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Abstract Background Pneumococcal meningitis (PM) is a severe and life-threatening disease that is associated with cognitive impairment including learning difficulties, cognitive slowness, short-term memory deficits and poor academic performance. There are limited data on cognitive outcomes following exposure to PM from Africa mainly due to lack of culturally appropriate tools. We report cognitive processes of exposed children as measured by auditory and visual event-related potentials. Methods Sixty-five children (32 male, mean 8.4 years, SD 3.0 years) aged between 4-15 years with a history of PM and an age-matched control group of 93 children (46 male; mean 8.4 years, SD 2.7 years) were recruited from a well-demarcated study area in Kilifi. In the present study, both baseline to peak and peak-to-peak amplitude differences are reported. Results Children with a history of pneumococcal meningitis had significantly longer auditory P1 and P3a latencies and smaller P1 amplitudes compared to unexposed children. In the visual paradigm, children with PM seemingly lacked a novelty P3a component around 350 ms where control children had a maximum, and showed a lack of stimulus differentiation at Nc. Further, children with exposure to PM had smaller peak to peak amplitude (N2-P1) compared to unexposed children. Conclusion The results suggest that children with a history of PM process novelty differently than do unexposed children, with slower latencies and reduced or absent components. This pattern suggests poorer auditory attention and/or cognitive slowness and poorer visual attention orienting, possibly due to disruption in the functions of the lateral prefrontal and superior temporal cortices. ERPs may be useful for assessment of the development of perceptual-cognitive functions in post brain-injury in African children by providing an alternate way of assessing cognitive development in patient groups for whom more typical standardized neuropsychological assessments are unavailable.

Abstract Background A global proteomic strategy was used to identify proteins, which are differentially expressed in the murine model of severe malaria in the hope of facilitating future development of novel diagnostic, disease monitoring and treatment strategies. Methods Mice (4-week-old CD1 male mice) were infected with Plasmodium berghei ANKA strain, and infection allowed to establish until a parasitaemia of 30% was attained. Total plasma and albumin depleted plasma samples from infected and control (non-infected) mice were separated by two-dimensional gel electrophoresis (2-DE). After staining, the gels were imaged and differential protein expression patterns were interrogated using image analysis software. Spots of interest were then digested using trypsin and the proteins identified using matrix-assisted laser desorption and ionization-time of flight (MALDI-TOF) mass spectrometry (MS) and peptide mass fingerprinting software. Results Master gels of control and infected mice, and the corresponding albumin depleted fractions exhibited distinctly different 2D patterns comparing control and infected plasma, respectively. A wide range of proteins demonstrated altered expression including; acute inflammatory proteins, transporters, binding proteins, protease inhibitors, enzymes, cytokines, hormones, and channel/receptor-derived proteins. Conclusions Malaria-infection in mice results in a wide perturbation of the host serum proteome involving a range of proteins and functions. Of particular interest is the increased secretion of anti-inflammatory and anti apoptotic proteins.

Abstract Background Pentoxifylline (PTX) affects many processes that may contribute to the pathogenesis of severe malaria and it has been shown to reduce the duration of coma in children with cerebral malaria. This pilot study was performed to assess pharmacokinetics, safety and efficacy of PTX in African children with cerebral malaria. Methods Ten children admitted to the high dependency unit of the Kilifi District Hospital in Kenya with cerebral malaria (Blantyre coma score of 2 or less) received quinine plus a continuous infusion of 10 mg/kg/24 hours PTX for 72 hours. Five children were recruited as controls and received normal saline instead of PTX. Plasma samples were taken for PTX and tumour necrosis factor (TNF) levels. Blantyre Coma Score, parasitemia, hematology and vital signs were assessed 4 hourly. Results One child (20%) in the control group died, compared to four children (40%) in the PTX group. This difference was not significant (p = 0.60). Laboratory parameters and clinical data were comparable between groups. TNF levels were lower in children receiving PTX. Conclusions The small sample size does not permit definitive conclusions, but the mortality rate was unexpectedly high in the PTX group.

