them, as treatment modality and length differs. In an older child with encephalitis the classical triad of fever, headache and decreased conscious level should be apparent. Seizures and/or focal neurology may also be presenting (or subsequent) features. Dr Lucy Cliffe Page 3 of 14 December 2016

Usual organisms causing bacterial meningitis: Birth 12 weeks Group B Streptococcus E.Coli & other gram ve organisms Listeria monocytogenes 3 months 4 years Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae type b (now rare) TB (rare but must be considered) Over 4years Neisseria meningitides Streptococcus pneumoniae TB (rare but must be considered) Causes of viral meningitis or encephalitis: Enteroviruses (eg echoviruses, coxsackieviruses, polioviruses, EV 71) Herpes Simplex Virus 1 and 2 Varicella Zoster Virus Respiratory Viruses (eg Influenza, RSV) Assessment Call for senior help Airway and apply 15 l/min facial O 2 Breathing support as necessary Circulation o IV cannulae (IO if unable to gain access) - with bloods as below o If shocked (tachycardia, cold peripheries, capillary refill >2 seconds) o Treat with fluid bolus - 20ml/Kg 0.9% Saline, reassess and repeat as necessary. o Measure BP o If concern re Septic shock consult Sepsis guideline also (link) Disability o Check blood sugar (BM Stix) o Assess conscious level (GCS or AVPU) o Assess for signs of raised intra-cranial pressure o (raised BP, low Heart rate, reduced GCS) o Assess neurology cranial nerves, focal signs? Exposure o Temperature o Rashes eg meningococcal, varicella, herpes o Sticky eyes Dr Lucy Cliffe Page 4 of 14 December 2016

Investigations The following investigations should be performed on all children with suspected meningitis/encephalitis. If there is encephalopathy without clear infective cause please also consult the acute encephalopathy guideline for further investigations and management (link). Bloods Haematology Chemistry Microbiology Other FBC Clotting CRP U&E, Osmolality, Ca, Mg, PO4 LFT Glucose Blood culture Meningococcal & Pneumococcal PCR (1ml, EDTA) * Blood for HSV PCR (EDTA) ONLY <28 days old * Venous/Capillary blood gas Others Microbiology Urine MC&S Viral throat swab for respiratory viruses and enterovirus PCR Bacterial throat swab Stool for virology inc enterovirus RNA PCR Viral swabs (in pink viral transport medium) of skin lesions/sticky eyes/mouth * Microbiology will phone the next day before processing these samples If meningitis is suspected, a lumbar puncture should be performed as soon as possible and if safe to do so before starting treatment (e.g. in A&E at QMC), as culture and sensitivity results are invaluable in guiding treatment. However do not allow a delay in giving antibiotics patients with suspected bacterial meningitis should receive IV or IO antibiotics within 1 hour of arrival to hospital. If possible CSF pressures should be measured but this should not delay treatment. Please consult Lumbar Puncture guideline when carrying out this procedure (link here). Contraindications to Acute Lumbar Puncture: Signs suggesting raised intracranial pressure reduced or fluctuating level of consciousness (Glasgow Coma Scale score less than 9 or a drop of 3 or more) relative bradycardia and hypertension focal neurological signs abnormal posture or posturing unequal, dilated or poorly responsive pupils papilloedema abnormal doll s eye movements Shock Extensive or spreading purpura Convulsions until stabilised Coagulation abnormalities coagulation results (if obtained) outside the normal range platelet count below 100 x 109/litre receiving anticoagulant therapy Local superficial infection at the lumbar puncture site Respiratory insufficiency (lumbar puncture is considered to have a high risk of precipitating respiratory failure in the presence of respiratory insufficiency). Dr Lucy Cliffe Page 5 of 14 December 2016

