LITERATURE REVIEW J Neurosurg 130:1107–1126, 2019

Epidemiology of central nervous system infectious diseases: a meta-analysis and with implications for neurosurgeons worldwide

*Faith C. Robertson, BS,1,2 Jacob R. Lepard, MD,3 Rania A. Mekary, MSc, PhD,2,4 Matthew C. Davis, MD, MPH,3 Ismaeel Yunusa, PharmD,2,4 William B. Gormley, MD, MPH, MBA,1,2,5 Ronnie E. Baticulon, MD,6 Muhammad Raji Mahmud, MD,7 Basant K. Misra, MD,8 Abbas Rattani, MBe,9,10 Michael C. Dewan, MD, MSCI,10,11 and Kee B. Park, MD10

1Harvard Medical School; 2Computational Outcomes Center, Brigham and Women’s Hospital, Department of , Boston, Massachusetts; 3Department of Neurosurgery, University of Alabama, Birmingham, Alabama; 4MCPHS University, Department of Pharmaceutical Business and Administrative Sciences, School of Pharmacy, Boston; 5Department of Neurological Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 6University of the Philippines College of Medicine, Philippine General Hospital, Manila, Philippines; 7Department of Surgery, National Hospital Abuja, PMB 425, Federal Capital Territory, Nigeria; 8Department of Neurosurgery & Gamma Knife Radiosurgery, P. D. Hinduja National Hospital, Mahim, Mumbai, India; 9Meharry Medical College, School of Medicine, Nashville, Tennessee; 10Global Neurosurgery Initiative, Program in Global Surgery and Social Change, Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts; and 11Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee

OBJECTIVE Central nervous system (CNS) infections cause significant morbidity and mortality and often require neu- rosurgical intervention for proper diagnosis and treatment. However, neither the international burden of CNS infection, nor the current capacity of the neurosurgical workforce to treat these diseases is well characterized. The objective of this study was to elucidate the global incidence of surgically relevant CNS infection, highlighting geographic areas for targeted improvement in neurosurgical capacity. METHODS A systematic literature review and meta-analysis were performed to capture studies published between 1990 and 2016. PubMed, EMBASE, and Cochrane databases were searched using variations of terms relating to CNS infection and (incidence, prevalence, burden, case fatality, etc.). To deliver a geographic breakdown of disease, results were pooled using the random-effects model and stratified by WHO region and national income status for the different CNS infection types. RESULTS The search yielded 10,906 studies, 154 of which were used in the final qualitative analysis. A meta-analysis was performed to compute disease incidence by using data extracted from 71 of the 154 studies. The remaining 83 studies were excluded from the quantitative analysis because they did not report incidence. A total of 508,078 cases of CNS infections across all studies were included, with a total sample size of 130,681,681 individuals. Mean patient age was 35.8 years (range: newborn to 95 years), and the male/female ratio was 1:1.74. Among the 71 studies with incidence data, 39 were based in high-income countries, 25 in middle-income countries, and 7 in low-income countries. The pooled incidence of studied CNS infections was consistently highest in low-income countries, followed by middle- and then high-income countries. Regarding WHO regions, Africa had the highest pooled incidence of bacterial meningitis (65 cases/100,000 people), neurocysticercosis (650/100,000), and tuberculous spondylodiscitis (55/100,000), whereas Southeast Asia had the highest pooled incidence of intracranial abscess (49/100,000), and Europe had the highest pooled incidence of nontuberculous vertebral spondylodiscitis (5/100,000). Overall, few articles reported data on deaths associated with infection. The limited case fatality data revealed the highest case fatality for tuberculous meningitis/ spondylodiscitis (21.1%) and the lowest for neurocysticercosis (5.5%). In all five disease categories, funnel plots assess- ing for publication bias were asymmetrical and suggested that the results may underestimate the incidence of disease.

ABBREVIATIONS AFR = African Region; AMR-L = Region of the Americas–Latin America; AMR-US/Can = Region of the Americas–United States/Canada; BM = bacterial meningitis; CNS = central nervous system; EMR = Eastern Mediterranean Region; EUR = European Region; HIC = high-income country; HIV = human immunodeficiency virus; LIC = low-income country; LMICs = low- and middle-income countries; MIC = middle-income country; NCC = neurocysticercosis; SEAR = Southeast Asia Region; TB = tuberculosis; WPR = Western Pacific Region. SUBMITTED March 16, 2017. ACCEPTED October 24, 2017. INCLUDE WHEN CITING Published online June 15, 2018; DOI: 10.3171/2017.10.JNS17359. * F.C.R. and J.R.L. contributed equally to this work and share first authorship.

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CONCLUSIONS This systematic review and meta-analysis approximates the global incidence of neurosurgically rel- evant infectious diseases. These results underscore the disproportionate burden of CNS infections in the developing world, where there is a tremendous demand to provide training and resources for high-quality neurosurgical care. https://thejns.org/doi/abs/10.3171/2017.10.JNS17359 KEYWORDS burden of disease; CNS infection; epidemiology; global surgery; neurocysticercosis; neurosurgery

entral nervous system (CNS) infections continue and Meta-Analyses (PRISMA) guidelines.117 A complete to cause significant morbidity and mortality world- review of the literature was conducted using PubMed, wide, despite the advent of antibiotics, vaccines, EMBASE, and the Cochrane Database of Systematic Cand other medical therapies. The causative organisms— Reviews in November 2016 to capture studies published bacteria, viruses, parasites, fungi, and prions—can lead between 1990 and 2016. The list of search terms, which to meningitis, encephalitis, spinal and cranial abscesses, aimed to capture region-specific epidemiological data on discitis, epilepsy, and other severe complications. In fact, CNS infectious diseases, can be found in the Supplemen- neurocysticercosis (NCC) infection is the leading cause tal Appendix. In summary, MeSH and title/abstract terms of preventable epilepsy in the developing world14,109 and is were used to maximize the inclusion of publications re- on the rise in developing nations.45,56 The spread of other garding CNS infection epidemiology (incidence, preva- CNS infections remains a concern in light of increased lence, burden, mortality, etc.). Titles and abstracts of the migration and tourism travel,68,95 drug-resistant organisms, yielded articles were screened separately by two reviewers and immunosuppressed individuals.50,51,112,134 While medi- (F.C.R., J.R.L.). Articles containing epidemiological data cal treatment is necessary for most CNS infections, neuro- on CNS infection volume (i.e., incidence, prevalence) and surgical involvement can be required for biopsy, debride- disease burden were included. All case reports, case-con- ment, decompression, or reconstruction. trol studies, comparison studies, randomized controlled Geographically, the burden of CNS infection is un- trials, historical articles, commentaries, and practice equally distributed and predominantly impacts low- and guidelines were excluded. Inconsistencies between article middle-income countries (LMICs); unfortunately, these inclusion/exclusion were resolved by joint re-evaluation same countries face a neurosurgeon workforce deficit.51 (F.C.R., J.R.L.) by both investigators before a full-text re- For instance, in many Sub-Saharan African countries, the view. Subsequently, a review team (F.C.R., J.R.L., M.C. current workforce is approximately one neurosurgeon per Davis) obtained the full-text articles and performed data 10 million people, although the expected ratio is at least extraction. To ensure selection accuracy, reviewers jointly 52,147 1 neurosurgeon per 100,000 people. Moreover, only reviewed a random subset of articles at both the abstract 42% of African countries and 75% of Latin American 146 review and full-text review stages to form a consensus on countries offer in-country training of neurosurgeons. the application of selection criteria. At this time, the refer- Therefore, in an era in which CNS infections remain a ma- ences of all included studies were cross-examined for rel- jor challenge, there may be an imminent need to increase evant cited articles, which were included if they fulfilled the neurosurgical workforce, particularly in countries with the selection criteria. the greatest disease burden. However, obtaining a reliable A 6-point scale was used to grade the methodologi- global estimate of the volume and burden of CNS infec- cal quality of each study. Articles were assigned points tions has been difficult because population-wide data are for prospective data collection, research setting (institu- limited, the heterogeneity in CNS infection type and loca- tional vs population), ideal population type, sample size tion is tremendous, and underdiagnosis and underreport- (> 50), and reporting of incidence. Studies were ranked ing in resource-limited settings are suspected. accordingly from 0 to 5.54 A minimal inclusion threshold The aim of this study was to assess the incidence and was set to select for high-quality research; studies from manifestation of CNS infection at the national, regional, high-income countries (HICs) required a score of 4 or 5 and global levels to further characterize the global burden for meta-analysis inclusion, whereas scores of 2–5 were of neurological infection. Through a systematic review of accepted for studies based in LMICs to prevent publica- the literature, we have pooled the reported incidence of tion bias secondary to a paucity of high-quality research CNS infections in various countries to estimate the re- in resource-poor settings. gion-specific incidence via a meta-analysis. As a number of CNS infections mandate surgical involvement for diag- Data Reporting nosis and treatment, a better understanding of the global burden of CNS infections requiring neurosurgical inter- Descriptive statistics were reported as proportions of vention will elucidate the demand for capacity-building a population, including age (mean, median, range, and efforts in neurosurgery. standard deviation), sex, case fatality rate, and surgical burden. Case fatality was defined as the number of deaths divided by the number of cases. Surgical volume burden Methods was defined as the proportion (%) of reported cases that Systematic Review required surgical intervention. To deliver a regional break- Our systematic review was conducted in accordance down of disease, results were organized and presented in with the Preferred Reporting Items for Systematic Reviews relation to the WHO region from which each study was