Abstract Background Acute seizures are common among children admitted to hospitals in resource poor countries. However, there is little data on the burden, causes and outcome of neonatal seizures in sub-Saharan Africa. We determined the minimum incidence, aetiology and immediate outcome of seizures among neonates admitted to a rural district hospital in Kenya. Methods From 1st January 2003 to 31st December 2007, we assessed for seizures all neonates (age 0-28 days) admitted to the Kilifi District Hospital, who were resident in a defined, regularly enumerated study area. The population denominator, the number of live births in the community on 1 July 2005 (the study midpoint) was modelled from the census data. Results Seizures were reported in 142/1572 (9.0%) of neonatal admissions. The incidence was 39.5 [95% confidence interval (CI) 26.4-56.7] per 1000 live-births and incidence increased with birth weight. The main diagnoses in neonates with seizures were sepsis in 85 (60%), neonatal encephalopathy in 30 (21%) and meningitis in 21 (15%), but only neonatal encephalopathy and bacterial meningitis were independently associated with seizures. Neonates with seizures had a longer hospitalization [median period 7 days - interquartile range (IQR) 4 to10] -compared to 5 days [IQR 3 to 8] for those without seizures, P = 0.02). Overall, there was no difference in inpatient case fatality between neonates with and without seizures but, when this outcome was stratified by birth weight, it was significantly higher in neonates ≥ 2.5 kg compared to low birth weight neonates [odds ratio 1.59 (95%CI 1.02 to 2.46), P = 0.037]. Up to 13% of the surviving newborn with seizures had neurological abnormalities at discharge. Conclusion There is a high incidence of neonatal seizures in this area of Kenya and the most important causes are neonatal encephalopathy and meningitis. The high incidence of neonatal seizures may be a reflection of the quality of the perinatal and postnatal care available to the neonates.

Abstract Background Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage. Methods An everyday memory battery was administered on 152 children with cerebral malaria (CM) (mean age, 7 y 4 months [SD 13 months]; 77 males) 156 children (mean age, 7 y 4 months [SD, 14 months]; 72 males) with malaria plus complex seizures (MS) and 179 children (mean age, 7 y 6 months [SD, 13 months]; 93 males) unexposed to either condition. Results CM was associated with poorer everyday memory [95% CI, -2.46 to -0.36, p = 0.004] but not MS [95% CI, -0.91 to 1.16, p = 1.00] compared to unexposed children. Children with exposure to CM performed more poorly in recall [95% CI, -0.79 to -0.04, p = 0.024] and recognition subtests [95% CI, -0.90 to -0.17, p = 0.001] but not in prospective memory tests compared to controls. The health factors that predicted impaired everyday memory outcome in children with exposure to CM was profound coma [95% CI, 0.02 to 0.88, p = 0.037] and multiple episodes of hypoglycaemia [95% CI, 0.05 to 0.78, p = 0.020], but not seizures. Discussion The findings show that exposure to CM was associated with a specific impairment of everyday memory. Seizures commonly observed in severe malaria may not have a causal relationship with poor outcome, but rather be associated with profound coma and repeated metabolic insults (multi-hypoglycaemia) that are strongly associated with impaired everyday memory.

Abstract Background Severe anaemia requiring emergency blood transfusion is a common complication of malaria in children. To ensure access for urgent blood transfusion, the World Health Organization has developed clear guidelines with haemoglobin thresholds prevent unwarranted transfusion,. Few studies have reported outcome and haematological recovery of children with severe malaria where transfusion practice complies with WHO recommendations. Methods A prospective observational study of survivors of severe and complicated malaria transfused in accordance with WHO guidelines. Children were invited for review at one month post-discharge. Non-attendees were traced in the community to ascertain survival. Results Outcome was assessed in 213 survivors. Those transfused were younger, had a higher base deficit, mean lactate levels and a higher prevalence of respiratory distress. As expected mean admission haemoglobin (Hb) was significantly lower amongst transfused [5.0 g/dL SD: 1.9] compared to non-transfused children [8.3 g/dL SD: 1.7] (p < 0.001). At discharge mean Hb was similar 6.4 g/dL [SD: 1.5] and 6.8 g/dL [SD: 1.6] respectively (p = 0.08), most children remained moderately to severely anaemic. At one month follow up 166 children (78%) returned, in whom we found no differences in mean Hb between the transfused (10.2 g/dL [SD: 1.7]) and non-transfused (10.0 g/dL [SD: 1.3]) survivors (p = 0.25). The major factors affecting haematological recovery were young age ( Conclusion This data supports the policy of rational use of blood transfusion, as proposed in the WHO guidelines, for children with anaemia in areas where access to emergency transfusion is not guaranteed. We have provided empirical data indicating that transfusion does not influence superior recovery in haemoglobin concentrations and therefore cannot be justified on this basis alone. This may help resolve the disparity between international policy and current clinical practice. Effective anti-malarial treatment at discharge may prevent reoccurrence of anaemia.