A laboratory diagnosis is important for epidemiological purposes and management decisions. However if the diagnosis is clinically evident as in meningism with a purpuric rash i.e. meningococcal sepsis and meningitis then it would be appropriate for a senior paediatrician to review if a LP is required. CSF Microbiology send bottles 1 & 3 Chemistry send bottle 2 Microscopy, culture and sensitivity (10 drops universal container) HSV, VZV, enterovirus PCR (10 drops universal container) Glucose, protein (5-10 drops universal container and grey blood bottle) Please remember to check serum glucose at time of LP CSF Normal results Age of Child RBC/mm 3 WBC/mm 3 Protein (mg/l) Gluc (mmol/l) <28 days <10 <20 1 150 1000 2 2.8-4.4 >28 days <10 <5 150-450 2.8-4.4 1 - There is insufficient evidence to guide recommendations for defining the likelihood of bacterial meningitis in neonates based on the CSF WBC alone. It is recognised that neonates can have normal CSF WBCs up to 20 cells/ mm 3. However bacterial meningitis should still be considered if other signs or symptoms are present even in the context of a CSF WBC in the currently accepted normal range. 2 Our laboratory quotes general paediatric CSF protein reference ranges (i.e. no specific neonatal range) however it is recognised that neonates can have higher CSF protein values. Interpretation of CSF In a traumatic tap, allow 1 WBC for every 600 RBCs. CSF glucose: should be greater than 50% of blood glucose. Low CSF glucose can be seen in bacterial meningitis and TB meningitis. A predominance of polymorphs is suggestive of a bacterial cause, and lymphocytes suggest a viral cause. However, polymorph predominance often occurs in early encephalitis. A raised protein level can be seen in bacterial meningitis, TB meningitis, tumours, intracranial injury, blood in the CSF and any CNS inflammation. If a child has uniformly blood stained CSF in a non traumatic tap then intracranial haemorrhage should be excluded by CT scan (consider NAI) Dr Lucy Cliffe Page 6 of 14 December 2016

Management Antibiotics Prior to determination of bacterial organisms: (Dexamethasone may also be required - check criteria and doses below) Age Antibiotic Dose <28 days Cefotaxime 1 50 mg/kg BD 0-6 days, TDS 7-21days, QDS >21days Amoxicillin 100mg/kg BD 0-6 days, TDS 7-28 days Gentamicin 2 4mg/kg OD by slow bolus over 3 mins or infusion over 30 mins 28 days Cefotaxime 1 50mg/kg QDS <3 months Amoxicillin 50mg/kg QDS Gentamicin 2 7mg/kg OD by infusion over 30 mins 3 months onwards Ceftriaxone 3 Gentamicin 2 Only if diagnosis is uncertain and differential includes sepsis 4 80mg/kg OD by infusion over 30 mins or slow IV bolus in emergency 7mg/kg OD by infusion over 30 mins 1 - In this age group, ceftriaxone may be used as an alternative to cefotaxime once clinical recovery is evident, but ceftriaxone should not be used in premature babies or in babies with jaundice, hypoalbuminaemia or acidosis. 2 Actual age can be used to dose all antibiotics unless postmenstrual age < 32 weeks. See Neonatal guideline (No 27) for Gentamicin if postmenstrual age < 32 weeks as dosing interval is different. See Gentamicin Guideline. 3 - Do not use Ceftriaxone with calcium containing infusions, instead use Cefotaxime. Therefore if child likely to require PICU consider using Cefotaxime (50mg/kg QDS) 4 -Gentamicin is given here to treat non-meningococcal sepsis, which may present similarly to meningitis in some cases. Gentamicin should be stopped once it is clear that sepsis is not the focus of treatment. In neonates this should wait until after culture results are available. In older children who have a clear presentation of meningitis without a sepsis component this can be withheld or stopped earlier after senior review. Multiple daily dosing for meningitis, as mentioned in BNFc is in reference to treatment for listeria meningitis (see below). If the child has recently travelled outside the UK or had multiple courses of antibiotics i.e. NICU stay consider adding Vancomycin, to cover possible resistant organisms. Therapy should be altered in light of culture and sensitivity results (discuss with Microbiology Consultant). Dr Lucy Cliffe Page 7 of 14 December 2016

