Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review

Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review Open Forum Infectious Diseases REVIEW ARTICLE Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review 1,a 2,3,a 4 1,4,5 Drew W. Goldberg, Mark W. Tenforde, Hannah K. Mitchell, and Joseph N. Jarvis 1 2 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia; Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle; Department of 4 5 Epidemiology, University of Washington School of Public Health, Seattle; Botswana-UPenn Partnership, Gaborone, Botswana; Department of Clinical Research, Faculty of Infectious Diseases and Tropical Medicine, London School of Hygiene and Tropical Medicine, United Kingdom e hig Th h human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa has markedly changed the epidemiology and presentation of adult meningitis. We conducted a systematic review using PubMed, Embase, Ovid, CENTRAL, and African Index Medicus to identify studies in Africa with data on neurological outcomes in adults aer m ft eningitis. We found 22 articles meeting inclusion criteria. From 4 studies with predominately pneumococcal meningitis, a median of 19% of survivors experienced hearing loss up to 40 days. Two studies of cryptococcal meningitis evaluated 6- to 12-month outcomes; in one, 41% of survivors had global neurocognitive impairment and 20% severe impairment at 1 year, and in a second 30% of survivors had intermediate disability and 10% severe disability at 6 months. A single small study of patients with tuberculosis/HIV found marked disability in 20% (6 of 30) at 9 months. Despite the high burden of meningitis in sub-Saharan Africa, little is known about neurological outcomes of patients with HIV-associated meningitides. Keywords. Africa; HIV; meningitis; neurological complications; neurological sequelae. Meningitis is associated with high morbidity and mortality in and children, and little is known about long-term outcomes of resource-rich and resource-limited settings [1]. The human adult meningitis in Africa. From population-based estimates immunodeficiency virus (HIV) epidemic in sub-Saharan in rural Kenya, meningitis was one of the leading causes of Africa (SSA) led to an increase in incidence of meningitis, disability-adjusted life years lost due to high case-fatality rates especially in adults with advanced HIV disease [2, 3]. Case- and long-term disability in HIV-uninfected survivors [7]. fatality estimates for 3 of the main causes of adult meningitis A clear understanding of long-term disability of adult menin- in SSA—cryptoccoccal, pneumococcal, and tuberculous men- gitis survivors in the context of the high regional burden of ingitis—range from 41% to 70%, and meningitis is the cause of HIV-associated meningitis has important public health and up to 20% of deaths in HIV-infected cohorts [4–6]. In addition economic implications for low- and middle-income countries to the high mortality, ongoing disability from neurological [6, 11]. The aim of this systematic review is to describe our cur - sequelae in survivors further increases the burden of disease rent understanding of neurologic sequelae in adult survivors of due to meningitis [7]. meningitis in Africa. Multiple studies from Africa have reported neurological METHODS sequelae in pediatric survivors of meningitis [8]. Pediatric studies show an increased risk of mortality from bacterial men- Literature Search Strategy ingitis in HIV-infected versus uninfected children and greater We conducted a systematic review of articles published on risk of recurrence, suggesting that these patients are more sus- neurological sequelae of adult meningitis in Africa with no ceptible to poor outcomes [9, 10]. However, the epidemiology lower limit on start date until June 30, 2017. A search strategy and etiology of meningitis differs markedly between adults was developed with 3 components: one identifying articles on “meningitis” or “meningoencephalitis,” a second limiting the search to articles from Africa, and a third identifying articles reporting on neurological sequelae of disease. We searched 5 Received 24 August 2017; editorial decision 1 November 2017; accepted 8 November 2017. Correspondence: M.  W. Tenforde, MD, MPH, University of Washington Medical Center, databases, including PubMed, Embase, Ovid, CENTRAL, and Health Sciences Division 356423, Seattle, WA 98195 (mark.tenforde@gmail.com). a African Index Medicus. The full search strategy is shown in D. W. G. and M. W. T. contributed equally to this work. Table 1. Three reviewers (D. W. G., H. K. M., and M. W. T.) inde- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases pendently screened the databases using these search terms. We Society of America. This is an Open Access article distributed under the terms of the Creative identified relevant supplemental articles through review of ref- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any erence lists of relevant articles (published reviews and included medium, provided the original work is not altered or transformed in any way, and that the work studies) in the primary search. Citations were uploaded into an is properly cited. For commercial re-use, please contact journals.permissions@oup.com EndNote Library and duplicate articles were removed. DOI: 10.1093/ofid/ofx246 Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. PubMed Search Terms Search component 1 [meningitis OR meningoencephalitis] Search component 2 [Africa OR African OR Algeria OR Algerian OR Angola OR Angolan OR Benin OR Beninese OR Beninoise OR Botswana OR Botswanan OR Motswana OR Batswana OR Burkina Faso OR Burkinabe OR Burundi OR Burundian OR Cameroon OR Cameroonian OR cape Verde OR cape Verdean OR cab Verdeans OR central African republic OR central African OR chad OR Chadian OR Comoros OR Comorian OR democratic republic of the Congo OR Congolese OR republic of the Congo OR congo-brazzaville OR cote d’ivoire OR ivory coast OR Ivorian OR Ivoirian OR Djibouti OR Djiboutian OR Egypt OR Egyptian OR equatorial guinea OR equatorial guinean OR Equatoguinean OR Eritrea OR Eritrean OR Ethiopia OR Ethiopian OR Gabon OR Gabonese OR Gambia OR Gambian OR Ghana OR Ghanaian OR guinea OR Guinean OR Guinea- Bissau OR Bissau OR Kenya OR Kenyan OR Lesotho OR Basotho OR Mosotho OR Libya OR Libyan OR Madagascar OR Malagasy OR Malawi OR Malawian OR Mali OR Malian OR Mauritania OR Mauritanian OR Mauritius OR Mauritian OR Mayotte OR Mahuran OR morocco OR Moroccan OR Mozambique OR Mozambican OR Namibia OR Namibian OR Niger OR nigerien OR Nigeria OR Nigerian OR Rwanda OR Rwandan OR Rwandese OR Senegal OR Senegalese OR Seychelles OR Seychellois OR seychelloise OR sierra Leone OR sierra Leonean OR Somalia OR Somali OR south Africa OR south African OR Sudan OR Sudanese OR Swaziland OR Swazi OR Tanzania OR Tanzanian OR Togo OR Togolese OR Tunisia OR Tunisian OR Uganda OR Ugandan OR western Sahara OR western Saharan OR Zambia OR Zambian OR Zimbabwe OR Zimbabwean] Search component 3 [cognitive OR cognition OR neurocognitive OR neurocognition OR complications OR attention OR behavior OR behavioral OR behaviors OR sequelae OR impairment OR retardation OR epilepsy OR disorder OR learning OR memory OR func- tion OR functions OR functional OR dysfunction OR dysfunctional OR dysfunctions OR deficit OR neuropsychological OR psychological OR psychomotor OR motor OR hyperactivity OR disability OR disabilities OR iq OR intelligence OR hearing OR sensorineural OR deaf OR deafness OR “rankin scale”] Citation Screening (Inclusion/Exclusion Criteria) Data Abstraction and Analysis We screened citations against standardized eligibility cri- Study information was entered into Microsoft Excel spread- teria with initial title and abstract search followed by full sheets, and accuracy was verified through consensus from text review of potentially eligible articles. Inclusion criteria all authors. Study year(s), country and clinical setting, study included the following: (1) involving patients ≥12  years of design, meningitis pathogen(s), patient clinical characteris- age; (2) conducted at health centers in Africa; (3) reporting tics (age distribution and HIV status), follow-up period, out- on prevalence or incidence of any neurologic sequelae in comes measured, and outcomes data including both death and patients with meningitis; and (4) using a prospective or ret- neurological sequelae were entered into spreadsheets (Table  2 rospective observational cohort methodology or randomized and Table  3). We categorized outcomes according to common controlled trials. We excluded case studies and case series sequelae, eg, hearing loss, as performed in previous meningitis with less than 20 patients, because of concern for heteroge- reviews [8, 13]. Tables were organized by main causative patho- neity of reported outcomes and high likelihood of publica- gen and further sorted by year of publication. tion of nonrepresentative cases in case reports or case series, No formal meta-analysis was undertaken due to the small as well as published conference abstracts. For studies with number of studies meeting inclusion criteria as well as heter- pediatric and adult outcomes data separately reported, we ogeneity in causative pathogen, follow-up period, and neuro- excluded pediatric patients in our analysis. Adult and pedi- logical sequelae evaluated. Descriptive statistics were used to atric meningitis outcome data were intermixed in several analyze outcomes using percentage, median and interquar- included studies, primarily studies of Neisseria meningitidis tile range, mean and standard deviation, or other descriptive meningitis. Inclusion of patients ≥12 years of age was decided measures as indicated. We did not report pooled neurological as a developmentally meaningful cutoff (following rapid neu- sequelae of individual studies due to significant heterogeneity rodevelopmental change, particularly in the first decade of in types of sequelae evaluated, method of sequelae evaluation life). We included studies reporting outcomes from micro- between studies, and limited number of studies for most major biologically confirmed meningitis or meningitis diagnosed causative pathogens. using molecular methods, and we also included studies with RESULTS cases diagnosed using a combination of microbiological and/ or molecular methods and cerebrospinal fluid (CSF) profiles Literature Search and Citation Screening suggestive of bacterial meningitis (CSF with polymorphonu- The search yielded 6204 original articles for review on June clear cell pleocytosis), as well as N meningitidis diagnosed 30, 2017. The database was deduplicated, and then a primary clinically during meningococcal meningitis epidemics. No screen by article title was executed (Figure  1); 3241 articles language restrictions were placed on the search. Although no were excluded at this point. Most references were screened formal quality criteria were used to determine inclusion or out because they contained data in neonatal and/or pediat- exclusion of articles, we undertook a subjective assessment of ric populations or described case studies or small case series. trial quality based on established guidelines [12]. A secondary screening of full abstracts was then conducted in 2 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 fi Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Articles Included in Review Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Neisseria meningitidis Meningitis Coldiron, 2016 Niger, home visits, Retrospective Of 194 CSF samples with 369 60% (220 of Median 5–14‡ NS Reported standard Single evaluation Paralysis, anosmia, [45] 2015 cohort positive PCR testing, 369) treatment ceftriax- 3.5–9 months after convulsions, identified N meningitis one ×5 days meningitis hearing loss, loss serogroup C (74%), of developmen- serogroup W (19%) tal milestones, Streptococcus pneumo- persistent mental niae (6%), N meningitidis incapacity serogroup unspecified (1%) Jusot, 2013 [46] Niger, health Prospective N meningitidis serogroup W 67 53% (44 of 13‡ NS NS Range 50–141 days Functional symp- facilities from cohort (87%), serogroup A (6%), 83)† toms, hearing 4 of 8 regions, and serogroup C (1%), S loss, motor 2010–2011 pneumoniae (6%) impairment, psy- chological troubles (using Conners’ questionnaire) Seydi, 2002 [20] Senegal, referral Prospective N meningitidis serogroup 70 60% (42 of Median 20 (range NS Chloramphenicol