Paediatric focal intracranial suppurative infection: a UK single-centre retrospective cohort study

Focal intracranial suppurative infections are serious conditions rarely seen in children. [1‐5] They are divided in three categories: brain abscess (BA), subdural empyema (SDE), and extradural empyema (EDE). In the pre-antibiotic era, mortality reached nearly 100% [6], decreasing to around 36–60% in the 1970s when antibiotics became more readily available. [3, 7] Since then mortality has dropped further, ranging 3.7–24%, as computed tomography was introduced and cranial imaging improved, and metronidazole became part of most standard empirical regimens in the 1980s. [7‐14]

Although mortality has dropped, these infections continue to cause significant mortality and morbidity, and can lead to rapid patient deterioration, thus adequate diagnostics and early aggressive treatment are crucial to optimise chances of complete recovery. [4, 9, 10, 14‐16]

The annual estimated incidence is 4–5.3/1,000,000 [2, 12], with higher incidences in developing countries. [15, 17] For the United Kingdom (UK) this translates to approximately 3 paediatric cases per tertiary healthcare centre annually.

In 74.4–91.6% a predisposing factor can be determined. [7, 14, 18] Compared to adults, congenital heart disease (CHD) and immunosuppression occur more frequently in children. [2] Other common predispositions in children are meningitis and sinusitis. [4, 9, 16, 17] Patients can present with a variety of symptoms. The classic triad consisting of headache, fever, and focal neurological deficits is reported in 8.4–20% of children. [3, 12, 14, 18] Treatment is multidisciplinary consisting of antibiotics and neurosurgery. [3, 5] Neurosurgical intervention aids pathogen identification, reduces lesion size and decompresses, aiming to reduce effects on surrounding structures. [19]

Several microorganisms have been implicated, but most commonly cultured are Streptococci and Staphylococci. [1, 2, 10, 12, 14, 16, 20‐22] 11.1–33% of patients grow anaerobic species [3, 7, 12], and 14.3–27% of BAs is polymicrobial. [11, 14] Empirical antibiotic treatment is broad-spectrum to cover these organisms, and rationalised on microbiological guidance.

There is no standardised empirical antibiotic treatment. [9, 16, 23, 24] Often first-choice empirical treatment is a third-generation cephalosporin plus metronidazole. [12, 19] These antibiotics have adequate pharmacokinetics and pharmacodynamics to achieve therapeutic concentrations within the central nervous system. [25]

In the UK there are currently no national guidelines regarding treatment of paediatric suppurative intracranial infections. [12] Internationally proposed consensus documents and guidelines are controversial [19, 23, 24, 26], because they are based on combined adult and paediatric literature. Paediatric evidence remains sparse, mainly consisting of case-series with small patient populations. [3, 11, 18, 21]

Published guidelines suggest antibiotic treatment for 6–8 weeks by intravenous administration only. [24] However, guidelines from The Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy [27] recommend 1–2 weeks of intravenous administration and to consider conversion to oral administration, depending on clinical response and decreasing C-reactive protein (CRP), to complete the antibiotic course.

This study evaluated local management of paediatric focal intracranial suppuration and reviewed antibiotic practice in order to consider empirical antibiotic guidelines.

This single-centre retrospective cohort study reviewed paediatric patients with BA, SDE, and EDE, admitted to the Great North Children’s Hospital (GNCH), a tertiary healthcare centre for paediatric infectious diseases and neurosurgery in the North East of England between January 2001 and June 2016. Local Caldicott approval was obtained.

107 eligible cases were identified. 7 cases were excluded due to incorrect coding, case notes were unavailable for 3, and 2 patients were primarily treated in other healthcare centres. 95 cases were suitable for analysis, of which 2 had chronic granulomatous disease (CGD) whose data were only suitable for diagnosis, predisposing factors and mortality analysis (Fig. 1).

This centre treated on average 6.13 cases annually. All patients originated from the GNCH catchment area. The child population (aged 0–19 years) of this area was 697,200 in 2014. [29, 30] This leads to an estimated annual incidence of 8.79/1,000,000.

