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Objective: This study investigated the incidence of postoperative subdural collections in a cohort of African infants with postinfectious hydrocephalus. The authors sought to identify preoperative factors associated with increased risk of development of subdural collections and to characterize associations between subdural collections and postoperative outcomes., Methods: The study was a post hoc analysis of a randomized controlled trial at a single center in Mbale, Uganda, involving infants (age < 180 days) with postinfectious hydrocephalus randomized to receive either an endoscopic third ventriculostomy plus choroid plexus cauterization or a ventriculoperitoneal shunt. Patients underwent assessment with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III; sometimes referred to as BSID-III) and CT scans preoperatively and then at 6, 12, and 24 months postoperatively. Volumes of brain, CSF, and subdural fluid were calculated, and z-scores from the median were determined from normative curves for CSF accumulation and brain growth. Linear and logistic regression models were used to characterize the association between preoperative CSF volume and the postoperative presence and size of subdural collection 6 and 12 months after surgery. Linear regression and smoothing spline ANOVA were used to describe the relationship between subdural fluid volume and cognitive scores. Causal mediation analysis distinguished between the direct and indirect effects of the presence of a subdural collection on cognitive scores., Results: Subdural collections were more common in shunt-treated patients and those with larger preoperative CSF volumes. Subdural fluid volumes were linearly related to preoperative CSF volumes. In terms of outcomes, the Bayley-III cognitive score was linearly related to subdural fluid volume. The distribution of cognitive scores was significantly different for patients with and those without subdural collections from 11 to 24 months of age. The presence of a subdural collection was associated with lower cognitive scores and smaller brain volume 12 months after surgery. Causal mediation analysis demonstrated evidence supporting both a direct (76%) and indirect (24%) effect (through brain volume) of subdural collections on cognitive scores., Conclusions: Larger preoperative CSF volume and shunt surgery were found to be risk factors for postoperative subdural collection. The size and presence of a subdural collection were negatively associated with cognitive outcomes and brain volume 12 months after surgery. These results have suggested that preoperative CSF volumes could be used for risk stratification for treatment decision-making and that future clinical trials of alternative shunt technologies to reduce overdrainage should be considered.

Objective: The study of brain size and growth has a long and contentious history, yet normal brain volume development has yet to be fully described. In particular, the normal brain growth and cerebrospinal fluid (CSF) accumulation relationship is critical to characterize because it is impacted in numerous conditions of early childhood in which brain growth and fluid accumulation are affected, such as infection, hemorrhage, hydrocephalus, and a broad range of congenital disorders. The authors of this study aim to describe normal brain volume growth, particularly in the setting of CSF accumulation., Methods: The authors analyzed 1067 magnetic resonance imaging scans from 505 healthy pediatric subjects from birth to age 18 years to quantify component and regional brain volumes. The volume trajectories were compared between the sexes and hemispheres using smoothing spline ANOVA. Population growth curves were developed using generalized additive models for location, scale, and shape., Results: Brain volume peaked at 10-12 years of age. Males exhibited larger age-adjusted total brain volumes than females, and body size normalization procedures did not eliminate this difference. The ratio of brain to CSF volume, however, revealed a universal age-dependent relationship independent of sex or body size., Conclusions: These findings enable the application of normative growth curves in managing a broad range of childhood diseases in which cognitive development, brain growth, and fluid accumulation are interrelated.