Abstract Background Acute seizures are a common cause of paediatric admissions to hospitals in resource poor countries and a risk factor for neurological and cognitive impairment and epilepsy. We determined the incidence, aetiological factors and the immediate outcome of seizures in a rural malaria endemic area in coastal Kenya. Methods We recruited all children with and without seizures, aged 0–13 years and admitted to Kilifi District hospital over 2 years from 1st December 2004 to 30th November 2006. Only incident admissions from a defined area were included. Patients with epilepsy were excluded. The population denominator, the number of children in the community on 30th November 2005 (study midpoint), was modelled from a census data. Results Seizures were reported in 900/4,921(18.3%) incident admissions and at least 98 had status epilepticus. The incidence of acute seizures in children 0–13 years was 425 (95%CI 386, 466) per 100,000/year and was 879 (95%CI 795, 968) per 100,000/year in children Conclusion There is a high incidence of acute seizures in children living in this malaria endemic area of Kenya. The most important causes are diseases that are preventable with available public health programs.

Abstract Background Kenya introduced a pentavalent vaccine including the DTP, Haemophilus influenzae type b and hepatitis b virus antigens in Nov 2001 and strengthened immunization services. We estimated immunization coverage before and after introduction, timeliness of vaccination and risk factors for failure to immunize in Kilifi district, Kenya. Methods In Nov 2002 we performed WHO cluster-sample surveys of >200 children scheduled for vaccination before or after introduction of pentavalent vaccine. In Mar 2004 we conducted a simple random sample (SRS) survey of 204 children aged 9–23 months. Coverage was estimated by inverse Kaplan-Meier survival analysis of vaccine-card and mothers' recall data and corroborated by reviewing administrative records from national and provincial vaccine stores. The contribution to timely immunization of distance from clinic, seasonal rainfall, mother's age, and family size was estimated by a proportional hazards model. Results Immunization coverage for three DTP and pentavalent doses was 100% before and 91% after pentavalent vaccine introduction, respectively. By SRS survey, coverage was 88% for three pentavalent doses. The median age at first, second and third vaccine dose was 8, 13 and 18 weeks. Vials dispatched to Kilifi District during 2001–2003 would provide three immunizations for 92% of the birth cohort. Immunization rate ratios were reduced with every kilometre of distance from home to vaccine clinic (HR 0.95, CI 0.91–1.00), rainy seasons (HR 0.73, 95% CI 0.61–0.89) and family size, increasing progressively up to 4 children (HR 0.55, 95% CI 0.41–0.73). Conclusion Vaccine coverage was high before and after introduction of pentavalent vaccine, but most doses were given late. Coverage is limited by seasonal factors and family size.

Abstract Background Abnormal motor posturing is often observed in children with cerebral malaria, but the aetiology and pathogenesis is poorly understood. This study examined the risk factors and outcome of posturing in Kenyan children with cerebral malaria. Methods Records of children admitted to Kilifi district hospital with cerebral malaria from January, 1999 through December, 2001 were reviewed for posturing occurring on or after admission. The clinical characteristics, features of raised intracranial pressure, number of seizures and biochemical changes in patients that developed posturing was compared to patients who did not. Results Of the 417 children with complete records, 163 (39.1%) had posturing: 85 on admission and 78 after admission to hospital. Decorticate posturing occurred in 80, decerebrate in 61 and opisthotonic posturing in 22 patients. Posturing was associated with age ≥ 3 years (48.1 vs 35.8%, p = 0.01) and features of raised intracranial pressure on funduscopy (adjusted OR 2.1 95%CI 1.2–3.7, p = 0.009) but not other markers of severity of disease. Unlike decorticate posturing, decerebrate (adjusted OR 1.9 95%CI 1.0–3.5) and opisthotonic posturing (adjusted OR 2.9 95%CI 1.0–8.1) were, in addition, independently associated with recurrence of seizures after admission. Opisthotonus was also associated with severe metabolic acidosis (OR 4.2 95%CI 3.2–5.6, p < 0.001). Thirty one patients with posturing died. Of these, 19 (61.3%) had features suggestive of transtentorial herniation. Mortality and neurological deficits on discharge were greatest in those developing posturing after admission. Conclusion Abnormal motor posturing is a common feature of cerebral malaria in children. It is associated with features of raised intracranial pressure and recurrence of seizures, although intracranial hypertension may be the primary cause.