In-hospital Hearing loss hospital, 1999 cohort A (100%) 70) 1–68)‡ 50 mg/kg IM daily in 3 doses ×8 days average (84%); cefo- taxime 50 mg/kg IV daily ×5 days (9%); ceftriaxone 50 mg/ kg IM/IV daily ×5 days (7%) Hodgson, 2001 Ghana, district hos- Prospective N meningitidis serogroup A 505 44% (225 of 24 (15)‡ NS NS Surviving patients eval- Cerebellar disorder, [47] pital, 1999 cohort 505) uated 2 years after cranial nerve outbreak palsy, hydrocepha- lus, motor deficit Heyman, 1998 Zaire (Democratic Retrospective Bacterial meningitis during 45 48% (25 of 13 (standard error of 12% (2 of Penicillin 4 million units In-hospital Clinically obvious [25] Republic of cohort N meningitis epidemic 52)† the mean 1)‡ 17) IV 6 times/day + neurological Congo), refugee (included cases con- chloramphenicol 1 damage eld hospital, firmed by CSF positive for gram 4 times/ 1994 Gram-negative diplococci, day (29 of 37 [78%] culture, or soluble antigen patients with test OR based on clinical records); chloram- picture and turbid CSF) phenicol (6 of 37 [16%]); penicillin (1 of 37) [3%]; cip- rofloxacin (1 of 37 [3%]) 4 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Fekade, 1992 Ethiopia, referral Prospective Bacterial meningitis (CSF 204 64% (179 of Range 15–49; 57% in NS Penicillin-based therapy In-hospital Cranial nerve [48] hospital, 1988 cohort with polymorphonuclear 278)† age group 15–19† (80%); Combination palsy, deafness, cell pleocytosis, low glu- penicillin and chlo- hemiplegia cose, and high protein OR ramphenicol (20%); positive Gram stain OR treatment duration bacterial culture OR clin- 7–10 days ical presentation consist- ent with N meningitis); all presumed N meningitidis (serogroup A) Girgis, 1989 [18] Egypt, referral Prospective N meningitidis (62%), S 429 65% (278 of 14 (9) in group treated NS Ampicillin 160 mg/kg Monthly ×6 months Hearing loss, hospital and US unblinded pneumoniae (25%), 429) with dexametha- IV daily in 4 doses hemiparesis Navy research RCT Haemophilus influenzae sone; 13 (9) in con- + chloramphenicol unit, 1983-NS (13%) trol group‡ 100 mg/ kg IV daily in 4 doses ×8 days ±dexa- methasone 12 mg IV every 12 hours ×3 days Smith, 1988 [49] Gambia, outpa- Prospective Presumed N meningitidis 157 50% (78 of Median 10–14‡ NS Chloramphenicol 3 6–12 months Generalized sequelae tient therapy, cohort serogroup A during 157) grams IM once (irritability/poor 1982–1983 epidemic; 15.3% (25 of cooperation, slow 157) bacteriologically con- response, mental firmed by CSF or blood retardation, severe culture with most cases brain damage), diagnosed clinically coordination impairment, cra- nial nerve palsy, hearing loss, motor deficit, visual loss Habib, 1979 [16] Egypt, referral Prospective N meningitidis (100%) 375 56% (438 of ≥10 years; 73% in age N/A NS Monthly ×6 months Hearing loss hospital and US cohort (≥10 years) 775)† group 10–19‡ Navy research unit, 1966–1973 Streptococcus pneumoniae Meningitis Ajdukiewicz, Malawi, refer- Prospective Bacterial meningitis (CSF 125§ 48% (61 of Median 32 (IQR, 84% (104 of Ceftriaxone 2 grams IV 40 days Hearing loss, neuro- 2011 [22] ral hospital, RCT with >100 white cells/μL 128)† 27–38)† 124) twice daily ×mini- logical disability by 2006–2008 with polymorphonuclear mum 10 days Glasgow Outcome cell predominance or Score cloudy CSF); 41% con- firmed S pneumoniae and 42% overall confirmed bacterial Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Manga, 2008 Senegal, refer- Retrospective S pneumoniae (100%) 73 67% (49 of 44 (19.5) 12% (9 of Ampicillin or amoxicillin In-hospital Deafness, facial [21] ral hospital, cohort 73) 73) 200 mg/kg IV daily in palsy, hemipare- 1995–2004 3 doses; cefotaxime sis, oculomotor 100–200 mg/kg IV paralysis 3 times daily; ceftri- axone 50–75 mg/kg IV daily; gentamicin 3 mg/kg IV daily with a β-lactam; chloram- phenicol 100 mg/ kg IV daily Scarborough, Malawi, refer- Prospective Bacterial meningitis (CSF 465 49% (230 of 32 (11) 90% (389 of Ceftriaxone 2 grams 40 days Blindness, debility, 2007 [23] ral hospital, RCT with >100 white cells/μL 465) 434) IV/IM twice daily hearing loss, 2002–2005 or cloudy CSF); ×10 days ±dexa- intellectual impair- S pneumoniae (56%), methasone 16 mg IV ment, paresis, N meningitidis (4%), twice daily ×4 days seizure disorder other Gram-negative organism (6%), other (1%) Okome- Gabon, referral hos- Retrospective S pneumoniae (65%), N 85 71% (60 of Median 33 (range 18% (15 of Amoxicillin/clavulanate In-hospital Deafness Nkoumou, pital, 1991–1995 cohort meningitidis (29%), 85) 16–60) 85) 12 grams IV daily 1999 [26] Escherichia coli (4%), ×15 days (19%); Pseudomonas aeruginosa cefotaxime 6 grams (2%) IV daily ×10 days (56%); cefotaxime 6 grams IV daily + dexamethasone 0.5 mg IV twice daily ×10 days (25%) Ford, 1994 [27] Swaziland, national Prospective Bacterial meningitis (CSF 24 adults NS ≥15 (no further 12% (3 of Benzyl-penicillin 4 mil- In-hospital Ataxia, confu- report system at cohort with >1000 white cells/ (≥15 years) break-down) 24) with lion units IV every sion, cranial 4 district hospi- mm , >75% polymor- known 4 hours + chloram- nerve palsy, tals, 1991–1992 phonuclear cells, glucose HIV (likely phenicol 25 mg/ deafness, devel- <1.9 mmol/L, and protein signifi- kg IV every 6 hours opmental delay, >1 g/L, or positive Gram cantly ×7–10 days hemiparesis, stain OR bacterial cul- higher) hydrocephalus, ture); in larger cohort of seizure disorder, 85 patients (including confusion children), S pneumoniae (29%), N meningitidis (12%), H influenzae (9%), others (9%) Other/Mixed Bacterial Meningitis 6 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded El-Gindy, 2015 Egypt, fever hospi- Prospective Confirmed bacterial menin- 61 adults 69% (42 of 61% (37 of 61) 16–40, NS NS In-hospital Mini-Mental status [28] tal, 2013–2015 cohort gitis (positive CSF stain (≥16 years 61) 24% (15 of exam (MMSE), and/or culture); including 61) 41–60, 15% (9 Wechsler Memory 26% (16 of 61) tuber- of 61) ≥61 Scale (WMS), culous meningitis; 74% Glasgow Outcome (45 of 61) other bacterial Scale (GOS), cra- meningitis, including nial nerve palsy, S pneumoniae (40%), ischemic brain N meningitidis (20%), insult, seizures, H influenzae (22%), S speech disorders, aureus (13%), E coli (4%) hydrocephalus Hammad, 2011 Egypt, referral Retrospective All gram-negative bacilli; E 95 64% (61 of 13 (6) in cases of pri- NS Ceftriaxone 3 grams In-hospital Cerebral damage, [17] hospital and US cohort coli (25%), Proteus mira- 95) mary meningitis; 32 IV daily ×10 days hearing loss, Navy research bilis (22%), P aeruginosa (8) in cases of sec- + dexamethasone hemiplegia, hydro- unit, 1993–2009 (17%), Salmonella typhi ondary meningitis‡ 0.2 mg/kg IV ×3 days cephalus, optic (17%), Klebsiella pneumo- atrophy, seizure niae (14%), Enterobacter disorder spp (5%) TB Meningitis Marais, 2013 South Africa, Prospective Tuberculous meningitis (both 34 56% (19 of Median 33 (IQR, 100% (34 Antituberculous therapy 2, 4, 6, and 12 weeks, Marked cognitive [33] referral hospital, cohort “definite” cases with CSF 34) 29–44) of 34); given according to 6 months, 9 months impairment by 2009–2010 acid-fast stain positive all anti- national guidelines International HIV and/or culture positive retroviral with prednisone Dementia Scale, AND “probable” cases naive 1.5 mg/kg PO daily × hemiparesis, hear- with clinical, laboratory, 6 weeks then predni- ing loss and radiographic features sone 0.75 mg/ in absence of other kg PO daily × 2 diagnosis) weeks (unless TB-IRIS); antiretrovi- ral therapy initiated at 2 weeks Girgis, 1998 [19] Egypt, referral Prospective Tuberculous meningitis 857 58% (497 of 17 (13)‡ NS (all P-aminosalicylic Eye exam weekly Cerebral atrophy, hospital and US cohort (100% culture-confirmed) 857) patients acid + isoniazid + ×6 months during hos- cranial nerve Navy research who streptomycin; eth- pital stay then monthly palsy, fundus unit, 1976–1996 received ambutol + isoniazid outpatient visits up to changes, hemipa- HIV test- + streptomycin; 2 years resis-paraplegia, ing were ethambutol + isoni- hydrocephalus negative) azid + streptomycin ± dexamethasone; rifampin + isoniazid + streptomycin; all patients treated for 2 years Cryptococcal Meningitis fi Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Montgomery, Uganda, refer- Prospective Cryptococcal meningitis 90 60% (54 of Median 36 (IQR, 100% (90 of Amphotericin B 0.7– Single evaluation Battery of neuro- 2017 [32] ral hospital, RCT (100%) 90) 30–40) 90) 1.0 mg/kg IV daily + 1 month after meningi- psychological 2010–2012 fluconazole 800 mg tis diagnosis tests evaluating PO daily ×2 weeks; 8 domains; calcu- then fluconazole lated quantitative 800 mg PO daily ×3 neurocognitive weeks; then fluco- performance nazole 400 mg PO score (QNPZ-8) daily ×8 weeks; then as mean of indi- fluconazole 200 mg vidual z-scores PO daily; antiretrovi- and compared ral therapy initiated with age- and at 5 weeks; partic- education-ad- ipants randomized justed scores of to early (1–2 weeks HIV-uninfected after diagnosis) or Ugandans; also late (5 weeks after tested Karnofsky, diagnosis) antiretro- International HIV viral therapy Dementia Scale, and Center for Epidemiologic Studies Depression (CES- D) Scale scores Beardsley, 2016 Malawi, Uganda, Prospective Cryptococcal meningitis 226 (exclud- 58% (132 of Median 35 (IQR, 100% (226 Amphotericin B 1.0 mg/ 10 weeks and 6 months Visual acuity at 10 [30] Indonesia, RCT (100%) ing 226) 30–40) of 226) kg IV daily + fluco- weeks, level Laos, Thailand, patients nazole 800 mg PO of disability Indonesia, refer- treated daily ×2 weeks; then at 10 weeks ral hospitals, with fluconazole 800 mg and 6 months 2013–2014 adjunctive PO daily ×8 weeks; (assessed by com- dexameth- then fluconazole bination of modi- asone) 200 mg PO daily; ed Rankin scale antiretroviral therapy and 2 questions initiated at 5 weeks [does the patient require help from anybody for every- day activities, and has the illness left the patient with any other problems?]) 8 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Carlson, 2014 Uganda, refer- Prospective Cryptococcal meningitis 78 62% (48 of 35 (8) 100% (78 of Amphotericin B 0.7– 1, 3, 6, and 12 months Battery of neuro- [29] ral hospital, cohort (100%) 78) 78) 1.0 mg/kg IV daily + psychological 2010–2013 fluconazole 800 mg tests evaluating PO daily ×2 weeks; 8 domains; calcu- then fluconazole lated quantitative 800 mg PO daily ×3 neurocognitive weeks; then fluco- performance nazole 400 mg PO score (QNPZ-8) daily ×8 weeks; then as mean of indi- fluconazole 200 mg vidual z-scores PO daily; antiretrovi- and compared ral therapy initiated with age- and at 5 weeks education-ad- justed scores of HIV-uninfected Ugandans Rothe, 2013 [24] Malawi, refer- Prospective Cryptococcal meningitis 60 55% (33 of Median 32 (IQ,R 100% (60 of Fluconazole 800 mg PO 4 weeks, 10 weeks, 52 Neurological func- ral hospital, cohort (100%) 60) 29–39) 60) ×2 weeks; then flu- weeks tion tested at 2010–2011 conazole 400 mg PO 52 weeks by daily ×6 weeks; then modified Rankin fluconazole 200 mg Scale score and PO daily; antiretrovi- Abbreviated ral therapy initiated Mental Test Score at 4 weeks Abbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IM, intramuscular; IV, intravenous; IQR, interquartile range; N/A, not applicable; NS, not stated; OR, odds ratio; PCR, polymerase chain reaction; PO, per os (oral); RCT, randomized controlled trial; SD, standard deviation; TB-IRIS, tuberculosis-associated immune reconstitution inflammatory syndrome. *Unless otherwise stated. †Included additional patients lost to follow up, not included, or without outcomes data. ‡Included some pediatric patients (<12 years). §Excluded intervention arm receiving glycerol, which was associated with significantly higher mortality and disability. Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 9 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Results Including Death and Neurological Complications From Included Articles Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Neisseria meningitidis meningitis Coldiron, 2016 [45] Single evaluation N meningitidis pri- 17% (64 of 12% (15 of 3% (4 of 126) with any 11% (33 of 305) of surviv- 3.5–9 months mary pathogen 369) of patient 126) of patients confirmed pathogen ing patients, including after identified (94% households any confirmed had persistent mental 15% (19 of 126) with meningitis of CSF samples with home pathogen had incapacity or loss of confirmed N meningit- with positive visits; 12% any hearing milestones idis serogroup C had PCR) (23 of 189) of loss any sequellae reported patients with confirmed N meningitidis serogroup C Jusot, 2013 [46] Range N meningitidis N/A 31% (21 of 12% (8 of 65) walk- Asthenia 37% (24 of 65); 50–141 days (94%) 67) any hearing ing or tonus headache 31% (21 of loss; 10% (7 impairment 67); psychological trou- of 67) severe bles 16%; vertigo 22% hearing loss (15 of 67) Seydi, 2002 [20] In-hospital N meningitidis 3% (3 of 73) 3% (2 of 71) deaf Hodgson, 2001 2 years N meningitidis N/A 6% (32 of 1% (3 of Hydrocephalus 0% (0 of [47] 496) any hear- 505) decreased 505); hyperreflexia of ing loss; 2% (8 motor strength upper limbs 15% (78 of 496) severe of 505) hearing loss Heyman, 1998 In-hospital N meningitidis 13% (6 of 45) Residual neurological dam- [25] age 5% (2 of 39) Fekade, 1992 [48] In-hospital Mostly N 21% (43 of 204) 2% (3 of 2% (4 of Cranial nerve palsy 2% (3 meningitidis 161) deaf 161) hemiplegia of 161) Girgis, 1989 [18] Monthly Majority N menin- 14% (62 of 3% (9 of 1% (3 of 367) hemipa- ×6 months gitidis (62%) 429) [lower 367) severe resis (all in patients case fatality hearing loss with N meningitidis rate in steroid infection) group] Smith, 1988 [49] 6–12 months N meningitidis N/A 23% (23 of 102) any 6% (9 of 155) any 17% (27 of 156) any; 13% (21 of 156) at Coordination impairment visual loss; 6% (6 of sensorineural 3% (5 of 156) moder- least mild motor 11% (17 of 155); cranial 102) moderate-to-se- hearing loss; ate-to-severe defect; 2% (3 nerve palsy 9% (14 vere 4% (6 of of 156) moder- of 155) 155) severe-to- ate-to-severe profound Habib, 1979 [16] Monthly N meningitidis N/A 4% (16 of ×6 months 375) any hear- ing loss; 2% (7 of 375) deaf Streptococcus pneumoniae Meningitis 10 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Continued Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Ajdukiewicz, 2011 40 days S pneumo- 49% (61 of 125); 34% (14 of Persistent vegetative state [22] niae (41% 39% (20 41) deaf 22% (14 of 63) confirmed) of 51) with proven S pneumoniae Manga, 2008 [21] In-hospital S pneumoniae 70% (51 of 73) 4% (1 of 22) deaf 32% (7 of 22) motor Cranial nerve palsy 23% (100%) deficit of extremity (5 of 22) Scarborough, 40 days Majority S pneu- 54% (249 of 3% (7 of 202) blind 34% (66 of 6% (13 of 202) 8% (17 of 202) 1% (2 of 202) Debility 5% (10 of 202) 2007 [23] moniae (56%) 459); 51% 195) any (140 of hearing loss; 272) proven S 12% (24 of pneumoniae 195) severe hearing loss Okome-Nkoumou, In-hospital Majority S pneu- 17% (15 of 85) 3% (2 of 70) hear- 1999 [26] moniae (65%) ing loss Ford, 1994 [27] In-hospital S pneumoniae 62% (15 of 24) Any neurological sequelae (29%) most in 33% (3 of 9) common isolate Other Bacterial Meningitis El-Gindy 2015 [28] In-hospital Mix confirmed 33% (20 of 61); Bacterial meningitis 13% Bacterial meningitis Bacterial meningitis bacterial menin- 31% (5 of (4 of 30) severe impair- 3% (1 of 30) with 23% (7 of 30) cranial gitis pathogens 16) with tuber- ment by MMSE and seizures nerve palsy, 33% and tuberculous culous menin- 30–47% impairment in (10 of 30) ischemic meningitis gitis and 33% WMS domains; tuber- brain insult, 3% (1 (15 of 45) with culous meningitis 27% of 30) speech disor- bacterial (3 of 11) severe impair- der, and 43% (13 of meningitis ment by MMSE and 30) survivors with 18–54% impairment in severe disability by WMS domains GOS; tuberculous meningitis 9% (1 of 11) cranial nerve palsy, 54% (6 of 11) ischemic brain insult, 9% (1 of 11) hydrocephalus, and 45% (5 of 11) survivors with severe disability by GOS score Hammad, 2011 In-hospital Gram-negative 29% (28 of 95) 9% (6 of 67) optic 6% (4 of 67) hear- 7% (5 of 7% (5 of 67) Cerebral damage 1% (1 of [17] bacilli atrophy ing loss 67) hemiplegia 67); hydrocephalus 7% (5 of 67) TB Meningitis Marais, 2013 [33] 2, 4, 6, and Mycobacterium 12% (4 of 34) 3% (1 of 30) hear- 20% (6 of 30) cognitive 7% (2 of 12 weeks, tuberculosis ing loss impairment 30) hemiparesis 6 months, 9 months Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 11 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Continued Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Girgis, 1998 [19] Once weekly M tuberculosis 57% (490 of 857) 5% (20 of Cerebral atrophy 3% (11 ×6 months 367) hemiparesis/ of 367); cranial nerve then monthly hemiplegia palsy 5% (20 of 367); through fundus changes 8% (30 2 years of 367); hydrocephalus 8% (30 of 367) Cryptococcal Meningitis Montgomery, 1 month after HIV Cryptococcus N/A 92% with International Median Karnofsky score 2017 [32] ‡ diagnosis neoformans HIV Dementia Scale 60 (IQR, 50–70); higher score ≤10 (indicative of rates of depression possible HIV-associated than HIV-infected neurocognitive disor- controls without men- der) compared with ingitis (median CES-D 66% of HIV-infected score 23 [IQR, 16–30] controls without men- and 9 [IQR, 5–17], ingitis; mean QNPC-8 respectively) z-score −2.22 (refer- enced against age- and education-adjusted, HIV-negative Ugandan population) Beardsley, 2016 10 weeks and C neoformans 48% (109 of 4% (5 of 127) decreased 36% (46 of 127) survivors [30] 6 months 226) at visual acuity at 10 with intermediate and 6 months weeks 20% (26 of 127) with severe disability at 10 weeks; 30% (34 of 114) with interme- diate and 10% (12 of 114) with severe disabil- ity at 6 months Carlson, 2014 1, 3, 6, and C neoformans 12% (9 of 78)† 89% (69 of 78) with com- Inability to work at [29] ‡ 12 months posite z-score < −1 at 12 months 11% (7 1 month, 59% (41 of of 62) 69) at 3 months, 47% (32 of 68) at 6 months, and 41% (26 of 64) at 12 months Rothe, 2013 [24] 4 weeks, 10 C neoformans 72% (43 of 60) at 0% (0 of 6) tested at 52 weeks, 52 12 months; weeks had significant weeks additional 4 disability by modified patients lost Rankin Scale score and to follow-up Abbreviated Mental Test Score Abbreviations: CSF, cerebrospinal fluid; CES-D, Center for Epidemiologic Studies Depression; GOS, Glasgow Outcome Scale; HIV, human immunodeficiency virus; IQR, interquartile range; MMSE, Mini-Mental Status Exam; N/A, not applicable; PCR, polymearse chain reaction; RCT, randomized controlled trial; TB, tuberculosis; WMS, Wechsler Memory Scale. *Included hemiparesis, hemiplegia, unspecified motor deficit in category. †Overall 6-month mortality in study 38% (67 of 177). ‡Included outcomes of patients from the same prospective RCT. Steptococcus pneumoniae and Other Bacterial Meningitides which a further 943 articles were excluded for not including Five studies including 772 patients reported on neurological data on neurological outcomes. In articles that did not include outcomes with Streptococcus pneumoniae as the single or most abstracts, we reviewed full-text articles. Three additional review commonly confirmed pathogen. Streptococcus pneumoniae was articles were identified, and relevant references from these the only pathogen in 1 study [21], was identified in 65% of cases reviews were included in the final article list [8, 14, 15]. Full in 1 study limited to microbiologically confirmed cases [26], text of the remaining 380 articles was obtained and each article and was isolated in 29%–56% of cases from 3 studies with a large was reviewed. Of these, 22 met  all inclusion criteria and were percentage of cases diagnosed by CSF cellular profile [22, 23, included in the final review. 27]. Treatment differed between studies, and adjunctive dexa- Articles in the Review methasone was used for a subgroup of patients in only 2 studies We identified 22 articles meeting inclusion criteria with 12 [23, 26]. Human immunodeficiency virus prevalence was high African countries represented (Figure  2). In all but 1 study, across studies, between 12% and 90%. Follow-up ranged from patients were treated for meningitis in hospital settings, with in-hospital to 40  days. Males constituted 53% (400 of 751)  of treatment provided at referral centers in 17 studies. The only cases (Table 2). or predominate cause of meningitis was nontuberculous bac- Two prospective RCTs from Malawi of primarily HIV-infected terial in 16 studies, Mycobacterium tuberculosis in 2 studies, and adult patients were high quality with the remaining studies of rel- Cryptococcus in 4 studies. atively poor quality [22, 23]. Reported case-fatality rate ranged Four studies were published at a single referral hospital/US from 17% to 70% (median 54%). In the 2 Malawian prospective Navy research unit in Egypt [16–19] and 2 at a single referral RCTs with mostly HIV-infected adults, mortality ranged from hospital in Senegal [20, 21], both countries with a low HIV prev- 49% to 54% overall and 39% to 51% in cases of proven pneumo- alence. Three studies were published from a single large referral coccal meningitis, all managed with ceftriaxone (±dexametha- hospital in Malawi with predominately HIV-infected patients sone). Hearing loss was reported to aeff ct 3%–34% (median (84%–100% HIV prevalence) [22–24]. Follow-up duration was 19%) of patients in 4 studies, with severe/profound hearing loss variable: 8 of the 22 studies presented only in-hospital neurolog- reported in 4%–34% (median 12%) of patients in 3 studies. Motor ical sequelae of survivors, and follow-up for the remaining 14 deficits were reported at 8%–32% in 2 studies, with no other out- studies ranged from 1 month to 2 years. Twelve articles were pro- come documented in more than a single study (Table 3). spective cohort studies, 5 were retrospective cohort studies, and 5 e 2 M Th alawian studies with predominately HIV-infected were prospective randomized-controlled trials (RCTs) [Table 2]. patients reported high rates of neurological sequelae in survi- Neisseria meningitidis Meningitis vors [22, 23]. In Ajdukiewicz et al [22], 22% (14 of 63) survivors, Neisseria meningitidis was the principle pathogen identified in 9 with or without pneumococcal disease, remained in a persis- bacterial studies with 2718 patients. Neisseria meningitidis was tent vegetative state (Glasgow Outcome Score 2) at 40 days. In the only pathogen isolated from 6 studies. Penicillin or ampi- Scarborough et al [23], 23% (47 of 202) of 40-day survivors and cillin and/or chloramphenicol were used to treat patients in 29% (38 of 130) of those with proven pneumococcal meningitis most studies. Only 1 study [25] gave any information on HIV had 1 or more neurological sequelae (blindness, debility, com- serostatus and reported low prevalence. Follow-up ranged from plete deafness, intellectual impairment, paresis, or recurrent in-hospital to a 2-year follow-up of survivors. Males constituted seizures). 56% (1529 of 2718) of patients (Table 2). One retrospective cohort study from Egypt evaluated neu- Ascertainment of adult outcomes was imperfect because most rological sequelae in 95 patients with microbiologically con- (8 of 9) studies included both adult and pediatric patients with- firmed, Gram-negative, bacillary meningitis [17]. This study out separation by age category. Mortality data were included in included both adults and children and did not include data on 5 studies and ranged from 3% to 21% (median 13%). In men- HIV status. The case-fatality rate was 29% (28 of 95), and the ingitis survivors, hearing loss (8 studies) and motor deficits (5 rate of pooled in-hospital sequelae (cerebral damage, hearing studies) were the most commonly reported neurological seque- loss, hemiplegia, hydrocephalus, optic atrophy, and/or seizure lae. Any hearing loss was found in 2%–31% of patients (median disorder) in survivors was 39% (26 of 67). Six percent (4 of 5%) with severe/profound hearing loss reported in 2%–10% 67) of survivors had hearing loss, 7% (5 of 67) had hemiplegia, of patients (median 3%). Motor deficits were variably defined 7% (5 of 67)  had seizure disorder, and 9% (6 of 67)  had optic and ranged from 1% to 13% (median 2%) in 5 studies with atrophy. Another study from Egypt included patients with a mix moderate-to-severe disability (eg, hemiplegia/hemiparesis) in of microbiologically confirmed bacterial meningitis and tuber - 1%–2% (median 2%) from 3 studies. One study reported 6% culous meningitis [28]. At hospital discharge, 43% (13 of 30) of of patients with moderate-to-severe visual loss and 3% with survivors with bacterial meningitis and 45% (5 of 11)  with moderate-to-severe neurocognitive deficit at evaluation 6 to tuberculous meningitis had severe disability determined by 12 months aer t ft he meningitis episode (Table 3). Glasgow Outcomes Scale score. 