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Unauthenticated | Downloaded 10/10/21 02:45 PM UTC F. C. Robertson et al. conducted. The WHO regions are classified as follows: Results African Region (AFR), Region of the Americas–United Literature Yield States/Canada (AMR-US/Can), Region of the Americas– Latin America (AMR-L), Southeast Asia Region (SEAR), A detailed description of the inclusion/exclusion process European Region (EUR), Eastern Mediterranean Region is noted in Fig. 1. The initial literature search of the PubMed, (EMR), and Western Pacific Region (WPR). The World EMBASE, and Cochrane databases yielded 10,906 arti- Bank database (2016) was used to characterize the in- cles, which were screened according to the aforementioned come level for each country using gross national income methods. A review of each article’s reference section added per capita. Country and region populations were also ob- 13 relevant articles, yielding a total of 154 articles for this tained from World Bank population metadata (https://data. review. Of the 154 studies that met selection criteria, 83 did not report incidence for the total population (for example, worldbank.org/data-catalog/population-projection-tables). many NCC studies presented incidence within an epilepsy population); therefore, these studies were included in the Meta-Analysis qualitative analysis but excluded from the quantitative Data were analyzed with Comprehensive Meta-Analy- meta-analysis. These excluded studies provide a valuable sis Version 3 (Biostat Inc.) and Stata 14.0 software (Stata- review of the literature regarding reported disease in the Corp). To account for variation between and within stud- developing world, containing information on demograph- ies, the DerSimonian and Laird random-effects model was ics and outcomes (age, sex, rates of infection requiring used to obtain overall incidence estimates and 95% con- surgical intervention, and mortality rates); these are sum- fidence intervals.49 Forest plots allowed visualization of marized in Supplemental Table 1.2,3,​8,10,11,19–23,25–27,33,37,38,40,​ individual and summary estimates. Heterogeneity among 4 1 , ​4 3 , ​4 6 , ​5 0 , ​5 5 , ​5 6 , ​6 3 , ​6 7 , ​6 9 , ​7 6 – 7 9 , ​8 3 – 8 5 , ​8 8 , ​8 9 , ​8 2 , ​9 1 , ​9 3 , ​9 6 , ​9 7 , ​1 0 0 , ​1 0 4 , ​1 0 6 , ​108,113,115,121, ​1 2 3 , ​ studies was evaluated using Cochran’s Q test (p < 0.10) 125–128,137,139,141–145,148,150,153,156,161,163,164,166,169,170,​173,​176,​177,180,​182,​186,​190,​ and I2 to measure the proportion of between-study vari- 192,​193,​195,​196,​198,​199,201 The 71 papers that did report incidence ance. An I2 value > 50% was considered high.31 Subgroup were included in the statistical meta-analysis (Table 1).4,5,​ analyses by categorical covariates were used to explore 7 , 9 , ​1 2 , ​1 5 , ​1 8 , ​2 4 , ​3 2 , ​34–36,42,44,47,48,53,57–62,65,66,70,71, ​73–75,80–82,86, ​8 7 , ​9 0 , ​9 4 , ​9 5 , ​9 8 , ​9 9 , ​ potential sources of heterogeneity, that is, disease type 101–103,​105,​110,​114,​118,​120,122,129,132,133,135,138,140,151,152,​154,​157–160,165,172,174,178,​ (NCC, bacterial meningitis [BM], intracranial abscess, 179,​183,​184,​187–189,​194,200 tuberculosis [TB] meningitis/osteomyelitis, and non-TB The final 71 studies included data from 42 individual spinal osteomyelitis), WHO region, and World Bank in- countries, which were representative of the global com- come classification. Total world incidence of a disease munity and all seven WHO regions: 10 studies from Af- was estimated by multiplying our derived WHO regional rica, 6 from the US/Canada, 16 from Latin America, 5 incidence by public WHO region population data, and all from Southeast Asia, 21 from Europe, 6 from the Eastern seven regions were summed to provide a global total. Mediterranean, and 7 from the Western Pacific. Of the 71 The criteria for surgical versus nonsurgical CNS infec- full-text studies, 39 originated from HICs, 25 from MICs, tious disease were decided unanimously among the au- and 7 from LICs. Article details including individual con- thors. Publications on cerebral malaria, cryptococcal men- siderations and relative limitations are outlined further in ingitis, unspecified CNS infections, and human immuno- Table 1 and Supplemental Table 1. deficiency virus (HIV)-related CNS infections were not included as those disease entities are primarily managed Incidence, Demographics, and Subtype medically, with less relevance for neurosurgical interven- A total of 508,078 cases of CNS infections across tion. To explore sources of heterogeneity, stratification by all studies were included, with a total sample size of WHO region and income level was done for each disease 130,681,681 individuals. There was a high degree of het- category. Once aggregate incidence data were obtained for erogeneity across all disease categories (not shown), with each disease category by WHO region and income level, I2 values ranging from 42.9% for toxoplasmosis to 79.6% these values were summed to a total disease volume of for TB–spinal/cranial to 91.7% for NCC. The incidence of CNS infections. When published data were not available studied CNS infection was consistently highest in LICs, fol- for a disease in a given WHO region, the incidence was lowed by MICs and then HICs (Table 2). Regarding WHO estimated using the weighted proportion of HIC/MIC/ regions, Africa had the highest rates of BM, NCC, and TB- LIC within that region multiplied by the incidence rate of related disease, whereas Southeast Asia had the highest the disease by income level. When this method yielded reported rates of intracranial abscess, and Europe had the an estimate greater than one deviation from the averaged highest reported rates of non-TB spinal osteomyelitis (Ta- incidences, the value underwent logarithmic transforma- ble 3). The global burden of these five CNS infections by tion to prevent significant outliers.124 There were rare in- WHO region and the proportion of infections by pathology stances in which the literature provided no incidence rate are depicted in Fig. 2. Case fatality was calculated from the of a disease for a particular income level. In these cases, included studies; however, because of the sporadic and lim- the incidence was then removed from the meta-analysis. ited reporting of mortality, the resultant calculations may Potential publication bias was assessed using Egger’s lin- represent an over- or underestimation of the true rates. ear regression test and Begg’s correlation test. If publica- tion bias was indicated, the number of missing studies was Bacterial Meningitis evaluated by the trim-and-fill method. A p < 0.05 was con- Twenty-two studies on BM were suitable for inclu- sidered significant unless otherwise indicated. sion. Nine studies were from Europe, four from Africa,

