• 
• 

Three Part Question

In [infants and children with meningitis], does [prophylactic antiepileptic medication] [reduce the frequency of seizures?]

Clinical Scenario

A 2 month old infant is admitted to hospital with 2 day history of fever, irritability and reduced feeding. A septic work-up including lumbar puncture is performed. CSF white cells are raised and culture confirms Neisseria meningitidis organism. The infant is appropriately started on antibiotic regime as per local anti-microbial guidelines. On day 2 of admission, the infant develops focal motor seizures.
It is well established that infants with a diagnosis of meningitis are at risk of developing seizures. You wonder whether the infant should have been prophylactically started on an antiepileptic medication when the diagnosis of meningitis was confirmed.

Search Strategy

Primary Sources
MEDLINE was searched via PubMed, from 1976 to November 2019. Advanced search mode was used using the following search terms:
• “Meningitis” AND “prophylactic” AND “antiepileptic” OR “seizures” (29 results)
• “Meningitis" AND "infant” OR “child” AND "antiepileptic" AND “seizures” (546 results)
Only studies in English were reviewed. Relevant studies included those that described the use of prophylactic antiepileptic medication in meningitis.
Secondary Sources:
Search of Cochrane Library using terms “meningitis” and “seizures” was performed. Sixty-one (61) abstracts were reviewed, however none were deemed to be relevant to the clinical question.
A total of 636 abstracts with keywords as described in search criteria were reviewed. Two studies were identified as relevant to the clinical question. One was in German and therefore excluded.Only one study was suitable for full text review and critical appraisal.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
NAKAPI TEFUARANI & JOHN D. VINCE 31/03/1992 Papua New Guinea	108 children (neonatal period up to 10 years) admitted to hospital in Papua New Guinea with purulent meningitis between May 1989 and May 1990	Prospective cohort study	Presentation, clinical features and outcome of the cohort	84% less than 2 years 52% (48/95) of children less than 2 years had a seizure at some stage during their illness compared to 23% (3/13) of older children. 89% (16/18) children who died had a seizure 9/90 had neurological sequelae	This paper is 30 years old and lacks evidence to support the of use prophylactic phenobarbitone in all children less than two years of age. The authors failed to report the percentage of infants and children who developed seizures after prophylactic phenobarbitone compared to those who did not. In addition, vaccinations, antibiotic prescribing, intensive-care medicine and health-care access have all improved since this study. H. influenza, which is associated with a high rate of seizures, was the most common organism isolated in this study, however this is now a rare cause of meningitis thanks to successful vaccination programmes. Therefore, the current incidence of meningitis and seizures is likely lower than reported in this study. In the study population 52% of all children less than 2 years had a seizure. This is significantly higher than other more recent studies reporting seizure frequency in bacterial meningitis.
			Mortality	16.7% (18/108) died Factors associated with mortality included • Duration of illness > 3days (p=0.05) • Seizures before or during illness (p= <0.001) • Coma on admission (p= <0.001) Mortality was 31% in infant and children with seizures compared to 3.5% in those without seizures.
			Compliance to standard treatment regime defined as: 1) local antibiotic protocol 2) phenobarbitone administered to children who had one or more seizures prior to admission and all children < 2 years of age	Phenobarbitone treatment was delayed in 13.5%, loading dose omitted in 20% and maintenance therapy omitted in 11% of patients

Comment(s)

On review of the available literature, there is an absence of studies investigating our clinical question of whether the use of prophylactic antiepileptic medication reduces the frequency of seizures in meningitis. We believe this is an important clinical question to be studied. Seizures are reported in 12.6–52% of meningitis and independently associated with a poorer neurological and neurodevelopmental outcomes and higher mortality rate (31% versus 13.5%).[1–3] Therefore, it is postulated that the prevention of seizures or minimizing seizure burden may improve the long-term neurological co-morbidities associated with meningitis. The only paper identified recommending prophylactic antiepileptic medication is 30 years old and lacks evidence to support the of use prophylactic phenobarbitone in all children less than two years of age.[1] The authors failed to report the percentage of infants and children who developed seizures after prophylactic phenobarbitone compared to those who did not. In addition, vaccinations, antibiotic prescribing, intensive-care medicine and health-care access have all improved since this study. H. influenza, which is associated with a high rate of seizures, was the most common organism isolated in this study, however this is now a rare cause of meningitis thanks to successful vaccination programmes.[2, 4] Therefore, the current incidence of meningitis and seizures is likely lower than reported in this study. In the study population 52% of all children less than 2 years had a seizure. This is significantly higher than other more recent studies reporting seizure frequency in bacterial meningitis (12-30%).[1–3] In summary, we have identified the need for a randomised controlled trial to assess if prophylactic antiepileptic medications reduce seizure frequency and have an impact on long-term neurological sequelae in meningitis.

Clinical Bottom Line

• Seizures are a significant complication in infants and children admitted with meningitis. • There is a lack of clinical evidence regarding best practice in the prevention of seizures in infants and children with meningitis.

References

1. Tefuarani N and Vince JD. Purulent meningitis in children: Outcome using a standard management regimen with chloramphenicol. Ann Trop Paediatrics 1992;12:375–83. doi:10.1080/02724936.1992.11747602
2. Edmond K, Clark A, Korczak VS, et al. Global and regional risk of disabling sequelae from bacterial meningitis: A systematic review and meta-analysis. Lancet Infect. Dis. 2010;10:317–28. doi:10.1016/S1473-3099(10)70048-7
3. Tacon CL, Flower O. Diagnosis and Management of Bacterial Meningitis in the Paediatric Population: A Review. Emerg Med Int 2012;2012:1–8. doi:10.1155/2012/320309
4. Oordt-Speets AM, Bolijn R, Van Hoorn RC, et al. Global etiology of bacterial meningitis: A systematic review and meta-analysis. PLoS One. 2018. doi:10.1371/journal.pone.0198772