Duration Meningococcus Cefotaxime/Ceftriaxone 7 days H. Influenzae Cefotaxime/Ceftriaxone 10 days Pneumococcus Cefotaxime/Ceftriaxone 14 days Group B Streptococcus Cefotaxime/Ceftriaxone 14 days E.Coli Cefotaxime/Ceftriaxone 21 days Listeria Amoxicillin AND 21 days Gentamicin* 7 days *Requires change to multiple daily dosing see BNFc Culture negative Cefotaxime/Ceftriaxone see below If CSF and blood cultures are negative but there is a raised white cell count and/or CRP along with a clinical picture suggestive of meningitis, treat as culture negative bacterial meningitis i.e. 14 days of antibiotics if <3months and 10 days of antibiotics if 3 months or older. If cultures are negative AND EITHER no clinical concerns of meningitis OR highly likely viral meningitis (suggested by low inflammatory markers and lymphocyte predominance on CSF), after discussion with consultant paediatrician and microbiologist, antibiotics may be stopped after 24-48hrs. If failure to respond to treatment (for example still febrile at 72hrs) consider sub-dural collections especially with pneumococcal meningitis. Consider antibiotic resistance and check for any history of travel. Anti-viral Therapy 0-28 days of age Criteria for starting IV aciclovir: If history of primary genital herpes at delivery OR Suspicious skin, eye or mouth lesions (SEM disease- needs assessment for CNS & disseminated disease i.e. LP, blood HSV PCR and LFTs) OR Consider when 2 or more of: Temperature instability CSF pleocytosis for age (see table above) and gram stain negative Raised ALT (marker of disseminated HSV disease) History of previous maternal genital herpes or recent cold sore in close family member Seizures/abnormal neurology Pneumonitis Aciclovir 20mg/kg IV TDS for 21 days for disseminated or CNS disease and 14 days for SEM disease. Need to monitor renal function during treatment and maintain adequate hydration. Neonatal HSV can relapse. If diagnosis is confirmed consider oral prophylaxis following treatment. Discuss this with virology or a consultant in paediatric infectious diseases. Stopping treatment: If another cause for illness (eg bacterial meningitis) is found If SEM swabs are PCR negative for herpes. If CSF and/or serum PCR is negative and on going suspicion of HSV disease is low. Dr Lucy Cliffe Page 8 of 14 December 2016

>28 days of age Criteria for starting IV aciclovir Encephalopathy with no other cause initially evident CSF count indicative (see table) Additional features that may aid diagnosis Focal Neurological signs Seizures Current/recent chicken pox /shingles/herpes Aciclovir 1-<3 Months 20mg/kg IV tds for 21 days 3 Months to <12 years 500mg/m 2 IV tds for 21 days 12-18 Years 10mg/kg IV tds for 21 days Dose on ideal body weight if obese. Need to monitor renal function during treatment and maintain adequate hydration. Other investigations MRI EEG An abnormal MRI and/or EEG with changes typically affecting the temporal lobes would strengthen a clinical suspicion of HSV encephalitis. Reviewing treatment: If after 48 hours the clinical course is not suggestive of HSV encephalitis (eg rapid resolution of symptoms) or another cause of the encephalopathy is found then stop Aciclovir. If clinical cause concerning; continue Aciclovir and secure long term iv access (long line). Continue until CSF or blood PCR negative and MRI and EEG not suggestive. It is worth noting that in 3-5% of patients with HSV encephalitis the CSF is completely normal and therefore if there is strong evidence of encephalitis, a negative HSV PCR on CSF does not exclude the diagnosis. If there are ongoing suspicions of HSV encephalopathy and 1 st CSF was inconclusive, consider repeating sample after 48-72hrs, including a repeat PCR. If HSV encephalitis is diagnosed or strongly suspected 21 days of IV Aciclovir is indicated. The oral bioavailability of aciclovir and valaciclovir is unpredictable and can be less than 50% of IV Aciclovir. The use of oral antivirals in the treatment of herpes encephalitis cannot be recommended. Enterovirus encephalitis does not respond to aciclovir. IV aciclovir should not be used to treat viral meningitis. Dexamethasone A recent Cochrane review has recommended that dexamethasone be given to all children over 3 months of age with bacterial meningitis. Bacterial meningitis is suggested by any of the following: frankly purulent CSF bacteria on Gram stain a CSF white blood cell count greater than 1000/microlitre CSF pleocytosis and a protein concentration greater than 1 g/litre clinical suspicion of meningitis but LP contraindicated Dose: 3 months to 18 years - 0.15mg/kg IV QDS for 4 days (maximum dose of 10mg per dose). Ideally starting with or before first dose of antibiotic. However, benefit still if given within 12 hours of administration of antibiotics. Dr Lucy Cliffe Page 9 of 14 December 2016