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FIG. 1. PRISMA diagram summarizing the search process. From a total of 10,906 studies, 154 were incorporated into the review, with 71 in the quantitative analysis. five from the Western Pacific, two from the Eastern Medi- of 650 cases/100,000 people (95% CI 195–1333/100,000). terranean, and one each from the US/Canada and Latin Sixteen studies were from MICs, four from LICs, and sev- America (Fig. 3). The estimate of individuals affected en from HICs (Fig. 6). The estimated incidence was 401 by BM worldwide was 2,907,146 each year (Table 3). cases/100,000 people in LICs (95% CI 16–1173/100,000), Occurrence was highest in Africa, with an incidence of 256/100,000 in MICs (95% CI 54–569/100,000), and 65 cases/100,000 people (95% CI 13–155/100,000), and 0.40/100,000 in HICs (95% CI 0.11–0.83/100,000; p < lowest in the US/Canada, with an incidence of 2/100,000 0.001). Case fatality for NCC was only available in two (95% CI 2–3; p-interaction comparing the different studies,137,189 both of which came from the US, with record- groups < 0.001). Fifteen studies were from HICs, five ings of 1.2% and 9.8% (mean 5.5%, 95% CI 0.0%–60.5%). from MICs, and two from LICs (Fig. 4). Incidence was 85 cases/100,000 people in LICs (95% CI 78–93/100,000), Intracranial Abscess 42/100,000 in MICs (95% CI 11–92/100,000; I2 = 99.1%; 5 Eight studies on intracranial abscesses, which include studies), and 6/100,000 in HICs (95% CI 4–8/100,000; I2 = extradural and subdural empyema, were suitable for inclu- 98.3%; 15 studies; p-interaction < 0.001). sion, with two studies each from Africa and the Western Case fatality was available in 13 studies,3 3 , 3 4 , ​4 0 , ​5 3 , ​5 9 , ​7 5 , ​8 6 , ​ Pacific, and one each from Latin America, US/Canada, 98,​107,​113,140,​148,198 giving an overall average of 15.9% (95% Eastern Mediterranean, and Europe (Supplemental Figs. 1 CI 9.2%–22.5%), with the highest rate of 32.7% in Swazi- and 2); estimates for Southeast Asia data were calculated land59 and the lowest rate of 2.4% in Singapore.34 The most as described above in the Methods. The overall estimate common offending pathogens were reported by 21 studies; of the global population affected by intracranial abscesses these results are summarized in Table 4. was 1,088,237 each year (Table 3). Reported incidence ranged from 0.15 cases/100,000 people to 49/100,000. Neurocysticercosis Incidence was lowest in the Western Pacific (0.15 cas- Twenty-seven studies on NCC were suitable for inclu- es/100,000 people, 95% CI 0.05–0.25) and highest in sion (Fig. 5). Six WHO regions were included, with 14 Southeast Asia (49/100,000, 95% CI 6–62). Reported inci- studies from Latin America, four from the US/Canada, dence in HIC and MIC was similar at 0.54 cases/100,000 three each from Southeast Asia and Africa, two from the and 0.52/100,000, respectively (p-interaction = 0.19). Only Eastern Mediterranean, and one from Europe. The overall one study from an LIC was included and had a reported in- estimate of the global population affected by NCC was cidence of 240 cases/100,000 people (95% CI 86–672).184 24,743,893 people each year (Table 3). The occurrence Case fatality data were not available for intracranial ab- rate was highest in Africa, with an estimated incidence scess in the included studies.

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Unauthenticated | Downloaded 10/10/21 02:45 PM UTC F. C. Robertson et al. » CONTINUED ON PAGE 1112 1112 ON PAGE CONTINUED Limitations/Considerations Nationwide database–vertebral osteomyelitis Children aged <5 yrs only Tertiary only; MRI reviewed CT diagnosis, sporadic data collection Pediatric neurologyPediatric unit Tertiary only Tertiary only Adults only; tertiary only; Adults only hospital Tertiary only Tertiary only S. aureus only Study completed in pediatrics completed in Study /neurosurgery database BM Postop Tertiary only; adults only Tertiary only; yrs age > 14 Autopsy–patients who died w/ abscess Autopsy capture–recapture w/ study Prospective models Cranial CT patients in hospital Tertiary only Neonates only <90 (age days) S. aureus only Pneumococcal meningitis 3 5 4 3 4 4 4 2 4 4 4 5 3 4 4 4 5 4 4 2 5 3 3 3 5 5 5 4 3 3 4 4 4 4 3 4 Score Method Method Hosp Pop Hosp Pop Hosp Hosp Pop Hosp Hosp Hosp Hosp Hosp Pop Hosp Pop Hosp Hosp Pop Hosp Pop Hosp Pop Pop Pop Pop Pop Hosp Hosp Hosp Pop Pop Pop Pop Pop Pop Pop Scale Study Study Study Study Retro Retro Retro Pros Retro Retro Cross Retro Retro Retro Retro Retro Retro Retro Retro Retro Retro Pros Retro Cross Retro Retro Retro Other Cross Other Retro Retro Retro Pros Pros Pros Pros Retro Retro Retro Design 2007 1994 2004 2004 Study Study Period 2007–2011 2007–2010 1999–2001 1998–2002 1991–2002 1990–1995 1993–2011 2004–2009 1996–2000 1983–2003 1993–1999 1981–1996 1993–2000 1980–1990 1985–1991 2001–2003 1992–2001 1994–1997 1985–1987 1996–2009 1970–2008 2005–2009 1995–1996 1964–1989 1993–2003 1977–1994 1985–1994 1980–1990 1991–1992 1995–2008 1994–2009 2001–2008 ) ʹ 1.8 4.25 0.2 6.4 2.0 6.5 2.4 6.3 3.6 8.0 8.1 11.6 67.3 74.0 14.6 13.2 13.3 15.5 15.7 24.4 18.0 18.7 28.0 89.0 23.0 30.4 60.2 80.6 58.5 (n 471.9 120.0 192.0 109.2 232.0 355.9 2,006.5 Incidence ) ʹ 863 6,118 1,723 1,337 6,975 4,706 1,009 9,254 2,548 6,500 8,000 12,724 63,816 35,473 50,000 547,743 727,760 483,123 127,000 103,484 750,000 255,599 438,503 550,000 399,000 500,000 300,000 508,900 Sample Sample Size (N Size 2,400,000 4,000,000 3,000,000 5,000,000 5,000,000 11,600,000 28,333,333 16,000,000 Level Income Middle Middle Low High High High Middle Low High High Low Middle High Low High High High High Middle High Middle High High High Middle Middle Middle Middle Middle Middle High Middle High High High High WHO Region WHO EMR AFR SEAR EUR SEAR EUR SEAR AFR EUR EUR AFR AFR EUR AFR EUR WPR EUR EUR AMR-L EUR WPR EMR AMR-US/Can AMR-L AFR AMR-L AMR-L AMR-L AMR-L AMR-L EUR AMR-L EUR EUR EMR EUR Country Yemen South Africa Nepal Netherlands Japan Sweden India Mozambique Italy Spain Niger Nigeria England Nigeria Spain Singapore Denmark Denmark Mexico Germany China Arabia Saudi USA Chile Swaziland West Indies West Ecuador Brazil Brazil Cuba Denmark Brazil Denmark Finland Israel Austria Disease Disease Category BM IA NCC BM SO-nonTB SO-nonTB NCC NCC IA TB-s/c BM BM SO-nonTB BM NCC BM SO-nonTB SO-nonTB NCC BM BM IA NCC BM BM IA NCC NCC NCC NCC BM NCC SO-nonTB BM NCC BM Authors & Year Al Khorasani & Banajeh, 2006 Anwary 2015 et al., Adhikari 2013 al., et Adriani 2007 al., et Akiyama 2013 et al., Beronius 2001 al., et Azad 2003 al., et Assane 2017 al., et TABLE 1. Review studies 1. ofTABLE 71 included in the quantitative meta-analysis 1999 al., et Campagne 2011 Frank-Briggs Alikor, & Gallitelli et al., 2005 al., Gallitelli et Garcia-Lechuz 2002 al., et Granerod 2013 al., et Chapp-Jumbo, 2004 Gómez Rodríguez 2004 al., et Chan et al., 2002Chan al., et Jensen 1998 al., et Jensen 1997 al., et Fleury 2010 al., et Fluegge 2006 al., et Hui 2005 al., et Jamjoom 1994 al., et del la Garza 2005 al., et Ferreccio 1990 al., et Ford & Wright, 1994 Char et al., 2010 Char al., et Cruz 1999 al., et Del Brutto, 2005 al., et Grazziotin 2010 al., et Hernández-Cossio1999 al., et Howitz & Homøe, 2014 de Almeida 2011 al., et Kehrer 2014 al., et Kalliola 1999 al., et Leshem et al., 2010 Leshem 2010 al., et Klobassa 2014 al., et

