Postinfectious Hydrocephalus Research Articles

1328. Paenibacillosis: An Emerging Cause of Neonatal Sepsis and Postinfectious Hydrocephalus

Abstract Background The etiology of neonatal sepsis is often not identified. Molecular methods can identify pathogens that culture-based methods miss. Most cases of neonatal sepsis globally are treated empirically per WHO guidelines with intravenous ampicillin and gentamicin, which may not be the best regimen for all pathogens. Methods We prospectively enrolled 800 neonates presenting with signs of sepsis to two Ugandan hospitals. Blood and cerebrospinal fluid were subjected to 16S rRNA sequencing, which identified Paenibacillus thiaminolyticus in 33/800 (4%) neonates. We confirmed the presence of P. thiaminolyticus by quantitative polymerase chain reaction (PCR). We describe neonatal and birth characteristics, presenting signs, and 12-month developmental outcomes for neonates with paenibacillosis. We performed antibiotic susceptibility testing and genomic analyses on three clinical isolates successfully grown in the laboratory. Results Neonates presented at a median age of 3 (1, 7) days. Fever (86%), irritability (78%) and seizures (52%) were common presenting signs (Figure). Most neonates were born vaginally (73%) at a medical facility (79%). Twelve (36%) had an adverse outcome: 5 (15%) neonates died; 4 (14%) survivors developed postinfectious hydrocephalus and three (9%) additional survivors had neurodevelopmental impairment. All three isolates were resistant to vancomycin, two were resistant to penicillin and ampicillin and one was unlikely to be sensitive to ceftriaxone; all were susceptible to gentamicin and meropenem. The genomes of all three strains contained multiple beta-lactamase genes and a cluster of genes that encodes a type IV pilus. Clinical signs at presentation for neonates with good and poor outcomes followng paenibacillosis Conclusion Molecular methods such as 16S rRNA sequencing and PCR can be used to improve the identification of pathogens causing neonatal sepsis. Paenibacillosis is an important emerging cause of neonatal sepsis in Uganda and is likely an underrecognized cause of postinfectious hydrocephalus in the region and possibly elsewhere. Antibiotics commonly used for neonatal sepsis may be inadequate for the treatment of paenibacillosis. Additional studies to understand the pathophysiology and optimal treatment of this novel infection are urgently needed to prevent neonatal mortality and morbidity including postinfectious hydrocephalus. Disclosures Jessica E. Ericson, MD, MPH, Abbvie: Advisor/Consultant Abhaya Kulkarni, MD, MSc, PhD, Medtronic: Advisor/Consultant.

Children hydrocephalus in Togo: etiologies, treatment, and outcomes.

Hydrocephalus is frequent in sub-Saharan African countries. The postinfectious hydrocephalus tends to decrease. The objective of this study was to identify the etiologies and outcomes of hydrocephalus. This was a retrospective study of hydrocephalus cases (0-15 years old) treated in the neurosurgery unit of the Sylvanus Olympio Hospital in Lomé over 10 years (2012-2021). At 1 year, the evolution distinguished in two categories: (1) Good psychomotor development: no delay in the acquisition of walking, language, and school. (2) Psychomotor delay: delay in the acquisition of walking, language, and school. We reported 305 children treated for hydrocephalus representing 1.8% of all neurosurgery unit patients and 34.2% of pediatric pathologies. There was a male predominance (60.6%). We noted second degree consanguinity in 8.5%. The positive maternal serologies were HIV (12.4%), syphilis (8.2%), and toxoplasmosis (2.6%). A malaria episode had been treated during the first trimester in 36.7% of the mothers. The main clinical sign of hydrocephalus was 91.5% of Macrocephalus. Congenital Malformafions were the most common etiologies of hydrocephalus (68.5%). Ventriculoperitoneal shunt was the main surgical method used and 16 deaths were recorded. The medium-term evolution (1 year) was evaluated in 36.1% and noted 61.8% of psychomotor retardation. This study confirms the trend of the predominance of congenital causes of hydrocephalus in Africa, even if maternal infections can be involved in the development of some of them. The morbimortality of this pathology remains important, especially concerning neurocognitive outcomes.