Our study is the largest single-centre study assessing local management of paediatric focal intracranial suppurative infection in order to analyse effectiveness of local management, identify causative pathogens and guide empirical antibiotic therapy. Our findings extended on Cole et al. [9] and demonstrated similarities and differences compared to case-series by other centres.

Our estimated annual incidence was higher than the 5.3/1,000,000 previously reported in the UK. [12] The annual incidence in this tertiary centre was three times higher than in other developed countries. [3, 11, 16, 18, 20, 21] Our local annual incidence showed similarity with a Cameroonian study. [17] Reasons for this may lie in high rates for non-specific symptoms and subsequent lower suspicion for focal intracranial suppuration, and less health-seeking behaviour for upper respiratory tract infections. Median age at admission and bimodal age distribution are consistent with other studies. [12, 17]

Mortality in this cohort was 3.2%, which is at the lower end of the spectrum previously reported (2.6–21.4%). [3, 7, 11, 12, 15‐18, 20‐22] Neurological morbidity remains a significant problem, yet rates concur with other centres. [11, 12, 17, 18, 31] Long-term neurological sequelae affected a smaller proportion than short-term neurological sequelae, but might be underreported as follow-up in tertiary care ended, and neuropsychological effects and mild cognitive impairments are difficult to diagnose.

Predisposing factors were identified in 90.5%. Meningitis was associated with younger and sinusitis with older age, which is unsurprising given sinus maturation. High rates of sinusitis and meningitis may be explained by the number of SDE patients in this cohort. There is an association between SDE and meningitis and sinusitis, previously demonstrated by Legrand et al. [16] Adolescent patients are more at risk for intracranial complications of sinusitis compared to younger children and adults, and sinusitis patients were mostly adolescents. [32] Adolescents are more likely to develop intracranial extension of sinusitis, as vascularity and blood supply of diploic veins is known to be increased compared to adults. [33] CHD as a predisposing factor in this study was rare. This has been reported by other centres [3, 17, 31], although some centres report CHD as their main predisposing factor in 20.8–40%. [7, 18, 20, 21]

35.6% had focal neurological deficits at presentation and 23.7% seizures at admission. This is similar to other centres [11, 17, 18], although rates go up to 53% [12] and 48% [21] respectively. In this study the most common symptoms were non-specific. The classic triad was seldom seen. This is in accordance to literature from developed countries [3, 18], while developing countries see the triad in up to 52% [17]. Children with poorer outcome had shorter symptom duration, and tended to have more severe altered levels of consciousness, which may be attributed to more rapid deterioration. Although otorhinolaryngological infections were prevalent in this cohort, concurrent symptoms were not often reported and may be underreported since patients often had more severe presenting clinical features.

Streptococci were most commonly isolated with Streptococcus milleri group organisms as most common species. The second largest group were Staphylococci, although it is debatable how many coagulase-negative isolates were pathogenic. The predominance of Streptococci has been described previously in the UK [12], as well as in other countries [3, 7, 11, 16, 20‐22, 31]. 12.9% of isolates were anaerobic which concurs with published literature. [11, 12] Interestingly Prevotella spp. were most common, whereas other centres report Fusobacterium spp. as the most common anaerobic isolate. [3, 11, 20]

This study showed great variability in empirical regimens and in antibiotic treatment duration. This has been noted previously [3, 11, 12], and demonstrates the lack of uniform guidelines and potentially a change in practice over the 15 years covered by the study. Nonetheless, chosen regimens provided sufficient coverage in the majority of patients. Broad-spectrum antibiotics remain necessary before microbiology results, as gram-positive, gram-negative and anaerobe microorganisms were all cultured in this cohort. Combinations including third-generation cephalosporins plus metronidazole were successful in the majority of patients. 90.5% of patients with growth-positive cultures would have been sufficiently covered with a third-generation cephalosporin plus metronidazole, and most patients with negative cultures improved clinically on this regime. Therefore, we recommend this regime as first-choice empirical antibiotic treatment. Despite meropenem plus linezolid covering a greater proportion, this regimen should be reserved for severe or treatment non-responsive cases. Over the 15.5-year period, there have not been any anaerobic pathogens cultured in the < 1 and > 15-years age groups. In infants, the routine use of metronidazole might be reconsidered if anaerobic cultures are negative. The > 15-years age group was too small to make a similar recommendation.