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Unauthenticated | Downloaded 10/10/21 02:45 PM UTC F. C. Robertson et al. » CONTINUED ON PAGE 1113 1113 ON PAGE CONTINUED Limitations/Considerations Neurology neurosurgery & database Tertiary only Autopsy data Autopsy Travel episodes to endemic countries endemic episodes to Travel Haemophilus meningitis B children only; only Epilepsy only Epilepsy Clustered randomClustered sampling. Neurology/neurosurgery only patients only patients Epilepsy Door-to-door survey; imaged suspects epilepsy Pneumococcal meningitis only Door-to-door survey; imaged suspects epilepsy Children only yrs age <10 Age >16 yrs onlyAge >16 Village tested study, serum then CT Tertiary only Adult patients only 2 3 4 4 4 4 4 3 4 4 4 5 3 4 5 5 4 3 4 4 4 4 4 4 5 4 5 5 4 4 4 3 4 Score Method Method Hosp Hosp Pop Hosp Pop Pop Hosp Pop Pop Hosp Pop Pop Pop Hosp Pop Pop Pop Hosp Hosp Pop Pop Pop Hosp Hosp Pop Hosp Pop Pop Pop Hosp Pop Hosp Pop Scale Study Study Study Study Retro Retro Retro Retro Retro Cross Retro Retro Retro Retro Cross Cross Pros Retro Cross Retro Retro Retro Pros Retro Cross Retro Retro Retro Cross Retro Retro Cross Pros Cross Retro Retro Retro Design 2010 1995 2007 2003 2004 Study Study Period 2011–2015 1986–2000 1999–2006 1974–1997 1994–1996 1994–2009 1986–1999 1990–1999 1935–1981 2006–2007 1995–1996 2006–2007 1984–1999 1992–1995 1994–1998 1996–1998 1990–2000 1999–2000 1996–2005 1980–1989 2004–2005 1986–1999 1975–1994 2009–2010 1992–1993 1990–2002 2001–2003 2008–2011 ) ʹ 7.6 1.3 1.8 4.6 0.8 0.8 6.8 8.2 6.0 2.5 6.6 3.0 17.7 11.0 12.8 19.0 15.5 15.0 15.5 10.6 10.0 18.3 39.3 20.0 93.5 23.0 34.0 (n 157.0 109.0 109.0 248.0 269.6 236.0 Incidence ) 67 39 ʹ 403 888 1,374 2,313 1,080 1,004 2,209 2,554 10,124 20,197 47,323 20,610 93,532 131,786 367,283 907,580 225,970 255,303 484,483 250,000 490,000 483,000 500,000 900,000 Sample Sample 2,120,000 5,441,000 5,441,000 5,404,624 Size (N Size 1,868,298 2,400,000 10,281,746 Level Income High High Middle Middle Middle High High High Middle Middle High High Low Middle Middle Middle Middle High High High Middle High Middle High High High High High Low Middle High High Low WHO Region WHO WPR WPR AFR WPR AMR-L EMR EMR EUR AMR-L AMR-L AMR-US/Can EMR AFR AMR-L AMR-L AMR-L AMR-L AMR-US/Can EUR AMR-US/Can SEAR EUR SEAR AMR-US/Can WPR EUR EUR EUR AFR AMR-L EUR EUR AFR Faso Country Taiwan Taiwan Cameroon Philippines Brazil Israel UAE Denmark Peru Bolivia USA Oman Burkina Peru Peru Brazil Brazil USA France USA Malaysia Denmark India USA Japan Norway Spain Iceland Senegal Brazil Spain England Senegal Disease Disease Category IA BM TB-s/c BM NCC NCC BM BM NCC NCC IA SO-nonTB NCC NCC NCC NCC NCC NCC BM NCC TB-s/c BM NCC BM BM SO-nonTB TB-s/c BM NCC NCC SO-nonTB SO-nonTB IA 21 20 Authors & Year 2005 CONTINUED FROM PAGE 1111 FROM PAGE CONTINUED Lu et al., 2002 al., Lu et 2000 al., Lu et Looti 2010 al., et Limcangco 2000 al., et Lino 1999 al., et Leshem 2011 al., et Moyano 2012 et al., Mahmoud 2002 al., et TABLE 1. Review studies 1. ofTABLE 71 included in the quantitative meta-analysis 2016 Serour, & Menon 1996 et al., Takayanagui Nørgaard 2003 al., et Montano 2005 al., et Nicoletti 2005 et al., Nicolosi 1991 al., et Millogo 2012 al., et Moyano 2012 et al., Narata 1998 et al., Ong 2002 al., et Reinert 1993 al., et Ptaszynski 2007 al., et Rasit 2001 al., et Østergaard 2005 al., et Raina 2012 al., et Schuchat 1997 et al., Sakata, 2007 Riise 2008 al., et Rodriguez-Gomez 2002 al., et Sigurdardóttir 1997 al., et Secka 2011 al., et Silva-Vergara 1994 al., et Solís-García del al., Pozo et Sur et al., 2015 Sur al., et Soumaré 2005 al., et »

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TABLE 2. Worldwide estimated totals for CNS infectious diseases separated by World Bank income level per 100,000 people CNS Infection LIC MIC HIC BM 85 42 6 NCC 401 256 0.4 IA 240 0.52 0.54 SO-nonTB UN UN 4 TB-related disease* UN 0.57 0.56 UN = data unavailable in literature.