Postinfectious hydrocephalus in African infants: common, under-recognised, devastating, and potentially preventable

With an almost 200 000 estimated new cases of infant hydrocephalus annually, this disease constitutes a heavy burden of disease in sub-Saharan Africa.1 A 2011 analysis estimated that untreated infant hydrocephalus in these countries could result in annual economic losses of more than US$50 billion.2 Currently, the only available treatments for infant hydrocephalus require neurosurgical intervention, to which there is very poor access across Africa. This means that many, and perhaps most, of these infants are never treated, resulting in unnecessary suffering, disability, and death.

Aetiology and diagnostics of paediatric hydrocephalus across Africa: a systematic review and meta-analysis

We aimed to identify the aetiological distribution and the diagnostic methods for paediatric hydrocephalus across Africa, for which there is currently scarce evidence. In this systematic review and meta-analysis, we searched MEDLINE (Ovid), the Cochrane Database of Systematic Reviews (Wiley), Embase (Ovid), Global Health (Ovid), Maternity & Infant Care (Ovid), Scopus, African Index Medicus (Global Index Medicus, WHO) and Africa-Wide Information (EBSCO) from inception to Nov 29, 2021. We included studies from any African country reporting on the distribution of hydrocephalus aetiology in children aged 18 years and younger, with no language restrictions. Hydrocephalus was defined as radiological evidence of ventriculomegaly or associated clinical symptoms and signs of the disorder, or surgical treatment for hydrocephalus. Exclusion criteria were studies only reporting on one specific subgroup or one specific cause of hydrocephalus. We also excluded conference and meetings abstracts, grey literature, editorials, commentaries, historical reviews, systematic reviews, case reports and clinical guidelines, as well as studies on non-humans, fetuses, or post-mortem reports. The proportions of postinfectious hydrocephalus, non-postinfectious hydrocephalus, and hydrocephalus related to spinal dysraphism were calculated using a random-effects model. Additionally, we included a category for unclear cases. Diagnostic methods were described qualitatively. To assess methodological study quality, we applied critical appraisal checklists provided by the Joanna Briggs Institute. The study was registered in Prospero (CRD42020219038). Our search yielded 3783 results, of which 1880 (49·7%) were duplicates and were removed. The remaining 1903 abstracts were screened and 122 (6·4%) full articles were sought for retrieval; of these, we included 38 studies from 18 African countries that studied a total of 6565 children. The pooled proportion of postinfectious hydrocephalus was 28% (95% CI 22-36), non-postinfectious hydrocephalus was 21% (95% CI 13-30), and of spinal dysraphism was 16% (95% CI 12-20), with substantial heterogeneity. The pooled proportion of hydrocephalus of unclear aetiology was 20% (95% CI 13-28). Our findings suggest that postinfectious hydrocephalus is the single most common cause of paediatric hydrocephalus in Africa. For targeted investments to be optimal, there is a need for consensus regarding the aetiological classification of hydrocephalus and improved access to diagnostic services. Rikshospitalet, Oslo University Hospital, Oslo, Norway.

Type IV Pili Are a Critical Virulence Factor in Clinical Isolates of Paenibacillus thiaminolyticus.