Aim: To investigate geographical change over time in the burden of neurological impairments in school‐aged children in a demographic surveillance area. Method: We investigated changes in neurological impairment prevalence in five domains (epilepsy and cognitive, hearing, vision, and motor impairments) using similar two‐phase surveys conducted in 2001 (n=10 218) and 2015 (n=11 223) and determined changes in location‐level prevalence, geographical clustering, and significant risk factors for children aged 6 to 9 years (mean 7y 6mo, SD 1y) of whom 50.4% were males. Admission trends for preterm birth, low birthweight (LBW), and encephalopathy were determined using admission data to a local hospital. Results: Overall prevalence for any neurological impairment decreased from 61 per 1000 (95% confidence interval [CI] 48.0–74.0) in 2001 to 44.7 per 1000 (95% CI 40.9–48.6) in 2015 (p<0.001). There was little evidence of geographical variation in the prevalence of neurological impairments in either survey. The association between neurological impairments and some risk factors changed significantly with year of survey; for example, the increased association of adverse perinatal events with hearing impairments (exponentiated coefficient for the interaction=5.94, p=0.03). Annual admission rates with preterm birth (rate ratio 1.08, range 1.07–1.09), LBW (rate ratio 1.08, range 1.06–1.10), and encephalopathy (rate ratio 1.08, range 1.06–1.09) significantly increased between 2005 and 2016 (p<0.001). Interpretation: There was a significant decline in the prevalence of neurological impairments and differential changes in the associations of some risk factors with neurological impairments over the study period. Limited geographical variation suggests that similar interventions are appropriate across the defined area. This original article is commented by Olusanya on pages 280–281 of this issue. [ABSTRACT FROM AUTHOR]

The passive construction is acquired relatively late by children learning to speak many languages, with verbal passives not fully acquired until age 6 in English. In other languages it appears earlier, around age 3 or before. Use of passive construction in young children was examined in two Eastern Bantu languages spoken in Kenya (Kiswahili and Kigiriama), both with frequent use of passive. The passive was used productively very early (2;1) in these languages, regardless of the method used to measure productivity. In addition, non-actional passives, particularly rare in English and some other European languages, were seen at these early ages. The proportion of verbs that were passive varied between individuals, both in children’s speech and in the input to children. Pragmatic and grammatical features of the passive in some languages have previously been suggested to drive early passive acquisition, but these features are not found consistently in the two languages studied here. Findings suggest that the relatively high frequency of input found in these languages is the most plausible reason for early productive use of the passive. [ABSTRACT FROM AUTHOR]

Objective: To describe the prevalence of hypoxaemia in children admitted to a hospital in Kenya for the purpose of identifying clinical signs of hypoxaemia for emergency triage assessment, and to test the hypothesis that such signs lead to correct identification of hypoxaemia in children, irrespective of their diagnosis., Methods: From 2002 to 2005 we prospectively collected clinical data and pulse oximetry measurements for all paediatric admissions to Kilifi District Hospital, Kenya, irrespective of diagnosis, and assessed the prevalence of hypoxaemia in relation to the WHO clinical syndromes of 'pneumonia' on admission and the final diagnoses made at discharge. We used the data collected over the first three years to derive signs predictive of hypoxaemia, and data from the fourth year to validate those signs., Findings: Hypoxemia was found in 977 of 15 289 (6.4%) of all admissions (5% to 19% depending on age group) and was strongly associated with inpatient mortality (age-adjusted risk ratio: 4.5; 95% confidence interval, CI: 3.8-5.3). Although most hypoxaemic children aged > 60 days met the WHO criteria for a syndrome of 'pneumonia' on admission, only 215 of the 693 (31%) such children had a final diagnosis of lower respiratory tract infection (LRTI). The most predictive signs for hypoxaemia included shock, a heart rate < 80 beats per minute, irregular breathing, a respiratory rate > 60 breaths per minute and impaired consciousness. However, 5-15% of the children who had hypoxaemia on admission were missed, and 18% of the children were incorrectly identified as hypoxaemic., Conclusion: The syndromes of pneumonia make it possible to identify most hypoxaemic children, including those without LRTI. Shock, bradycardia and irregular breathing are important predictive signs, and severe malaria with respiratory distress is a common cause of hypoxaemia. Overall, however, clinical signs are poor predictors of hypoxaemia, and using pulse oximetry in resource-poor health facilities to target oxygen therapy is likely to save costs.