Fluid Management See the sepsis guideline (Link) Children may require fluid boluses to maintain circulation. After 40ml/kg, and persistent shock, contact PICU and anaesthetics for assistance in intubation. Use 4.5% HAS for subsequent boluses. Consider the use of inotropes early. Normal maintenance fluids unless SIADH suspected (serum- low Na & low osmolality, Urineraised Na / high osmolality) when restrict to 2/3rds. Strict fluid balance is essential. Reduced circulating volume e.g. poor perfusion with CRT< 2 seconds requires volume boluses and needs re-evaluation and possible PICU admission refer to sepsis guideline. Raised Intra-cranial Pressure Consider Raised ICP in the presence of the following: reduced or fluctuating level of consciousness (Glasgow Coma Scale score less than 9 or a drop of 3 or more) relative bradycardia and hypertension focal neurological signs abnormal posture or posturing unequal, dilated or poorly responsive pupils papilloedema apnoea persistent vomiting in infants, a tense, non-pulsatile fontanelle or sutural separation may be present along with above symptoms If you suspect the child has raised ICP Nurse head up, head in-line. Consider: o 2.7% Saline (5ml/kg over 30 min) or o Mannitol (0.25g/kg over 30min) Call PICU (may require intubation and ventilation) Seizures Seizures may present as a complication of meningitis or encephalitis. Follow standard acute management as per prolonged seizure guideline and ensure child is having neuro observations taken and PEW scoring. Indications for PICU admission GCS 8 or AVPU Symptomatic raised intracranial pressure Shock (>40ml/Kg fluid bolus) likely to need intubation +/- inotropic support. Other children can be managed on the ward with initially 1/2 hourly observations (including neuro obs) and strict fluid balance. If in doubt discuss with on call consultant. Ward management On-going close monitoring of observations (including BP, GCS, urine output) including PEW scoring at least 1 hourly until stable Masks needed for staff for suction / physio. Children under 12 months should have an initial head circumference measured & repeated daily. IV access: consider long line / PICC line once diagnosis known for long term antibiotics or aciclovir. Dr Lucy Cliffe Page 10 of 14 December 2016

CT scan Should be performed if diagnosis of meningitis is in doubt. Consider if differential diagnosis includes hydrocephalus, cerebral abscess or NAI. It can be useful to detect sub-dural collections consider if still febrile after 72 hours. A CT does not predict CSF opening pressure. There is no place for CT in acute meningitis as a screening process for raised intracranial pressure prior to LP - this should be assessed clinically. Prophylaxis in Meningococcal Meningitis and HIB Prophylaxis is used to eliminate asymptomatic carriage of the bacterium with consequent control of further cases. Antibiotics such as Rifampicin, Ciprofloxacin and Ceftriaxone are effective in eliminating carriage. It is not known if Cefotaxime eradicates carriage therefore patients who have only received Cefotaxime should also receive chemoprophylaxis before discharge from hospital. Ciprofloxacin and rifampicin are not advised in pregnancy with Ceftriaxone the recommended alternative. Please discuss with the health protection agency and consult BNF/BNF-C for recommended doses and treatment length. Hearing Test Patients with a diagnosis of bacterial meningitis or aseptic meningitis should have a hearing assessment ideally before discharge from hospital or if this is not possible within 4 weeks of being medically fit to undergo testing. Hearing tests are requested as evoked potentials via Notis or at Children s Hearing Assessment Centre at the Ropewalk (needs referral letter) dependent on age. Patients with isolated Enteroviral meningitis, with a routine clinical course, generally recover without neurological sequelae. Some studies have suggested possible long-term neurological abnormalities but observations have been inconsistent. Follow up hearing assessments for these patients can be considered. Outpatient Follow Up Patients should be seen in outpatients for a consultant review 6 weeks following discharge from hospital. Notification and contact tracing Notify Health Protection Agency (formally public health) at the earliest opportunity. Consultant for Communicable Disease Control Health Protection Agency East Midlands North Institute of Population Health Nottingham City Hospital Hucknall Road Nottingham NG5 1PB Telephone 0844 225 4524 Dr Lucy Cliffe Page 11 of 14 December 2016