Limitations/Considerations * Meningitis/osteomyelitis.

Tertiary only Nontuberculous Osteomyelitis Ten studies on spinal nontuberculous osteomyelitis and 4 4 discitis were suitable for inclusion (Supplemental Figs. 3 Score Method Method and 4). Eight studies were performed in Europe, and one each was performed in the Eastern Mediterranean and Hosp Hosp Scale Study Study Southeast Asia. The overall estimate of the total popula- tion affected was 108,426 per annum (Table 3). The re- ported incidence from individual studies ranged from 0.27 Study Study Retro Retro Design cases/100,000 people (95% CI 0.16–0.45) to 39.7/100,000 (95% CI 34.5–45.8). All included studies originated from HICs, and the overall pooled estimate of incidence was 4

Study Study cases/100,000 people (95% CI 1–9). Case fatality for non- Period 24,37,​76,82,​186,187 1995–2000 1986–2002 TB osteomyelitis was available in six studies, giving an overall rate of 13.6% (95% CI 3.8%–23.5%), )

ʹ with the highest report of 26.8% in an elderly population 12.2 10.5 (n in New Zealand76 and the lowest (< 0.01%) in England.187 Incidence Study quality was not a source of heterogeneity in a meta- )

ʹ regression analysis (p = 0.99). 4,452 Tuberculous Meningitis/Osteomyelitis Sample Sample 6,100,000 Size (N Size Four studies on tuberculous meningitis and/or osteomy- elitis were suitable for inclusion (Supplemental Figs. 5 and

Level 6). Two studies originated from HICs in Europe, and one Income High High ; TB-s/c = tuberculosis–spinal/cranial; WPR = Western Pacific Region. study each originated from a MIC in Africa and Southeast Asia. The overall estimate of the global population affected by TB meningitis or osteomyelitis was 1,005,612 each year (Table 3). The reported incidence from individual studies ranged from 0.51 cases/100,000 in a European HIC (95% WHO Region WHO AMR-US/Can WPR CI 0.16–1.66) to 54.8/100,000 in an African MIC (95% CI 11.4–263.8; Supplemental Figs. 5 and 6). Case fatality for TB osteomyelitis was only available in one Turkish study, 78

Country with a case fatality of 21.1%. All deaths were associated

USA Taiwan with stage III recrudescent disease. S. aureus aureus = Staphylococcus Study Quality

Disease Disease Study quality was assessed as a potential source of Category NCC IA heterogeneity for each of the outcomes and hence was in- cluded in a meta-regression analysis. For BM, there was no evidence of an effect modification by study quality (slope = -0.82, p = 0.21). After adjusting for WHO region, in- come level, and study quality in the model, the multivari- ate meta-regression revealed that study quality was not a source of heterogeneity (p = 0.15). Similarly, for NCC,

Authors & Year meta-regression revealed there was no evidence of an ef- fect modification by study quality (slope = -0.65, p = 0.41). This remained unchanged even after adjusting for WHO CONTINUED FROM PAGE 1112 FROM PAGE CONTINUED Townes et al., 2004 al., et Townes Xiao 2005 al., et TABLE 1. Review studies 1. ofTABLE 71 included in the quantitative meta-analysis AFR = African Region; AMR-L = Region of the Americas–Latin America; AMR-US/Can = Region of the Americas–United States/Canada;Region; EUR = European BM = bacterial Region; Hosp = hospital meningitis; based; Cross IA = intracranial = cross-sectional; abscess; NCC EMR = neurocysticercosis; = Eastern Mediterranean Pop = population based; Pros = prospective; Retro osteomyelitis–non-tuberculosis; = retrospective; spinal = nonTB SEAR = Southeast Asia Region; SO- » region (p = 0.18) or income level (p = 0.14). Study quality

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was not a source of heterogeneity for intracranial abscess (p = 0.53), nontuberculous osteomyelitis (p = 0.99), or tu- 5,134 3,573 berculous meningitis/osteomyelitis (p = 0.60). 10,993 64,806 Year 114,177 544,647 262,283 1,005,612

No. Affected/ No. Publication Bias Begg’s p value and Egger’s p value were nonsignificant for each of the five CNS infection types, except for NCC 1 0.57 TB-Related Disease* 14‡ 10 18‡ Mean 55

0.56 where the Egger’s test was significant (p = 0.02; Table 5).

Incidence The funnel plot was asymmetrical for all of the different disease outcomes, which suggests that studies showing a higher incidence could be missing, and, consequently, our results could be an underestimation. Because at least 10 † † † † 4,731 Year

57,856 studies are needed to assess publication bias with a funnel 45,839 108,426 plot, assessment of bias could not be completed for tuber- No. Affected/ No. culous meningitis/osteomyelitis (4 studies). SO-nonTB † † † † Discussion 3 5 0.73 Mean

Incidence This study represents the first comprehensive estimate of the global burden of neurosurgically relevant CNS in- fectious diseases. The results of this systematic review and meta-analysis underscore the epidemiological dispropor- 5,149 3,144 2,810 6,967 4,666 tions of disease by region, income status, and pathogen. Year 120,520 944,980

1,088,237 Areas of lower income are particularly vulnerable to the No. Affected/ No.

IA persistence and spread of infection due to poverty, over- crowding, inadequate access to clean water and proper sanitation systems, and insufficient access to 0.15 0.76 0.72 0.52 72,119,171 19 Mean 49‡ 0.88 overall. In our study of the five categories of CNS Incidence infection, LICs had an overall incidence of 726 cas- es/100,000 people and MICs had 299/100,000, compared with approximately 11/100,000 in the high-income coun- terparts. Furthermore, LMICs have the smallest neurosur- 9,168 1,491 1,894

Year gical workforce, with many LMICs in Sub-Saharan Africa 1,249,602 6,436,739 8,408,393 8,636,606

24,743,893 having only one neurosurgeon per 3–10 million constitu- No. Affected/ No.

NCC ents, in contrast to one per 20,000–60,000 in Europe and other HICs.1,52,147,162 The limited workforce and resources in LMICs compounded by the increased burden of CNS in- 1 0.23 Mean 197 461 436 650 0.53 fection highlight the importance of this public health issue. Incidence Bacterial Meningitis Bacterial meningitis remains a significant cause of CNS

7,145 infection worldwide, particularly in the region of Sub- 95,147 71,287 55,007 Year 974,194

643,674 6,116

2,907,146 Saharan African known as the “meningitis belt.” Our 1,060,692

No. Affected/ No. study revealed an annual incidence of 65 cases/100,000 BM people for the AFR, corroborating findings from the 2014 WHO Global Health Observatory database, which re- 2 6 11 15 52 65 55‡ ported an annual incidence ranging from 0.03/100,000 in Mean

Incidence Mauritania to 227/100,000 in the Democratic Republic of Congo (http://apps.who.int/gho/data). These similar con- clusions served as validation for our methodology. More- over, the significant contrast between the incidence in Af- rica and more Westernized regions such as the US/Canada 916,775,857 357,270,594 990,267,592 634,315,984 Population 648,060,427 per Region per and Europe (2 and 6/100,000, respectively) reinforces that 7,348,671,249 1,873,450,273 1,928,530,522 BM is primarily a disease of the developing world. Although BM is initially managed medically, unsuc- cessful or untimely treatment can result in sequelae, such as postinfectious hydrocephalus and subdural empyema, which can require neurosurgical intervention.64 Global