Objective: Hydrocephalus in infants, particularly that with a postinfectious etiology, is a major public health burden in Sub-Saharan Africa. The authors of this study aimed to determine whether surgical treatment of infant postinfectious hydrocephalus in Uganda results in sustained, long-term brain growth and improved cognitive outcome., Methods: The authors performed a trial at a single center in Mbale, Uganda, involving infants (age < 180 days old) with postinfectious hydrocephalus randomized to endoscopic third ventriculostomy plus choroid plexus cauterization (ETV+CPC; n = 51) or ventriculoperitoneal shunt (VPS; n = 49). After 2 years, they assessed developmental outcome with the Bayley Scales of Infant Development, Third Edition (BSID-III), and brain volume (raw and normalized for age and sex) with CT scans., Results: Eighty-nine infants were assessed for 2-year outcome. There were no significant differences between the two surgical treatment arms in terms of BSID-III cognitive score (p = 0.17) or brain volume (p = 0.36), so they were analyzed together. Raw brain volumes increased between baseline and 2 years (p < 0.001), but this increase occurred almost exclusively in the 1st year (p < 0.001). The fraction of patients with a normal brain volume increased from 15.2% at baseline to 50.0% at 1 year but then declined to 17.8% at 2 years. Substantial normalized brain volume loss was seen in 21.3% patients between baseline and year 2 and in 76.7% between years 1 and 2. The extent of brain growth in the 1st year was not associated with the extent of brain volume changes in the 2nd year. There were significant positive correlations between 2-year brain volume and all BSID-III scores and BSID-III changes from baseline., Conclusions: In Sub-Saharan Africa, even after successful surgical treatment of infant postinfectious hydrocephalus, early posttreatment brain growth stagnates in the 2nd year. While the reasons for this finding are unclear, it further emphasizes the importance of primary infection prevention and mitigation strategies along with optimizing the child's environment to maximize brain growth potential.

OBJECTIVE While there is a long history of interest in measuring brain growth, as of yet there is no definitive model for normative human brain volume growth. The goal of this study was to analyze a variety of candidate models for such growth and select the model that provides the most statistically applicable fit. The authors sought to optimize clinically applicable growth charts that would facilitate improved treatment and predictive management for conditions such as hydrocephalus. METHODS The Weibull, two-term power law, West ontogenic, and Gompertz models were chosen as potential models. Normative brain volume data were compiled from the NIH MRI repository, and the data were fit using a nonlinear least squares regression algorithm. Appropriate statistical measures were analyzed for each model, and the best model was characterized with prediction bound curves to provide percentile estimates for clinical use. RESULTS Each model curve fit and the corresponding statistics were presented and analyzed. The Weibull fit had the best statistical results for both males and females, while the two-term power law generated the worst scores. The statistical measures and goodness of fit parameters for each model were provided to assure reproducibility. CONCLUSIONS The authors identified the Weibull model as the most effective growth curve fit for both males and females. Clinically usable growth charts were developed and provided to facilitate further clinical study of brain volume growth in conditions such as hydrocephalus. The authors note that the homogenous population from which the normative MRI data were compiled limits the study. Gaining a better understanding of the dynamics that underlie childhood brain growth would yield more predictive growth curves and improved neurosurgical management of hydrocephalus.

Object: Accurate edge tracing segmentation remains an incompletely solved problem in brain image analysis. The authors propose a novel algorithm using a particle filter to follow the boundary of the brain in the style often used in autonomous air and ground vehicle navigation. Their goals were to create a versatile tool to segment brain and fluid in MRI and CT images of the developing brain, lay the foundation for an intelligent automated edge tracker that is modality independent, and segment normative data from MRI that can be applied to both MRI and CT., Methods: Simulated MRI data sets were used to train and evaluate the particle filter segmentation algorithm. The method was then applied to produce normative growth curves for children and adolescents from 0 to 18 years of age for brain and fluid from MR images from the National Institutes of Health pediatric database and these data were compared to historical results. The authors further adapted this method for use with CT images of pediatric hydrocephalus and compared the results with hand-segmented data., Results: Segmentation of simulated MRI data with varied levels of noise (0%-9%) and spatial inhomogeneity (0%-40%) resulted in percent errors ranging from 0.06% to 5.38% for brain volume and 2.45% to 22.3% for fluid volume. The authors used this tool to create normal brain and CSF growth curves from MR images. The calculated growth curves showed excellent consistency with historical data. Additionally, compared with manual segmentation the particle filter accurately segmented brain and fluid volumes from CT scans of 5 pediatric patients with hydrocephalus (p<0.001)., Conclusions: The authors have produced the first normative brain and CSF growth curves for children and adolescents 0-18 years of age. In addition, this study includes the first use of a particle filter as an edge tracker in image segmentation and offers a semiautomatic method to segment both pediatric and adult brain data from MR and CT images. The particle filter has the potential to be further automated toward a clinical rather than research tool with both of these modalities. Because of its modality independence, it has the capability to allow CT to be a more effective diagnostic tool for neurological disorders, a task of substantial importance in emergency settings and in developing countries where CT is often the only available method of brain imaging.