Hydrocephalus, the leading indication for childhood neurosurgery worldwide, is particularly prevalent in low- and middle-income countries. Hydrocephalus preceded by an infection, or postinfectious hydrocephalus, accounts for up to 60% of hydrocephalus in these areas. Since many children with hydrocephalus suffer poor long-term outcomes despite surgical intervention, prevention of hydrocephalus remains paramount. Our previous studies implicated a novel bacterial pathogen, Paenibacillus thiaminolyticus, as a causal agent of neonatal sepsis and postinfectious hydrocephalus in Uganda. Here, we report the isolation of three P. thiaminolyticus strains, Mbale, Mbale2, and Mbale3, from patients with postinfectious hydrocephalus. We constructed complete genome assemblies of the clinical isolates as well as the nonpathogenic P. thiaminolyticus reference strain and performed comparative genomic and proteomic analyses to identify potential virulence factors. All three isolates carry a unique beta-lactamase gene, and two of the three isolates exhibit resistance in culture to the beta-lactam antibiotics penicillin and ampicillin. In addition, a cluster of genes carried on a mobile genetic element that encodes a putative type IV pilus operon is present in all three clinical isolates but absent in the reference strain. CRISPR-mediated deletion of the gene cluster substantially reduced the virulence of the Mbale strain in mice. Comparative proteogenomic analysis identified various additional potential virulence factors likely acquired on mobile genetic elements in the virulent strains. These results provide insight into the emergence of virulence in P. thiaminolyticus and suggest avenues for the diagnosis and treatment of this novel bacterial pathogen. IMPORTANCE Postinfectious hydrocephalus, a devastating sequela of neonatal infection, is associated with increased childhood mortality and morbidity. A novel bacterial pathogen, Paenibacillus thiaminolyticus, is highly associated with postinfectious hydrocephalus in an African cohort. Whole-genome sequencing, RNA sequencing, and proteomics of clinical isolates and a reference strain in combination with CRISPR editing identified type IV pili as a critical virulence factor for P. thiaminolyticus infection. Acquisition of a type IV pilus-encoding mobile genetic element critically contributed to converting a nonpathogenic strain of P. thiaminolyticus into a pathogen capable of causing devastating diseases. Given the widespread presence of type IV pilus in pathogens, the presence of the type IV pilus operon could serve as a diagnostic and therapeutic target in P. thiaminolyticus and related bacteria.

Ventriculosubgaleal shunt as a proposed technique for post-infectious hydrocephalus

BackgroundThe management of post-infectious hydrocephalus (PIH) remains challenging for neurosurgeons. It requires a temporary diversion procedure till the normalization of CSF parameters prior to the permanent one. Ventriculosubgaleal shunt (VSGS) was widely used in pediatric cases with post-hemorrhagic hydrocephalus (PHH). However, its role in PIH is still lacking. This study was done to elucidate the safety and efficacy of VSGS as a temporary CSF diversion procedure before the permanent one in patients with PIH.Patients and methodsThis retrospective investigation analyzed the data of 50 consecutive cases who underwent VSGS for PIH.ResultsThe age of the included patients ranged between 1 and 10 months. Twenty-six cases had meningitis and or ventriculitis (52%), while the remaining had shunt infection. At follow-up, arresting of hydrocephalus was noted in ten patients (20%), while another 36 cases required the permanent diversion procedure within 35 days. Regarding the shunt complications, scalp infection, tissue breakdown, and shunt exposure were encountered in ten cases (20%), while CSF leakage was noted in 12 cases (24%). Shunt migration was noted in only two patients (4%). Shunt revision was needed in 16 cases (32%). Mortality was encountered in four cases (8%) because of sepsis. Risk factors for morbimortality included younger age, lower weight, male gender, and meningitis and or ventriculitis.ConclusionVSGS is a safe and effective procedure in infants awaiting definitive VPS for postinfectious hydrocephalus. It was proven that VSGS has shortened the hospital stay and the economic burden on the country.

Surgical Outcomes of Third Ventriculostomy in Patients of Obstructive Hydrocephalus