Appendix 1 Charts for display in Clinical Areas Empiric Antibiotics for Meningitis Age Antibiotic Dose <28 days Cefotaxime 1 50 mg/kg BD 0-6 days, TDS 7-21days, QDS >21days Amoxicillin 100mg/kg BD 0-6 days, TDS 7-28 days Gentamicin 2 4mg/kg OD by slow bolus over 3 mins or infusion over 30 mins 28 days Cefotaxime 1 50mg/kg QDS <3 months Amoxicillin 50mg/kg QDS Gentamicin 2 7mg/kg OD by infusion over 30 mins 3 months onwards Ceftriaxone 3 Gentamicin 2 Only if diagnosis is uncertain and differential includes sepsis 4 80mg/kg OD by infusion over 30 mins or slow IV bolus in emergency 7mg/kg OD by infusion over 30 mins 1 - In this age group, ceftriaxone may be used as an alternative to cefotaxime once clinical recovery is evident, but ceftriaxone should not be used in premature babies or in babies with jaundice, hypoalbuminaemia or acidosis. 2 Actual age can be used to dose all antibiotics unless postmenstrual age < 32 weeks. See Neonatal guideline (No 27) for Gentamicin if postmenstrual age < 32 weeks as dosing interval is different. 3 - Do not use Ceftriaxone with calcium containing infusions, instead use Cefotaxime. Therefore if child likely to require PICU consider using Cefotaxime (50mg/kg QDS) 4 -Gentamicin is given here to treat non-meningococcal sepsis, which may present similarly to meningitis in some cases. Gentamicin should be stopped once it is clear that sepsis is not the focus of treatment. In neonates this should wait until after culture results are available. In older children who have a clear presentation of meningitis without a sepsis component this can be withheld or stopped earlier after senior review. Multiple daily dosing for meningitis, as mentioned in BNFc is in reference to treatment for listeria meningitis (see below). Aciclovir Doses for Suspected Encephalitis See full guideline for indications Age Dose <3 months 20mg/kg IV tds 3 month <12 years 500mg/m 2 IV tds for 21 days 12 years onwards 10mg/kg IV tds for 21 days Dr Lucy Cliffe Page 12 of 14 December 2016

Investigations for Meningitis/Encephalitis The following investigations should be performed on all children with suspected meningitis/encephalitis. If there is encephalopathy without clear infective cause please also consult the acute encephalopathy guideline for further investigations and management (link). Bloods Haematology Chemistry Microbiology Other FBC Clotting CRP U&E, Osmolality, Ca, Mg, PO4 LFT Glucose Blood culture Meningococcal & Pneumococcal PCR (1ml, EDTA) * Blood for HSV PCR (EDTA) ONLY <28 days old * Venous/Capillary blood gas Others Microbiology Urine MC&S Viral throat swab for respiratory virus and enterovirus PCR Bacterial throat swab Stool for virology inc enterovirus RNA PCR Viral swabs (in pink viral transport medium) of skin lesions/sticky eyes/mouth * Microbiology will phone the next day before processing these samples If meningitis is suspected, a lumbar puncture should be performed as soon as possible and if safe to do so before starting treatment (e.g. in A&E at QMC), as culture and sensitivity results are invaluable in guiding treatment. See full guideline for contraindications to acute LP. CSF Microbiology send bottles 1 & 3 Chemistry send bottle 2 Microscopy, culture and sensitivity (10 drops universal container) HSV, VZV, enterovirus PCR (10 drops universal container) Glucose, protein (5-10 drops universal container and grey blood bottle) Please remember to check serum glucose at time of LP Dr Lucy Cliffe Page 13 of 14 December 2016

References Drug dosages taken from BNF-C. Caviness AC, et al. The Prevalence of Neonatal Herpes Simplex Virus Infection Compared with Serious Bacterial Illness in Hospitalized Neonates. J Pediatr. 2008; 153:164-9 Corey L, & Wald A. Maternal and Neonatal Herpes Simplex Virus Infections. N Engl J Med 2009;361:1376-85 van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD004405. DOI: 10.1002/14651858.CD004405.pub2. Bacterial Meningitis and Meningococcal Septicaemia. NICE guideline accessed at: http://guidance.nice.org.uk/cg102 Guidance for Public Health Management of Meningococcal Disease in the UK. Health Protection Agency Meningococcus Forum. Update August 2010 www.hpa.org.uk/topics/infectiousdiseases/infectionsaz/meningococcaldisease/guidelines Dr Lucy Cliffe Page 14 of 14 December 2016