Object: The evaluation of hydrocephalus remains focused on ventricular size, yet the goal of treatment is to allow for healthy brain development. It is likely that brain volume is more related to cognitive development than is fluid volume in children with hydrocephalus. This study tests this hypothesis by comparing brain and fluid volumes with neurocognitive outcome in pediatric patients with hydrocephalus., Methods: Warf and colleagues previously acquired CT scans for pediatric patients in Uganda with myelomeningocele, measured frontal-occipital horn ratio (FOHR), and administered the modified Bayley Scales of Infant Development, third edition (BSID-III) to measure neurocognitive outcome that did not correlate with FOHR. In this present study, brain and fluid volumes were measured in 33 of these patients, 26 of whom required surgical treatment for hydrocephalus. Linear discrimination analysis (LDA) was used to test whether age-normalized brain and fluid volumes can discriminate neurocognitive outcome., Results: Hydrocephalic patients show normal to small brain volumes and substantially larger fluid volumes compared with normal values. FOHR correlates highly with fluid volume (r=0.84, p<0.001) and substantially less with brain volume (r=-0.37, p=0.03), while brain and fluid volumes do not correlate with each other (p=0.99). Brain and CSF volumes correlated best with fine motor (p=0.03, p=0.01), cognitive (p=0.05, p=0.09), and expressive communication (p=0.08, p=0.08) scores. A combination of these 3 scores was used as a multivariate measure of neurocognitive outcome. Brain volume alone, unlike fluid volume, could discriminate high from low cognitive outcome (by t-test and ANOVA). It was shown that a combination of age-normalized brain and fluid volumes can discriminate neurocognitive outcome by 2-way LDA (p<0.01) and 3-way LDA (p<0.01). The multivariate LDA demonstrated the contribution of large fluid volume to a decrement in cognition., Conclusions: Hydrocephalus is treated by normalizing CSF, but normal brain development depends on brain growth. A combination of brain and CSF volumes appears to be significantly more powerful at predicting good versus poor neurocognitive outcomes in patients with hydrocephalus than either volume alone.

Object: The incidence of temporal lobe epilepsy (TLE) due to mesial temporal sclerosis (MTS) can be high in developing countries. Current diagnosis of MTS relies on structural MRI, which is generally unavailable in developing world settings. Given widespread effects on temporal lobe structure beyond hippocampal atrophy in TLE, the authors propose that CT volumetric analysis can be used in patient selection to help predict outcomes following resection., Methods: Ten pediatric patients received preoperative CT scans and temporal resections at the CURE Children's Hospital of Uganda. Engel classification of seizure control was determined 12 months postoperatively. Temporal lobe volumes were measured from CT and from normative MR images using the Cavalieri method. Whole brain and fluid volumes were measured using particle filter segmentation. Linear discrimination analysis (LDA) was used to classify seizure outcome by temporal lobe volumes and normalized brain volume., Results: Epilepsy patients showed normal to small brain volumes and small temporal lobes bilaterally. A multivariate measure of the volume of each temporal lobe separated patients who were seizure free (Engel Class IA) from those with incomplete seizure control (Engel Class IB/IIB) with LDA (p<0.01). Temporal lobe volumes also separate normal subjects, patients with Engel Class IA outcomes, and patients with Class IB/IIB outcomes (p<0.01). Additionally, the authors demonstrated that age-normalized whole brain volume, in combination with temporal lobe volumes, may further improve outcome prediction (p<0.01)., Conclusions: This study shows strong evidence that temporal lobe and brain volume can be predictive of seizure outcome following temporal lobe resection, and that volumetric CT analysis of the temporal lobe may be feasible in lieu of structural MRI when the latter is unavailable. Furthermore, since the authors' methods are modality independent, these findings suggest that temporal lobe and normative brain volumes may further be useful in the selection of patients for temporal lobe resection when structural MRI is available.