12 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Cryptococcal Meningitis RCT reported additional 1-month neurocognitive outcomes Four articles evaluated neurological sequelae of HIV-infected [32]. At 1 month, 92% of survivors had an International HIV adult patients with cryptococcal meningitis [24, 29–31]. One Dementia Scale score ≤10, suggesting possible HIV-associated good-quality study from Uganda reported global neurocogni- neurocognitive disorder. Six-month neurocognitive outcomes tive dysfunction, defined as mean composite score of multi- from another quality large prospective RCT found that 20% domain neurocognitive testing at least 1 standard deviation of survivors had severe disability at 10 weeks and 10% at below that of HIV-uninfected Ugandans (z-score < −1), seri- 6 months, defined as answering yes to the question “Does the ally over 1  year in cryptococcal meningitis survivors who patient require help from anybody for everyday activities?” received amphotericin-based induction therapy. At 1  month, or with a Modified Rankin Scale score of ≥3 (symptoms that 89% (69 of 78) of survivors had impaired neurocognitive func- restrict lifestyle and prevent totally independent living) [30]. tion. This improved to 41% (26 of 64) at 1 year [29]. Meningitis Of note, this study included patients from countries in both survivors had only slightly higher disability compared with Africa (Malawi and Uganda) and Asian countries, but neu- HIV-infected Ugandans without a prior history of neurolog- rocognitive outcomes were not disaggregated by country. We ical infection. The case-fatality rate for patients who lived to also excluded patients receiving experimental dexamethasone 1 month was 12% (9 of 78) at 1 year; 5 of those patients died therapy, which was associated with higher rates of mortal- before a 1-month follow up, and 3 patients died before the ity and other adverse outcomes and is not part of the usual 6-month follow up. A second study from the same prospective treatment. Records identified through Additional records identified primary database search through supplemental sources (n = 6204) (n = 34) Records after duplicates removed (n = 4564) Records excluded based on title review (n = 3241) Records screened (n = 1323) Full-text articles assessed for eligibility (n = 380) Article included in qualitative synthesis (n = 22) Bacterial meningitis Tuberculosis Crytococcal articles meningitis articles meningitis articles (n = 16) (n = 2) (n = 4) Figure 1. Diagram of literature search. Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 13 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Egypt: Niger: n = 5 n = 2 N/A <1% 1-5% Senegal: Ethiopia: n = 2 n = 1 5-10% >10% Gambia: n = 1 Uganda: n = 3 Ghana: Malawi: n = 1 n = 4 Gabon: n = 1 DRC*: Swaziland: n = 1 n = 1 South Africa: *DRC: Democratic republic n = 1 of Congo Figure 2. Origin of studies included in review and estimated human immunodeficiency virus prevalence. Tuberculosis Meningitis DISCUSSION We included 2 articles with 891 patients with sequelae data In our systematic review of neurological sequelae of adult men- for tuberculosis meningitis. One high-quality but small study ingitis in Africa, we identified 22 articles with neurological with 34 antiretroviral therapy (ART)-naive HIV-infected adults sequelae outcome data in meningitis survivors. This included with tuberculous meningitis (confirmed or suspected) evalu- 12 studies in counties with high HIV prevalence. These studies, ated patients for tuberculosis-associated immune reconstitu- published over a more than 35-year period, provide limited data tion inflammatory syndrome (TB-IRIS) after ART initiation. showing high rates of postmeningitis disability in adult men- The case-fatality rate was 12% (4 of 34)  at 9  months, with all ingitis survivors from resource-limited settings, particularly deaths occurring in patients with TB-IRIS at time points of 33, in those with HIV coinfection. More importantly, they reveal 53, 60, and 118 days after tuberculous meningitis diagnosis. Of the paucity of high-quality data regarding the frequency and 9-month survivors, 20% (6 of 30) had marked disability: 20% (6 spectrum of neurological sequelae after adult meningitis from of 30) cognitive impairment (5 of 6 marked impairment defined prospective studies, and they provide insight into gaps in our as HIV dementia scale score <10), 7% (2 of 30) hemiparesis, and current understanding of long-term disability of adult meningi- 3% (1 of 30) hearing loss [33]. A second study from a referral tis survivors. Accurate data regarding the long-term outcomes hospital in Egypt reported outcomes in a large cohort of patients in adult meningitis survivors are essential for accurate estimates treated for tuberculous meningitis over 2 decades (1976–1996) of disease burden and, given the frequency of adult meningitis [19]. This study included adults and children together, and in Africa, have broad public health and economic implications. no patients were known to be HIV-infected. Patients received Our review highlights that little is known about long-term 3-drug antituberculous therapy for 2  years, during which neurological sequelae in survivors of HIV-associated crypto- period they were serially assessed for neurological sequelae. In coccal meningitis and tuberculous meningitis, 2 of the principle total, 57% (490 of 857) of patients died and 30% (111 of 367) of causes of adult meningitis in sub-Saharan Africa. Two articles patients survived with severe neurological sequelae (including included Ugandan patients from a single prospective RCT cranial nerve palsy 5% [20 of 367], hemiparesis-paraplegia 5% [29, 32]. As in prior studies in the region, acute mortality was [20 of 367], and hydrocephalus 8% [30 of 367]). high at 38% by 26 weeks of follow up [4, 34–38]. These studies 14 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 found significant impairment in the early weeks aer in ft cident HIV recognition and initiation of ART coupled with timely and cryptococcal meningitis, with Montgomery et al [32] reporting appropriate antibiotic therapy [41]. 92% of survivors with an International AIDS Dementia Scale Our review has several important limitations. First, case score suggestive of neurocognitive impairment, compared with definitions, outcome measures, and means of assessment were 66% of HIV-infected controls without meningitis. With longer highly variable between studies. A lack of validated neurocog- follow-up, Carlson et  al [29] reported persistent neurocogni- nitive and limited neurological function assessments created tive deficits in approximately half of survivors at 1  year. The very heterogeneous data and prevented formal meta-analy- relationship between this long-term neurocognitive impair- sis. Second, follow-up periods differed considerably with only ment and cryptococcal meningitis remains unclear. Although approximately half of studies reporting outcomes aer h ft ospital cryptococcal meningitis survivors also showed worse neuro- discharge to characterize clinical evolution of disease. Third, cognitive function compared with HIV-infected Ugandans, because there were few studies evaluating outcomes in crypto- these differences were small by 1 year of follow-up, and the con- coccal and tuberculous meningitis, no firm conclusions could trol patients generally had less advanced HIV disease (mostly be drawn about neurological outcomes in survivors but rather stage II and III) [29]. Neurocognitive deficits may have been emphasizes the need for future studies, especially prospective a consequence of meningitis and/or other contributing fac- cohort studies, to include multidomain measures of neuro- tors, such as HIV-associated neurocognitive disorder [39, 40]. logical outcomes of disease. Finally, for most studies involving e c Th hoice of comparator also limits inferential reasoning and meningococcal meningitis, neurological sequelae of pediatric could be strengthened in this and other studies evaluating neu- and adult cases were not reported separately, which limited rocognitive domains with alternative comparator groups, such our ability to make firm conclusions about adult outcomes. In as HIV-infected populations started early on ART. A  second this mixed population, however, death and disability was sig- multicountry prospective RCT conducted in African and Asian nificantly lower than in cases of pneumococcal meningitis, as countries found that 20% and 10% of survivors reported requir- reported elsewhere [14]. ing help with everyday activities at 10 weeks and 6  months, respectively [30]. Taken together, these data suggest signifi- CONCLUSIONS cant impairment early aer ft incident cryptococcal meningitis, In conclusion, although settings with high HIV prevalence in a period during which adherence to ART and continuation of Africa have both a high incidence of meningitis and early mor- uco fl nazole maintenance therapy are critical to prevent crypto- tality, long-term sequelae in adult survivors remains poorly coccal meningitis relapse and for overall survival. characterized. Limited data suggest high rates of neurological dis- Five studies described neurological sequelae in adult menin- ability associated with HIV-related pneumococcal and TB men- gitis with S pneumoniae, the most common cause of bacterial ingitis. Little is known about neurological sequelae in survivors meningitis in HIV-infected adults, as the predominate patho- of HIV-associated cryptococcal meningitis, although studies sug- gen [2, 41]. Two of these studies [22, 23], both from Malawi, gest extremely high prevalence of neurocognitive and functional consisted largely of HIV-infected adults and found approxi- impairment in the early weeks after incident disease. Furthermore, mately half of patients died of meningitis with one quarter of long-term multidomain testing of neurological outcomes for sur- survivors left with severe disability, such as with persistent veg- vivors of HIV-associated cryptococcal meningitis and TB menin- etative states or hemiparesis. These adverse outcomes are sig- gitis is warranted. Tools need to be chosen carefully and consider nificantly higher than rates of death and disability reported in challenges with repeat testing, such as risk of learner bias. resource-rich countries with low HIV prevalence, but they are er Th e is a need for improved understanding of neurological more reflective of African pediatric populations [8, 14]. es Th e sequelae of adult meningitis in Africa. Pneumococcal meningi- data also likely underestimated the impact of pneumococcal tis in the setting of high HIV prevalence confers a high risk of meningitis in HIV-infected African cohorts because patients both death and severe neurological sequelae in survivors. Little were enrolled in controlled clinical trials at a large referral is published on sequelae from HIV-associated cryptococcal or hospital and given highly effective antibiotic therapy with cef- tuberculous meningitis, highlighting an urgent need to more triaxone. Because follow up was limited to 40  days, they may accurately define outcomes of survivors in future studies. also have underestimated delayed outcomes such as epilepsy [42]. Unfortunately, in Africa, pneumococcal vaccination has Acknowledgments demonstrated mixed efficacy for reducing invasive pneumococ- Financial suppport. This work was funded by University of Pennsylvania Center for AIDS Research Grant P30 AI 045008 (to J. N. J.). cal disease, and dexamethasone therapy has not been associated Potential conifl cts of interest. All authors: No reported conflicts of with lower mortality or neurological sequelae in HIV-infected interest. All authors have submitted the ICMJE Form for Disclosure of adults [23, 43, 44]. The best method for reduction in risk of Potential Conflicts of Interest Conflicts that the editors consider relevant to incident disease and associated neurological sequelae is early the content of the manuscript have been disclosed. 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Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review