Introduction: Hydrocephalus is the accumulation of excess cerebrospinal fluid (CSF) in the ventricular system of the brain. Objectives: The main objective of this study is to find the surgical outcomes of third ventriculostomy in patients of obstructive hydrocephalus. Material and methods: The data was collected through non-probability consecutive sampling technique. There were 60 patients which were included in the study. A flexible endoscopic telecamera and a Bugbee electrocautery wire and monitor were used for the procedure. The main causes of hydrocephalus have been identified. history of meningitis, ventriculitis, or illness prior to the development of hydrocephalus; x-rays indicating separation or septa within the ventricles; or postoperative residue of hemosiderin or the presence of yellowish deposits were all taken into consideration of post infectious hydrocephalus. Results: There were 49 male and 11 female patients. The mean age of the patients was 39.38 ± 11.2 years. 27 (45%) patients had hydrocephalus due to tumors, 21 (35%) patients had aqueductal stenosis while 12 (20%) patients had benign cysts. Intraoperative bleeding occurred in 24 patients. ETV was successful in 54/60 – 90percent of the patients. A CSF leak was recognised in 09 patients. 07 patient developed a transient gaze palsy which had resolved when he came for his follow up visit on 10th post operative day. Practical implication: Use effective method for treatment of hydrocephalus in hospitals Conclusion: It is concluded that endoscopic third ventriculostomy, in general, is a very effective method of treatment for hydrocephalus. Keywords: Obstructive Hydrocephalus, ETV, Outcome, CSF, Brain, Ventricular

Outcomes of Endoscopic Third Ventriculostomy in Pediatric Patients With Hydrocephalus.

BackgroundEndoscopic third ventriculostomy (ETV) is used to treat patients with obstructive hydrocephalus in infants. This study evaluated the postoperative outcomes of ETV among pediatric patients.MethodologyA retrospective study was undertaken at the Mardan Medical Complex between June 2018 and June 2021. All pediatric patients who underwent the procedure of ETV in both the absence and presence of choroid plexus cauterization (CPC) at our center were included in the study. Using medical history data, a comprehensive survey questionnaire was designed. The findings and effects were evaluated either as a success or failure.ResultsA total of 90 cases were reviewed during the study. The rate of in-hospital mortality was 1.1% while the most commonly identified causes of hydrocephalus were myelomeningocele and aqueductal stenosis. A total of 39 (43.33%) patients had a successful surgery. In patients where hydrocephalus was secondary to aqueductal stenosis, the success rate was the highest, while the success rate was quite low for post-infectious hydrocephalus and intraventricular hemorrhage (p < 0.0001). The postoperative complication rate was 55.56% in our study. The rate of in-hospital mortality was 1.1%.ConclusionsWe found that the success rate of ETV was dependent upon factors such as the cause of hydrocephalus, type of hydrocephalus, and the age of the patient. Therefore, ETV is not suitable for all patients, and vigilance must be undertaken in selecting patients for the procedure. The rate of postoperative infections in our institution was alarmingly high which is a concerning matter for the institution.

B.3 Activated gene pathways in post-infectious hydrocephalus (PIH):: proteogenomics and the PIH expressome

Background: Proteogenomics, the integration of proteomics and RNASeq expands the discovery landscape for candidate expressed gene networks to obtain novel insights into host response in post-infectious hydrocephalus (PIH). We examined the cerebrospinal fluid (CSF) of infants with PIH, and case controlled against age-matched infants with non-postinfectious hydrocephalus (NPIH) to probe the molecular mechanisms of PIH, leveraging molecular identification of bacterial and viral pathogens. Methods: Ventricular CSF samples of 100 infants ≤ 3 months of age with PIH (n=64) and NPIH (n=36) were analyzed with proteomics and RNASeq. 16S rRNA/DNA sequencing and virome capture identified Paenibacillus spp. and cytomegalovirus as dominant pathogenetic bacteria implicated in our PIH cohort. Proteogenomics assessed differential expression, gene set enrichment and activated gene pathways. Results: Of 616 proteins and 11,114 genes, there was enrichment for the immune system, cell-cell junction signaling and response to oxidative stress. Proteogenomics yielded 33 functionally and genetically associated gene sets related to neutrophil activation, platelet activation, and cytokines (interleukins and interferon) signaling. Conclusions: We identified PIH patients with severe disease at time of hydrocephalus surgery, to have differential expression of proteins/genes involved in neuroinflammation, ependymal barrier integrity and reaction to oxidative stress. Further studies are needed to examine those proteins/genes as biomarkers for PIH.