Object: Hydrocephalus is one of the most common brain disorders in children throughout the world. The majority of infant hydrocephalus cases in East Africa appear to be postinfectious, related to preceding neonatal infections, and are thus preventable if the microbial origins and routes of infection can be characterized. In prior microbiological work, the authors noted evidence of seasonality in postinfectious hydrocephalus (PIH) cases., Methods: The geographical address of 696 consecutive children with PIH who were treated over 6 years was fused with satellite rainfall data for the same time period. A comprehensive time series and spatiotemporal analysis of cases and rainfall was performed., Results: Four infection-onset peaks were found to straddle the twice-yearly rainy season peaks, demonstrating that the infections occurred at intermediate levels of rainfall., Conclusions: The findings in this study reveal a previously unknown link between climate and a neurosurgical condition. Satellite-derived rainfall dynamics are an important factor in driving the infections that lead to PIH. Given prior microbial analysis, these findings point to the importance of environmental factors with respect to preventing the newborn infections that lead to PIH.

Object: Neonatal infection is the most common cause of infant hydrocephalus in Uganda. Postinfectious hydrocephalus (PIH) is often accompanied by primary brain injury from the original infection. Since 2001, ETV (with or without choroid plexus cauterization) has been our primary treatment for PIH. The long-term outcome in these children is unknown., Methods: We studied the 5-year outcome in a cohort of 149 infants treated for PIH from 2001 to 2005 and who lived in 4 districts close to the hospital. Survival analysis was performed using the Kaplan-Meier method. Statistical significance was determined using the Fisher, Breslow, and log-rank tests., Results: The patients' mean age at presentation was 9.5 months (median 3.0 months). Eighty-four patients (56.4%) were successfully treated without a shunt. Operative mortality was 1.2% for ETV and 4.4% for shunt placement (p = 0.3). Five-year survival was 72.8% in the non-shunt-treated group and 67.6% in the shunt-treated group, with no difference in survival (log rank p = 0.43, Breslow p = 0.46). Of 43 survivors assessed at 5-11 years, those with shunts had significantly worse functional outcomes (p = 0.003-0.035), probably reflecting treatment selection bias since those with the worst sequelae of ventriculitis were more likely to be treated with shunt placement., Conclusions: Nearly one-third of treated infants died within 5 years, and at least one-third of the survivors were severely disabled. There was no survival advantage for non-shunt-treated patients at 5 years. A randomized trial of endoscopic third ventriculostomy versus shunt placement for treating PIH may be indicated. Public health measures that prevent these infections are urgently needed.