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Open Forum Infectious Diseases REVIEW ARTICLE Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review 1,a 2,3,a 4 1,4,5 Drew W. Goldberg, Mark W. Tenforde, Hannah K. Mitchell, and Joseph N. Jarvis 1 2 3 Perelman School of Medicine, University of Pennsylvania, Philadelphia; Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle; Department of 4 5 Epidemiology, University of Washington School of Public Health, Seattle; Botswana-UPenn Partnership, Gaborone, Botswana; Department of Clinical Research, Faculty of Infectious Diseases and Tropical Medicine, London School of Hygiene and Tropical Medicine, United Kingdom e hig Th h human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa has markedly changed the epidemiology and presentation of adult meningitis. We conducted a systematic review using PubMed, Embase, Ovid, CENTRAL, and African Index Medicus to identify studies in Africa with data on neurological outcomes in adults aer m ft eningitis. We found 22 articles meeting inclusion criteria. From 4 studies with predominately pneumococcal meningitis, a median of 19% of survivors experienced hearing loss up to 40 days. Two studies of cryptococcal meningitis evaluated 6- to 12-month outcomes; in one, 41% of survivors had global neurocognitive impairment and 20% severe impairment at 1 year, and in a second 30% of survivors had intermediate disability and 10% severe disability at 6 months. A single small study of patients with tuberculosis/HIV found marked disability in 20% (6 of 30) at 9 months. Despite the high burden of meningitis in sub-Saharan Africa, little is known about neurological outcomes of patients with HIV-associated meningitides. Keywords. Africa; HIV; meningitis; neurological complications; neurological sequelae. Meningitis is associated with high morbidity and mortality in and children, and little is known about long-term outcomes of resource-rich and resource-limited settings [1]. The human adult meningitis in Africa. From population-based estimates immunodeficiency virus (HIV) epidemic in sub-Saharan in rural Kenya, meningitis was one of the leading causes of Africa (SSA) led to an increase in incidence of meningitis, disability-adjusted life years lost due to high case-fatality rates especially in adults with advanced HIV disease [2, 3]. Case- and long-term disability in HIV-uninfected survivors [7]. fatality estimates for 3 of the main causes of adult meningitis A clear understanding of long-term disability of adult menin- in SSA—cryptoccoccal, pneumococcal, and tuberculous men- gitis survivors in the context of the high regional burden of ingitis—range from 41% to 70%, and meningitis is the cause of HIV-associated meningitis has important public health and up to 20% of deaths in HIV-infected cohorts [4–6]. In addition economic implications for low- and middle-income countries to the high mortality, ongoing disability from neurological [6, 11]. The aim of this systematic review is to describe our cur - sequelae in survivors further increases the burden of disease rent understanding of neurologic sequelae in adult survivors of due to meningitis [7]. meningitis in Africa. Multiple studies from Africa have reported neurological METHODS sequelae in pediatric survivors of meningitis [8]. Pediatric studies show an increased risk of mortality from bacterial men- Literature Search Strategy ingitis in HIV-infected versus uninfected children and greater We conducted a systematic review of articles published on risk of recurrence, suggesting that these patients are more sus- neurological sequelae of adult meningitis in Africa with no ceptible to poor outcomes [9, 10]. However, the epidemiology lower limit on start date until June 30, 2017. A search strategy and etiology of meningitis differs markedly between adults was developed with 3 components: one identifying articles on “meningitis” or “meningoencephalitis,” a second limiting the search to articles from Africa, and a third identifying articles reporting on neurological sequelae of disease. We searched 5 Received 24 August 2017; editorial decision 1 November 2017; accepted 8 November 2017. Correspondence: M.  W. Tenforde, MD, MPH, University of Washington Medical Center, databases, including PubMed, Embase, Ovid, CENTRAL, and Health Sciences Division 356423, Seattle, WA 98195 (mark.tenforde@gmail.com). a African Index Medicus. The full search strategy is shown in D. W. G. and M. W. T. contributed equally to this work. Table 1. Three reviewers (D. W. G., H. K. M., and M. W. T.) inde- Open Forum Infectious Diseases © The Author(s) 2017. Published by Oxford University Press on behalf of Infectious Diseases pendently screened the databases using these search terms. We Society of America. This is an Open Access article distributed under the terms of the Creative identified relevant supplemental articles through review of ref- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any erence lists of relevant articles (published reviews and included medium, provided the original work is not altered or transformed in any way, and that the work studies) in the primary search. Citations were uploaded into an is properly cited. For commercial re-use, please contact journals.permissions@oup.com EndNote Library and duplicate articles were removed. DOI: 10.1093/ofid/ofx246 Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 1. PubMed Search Terms Search component 1 [meningitis OR meningoencephalitis] Search component 2 [Africa OR African OR Algeria OR Algerian OR Angola OR Angolan OR Benin OR Beninese OR Beninoise OR Botswana OR Botswanan OR Motswana OR Batswana OR Burkina Faso OR Burkinabe OR Burundi OR Burundian OR Cameroon OR Cameroonian OR cape Verde OR cape Verdean OR cab Verdeans OR central African republic OR central African OR chad OR Chadian OR Comoros OR Comorian OR democratic republic of the Congo OR Congolese OR republic of the Congo OR congo-brazzaville OR cote d’ivoire OR ivory coast OR Ivorian OR Ivoirian OR Djibouti OR Djiboutian OR Egypt OR Egyptian OR equatorial guinea OR equatorial guinean OR Equatoguinean OR Eritrea OR Eritrean OR Ethiopia OR Ethiopian OR Gabon OR Gabonese OR Gambia OR Gambian OR Ghana OR Ghanaian OR guinea OR Guinean OR Guinea- Bissau OR Bissau OR Kenya OR Kenyan OR Lesotho OR Basotho OR Mosotho OR Libya OR Libyan OR Madagascar OR Malagasy OR Malawi OR Malawian OR Mali OR Malian OR Mauritania OR Mauritanian OR Mauritius OR Mauritian OR Mayotte OR Mahuran OR morocco OR Moroccan OR Mozambique OR Mozambican OR Namibia OR Namibian OR Niger OR nigerien OR Nigeria OR Nigerian OR Rwanda OR Rwandan OR Rwandese OR Senegal OR Senegalese OR Seychelles OR Seychellois OR seychelloise OR sierra Leone OR sierra Leonean OR Somalia OR Somali OR south Africa OR south African OR Sudan OR Sudanese OR Swaziland OR Swazi OR Tanzania OR Tanzanian OR Togo OR Togolese OR Tunisia OR Tunisian OR Uganda OR Ugandan OR western Sahara OR western Saharan OR Zambia OR Zambian OR Zimbabwe OR Zimbabwean] Search component 3 [cognitive OR cognition OR neurocognitive OR neurocognition OR complications OR attention OR behavior OR behavioral OR behaviors OR sequelae OR impairment OR retardation OR epilepsy OR disorder OR learning OR memory OR func- tion OR functions OR functional OR dysfunction OR dysfunctional OR dysfunctions OR deficit OR neuropsychological OR psychological OR psychomotor OR motor OR hyperactivity OR disability OR disabilities OR iq OR intelligence OR hearing OR sensorineural OR deaf OR deafness OR “rankin scale”] Citation Screening (Inclusion/Exclusion Criteria) Data Abstraction and Analysis We screened citations against standardized eligibility cri- Study information was entered into Microsoft Excel spread- teria with initial title and abstract search followed by full sheets, and accuracy was verified through consensus from text review of potentially eligible articles. Inclusion criteria all authors. Study year(s), country and clinical setting, study included the following: (1) involving patients ≥12  years of design, meningitis pathogen(s), patient clinical characteris- age; (2) conducted at health centers in Africa; (3) reporting tics (age distribution and HIV status), follow-up period, out- on prevalence or incidence of any neurologic sequelae in comes measured, and outcomes data including both death and patients with meningitis; and (4) using a prospective or ret- neurological sequelae were entered into spreadsheets (Table  2 rospective observational cohort methodology or randomized and Table  3). We categorized outcomes according to common controlled trials. We excluded case studies and case series sequelae, eg, hearing loss, as performed in previous meningitis with less than 20 patients, because of concern for heteroge- reviews [8, 13]. Tables were organized by main causative patho- neity of reported outcomes and high likelihood of publica- gen and further sorted by year of publication. tion of nonrepresentative cases in case reports or case series, No formal meta-analysis was undertaken due to the small as well as published conference abstracts. For studies with number of studies meeting inclusion criteria as well as heter- pediatric and adult outcomes data separately reported, we ogeneity in causative pathogen, follow-up period, and neuro- excluded pediatric patients in our analysis. Adult and pedi- logical sequelae evaluated. Descriptive statistics were used to atric meningitis outcome data were intermixed in several analyze outcomes using percentage, median and interquar- included studies, primarily studies of Neisseria meningitidis tile range, mean and standard deviation, or other descriptive meningitis. Inclusion of patients ≥12 years of age was decided measures as indicated. We did not report pooled neurological as a developmentally meaningful cutoff (following rapid neu- sequelae of individual studies due to significant heterogeneity rodevelopmental change, particularly in the first decade of in types of sequelae evaluated, method of sequelae evaluation life). We included studies reporting outcomes from micro- between studies, and limited number of studies for most major biologically confirmed meningitis or meningitis diagnosed causative pathogens. using molecular methods, and we also included studies with RESULTS cases diagnosed using a combination of microbiological and/ or molecular methods and cerebrospinal fluid (CSF) profiles Literature Search and Citation Screening suggestive of bacterial meningitis (CSF with polymorphonu- The search yielded 6204 original articles for review on June clear cell pleocytosis), as well as N meningitidis diagnosed 30, 2017. The database was deduplicated, and then a primary clinically during meningococcal meningitis epidemics. No screen by article title was executed (Figure  1); 3241 articles language restrictions were placed on the search. Although no were excluded at this point. Most references were screened formal quality criteria were used to determine inclusion or out because they contained data in neonatal and/or pediat- exclusion of articles, we undertook a subjective assessment of ric populations or described case studies or small case series. trial quality based on established guidelines [12]. A secondary screening of full abstracts was then conducted in 2 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 fi Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Articles Included in Review Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Neisseria meningitidis Meningitis Coldiron, 2016 Niger, home visits, Retrospective Of 194 CSF samples with 369 60% (220 of Median 5–14‡ NS Reported standard Single evaluation Paralysis, anosmia, [45] 2015 cohort positive PCR testing, 369) treatment ceftriax- 3.5–9 months after convulsions, identified N meningitis one ×5 days meningitis hearing loss, loss serogroup C (74%), of developmen- serogroup W (19%) tal milestones, Streptococcus pneumo- persistent mental niae (6%), N meningitidis incapacity serogroup unspecified (1%) Jusot, 2013 [46] Niger, health Prospective N meningitidis serogroup W 67 53% (44 of 13‡ NS NS Range 50–141 days Functional symp- facilities from cohort (87%), serogroup A (6%), 83)† toms, hearing 4 of 8 regions, and serogroup C (1%), S loss, motor 2010–2011 pneumoniae (6%) impairment, psy- chological troubles (using Conners’ questionnaire) Seydi, 2002 [20] Senegal, referral Prospective N meningitidis serogroup 70 60% (42 of Median 20 (range NS Chloramphenicol In-hospital Hearing loss hospital, 1999 cohort A (100%) 70) 1–68)‡ 50 mg/kg IM daily in 3 doses ×8 days average (84%); cefo- taxime 50 mg/kg IV daily ×5 days (9%); ceftriaxone 50 mg/ kg IM/IV daily ×5 days (7%) Hodgson, 2001 Ghana, district hos- Prospective N meningitidis serogroup