WHO Region WHO efforts to better characterize the transmission patterns of SEAR Worldwide AMR-US/CAN AMR-L WPR EUR EMR AFR TABLE 3. WorldwideTABLE estimated incidence for CNS infectious diseases separated by WHO region per 100,000 people, and total number of individuals affected per annum worldwide Meningitis/osteomyelitis.* † No income data available for estimation of mean incidence or number affected per Value counted year. as zero for worldwide estimate. ‡ Calculated based on income data for WHO region. BM in endemic regions are ongoing.6,30,136

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FIG. 2. Global incidence and burden of CNS infection. For the five CNS infection types studied, the combined incidence A( ) and global burden (B) of CNS infection are depicted, as are proportions of infection by pathology (C). Publications on cerebral malaria, cryptococcal meningitis, unspecified CNS infections, and HIV-related CNS infections were not included since those are primar- ily medically managed disease entities with less relevance for neurosurgical intervention. Map reproduced with permission from OpenStreetMap Contributors, CC BY-SA 2.0 (http://www.openstreetmap.org/copyright). Figure is available in color online only.

Neurocysticercosis cidence of NCC was noted in the Eastern Mediterranean Neurocysticercosis was the most reported individual at 0.23 cases/100,000 people. One proposed explanation disease in publications of CNS infections worldwide (27 is that predominantly Muslim regions have a smaller pork of 71 studies). The burden of NCC was most prominent industry and therefore a substantially lower rate of cysti- in Africa and in LMICs, where neurosurgeons are few,51 cercosis and subsequent fecal-oral transmission leading to with an incidence of 650 and 401 cases/100,000 people, NCC.114 respectively. Latin American countries contributed the Neurocysticercosis can require neurosurgical interven- greatest amount of high-quality research on NCC, and tion for biopsy, treatment of hydrocephalus, or alleviation WPR and SEAR had substantial rates of infection as well. of mass effect.16,155 Furthermore, as the most common Our results corroborate that NCC has been a known public cause of acquired seizures worldwide, NCC-related refrac- health problem in these four WHO regions and in indi- tory epilepsy often necessitates surgery.36,181 Overall, NCC vidual LMICs because of poor hygiene, methods of pig provokes sequelae that require surgical intervention and management and slaughter, and inadequate waste and wa- 151 contributes to the burden of neurosurgical disease, particu- ter management. Importantly, our estimates may involve larly in endemic areas. selection bias as many population-based studies were con- ducted in villages and regions of known endemnicity. For Intracranial Abscess instance, Secka et al. conducted a population-based radio- graphic survey within the Soutou village in a historically While our study showed a globally low incidence of endemic region of Senegal, which showed an incidence of intracranial abscess (1 case/100,000 people), LICs had a 516 cases/100,000 people. In contrast, several studies fo- significantly higher burden of disease. Latin America had cused only on symptomatic disease by screening within the highest incidence among the countries with available epileptic populations, which may have underestimated the figures (19 cases/100,000 people), although this statis- total incidence of NCC infection. The lowest regional in- tic was based on a single study in the West Indies.36 The

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FIG. 3. Forest plot demonstrating distribution of overall incidence of BM by WHO region. Twenty-two studies on BM were included, and data were analyzed according to WHO region. Overall incidence was highest in Africa and lowest in AMR-US/Can. Solid squares represent the point estimate of each study, and the diamonds represent the pooled estimate of the incidence for each subgroup. The width of the diamond denotes 95% CIs. The size of the solid squares is proportional to the weight of the study. ES = effect size. Figure is available in color online only. calculation of incidence in Southeast Asia using income peutic purposes, with aerobic, anaerobic, mycobacterial, data estimates (see Methods) showed abscess rates of 49 and fungal cultures to guide medical treatment;13 however, cases/100,000 people. The etiology of brain abscess is LICs are often forced to rely on empirical medical man- believed to relate directly to poor socioeconomic condi- agement because of limitations in both radiographic and tions,130 including both hematogenous and direct spread surgical resources. For instance, in a series of 112 cerebral from pneumonia, poor dental hygiene and associated abscesses in Burkina Faso, 47% of patients were treated cardiac valvular vegetations, previous surgery, or other with antibiotics alone, while 53% underwent surgery.85 contiguous sites.29,192 Successful management generally This contrasts with higher-income countries, where nearly requires surgical drainage for both diagnostic and thera- 90% of cases undergo surgical treatment28,80,130 and medi-

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FIG. 4. Forest plot demonstrating distribution of overall incidence of BM by World Bank income level. Twenty-two studies on BM were included, and data were analyzed according to LIC, MIC, and HIC World Bank indication. Figure is available in color online only. cally managed patients are closely monitored with serial tion, or spinal column invasion and compressive myelopa- imaging.61 Overall, reduced mortality in this disease pro- thy. In a Danish study of patients with spinal TB, 54/133 cess with the advent of CT imaging and neurosurgical in- (40.6%) had neurological deficits on admission and 17.3% tervention has been corroborated in other studies,29,130,191 presented with cauda equina syndrome, requiring surgi- emphasizing the importance of both imaging and surgery cal intervention.84 In a Filipino study of TB meningitis in as standard care. children, the mortality rate was 16%, and 71% of patients exhibited signs of hydrocephalus.93 Thus, neurosurgeons Tuberculosis-Related CNS Disease have a role to intervene in CNS TB for biopsy, spinal de- Tuberculosis-related CNS disease includes TB menin- compression and stabilization, and CSF diversion. Fur- gitis and TB spondylitis. The WHO data repository reports thermore, despite few publications on the epidemiology of an average annual incidence of systemic TB infection as CNS TB in LICs, it is suspected that in these countries, 244 cases/100,000 people over the last 5 years, of which the demand for CNS TB treatment is highest and should spondylodiscitis and meningitis represent approximately be investigated further. 2% and 3%, respectively.175,197 In our study, the region with the highest noted incidence was Africa with a rate of 55 Nontuberculous Osteomyelitis cases/100,000 people based on the single study in Cam- In our study, the nontuberculous vertebral spondylodis- eroon by Lootie et al.101 Interestingly, our review demon- citis was the least prevalent of the five diseases, affecting strated that much of the known epidemiological data for approximately 100,000 people each year worldwide. The CNS TB is limited to MICs and HICs, with no LIC in- surgical intervention rate ranged from 9.2% described by cluded in the quantitative meta-analysis. Grammatico et al. in France69 to 96.8% by Menon et al. These severe forms of extrapulmonary TB can cause in Oman.111 Of note, all 10 included studies were reflec- significant morbidity and mortality via the development of tive of HICs.17,24,62,66,69,75,101,110,157,160,185 This does not imply hydrocephalus, encephalitis, vasculitis, thrombosis, infarc- that the incidence of non-TB spondylodiscitis is zero for

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TABLE 4. Most common pathogens reported by each study for bacterial meningitis and intracranial abscess