374 Multi-omic Analysis Identifies a SPAK Kinase-regulated Ensemble of Choroid Plexus Ion Transport Proteins Relevant for Post-infectious Hydrocephalus

INTRODUCTION: Postinfectious hydrocephalus (PIH) is the most common cause of acquired hydrocephalus worldwide. Treatment is typically through CSF diversion via ventriculoperitoneal shunting, which has high rates of morbidity and is often unavailable in developing countries. METHODS: SPAK knockout (KO) rats were generated using Crispr/CAS9. Control and SPAK KO male rats were implanted with an infusion catheter to introduce E. coli (genetically engineered +/-LPS) or LPS into the lateral ventricles over 72 hours. CSF secretion was measured by catheter placement into the lateral ventricle, and ventricular size by MRI. ChP were harvested for immunohistochemistry (IHC), western blot (WB), genomic/proteomic analysis, and single-cell RNA sequencing (scRNAseq). To investigate SPAK-associated ChP targets, we purified the SPAK-protein complex, identified physical interactors using liquid chromatography/dual mass spectroscopy (LC-MS/MS), and validated top candidates by WB/IHC. RESULTS: Robust bumetanide-sensitive, SPAK-dependent, CSF hypersecretion and ventriculomegaly was observed and dependent on the presence of LPS. LPS triggered significant up-regulation of activating SPAK phosphorylation (Thr233/185), and the bumetanide-sensitive cation-chloride cotransporter NKCC1 (Thr203/207/212). LC-MS/MS pull-down assay additionally revealed three other important SPAK-bound ion transporters, alpha-1 subunit of Na/K ATPase, K+ channel KCNJ13/Kir7.1, and Cl- channel CLIC6. All SPAK-bound targets co-localized with pSPAK at the ChP apical membrane in LPS conditions. This interaction, as well as CSF hypersecretion and ventriculomegaly, were abrogated in LPS-treated SPAK KO animals. CONCLUSION: Multi-omic analysis identified a SPAK-regulated ensemble of ion transport proteins relevant for PIH at the ChP apical membrane. Given the recent development of SPAK kinase inhibitors, our findings uncover a targetable mechanism for the pharmacological treatment of PIH and potentially other forms of inflammation-associated acquired hydrocephalus.

Cytomegalovirus infections in infants in Uganda: Newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus

ObjectivesTo estimate the prevalence of cytomegalovirus (CMV) infections among newborn-mother pairs, neonates with sepsis, and infants with hydrocephalus in Uganda. Design and MethodsThree populations—newborn-mother pairs, neonates with sepsis, and infants (≤3 months) with nonpostinfectious (NPIH) or postinfectious (PIH) hydrocephalus—were evaluated for CMV infection at 3 medical centers in Uganda. Quantitative PCR (qPCR) was used to characterize the prevalence of CMV. ResultsThe overall CMV prevalence in 2498 samples across all groups was 9%. In newborn-mother pairs, there was a 3% prevalence of cord blood CMV positivity and 33% prevalence of maternal vaginal shedding. In neonates with clinical sepsis, there was a 2% CMV prevalence. Maternal HIV seropositivity (adjusted odds ratio [aOR] 25.20; 95% confidence interval [CI] 4.43–134.26; p = 0.0001), residence in eastern Uganda (aOR 11.06; 95% CI 2.30–76.18; p = 0.003), maternal age <25 years (aOR 4.54; 95% CI 1.40–19.29; p = 0.02), and increasing neonatal age (aOR 1.08 for each day older; 95% CI 1.00–1.16; p = 0.05), were associated risk factors for CMV in neonates with clinical sepsis. We found a 2-fold higher maternal vaginal shedding in eastern (45%) vs western (22%) Uganda during parturition (n = 22/49 vs 11/50, the Fisher exact test; p = 0.02). In infants with PIH, the prevalence in blood was 24% and in infants with NPIH, it was 20%. CMV was present in the cerebrospinal fluid (CSF) of 13% of infants with PIH compared with 0.5% of infants with NPIH (n = 26/205 vs 1/194, p < 0.0001). ConclusionsOur findings highlight that congenital and postnatal CMV prevalence is substantial in this African setting, and the long-term consequences are uncharacterized.