A 505 44% (225 of 24 (15)‡ NS NS Surviving patients eval- Cerebellar disorder, [47] pital, 1999 cohort 505) uated 2 years after cranial nerve outbreak palsy, hydrocepha- lus, motor deficit Heyman, 1998 Zaire (Democratic Retrospective Bacterial meningitis during 45 48% (25 of 13 (standard error of 12% (2 of Penicillin 4 million units In-hospital Clinically obvious [25] Republic of cohort N meningitis epidemic 52)† the mean 1)‡ 17) IV 6 times/day + neurological Congo), refugee (included cases con- chloramphenicol 1 damage eld hospital, firmed by CSF positive for gram 4 times/ 1994 Gram-negative diplococci, day (29 of 37 [78%] culture, or soluble antigen patients with test OR based on clinical records); chloram- picture and turbid CSF) phenicol (6 of 37 [16%]); penicillin (1 of 37) [3%]; cip- rofloxacin (1 of 37 [3%]) 4 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Fekade, 1992 Ethiopia, referral Prospective Bacterial meningitis (CSF 204 64% (179 of Range 15–49; 57% in NS Penicillin-based therapy In-hospital Cranial nerve [48] hospital, 1988 cohort with polymorphonuclear 278)† age group 15–19† (80%); Combination palsy, deafness, cell pleocytosis, low glu- penicillin and chlo- hemiplegia cose, and high protein OR ramphenicol (20%); positive Gram stain OR treatment duration bacterial culture OR clin- 7–10 days ical presentation consist- ent with N meningitis); all presumed N meningitidis (serogroup A) Girgis, 1989 [18] Egypt, referral Prospective N meningitidis (62%), S 429 65% (278 of 14 (9) in group treated NS Ampicillin 160 mg/kg Monthly ×6 months Hearing loss, hospital and US unblinded pneumoniae (25%), 429) with dexametha- IV daily in 4 doses hemiparesis Navy research RCT Haemophilus influenzae sone; 13 (9) in con- + chloramphenicol unit, 1983-NS (13%) trol group‡ 100 mg/ kg IV daily in 4 doses ×8 days ±dexa- methasone 12 mg IV every 12 hours ×3 days Smith, 1988 [49] Gambia, outpa- Prospective Presumed N meningitidis 157 50% (78 of Median 10–14‡ NS Chloramphenicol 3 6–12 months Generalized sequelae tient therapy, cohort serogroup A during 157) grams IM once (irritability/poor 1982–1983 epidemic; 15.3% (25 of cooperation, slow 157) bacteriologically con- response, mental firmed by CSF or blood retardation, severe culture with most cases brain damage), diagnosed clinically coordination impairment, cra- nial nerve palsy, hearing loss, motor deficit, visual loss Habib, 1979 [16] Egypt, referral Prospective N meningitidis (100%) 375 56% (438 of ≥10 years; 73% in age N/A NS Monthly ×6 months Hearing loss hospital and US cohort (≥10 years) 775)† group 10–19‡ Navy research unit, 1966–1973 Streptococcus pneumoniae Meningitis Ajdukiewicz, Malawi, refer- Prospective Bacterial meningitis (CSF 125§ 48% (61 of Median 32 (IQR, 84% (104 of Ceftriaxone 2 grams IV 40 days Hearing loss, neuro- 2011 [22] ral hospital, RCT with >100 white cells/μL 128)† 27–38)† 124) twice daily ×mini- logical disability by 2006–2008 with polymorphonuclear mum 10 days Glasgow Outcome cell predominance or Score cloudy CSF); 41% con- firmed S pneumoniae and 42% overall confirmed bacterial Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Manga, 2008 Senegal, refer- Retrospective S pneumoniae (100%) 73 67% (49 of 44 (19.5) 12% (9 of Ampicillin or amoxicillin In-hospital Deafness, facial [21] ral hospital, cohort 73) 73) 200 mg/kg IV daily in palsy, hemipare- 1995–2004 3 doses; cefotaxime sis, oculomotor 100–200 mg/kg IV paralysis 3 times daily; ceftri- axone 50–75 mg/kg IV daily; gentamicin 3 mg/kg IV daily with a β-lactam; chloram- phenicol 100 mg/ kg IV daily Scarborough, Malawi, refer- Prospective Bacterial meningitis (CSF 465 49% (230 of 32 (11) 90% (389 of Ceftriaxone 2 grams 40 days Blindness, debility, 2007 [23] ral hospital, RCT with >100 white cells/μL 465) 434) IV/IM twice daily hearing loss, 2002–2005 or cloudy CSF); ×10 days ±dexa- intellectual impair- S pneumoniae (56%), methasone 16 mg IV ment, paresis, N meningitidis (4%), twice daily ×4 days seizure disorder other Gram-negative organism (6%), other (1%) Okome- Gabon, referral hos- Retrospective S pneumoniae (65%), N 85 71% (60 of Median 33 (range 18% (15 of Amoxicillin/clavulanate In-hospital Deafness Nkoumou, pital, 1991–1995 cohort meningitidis (29%), 85) 16–60) 85) 12 grams IV daily 1999 [26] Escherichia coli (4%), ×15 days (19%); Pseudomonas aeruginosa cefotaxime 6 grams (2%) IV daily ×10 days (56%); cefotaxime 6 grams IV daily + dexamethasone 0.5 mg IV twice daily ×10 days (25%) Ford, 1994 [27] Swaziland, national Prospective Bacterial meningitis (CSF 24 adults NS ≥15 (no further 12% (3 of Benzyl-penicillin 4 mil- In-hospital Ataxia, confu- report system at cohort with >1000 white cells/ (≥15 years) break-down) 24) with lion units IV every sion, cranial 4 district hospi- mm , >75% polymor- known 4 hours + chloram- nerve palsy, tals, 1991–1992 phonuclear cells, glucose HIV (likely phenicol 25 mg/ deafness, devel- <1.9 mmol/L, and protein signifi- kg IV every 6 hours opmental delay, >1 g/L, or positive Gram cantly ×7–10 days hemiparesis, stain OR bacterial cul- higher) hydrocephalus, ture); in larger cohort of seizure disorder, 85 patients (including confusion children), S pneumoniae (29%), N meningitidis (12%), H influenzae (9%), others (9%) Other/Mixed Bacterial Meningitis 6 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded El-Gindy, 2015 Egypt, fever hospi- Prospective Confirmed bacterial menin- 61 adults 69% (42 of 61% (37 of 61) 16–40, NS NS In-hospital Mini-Mental status [28] tal, 2013–2015 cohort gitis (positive CSF stain (≥16 years 61) 24% (15 of exam (MMSE), and/or culture); including 61) 41–60, 15% (9 Wechsler Memory 26% (16 of 61) tuber- of 61) ≥61 Scale (WMS), culous meningitis; 74% Glasgow Outcome (45 of 61) other bacterial Scale (GOS), cra- meningitis, including nial nerve palsy, S pneumoniae (40%), ischemic brain N meningitidis (20%), insult, seizures, H influenzae (22%), S speech disorders, aureus (13%), E coli (4%) hydrocephalus Hammad, 2011 Egypt, referral Retrospective All gram-negative bacilli; E 95 64% (61 of 13 (6) in cases of pri- NS Ceftriaxone 3 grams In-hospital Cerebral damage, [17] hospital and US cohort coli (25%), Proteus mira- 95) mary meningitis; 32 IV daily ×10 days hearing loss, Navy research bilis (22%), P aeruginosa (8) in cases of sec- + dexamethasone hemiplegia, hydro- unit, 1993–2009 (17%), Salmonella typhi ondary meningitis‡ 0.2 mg/kg IV ×3 days cephalus, optic (17%), Klebsiella pneumo- atrophy, seizure niae (14%), Enterobacter disorder spp (5%) TB Meningitis Marais, 2013 South Africa, Prospective Tuberculous meningitis (both 34 56% (19 of Median 33 (IQR, 100% (34 Antituberculous therapy 2, 4, 6, and 12 weeks, Marked cognitive [33] referral hospital, cohort “definite” cases with CSF 34) 29–44) of 34); given according to 6 months, 9 months impairment by 2009–2010 acid-fast stain positive all anti- national guidelines International HIV and/or culture positive retroviral with prednisone Dementia Scale, AND “probable” cases naive 1.5 mg/kg PO daily × hemiparesis, hear- with clinical, laboratory, 6 weeks then predni- ing loss and radiographic features sone 0.75 mg/ in absence of other kg PO daily × 2 diagnosis) weeks (unless TB-IRIS); antiretrovi- ral therapy initiated at 2 weeks Girgis, 1998 [19] Egypt, referral Prospective Tuberculous meningitis 857 58% (497 of 17 (13)‡ NS (all P-aminosalicylic Eye exam weekly Cerebral atrophy, hospital and US cohort (100% culture-confirmed) 857) patients acid + isoniazid + ×6 months during hos- cranial nerve Navy research who streptomycin; eth- pital stay then monthly palsy, fundus unit, 1976–1996 received ambutol + isoniazid outpatient visits up to changes, hemipa- HIV test- + streptomycin; 2 years resis-paraplegia, ing were ethambutol + isoni- hydrocephalus negative) azid + streptomycin ± dexamethasone; rifampin + isoniazid + streptomycin; all patients treated for 2 years Cryptococcal Meningitis fi Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 7 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Montgomery, Uganda, refer- Prospective Cryptococcal meningitis 90 60% (54 of Median 36 (IQR, 100% (90 of Amphotericin B 0.7– Single evaluation Battery of neuro- 2017 [32] ral hospital, RCT (100%) 90) 30–40) 90) 1.0 mg/kg IV daily + 1 month after meningi- psychological 2010–2012 fluconazole 800 mg tis diagnosis tests evaluating PO daily ×2 weeks; 8 domains; calcu- then fluconazole lated quantitative 800 mg PO daily ×3 neurocognitive weeks; then fluco- performance nazole 400 mg PO score (QNPZ-8) daily ×8 weeks; then as mean of indi- fluconazole 200 mg vidual z-scores PO daily; antiretrovi- and compared ral therapy initiated with age- and at 5 weeks; partic- education-ad- ipants randomized justed scores of to early (1–2 weeks HIV-uninfected after diagnosis) or Ugandans; also late (5 weeks after tested Karnofsky, diagnosis) antiretro- International HIV viral therapy Dementia Scale, and Center for Epidemiologic Studies Depression (CES- D) Scale scores Beardsley, 2016 Malawi, Uganda, Prospective Cryptococcal meningitis 226 (exclud- 58% (132 of Median 35 (IQR, 100% (226 Amphotericin B 1.0 mg/ 10 weeks and 6 months Visual acuity at 10 [30] Indonesia, RCT (100%) ing 226) 30–40) of 226) kg IV daily + fluco- weeks, level Laos, Thailand, patients nazole 800 mg PO of disability Indonesia, refer- treated daily ×2 weeks; then at 10 weeks ral hospitals, with fluconazole 800 mg and 6 months 2013–2014 adjunctive PO daily ×8 weeks; (assessed by com- dexameth- then fluconazole bination of modi- asone) 200 mg PO daily; ed Rankin scale antiretroviral therapy and 2 questions initiated at 5 weeks [does the patient require help from anybody for every- day activities, and has the illness left the patient with any other problems?]) 8 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Continued Patient Sex Author, Assessed Distribution, Publication Year Country, Setting, for Sequelae %Male Age in Years, Mean HIV Status, Outcome Measures [Reference] Year(s) Study Type Meningitis Type ±Death (n/N) (SD)* % (n/N) Treatment Regimen Follow-Up Recorded Carlson, 2014 Uganda, refer- Prospective Cryptococcal meningitis 78 62% (48 of 35 (8) 100% (78 of Amphotericin B 0.7– 1, 3, 6, and 12 months Battery of neuro- [29] ral hospital, cohort (100%) 78) 78) 1.0 mg/kg IV daily + psychological 2010–2013 fluconazole 800 mg tests evaluating PO daily ×2 weeks; 8 domains; calcu- then fluconazole lated quantitative 800 mg PO daily ×3 neurocognitive weeks; then fluco- performance nazole 400 mg PO score (QNPZ-8) daily ×8 weeks; then as mean of indi- fluconazole 200 mg vidual z-scores PO daily; antiretrovi- and compared ral therapy initiated with age- and at 5 weeks education-ad- justed scores of HIV-uninfected Ugandans Rothe, 2013 [24] Malawi, refer- Prospective Cryptococcal meningitis 60 55% (33 of Median 32 (IQ,R 100% (60 of Fluconazole 800 mg PO 4 weeks, 10 weeks, 52 Neurological func- ral hospital, cohort (100%) 60) 29–39) 60) ×2 weeks; then flu- weeks tion tested at 2010–2011 conazole 400 mg PO 52 weeks by daily ×6 weeks; then modified Rankin fluconazole 200 mg Scale score and PO daily; antiretrovi- Abbreviated ral therapy initiated Mental Test Score at 4 weeks Abbreviations: CSF, cerebrospinal fluid; HIV, human immunodeficiency virus; IM, intramuscular; IV, intravenous; IQR, interquartile range; N/A, not applicable; NS, not stated; OR, odds ratio; PCR, polymerase chain reaction; PO, per os (oral); RCT, randomized controlled trial; SD, standard deviation; TB-IRIS, tuberculosis-associated immune reconstitution inflammatory syndrome. *Unless otherwise stated. †Included additional patients lost to follow up, not included, or without outcomes data. ‡Included some pediatric patients (<12 years). §Excluded intervention arm receiving glycerol, which was associated with significantly higher mortality and disability. Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 9 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Results Including Death and Neurological Complications From Included Articles Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Neisseria meningitidis meningitis Coldiron, 2016 [45] Single evaluation N meningitidis pri- 17% (64 of 12% (15 of 3% (4 of 126) with any 11% (33 of 305) of surviv- 3.5–9 months mary pathogen 369) of patient 126) of patients confirmed pathogen ing patients, including after identified (94% households any confirmed had persistent mental 15% (19 of 126) with meningitis of CSF samples with home pathogen had incapacity or loss of confirmed N meningit- with positive visits; 12% any hearing milestones idis serogroup C had PCR) (23 of 189) of loss any sequellae reported patients with confirmed N meningitidis serogroup C Jusot, 2013 [46] Range N meningitidis N/A 31% (21 of 12% (8 of 65) walk- Asthenia 37% (24 of 65); 50–141 days (94%) 67) any hearing ing or tonus headache 31% (21 of loss; 10% (7 impairment 67); psychological trou- of 67) severe bles 16%; vertigo 22% hearing loss (15 of 67) Seydi, 2002 [20] In-hospital N meningitidis 3% (3 of 73) 3% (2 of 71) deaf Hodgson, 2001 2 years N meningitidis N/A 6% (32 of 1% (3 of Hydrocephalus 0% (0 of [47] 496) any hear- 505) decreased 505); hyperreflexia of ing loss; 2% (8 motor strength upper limbs 15% (78 of 496) severe of 505) hearing loss Heyman, 1998 In-hospital N meningitidis 13% (6 of 45) Residual neurological dam- [25] age 5% (2 of 39) Fekade, 1992 [48] In-hospital Mostly N 21% (43 of 204) 2% (3 of 2% (4 of Cranial nerve palsy 2% (3 meningitidis 161) deaf 161) hemiplegia of 161) Girgis, 1989 [18] Monthly Majority N menin- 14% (62 of 3% (9 of 1% (3 of 367) hemipa- ×6 months gitidis (62%) 429) [lower 367) severe resis (all in patients case fatality hearing loss with N meningitidis rate in steroid infection) group] Smith, 1988 [49] 6–12 months N meningitidis N/A 23% (23 of 102) any 6% (9 of 155) any 17% (27 of 156) any; 13% (21 of 156) at Coordination impairment visual loss; 6% (6 of sensorineural 3% (5 of 156) moder- least mild motor 11% (17 of 155); cranial 102) moderate-to-se- hearing loss; ate-to-severe defect; 2% (3 nerve palsy 9% (14 vere 4% (6 of of 156) moder- of 155) 155) severe-to- ate-to-severe profound Habib, 1979 [16] Monthly N meningitidis N/A 4% (16 of ×6 months 375) any hear- ing loss; 2% (7 of 375) deaf Streptococcus pneumoniae Meningitis 10 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Continued Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Ajdukiewicz, 2011 40 days S pneumo- 49% (61 of 125); 34% (14 of Persistent vegetative state [22] niae (41% 39% (20 41) deaf 22% (14 of 63) confirmed) of 51) with proven S pneumoniae Manga, 2008 [21] In-hospital S pneumoniae 70% (51 of 73) 4% (1 of 22) deaf 32% (7 of 22) motor Cranial nerve palsy 23% (100%) deficit of extremity (5 of 22) Scarborough, 40 days Majority S pneu- 54% (249 of 3% (7 of 202) blind 34% (66 of 6% (13 of 202) 8% (17 of 202) 1% (2 of 202) Debility 5% (10 of 202) 2007 [23] moniae (56%) 459); 51% 195) any (140 of hearing loss; 272) proven S 12% (24 of pneumoniae 195) severe hearing loss Okome-Nkoumou, In-hospital Majority S pneu- 17% (15 of 85) 3% (2 of 70) hear- 1999 [26] moniae (65%) ing loss Ford, 1994 [27] In-hospital S pneumoniae 62% (15 of 24) Any neurological sequelae (29%) most in 33% (3 of 9) common isolate Other Bacterial Meningitis El-Gindy 2015 [28] In-hospital Mix confirmed 33% (20 of 61); Bacterial meningitis 13% Bacterial meningitis Bacterial meningitis bacterial menin- 31% (5 of (4 of 30) severe impair- 3% (1 of 30) with 23% (7 of 30) cranial gitis pathogens 16) with tuber- ment by MMSE and seizures nerve palsy, 33% and tuberculous culous menin- 30–47% impairment in (10 of 30) ischemic meningitis gitis and 33% WMS domains; tuber- brain insult, 3% (1 (15 of 45) with culous meningitis 27% of 30) speech disor- bacterial (3 of 11) severe impair- der, and 43% (13 of meningitis ment by MMSE and 30) survivors with 18–54% impairment in severe disability by WMS domains GOS; tuberculous meningitis 9% (1 of 11) cranial nerve palsy, 54% (6 of 11) ischemic brain insult, 9% (1 of 11) hydrocephalus, and 45% (5 of 11) survivors with severe disability by GOS score Hammad, 2011 In-hospital Gram-negative 29% (28 of 95) 9% (6 of 67) optic 6% (4 of 67) hear- 7% (5 of 7% (5 of 67) Cerebral damage 1% (1 of [17] bacilli atrophy ing loss 67) hemiplegia 67); hydrocephalus 7% (5 of 67) TB Meningitis Marais, 2013 [33] 2, 4, 6, and Mycobacterium 12% (4 of 34) 3% (1 of 30) hear- 20% (6 of 30) cognitive 7% (2 of 12 weeks, tuberculosis ing loss impairment 30) hemiparesis 6 months, 9 months Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 11 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 3. Continued Author, Publication Pathogen(s) %Hearing Deficit %Neurocognitive %Seizure Disorder Year [Reference] Follow-Up Period Studied %Died (n/N) %Visual Deficit (n/N) (n/N) Dysfunction (n/N) %Motor Deficit (n/N)* (n/N) %Other Outcomes (n/N) Girgis, 1998 [19] Once weekly M tuberculosis 57% (490 of 857) 5% (20 of Cerebral atrophy 3% (11 ×6 months 367) hemiparesis/ of 367); cranial nerve then monthly hemiplegia palsy 5% (20 of 367); through fundus changes 8% (30 2 years of 367); hydrocephalus 8% (30 of 367) Cryptococcal Meningitis Montgomery, 1 month after HIV Cryptococcus N/A 92% with International Median Karnofsky score 2017 [32] ‡ diagnosis neoformans HIV Dementia Scale 60 (IQR, 50–70); higher score ≤10 (indicative of rates of depression possible HIV-associated than HIV-infected neurocognitive disor- controls without men- der) compared with ingitis (median CES-D 66% of HIV-infected score 23 [IQR, 16–30] controls without men- and 9 [IQR, 5–17], ingitis; mean QNPC-8 respectively) z-score −2.22 (refer- enced against age- and education-adjusted, HIV-negative Ugandan population) Beardsley, 2016 10 weeks and C neoformans 48% (109 of 4% (5 of 127) decreased 36% (46 of 127) survivors [30] 6 months 226) at visual acuity at 10 with intermediate and 6 months weeks 20% (26 of 127) with severe disability at 10 weeks; 30% (34 of 114) with interme- diate and 10% (12 of 114) with severe disabil- ity at 6 months Carlson, 2014 1, 3, 6, and C neoformans 12% (9 of 78)† 89% (69 of 78) with com- Inability to work at [29] ‡ 12 months posite z-score < −1 at 12 months 11% (7 1 month, 59% (41 of of 62) 69) at 3 months, 47% (32 of 68) at 6 months, and 41% (26 of 64) at 12 months Rothe, 2013 [24] 4 weeks, 10 C neoformans 72% (43 of 60) at 0% (0 of 6) tested at 52 weeks, 52 12 months; weeks had significant weeks additional 4 disability by modified patients lost Rankin Scale score and to follow-up Abbreviated Mental Test Score Abbreviations: CSF, cerebrospinal fluid; CES-D, Center for Epidemiologic Studies Depression; GOS, Glasgow Outcome Scale; HIV, human immunodeficiency virus; IQR, interquartile range; MMSE, Mini-Mental Status Exam; N/A, not applicable; PCR, polymearse chain reaction; RCT, randomized controlled trial; TB, tuberculosis; WMS, Wechsler Memory Scale. *Included hemiparesis, hemiplegia, unspecified motor deficit in category. †Overall 6-month mortality in study 38% (67 of 177). ‡Included outcomes of patients from the same prospective RCT. Steptococcus pneumoniae and Other Bacterial Meningitides which a further 943 articles were excluded for not including Five studies including 772 patients reported on neurological data on neurological outcomes. In articles that did not include outcomes with Streptococcus pneumoniae as the single or most abstracts, we reviewed full-text articles. Three additional review commonly confirmed pathogen. Streptococcus pneumoniae was articles were identified, and relevant references from these the only pathogen in 1 study [21], was identified in 65% of cases reviews were included in the final article list [8, 14, 15]. Full in 1 study limited to microbiologically confirmed cases [26], text of the remaining 380 articles was obtained and each article and was isolated in 29%–56% of cases from 3 studies with a large was reviewed. Of these, 22 met  all inclusion criteria and were percentage of cases diagnosed by CSF cellular profile [22, 23, included in the final review. 27]. Treatment differed between studies, and adjunctive dexa- Articles in the Review methasone was used for a subgroup of patients in only 2 studies We identified 22 articles meeting inclusion criteria with 12 [23, 26]. Human immunodeficiency virus prevalence was high African countries represented (Figure  2). In all but 1 study, across studies, between 12% and 90%. Follow-up ranged from patients were treated for meningitis in hospital settings, with in-hospital to 40  days. Males constituted 53% (400 of 751)  of treatment provided at referral centers in 17 studies. The only cases (Table 2). or predominate cause of meningitis was nontuberculous bac- Two prospective RCTs from Malawi of primarily HIV-infected terial in 16 studies, Mycobacterium tuberculosis in 2 studies, and adult patients were high quality with the remaining studies of rel- Cryptococcus in 4 studies. atively poor quality [22, 23]. Reported case-fatality rate ranged Four studies were published at a single referral hospital/US from 17% to 70% (median 54%). In the 2 Malawian prospective Navy research unit in Egypt [16–19] and 2 at a single referral RCTs with mostly HIV-infected adults, mortality ranged from hospital in Senegal [20, 21], both countries with a low HIV prev- 49% to 54% overall and 39% to 51% in cases of proven pneumo- alence. Three studies were published from a single large referral coccal meningitis, all managed with ceftriaxone (±dexametha- hospital in Malawi with predominately HIV-infected patients sone). Hearing loss was reported to aeff ct 3%–34% (median (84%–100% HIV prevalence) [22–24]. Follow-up duration was 19%) of patients in 4 studies, with severe/profound hearing loss variable: 8 of the 22 studies presented only in-hospital neurolog- reported in 4%–34% (median 12%) of patients in 3 studies. Motor ical sequelae of survivors, and follow-up for the remaining 14 deficits were reported at 8%–32% in 2 studies, with no other out- studies ranged from 1 month to 2 years. Twelve articles were pro- come documented in more than a single study (Table 3). spective cohort studies, 5 were retrospective cohort studies, and 5 e 2 M Th alawian studies with predominately HIV-infected were prospective randomized-controlled trials (RCTs) [Table 2]. patients reported high rates of neurological sequelae in survi- Neisseria meningitidis Meningitis vors [22, 23]. In Ajdukiewicz et al [22], 22% (14 of 63) survivors, Neisseria meningitidis was the principle pathogen identified in 9 with or without pneumococcal disease, remained in a persis- bacterial studies with 2718 patients. Neisseria meningitidis was tent vegetative state (Glasgow Outcome Score 2) at 40 days. In the only pathogen isolated from 6 studies. Penicillin or ampi- Scarborough et al [23], 23% (47 of 202) of 40-day survivors and cillin and/or chloramphenicol were used to treat patients in 29% (38 of 130) of those with proven pneumococcal meningitis most studies. Only 1 study [25] gave any information on HIV had 1 or more neurological sequelae (blindness, debility, com- serostatus and reported low prevalence. Follow-up ranged from plete deafness, intellectual impairment, paresis, or recurrent in-hospital to a 2-year follow-up of survivors. Males constituted seizures). 56% (1529 of 2718) of patients (Table 2). One retrospective cohort study from Egypt evaluated neu- Ascertainment of adult outcomes was imperfect because most rological sequelae in 95 patients with microbiologically con- (8 of 9) studies included both adult and pediatric patients with- firmed, Gram-negative, bacillary meningitis [17]. This study out separation by age category. Mortality data were included in included both adults and children and did not include data on 5 studies and ranged from 3% to 21% (median 13%). In men- HIV status. The case-fatality rate was 29% (28 of 95), and the ingitis survivors, hearing loss (8 studies) and motor deficits (5 rate of pooled in-hospital sequelae (cerebral damage, hearing studies) were the most commonly reported neurological seque- loss, hemiplegia, hydrocephalus, optic atrophy, and/or seizure lae. Any hearing loss was found in 2%–31% of patients (median disorder) in survivors was 39% (26 of 67). Six percent (4 of 5%) with severe/profound hearing loss reported in 2%–10% 67) of survivors had hearing loss, 7% (5 of 67) had hemiplegia, of patients (median 3%). Motor deficits were variably defined 7% (5 of 67)  had seizure disorder, and 9% (6 of 67)  had optic and ranged from 1% to 13% (median 2%) in 5 studies with atrophy. Another study from Egypt included patients with a mix moderate-to-severe disability (eg, hemiplegia/hemiparesis) in of microbiologically confirmed bacterial meningitis and tuber - 1%–2% (median 2%) from 3 studies. One study reported 6% culous meningitis [28]. At hospital discharge, 43% (13 of 30) of of patients with moderate-to-severe visual loss and 3% with survivors with bacterial meningitis and 45% (5 of 11)  with moderate-to-severe neurocognitive deficit at evaluation 6 to tuberculous meningitis had severe disability determined by 12 months aer t ft he meningitis episode (Table 3). Glasgow Outcomes Scale score. 