Age Range Total Most Common Pathogen Authors & Year Country WHO (yrs) Cases 1st 2nd 3rd BM Adriani et al., 2007 Netherlands EUR 17 to 83 34 S. pneumoniae H. influenzae N. meningitidis Campagne et al., 1999 Niger AFR 0 to 40+ 7078 N. meningitidis S. pneumoniae H. influenzae Ford & Wright, 1994 Swaziland AFR 0 to 15+ 85 S. pneumoniae N. meningitidis H. influenzae Gebremariam, 1998 Ethiopia AFR <1 55 K. pneumoniae E. coli Enterobacter spp. Soumaré et al., 2005 Senegal AFR 2 to 85 62 S. pneumoniae N. meningitidis Salmonella spp. Ferreccio et al., 1990 Chile AMR-L 0 to 5 343 H. influenza only Schuchat et al., 1997 USA AMR-US/Can 0 to 60+ 248 S. pneumoniae N. meningitidis Group B streptococcus Al Khorasani & Banajeh, 2006 Yemen EMR 1 to 15 153 N. meningitidis S. pneumoniae H. influenzae Mahmoud et al., 2002 UAE EMR 0 to 29 125 H. influenzae S. pneumoniae N. meningitidis Fluegge et al., 2006 Germany EUR 0 to 3 mos 707 Group B streptococcus only Kalliola et al., 1999 Finland EUR 0 to 3 mos 485 Group B streptococcus only Klobassa et al., 2014 Austria EUR 0 to 5 74 S. pneumoniae only Nørgaard et al., 2003 Denmark EUR 0.5 to 88 45 S. aureus only Østergaard et al., 2005 Denmark EUR 22 to 69 187 S. pneumoniae only Reinert et al., 1993 France EUR 0 to 5 277 H. influenzae only Sigurdardóttir et al., 1997 Iceland EUR 16 to 45+ 132 N. meningitidis S. pneumoniae L. monocytogenes Chan et al., 2002 Singapore WPR 14 to 72 15 S. pneumoniae N. meningitidis Group B streptococcus Hui et al., 2005 China WPR 15 to 86 35 Unknown S. pneumoniae S. suis Limcangco et al., 2000 Philippines WPR 0 to 5 118 H. influenza only Lu et al., 2000 Taiwan WPR 18+ 202 K. pneumoniae P. aeruginosa S. pneumoniae Sakata, 2007 Japan WPR 0 to 9 52 H. influenza only IA Char et al., 2010 West Indies AMR-L 0 to 76 93 S. pneumoniae Proteus spp. S. aureus Jamjoom et al., 1994 Saudi Arabia EMR 0 to 80 22 S. aureus S. milleri Unknown Lu et al., 2002 Taiwan WPR 1 mo to 80 123 S. viridans Unknown Mixed Xiao et al., 2005 Taiwan WPR 2 mos to 84 178 S. viridans S. aureus Peptostreptococcus spp. H. influenzae = Haemophilus influenzae; K. pneumoniae = Klebsiella pneumoniae; L. monocytogenes = Listeria monocytogenes; N. meningitidis = Neisseria meningiti- des; P. aeruginosa = Pseudomonas aeruginosa; S. aureus = Staphylococcus aureus; S. milleri = Streptococcus milleri; S. pneumoniae = Streptococcus pneumoniae; S. suis = Streptococcus suis; S. viridans = Stretococcus viridans. all LICs and MICs, but rather that it is simply not known. While the five disease categories studied include pa- Note, however, that the high incidence in HICs indicates thology that often requires surgical intervention, this list that vertebral osteomyelitis may be a disease afflicting is not comprehensive and omits multiple diseases that may the developed world. Known risk factors include injection indeed require neurosurgery, such as HIV-related infec- drug use, diabetes, and a compromised immune system,7 tions. However, less common diseases that were omitted, several of which are prevalent in more developed nations such as cerebral schistosomiasis, prion disease, and neu- but are becoming increasingly common in the developing roborreliosis, are unlikely to greatly affect the estimated world.131,149 Our data indicate that vertebral osteomyelitis is volume of CNS infections. not currently a major contributor to the global neurosurgi- Additionally, regions in which CNS infections are sus- cal infectious volume; however, the continuation of ongo- pected to occur with the greatest frequency are also those ing epidemiological trends may show a rise in vertebral regions with studies of the lowest methodological quality. osteomyelitis in the near future. The exclusion of large regional and national registries ex- cludes a large body of data that could have greatly impact- Study Limitations and Future Directions ed the power of our approximations. To include data from The disease estimations presented in this study are the greatest possible number of regions and achieve our based on the most wide-ranging and comprehensive stud- goal of describing the global CNS infectious disease vol- ies available. Strengths of this study include the compre- ume, we used a lower methodological threshold for studies hensive literature search, large number of included stud- from LMICs. This may have resulted in either an over- ies, and emphasis on the inclusion of data from developing estimation or underestimation of incidence. Furthermore, countries. However, the findings are not without limita- many of the included studies focused on populations with tions. a known high prevalence of disease, further decreasing the

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FIG. 5. Forest plot demonstrating distribution of overall incidence of NCC by WHO region. Neurocysticercosis was the most reported individual disease in publications of CNS infections worldwide (27 of 71 included in the final statistical analysis). Overall incidence was highest in AFR and lowest in EMR. Solid squares represent the point estimate of each study, and the diamonds represent the pooled estimate of the incidence for each subgroup. The width of the diamond denotes 95% CIs. The size of the solid squares is proportional to the weight of the study. Figure is available in color online only. J Neurosurg Volume 130 • April 2019 1119

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FIG. 6. Forest plot demonstrating distribution of overall incidence NCC by World Bank income level. Twenty-seven studies regard- ing NCC were analyzed according to LIC, MIC, and HIC World Bank indication. Solid squares represent the point estimate of each study, and the diamonds represent the pooled estimate of the incidence for each subgroup. The width of the diamond denotes 95% CIs. The size of the solid squares is proportional to the weight of the study. Figure is available in color online only. generalizability to entire regions. However, this strategy of by the availability of resources. Finally, heterogeneity using a lower threshold for underrepresented regions fol- remained high in most categories despite stratifying by lows precedent.31 Furthermore, gold-standard diagnostic trial-level covariates; this could be attributable to residual testing is frequently unavailable in low-resource settings. confounding or variance in true rates rather than sampling Unsurprisingly, included studies with a broader definition error. Study quality did not appear to be a source of hetero- of infection (such as seropositivity for cysticercosis and geneity, likely because the studies that provided incidence history of seizure) had a higher rate of infection than those and were consequently entered in the meta-analysis were studies with a stricter definition of infection. While we re- generally of moderate to high quality. port the volume of CNS infections that are most likely to While these limitations are substantial, they highlight the require surgery, our estimates for true neurosurgical de- difficulty in obtaining high-quality epidemiological data on mand were restricted because few publications specifically infectious diseases affecting the CNS, particularly in low- indicated the proportion of patients requiring surgery in resource settings. Further research should specifically ad- their investigation. It would have been ideal to show this dress the limitations of this study, with particular emphasis proportion of surgical cases for each disease category, as on population-based epidemiological studies in LMICs. well as to describe and quantify the neurosurgical proce- dures performed in patients with neurosurgical infections on a global scale. This would allow comparison of neuro- Conclusions surgical treatment of CNS infections across WHO regions, Here, we performed a systematic review and meta- which could have differing management options dictated analysis of more than 10,000 titles and ultimately included