Object: Evidence from the CURE Children's Hospital of Uganda (CCHU) suggests that treatment for hydrocephalus in infants can be effective and sustainable in a developing country. This model has not been broadly supported or implemented due in part to the absence of data on the economic burden of disease or any assessment of the cost and benefit of treatment. The authors used economic modeling to estimate the annual cost and benefit of treating hydrocephalus in infants at CCHU. These results were then extrapolated to the potential economic impact of treating all cases of hydrocephalus in infants in sub-Saharan Africa (SSA)., Methods: The authors conducted a retrospective review of all children initially treated for hydrocephalus at CCHU via endoscopic third ventriculostomy or shunt placement in 2005. A combination of data and explicit assumptions was used to determine the number of times each procedure was performed, the cost of performing each procedure, the number of disability-adjusted life years (DALYs) averted with neurosurgical intervention, and the economic benefit of the treatment. For CCHU and SSA, the cost per DALY averted and the benefit-cost ratio of 1 year's treatment of hydrocephalus in infants were determined., Results: In 2005, 297 patients (median age 4 months) were treated at CCHU. The total cost of neurosurgical intervention was $350,410, and the cost per DALY averted ranged from $59 to $126. The CCHU's economic benefit to Uganda was estimated to be between $3.1 million and $5.2 million using a human capital approach and $4.6 million-$188 million using a value of a statistical life (VSL) approach. The total economic benefit of treating the conservatively estimated 82,000 annual cases of hydrocephalus in infants in SSA ranged from $930 million to $1.6 billion using a human capital approach and $1.4 billion-$56 billion using a VSL approach. The minimum benefit-cost ratio of treating hydrocephalus in infants was estimated to be 7:1., Conclusions: Untreated hydrocephalus in infants exacts an enormous price from SSA. The results of this study suggest that neurosurgical intervention has a cost/DALY averted comparable to other surgical interventions that have been evaluated, as well as a favorable benefit-cost ratio. The prevention and treatment of hydrocephalus in SSA should be recognized as a major public health priority.

Object: Infantile hydrocephalus in East Africa is predominantly postinfectious. The microbial origins remain elusive, since most patients present with postinfectious hydrocephalus after antecedent neonatal sepsis (NS) has resolved., Methods: To characterize this syndrome in Ugandan infants, the authors used polymerase chain reaction targeting bacterial 16S ribosomal DNA from CSF to determine if bacterial residua from recent infections were detectable. Bacteria were identified based on the relationship of genetic sequences obtained with reference bacteria in public databases. The authors evaluated samples from patients presenting during dry and rainy seasons and performed environmental sampling in the villages of patients., Results: Bacterial DNA was recovered from 94% of patients. Gram-negative bacteria in the phylum Proteobacteria were the most commonly detected. Within this phylum, Gammaproteobacteria dominated in patients presenting after infections during the rainy season, and Betaproteobacteria was most common following infections during the dry season. Acinetobacter species were identified in the majority of patients admitted after rainy season infection., Conclusions: Postinfectious hydrocephalus in Ugandan infants appears associated with predominantly enteric gram-negative bacteria. These findings highlight the need for linking these cases with antecedent NS to develop more effective treatment and prevention strategies.

Object: Hydrocephalus has traditionally been quantified by linear measures of ventricular size, with adjunct use of cortical mantle thickness. However, clinical outcome depends on cognitive function, which is more directly related to brain volume than these previous measures. The authors sought to quantify the dynamics of brain and ventricular volume growth in normal compared with hydrocephalic mice., Methods: Hydrocephalus was induced in 14-day-old C57BL/6 mice by percutaneous injection of kaolin into the cisterna magna. Nine hydrocephalic and 6 normal mice were serially imaged from age 2-12 weeks with a 14.1-T MR imaging unit. Total brain and ventricle volumes were calculated, and linear discriminant analysis was applied., Results: Two very different patterns of response were seen in hydrocephalic mice compared with mice with normative growth. In one pattern (3 mice) brain growth was normal despite accumulation of CSF, and in the second pattern (6 mice) abnormal brain enlargement was accompanied by increased CSF volume along with parenchymal edema. In this latter pattern, spontaneous ventricular rupture led to normalization of brain volume, implying edema from transmantle pressure gradients. These 2 patterns of hydrocephalus were significantly discriminable using linear discriminant analysis (p < 0.01). In contrast, clinically relevant measurements of head circumference or frontal and occipital horn ratios were unable to discriminate between these patterns., Conclusions: This study is, to the authors' knowledge, the first serial quantification of the growth of brain and ventricle volumes in normal versus hydrocephalic development. The authors' findings demonstrate the feasibility of constructing normative curves of brain and fluid growth as complements to normative head circumference curves. By measuring brain volumes, distinct patterns of brain growth and enlargement can be observed, which are more likely linked to cognitive development and clinical outcome than fluid volumes alone.