12 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Cryptococcal Meningitis RCT reported additional 1-month neurocognitive outcomes Four articles evaluated neurological sequelae of HIV-infected [32]. At 1 month, 92% of survivors had an International HIV adult patients with cryptococcal meningitis [24, 29–31]. One Dementia Scale score ≤10, suggesting possible HIV-associated good-quality study from Uganda reported global neurocogni- neurocognitive disorder. Six-month neurocognitive outcomes tive dysfunction, defined as mean composite score of multi- from another quality large prospective RCT found that 20% domain neurocognitive testing at least 1 standard deviation of survivors had severe disability at 10 weeks and 10% at below that of HIV-uninfected Ugandans (z-score < −1), seri- 6 months, defined as answering yes to the question “Does the ally over 1  year in cryptococcal meningitis survivors who patient require help from anybody for everyday activities?” received amphotericin-based induction therapy. At 1  month, or with a Modified Rankin Scale score of ≥3 (symptoms that 89% (69 of 78) of survivors had impaired neurocognitive func- restrict lifestyle and prevent totally independent living) [30]. tion. This improved to 41% (26 of 64) at 1 year [29]. Meningitis Of note, this study included patients from countries in both survivors had only slightly higher disability compared with Africa (Malawi and Uganda) and Asian countries, but neu- HIV-infected Ugandans without a prior history of neurolog- rocognitive outcomes were not disaggregated by country. We ical infection. The case-fatality rate for patients who lived to also excluded patients receiving experimental dexamethasone 1 month was 12% (9 of 78) at 1 year; 5 of those patients died therapy, which was associated with higher rates of mortal- before a 1-month follow up, and 3 patients died before the ity and other adverse outcomes and is not part of the usual 6-month follow up. A second study from the same prospective treatment. Records identified through Additional records identified primary database search through supplemental sources (n = 6204) (n = 34) Records after duplicates removed (n = 4564) Records excluded based on title review (n = 3241) Records screened (n = 1323) Full-text articles assessed for eligibility (n = 380) Article included in qualitative synthesis (n = 22) Bacterial meningitis Tuberculosis Crytococcal articles meningitis articles meningitis articles (n = 16) (n = 2) (n = 4) Figure 1. Diagram of literature search. Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review • OFID • 13 Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Egypt: Niger: n = 5 n = 2 N/A <1% 1-5% Senegal: Ethiopia: n = 2 n = 1 5-10% >10% Gambia: n = 1 Uganda: n = 3 Ghana: Malawi: n = 1 n = 4 Gabon: n = 1 DRC*: Swaziland: n = 1 n = 1 South Africa: *DRC: Democratic republic n = 1 of Congo Figure 2. Origin of studies included in review and estimated human immunodeficiency virus prevalence. Tuberculosis Meningitis DISCUSSION We included 2 articles with 891 patients with sequelae data In our systematic review of neurological sequelae of adult men- for tuberculosis meningitis. One high-quality but small study ingitis in Africa, we identified 22 articles with neurological with 34 antiretroviral therapy (ART)-naive HIV-infected adults sequelae outcome data in meningitis survivors. This included with tuberculous meningitis (confirmed or suspected) evalu- 12 studies in counties with high HIV prevalence. These studies, ated patients for tuberculosis-associated immune reconstitu- published over a more than 35-year period, provide limited data tion inflammatory syndrome (TB-IRIS) after ART initiation. showing high rates of postmeningitis disability in adult men- The case-fatality rate was 12% (4 of 34)  at 9  months, with all ingitis survivors from resource-limited settings, particularly deaths occurring in patients with TB-IRIS at time points of 33, in those with HIV coinfection. More importantly, they reveal 53, 60, and 118 days after tuberculous meningitis diagnosis. Of the paucity of high-quality data regarding the frequency and 9-month survivors, 20% (6 of 30) had marked disability: 20% (6 spectrum of neurological sequelae after adult meningitis from of 30) cognitive impairment (5 of 6 marked impairment defined prospective studies, and they provide insight into gaps in our as HIV dementia scale score <10), 7% (2 of 30) hemiparesis, and current understanding of long-term disability of adult meningi- 3% (1 of 30) hearing loss [33]. A second study from a referral tis survivors. Accurate data regarding the long-term outcomes hospital in Egypt reported outcomes in a large cohort of patients in adult meningitis survivors are essential for accurate estimates treated for tuberculous meningitis over 2 decades (1976–1996) of disease burden and, given the frequency of adult meningitis [19]. This study included adults and children together, and in Africa, have broad public health and economic implications. no patients were known to be HIV-infected. Patients received Our review highlights that little is known about long-term 3-drug antituberculous therapy for 2  years, during which neurological sequelae in survivors of HIV-associated crypto- period they were serially assessed for neurological sequelae. In coccal meningitis and tuberculous meningitis, 2 of the principle total, 57% (490 of 857) of patients died and 30% (111 of 367) of causes of adult meningitis in sub-Saharan Africa. Two articles patients survived with severe neurological sequelae (including included Ugandan patients from a single prospective RCT cranial nerve palsy 5% [20 of 367], hemiparesis-paraplegia 5% [29, 32]. As in prior studies in the region, acute mortality was [20 of 367], and hydrocephalus 8% [30 of 367]). high at 38% by 26 weeks of follow up [4, 34–38]. These studies 14 • OFID • Goldberg et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/1/ofx246/4617690 by Ed 'DeepDyve' Gillespie user on 16 March 2018 found significant impairment in the early weeks aer in ft cident HIV recognition and initiation of ART coupled with timely and cryptococcal meningitis, with Montgomery et al [32] reporting appropriate antibiotic therapy [41]. 92% of survivors with an International AIDS Dementia Scale Our review has several important limitations. First, case score suggestive of neurocognitive impairment, compared with definitions, outcome measures, and means of assessment were 66% of HIV-infected controls without meningitis. With longer highly variable between studies. A lack of validated neurocog- follow-up, Carlson et  al [29] reported persistent neurocogni- nitive and limited neurological function assessments created tive deficits in approximately half of survivors at 1  year. The very heterogeneous data and prevented formal meta-analy- relationship between this long-term neurocognitive impair- sis. Second, follow-up periods differed considerably with only ment and cryptococcal meningitis remains unclear. Although approximately half of studies reporting outcomes aer h ft ospital cryptococcal meningitis survivors also showed worse neuro- discharge to characterize clinical evolution of disease. Third, cognitive function compared with HIV-infected Ugandans, because there were few studies evaluating outcomes in crypto- these differences were small by 1 year of follow-up, and the con- coccal and tuberculous meningitis, no firm conclusions could trol patients generally had less advanced HIV disease (mostly be drawn about neurological outcomes in survivors but rather stage II and III) [29]. Neurocognitive deficits may have been emphasizes the need for future studies, especially prospective a consequence of meningitis and/or other contributing fac- cohort studies, to include multidomain measures of neuro- tors, such as HIV-associated neurocognitive disorder [39, 40]. logical outcomes of disease. Finally, for most studies involving e c Th hoice of comparator also limits inferential reasoning and meningococcal meningitis, neurological sequelae of pediatric could be strengthened in this and other studies evaluating neu- and adult cases were not reported separately, which limited rocognitive domains with alternative comparator groups, such our ability to make firm conclusions about adult outcomes. In as HIV-infected populations started early on ART. A  second this mixed population, however, death and disability was sig- multicountry prospective RCT conducted in African and Asian nificantly lower than in cases of pneumococcal meningitis, as countries found that 20% and 10% of survivors reported requir- reported elsewhere [14]. ing help with everyday activities at 10 weeks and 6  months, respectively [30]. Taken together, these data suggest signifi- CONCLUSIONS cant impairment early aer ft incident cryptococcal meningitis, In conclusion, although settings with high HIV prevalence in a period during which adherence to ART and continuation of Africa have both a high incidence of meningitis and early mor- uco fl nazole maintenance therapy are critical to prevent crypto- tality, long-term sequelae in adult survivors remains poorly coccal meningitis relapse and for overall survival. characterized. Limited data suggest high rates of neurological dis- Five studies described neurological sequelae in adult menin- ability associated with HIV-related pneumococcal and TB men- gitis with S pneumoniae, the most common cause of bacterial ingitis. Little is known about neurological sequelae in survivors meningitis in HIV-infected adults, as the predominate patho- of HIV-associated cryptococcal meningitis, although studies sug- gen [2, 41]. Two of these studies [22, 23], both from Malawi, gest extremely high prevalence of neurocognitive and functional consisted largely of HIV-infected adults and found approxi- impairment in the early weeks after incident disease. Furthermore, mately half of patients died of meningitis with one quarter of long-term multidomain testing of neurological outcomes for sur- survivors left with severe disability, such as with persistent veg- vivors of HIV-associated cryptococcal meningitis and TB menin- etative states or hemiparesis. These adverse outcomes are sig- gitis is warranted. Tools need to be chosen carefully and consider nificantly higher than rates of death and disability reported in challenges with repeat testing, such as risk of learner bias. resource-rich countries with low HIV prevalence, but they are er Th e is a need for improved understanding of neurological more reflective of African pediatric populations [8, 14]. es Th e sequelae of adult meningitis in Africa. Pneumococcal meningi- data also likely underestimated the impact of pneumococcal tis in the setting of high HIV prevalence confers a high risk of meningitis in HIV-infected African cohorts because patients both death and severe neurological sequelae in survivors. Little were enrolled in controlled clinical trials at a large referral is published on sequelae from HIV-associated cryptococcal or hospital and given highly effective antibiotic therapy with cef- tuberculous meningitis, highlighting an urgent need to more triaxone. Because follow up was limited to 40  days, they may accurately define outcomes of survivors in future studies. also have underestimated delayed outcomes such as epilepsy [42]. Unfortunately, in Africa, pneumococcal vaccination has Acknowledgments demonstrated mixed efficacy for reducing invasive pneumococ- Financial suppport. This work was funded by University of Pennsylvania Center for AIDS Research Grant P30 AI 045008 (to J. N. J.). cal disease, and dexamethasone therapy has not been associated Potential conifl cts of interest. All authors: No reported conflicts of with lower mortality or neurological sequelae in HIV-infected interest. All authors have submitted the ICMJE Form for Disclosure of adults [23, 43, 44]. The best method for reduction in risk of Potential Conflicts of Interest Conflicts that the editors consider relevant to incident disease and associated neurological sequelae is early the content of the manuscript have been disclosed. 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