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TABLE 5. Publication bias results for 5 disease outcomes 8. Al Ayed M, Al Jumaah S, AlShail E: Central nervous sys- tem and spinal tuberculosis in children at a tertiary care p Value, p Value, center in Saudi Arabia. Ann Saudi Med 33:6–9, 2013 CNS Infection Funnel Plot Begg’s Test Egger’s Test 9. Al Khorasani A, Banajeh S: Bacterial profile and clinical BM Asymmetrical 0.48 0.68 outcome of childhood meningitis in rural Yemen: a 2-year hospital-based study. J Infect 53:228–234, 2006 NCC Asymmetrical 0.29 0.02 10. Alavi SM, Sharifi M: Tuberculous spondylitis: risk factors IA Mildly asymmetrical 0.32 0.47 and clinical/paraclinical aspects in the south west of Iran. J SO-nonTB Asymmetrical 0.79 0.11 Infect Public Health 3:196–200, 2010 11. Alothman A, Memish ZA, Awada A, Al-Mahmood S, TB-related disease* Symmetrical† 1.00 0.89 Al-Sadoon S, Rahman MM, et al: Tuberculous spondylitis: Boldface type indicates statistical significance. analysis of 69 cases from Saudi Arabia. Spine (Phila Pa * Meningitis/osteomyelitis. 1976) 26:E565–E570, 2001 † Need at least 10 studies to assess publication bias. 12. Anwary MA: Intracranial suppuration: Review of an 8-year experience at Umtata General Hospital and Nelson Mandela Academic Hospital, Eastern Cape, South Africa. S Afr Med 154 articles to estimate the global volume of CNS in- J 105:584–588, 2015 13. Arlotti M, Grossi P, Pea F, Tomei G, Vullo V, De Rosa FG, fections that may require neurosurgical intervention. To et al: Consensus document on controversial issues for the our knowledge, this is the first study of its kind. In total, treatment of infections of the central nervous system: bacte- these studies included over 130,681,681 patients across 44 rial brain abscesses. Int J Infect Dis 14 (Suppl 4):S79– countries. While our study provides an approximation, S92, 2010 our results can be used as a benchmark against which lo- 14. Assana E, Lightowlers MW, Zoli AP, Geerts S: Taenia cal disease incidence can be compared. Overall, we have solium taeniosis/cysticercosis in Africa: risk factors, epide- described the estimated global and regional incidence of miology and prospects for control using vaccination. Vet five CNS infectious diseases of neurosurgical relevance. Parasitol 195:14–23, 2013 15. Assane YA, Trevisan C, Schutte CM, Noormahomed EV, The strength and quality of epidemiological information Johansen MV, Magnussen P: Neurocysticercosis in a rural regarding neurosurgical disease in the developing world is population with extensive pig production in Angónia dis- certainly lacking, yet those populations are the ones most trict, Tete Province, Mozambique. Acta Trop 165:155–160, afflicted by the burden of infectious CNS disease. The 2017 data in this study provide the neurosurgical community 16. 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176. Sheybani F, Arabikhan HR, Naderi HR: Herpes simplex 194. Varma A, Gaur KJ: The clinical spectrum of neurocysticer- encephalitis (HSE) and its outcome in the patients who were cosis in the Uttaranchal region. J Assoc Physicians India admitted to a tertiary care hospital in Mashhad, Iran, over a 50:1398–1400, 2002 10-year period. J Clin Diagn Res 7:1626–1628, 2013 195. Villarán MV, Montano SM, Gonzalvez G, Moyano LM, 177. Shrestha SR, Awale P, Neupane S, Adhikari N, Yadav BK: Chero JC, Rodriguez S, et al: Epilepsy and neurocysticer- Japanese encephalitis in children admitted at Patan Hospital. cosis: an incidence study in a Peruvian rural population. J Nepal Paediatr Soc 29:17–21, 2009 Neuroepidemiology 33:25–31, 2009 178. Sigurdardóttir B, Björnsson OM, Jónsdóttir KE, 196. Wang H, Li C, Wang J, Zhang Z, Zhou Y: Characteristics Erlendsdóttir H, Gudmundsson S: Acute bacterial men- of patients with spinal tuberculosis: seven-year experience ingitis in adults. A 20-year overview. 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Soumaré M, Seydi M, Ndour CT, Fall N, Dieng Y, Sow Disclosures AI, et al: [Epidemiological, clinical, etiological features of The authors report no conflict of interest concerning the materi- neuromeningeal diseases at the Fann Hospital Infectious als or methods used in this study or the findings specified in this Diseases Clinic, Dakar (Senegal).] Med Mal Infect paper. 35:383–389, 2005 (Fr) 185. Srinivas D, Veena Kumari HB, Somanna S, Bhagavatula I, Anandappa CB: The incidence of postoperative meningitis Author Contributions in neurosurgery: an institutional experience. Neurol India Conception and design: Robertson, Lepard, Rattani, Dewan, Park. 59:195–198, 2011 Acquisition of data: Robertson, Lepard, Davis. Analysis and inter- 186. Strauss I, Carmi-Oren N, Hassner A, Shapiro M, Giladi M, pretation of data: Robertson, Lepard, Mekary, Davis, Yunusa, Bat- Lidar Z: Spinal epidural abscess: in search of reasons for an iculon, Rattani, Dewan. Drafting the article: Robertson, Lepard, increased incidence. Isr Med Assoc J 15:493–496, 2013 Davis. Critically revising the article: Robertson, Lepard, Mekary, 187. Sur A, Tsang K, Brown M, Tzerakis N: Management of Davis, Gormley, Baticulon, Mahmud, Misra, Rattani, Dewan, adult spontaneous spondylodiscitis and its rising incidence. Park. Reviewed submitted version of manuscript: all authors. Ann R Coll Surg Engl 97:451–455, 2015 Approved the final version of the manuscript on behalf of all 188. Takayanagui OM, Castro e Silva AA, Santiago RC, authors: Robertson. Statistical analysis: Robertson, Lepard, Mek- Odashima NS, Terra VC, Takayanagui AM: [Compulsory ary, Yunusa. Administrative/technical/material support: Mekary, notification of cysticercosis in Ribeiräo Preto-SP, Brazil.] Gormley, Rattani, Dewan, Park. Study supervision: Robertson, Arq Neuropsiquiatr 54:557–564, 1996 (Portuguese) Lepard, Dewan, Park. Cartography/figures: Baticulon. 189. Townes JM, Hoffmann CJ, Kohn MA: Neurocysticercosis in Oregon, 1995­–2000. Emerg Infect Dis 10:508–510, Supplemental Information 2004 190. Trevisol-Bittencourt PC, da Silva NC, Figueredo R: Online-Only Content [Prevalence of neurocysticercosis among epileptic in- Supplemental material is available with the online version of the patients in the west of Santa Catarina–southern Brazil.] Arq article. Neuropsiquiatr 56:53–58, 1998 (Portuguese) Supplemental Materials. https://thejns.org/doi/suppl/10.3171/ 191. Tseng JH, Tseng MY: Brain abscess in 142 patients: factors 2017.10.JNS17359. influencing outcome and mortality. Surg Neurol 65:557– 562, 2006 Previous Presentations 192. Tsou TP, Lee PI, Lu CY, Chang LY, Huang LM, Chen JM, This work was presented as an abstract at the Congress of Neuro- et al: Microbiology and epidemiology of brain abscess and logical Surgeons Annual Meeting held on October 7–11, 2017, in subdural empyema in a medical center: a 10-year experi- Boston, MA. ence. J Microbiol Immunol Infect 42:405–412, 2009 193. van Well GTJ, Paes BF, Terwee CB, Springer P, Roord JJ, Donald PR, et al: Twenty years of pediatric tuberculous Correspondence meningitis: a retrospective cohort study in the western cape Faith Robertson: Harvard Medical School, Boston, MA. faith_ of South Africa. Pediatrics 123:e1–e8, 2009 [email protected].

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