Preoperative risk and postoperative outcome from subdural fluid collections in African infants with postinfectious hydrocephalus.

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. 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. 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. 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.

C.3 Activated Gene Pathways in Post-Infectious Hydrocephalus (PIH): Proteogenomics and the PIH Expressome

Background: Proteogenomics, the integration of proteomics and RNASeq expands the discovery landscape for candidate expressed gene networks to obtain novel insights into host response in post-infectious hydrocephalus (PIH). We examined the cerebrospinal fluid (CSF) of infants with PIH, and case controlled against age-matched infants with non-postinfectious hydrocephalus (NPIH) to probe the molecular mechanisms of PIH, leveraging molecular identification of bacterial and viral pathogens. Methods: Ventricular CSF samples of 100 infants ≤ 3 months of age with PIH (n=64) and NPIH (n=36) were analyzed with proteomics and RNASeq. 16S rRNA/DNA sequencing and virome capture identified Paenibacillus spp. and cytomegalovirus as dominant pathogenetic bacteria implicated in our PIH cohort. Proteogenomics assessed differential expression, gene set enrichment and activated gene pathways. Results: Of 616 proteins and 11,114 genes, there was enrichment for the immune system, cell-cell junction signaling and response to oxidative stress. Proteogenomics yielded 33 functionally and genetically associated gene sets related to neutrophil activation, platelet activation, and cytokines (interleukins and interferon) signaling. Conclusions: We identified PIH patients with severe disease at time of hydrocephalus surgery, to have differential expression of proteins/genes involved in neuroinflammation, ependymal barrier integrity and reaction to oxidative stress. Further studies are needed to examine those proteins/genes as biomarkers for PIH.

Brain growth after surgical treatment for infant postinfectious hydrocephalus in Sub-Saharan Africa: 2-year results of a randomized trial.

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. 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. 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. 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.

Cytomegalovirus Infections in Ugandan Infants:Newborns, Neonates with Sepsis and Infants with Hydrocephalus

Background: Congenital and postnatal cytomegalovirus (CMV) infections in Uganda is prevalent and may compromise the health of Ugandan children. The objective of this study is to estimate the prevalence of CMV infections in newborns, neonates with sepsis, and infants with hydrocephalus in Uganda. Methods: Three populations: (1) newborn-mother pairs, (2) neonates with sepsis, and (3) infants (≤ 3 months) with non-postinfectious (NPIH) or postinfectious (PIH) hydrocephalus, were evaluated over four years (2016-2019) for CMV infection at three medical centers – two in the Eastern (Mbale) and one in Western (Mbarara) Uganda. To characterize the prevalence of CMV we used quantitative PCR (qPCR) analysis. In newborn-mother pairs maternal blood (n=99) and a subset of matching cord blood (n=92), placental tissue (n=99), and vaginal specimens (n=99) were tested for CMV. In neonates and infants aged 3 months or less, peripheral blood (751 with sepsis, 399 with hydrocephalus) and cerebrospinal fluid samples (560 with sepsis, 399 with hydrocephalus (205 PIH, 194 NPIH) were also tested for CMV. Findings: The overall CMV prevalence across all groups was 9%. In newborn-mother pairs, a 3% (n=3/92; 95% CI, 1-9%) prevalence of cord blood positivity and 33% (n=33/99; 95% CI, 24-44%) prevalence of maternal vaginal shedding of CMV was estimated. In neonates with clinical sepsis, a 2% (n=17/751; 95% CI, 1-4%) CMV prevalence was estimated. Maternal HIV seropositivity (adjusted odds ratio [aOR], 21.09; 95% CI, 4-109; p= 0.0002), residence in Eastern Uganda (aOR, 11.10; 95% CI, 3-77; p=0 .003), maternal age < 25 years (aOR, 4.91; 95% CI, 2-20; p=0.012), and older neonatal age (9 days vs. 5 days; p= 0.006) were associated with CMV in neonates with clinical sepsis. In infants with PIH, the prevalence in blood was 24% (n=50/205; 95% CI, 19-31%) and in infants with NPIH it was 20% (n=39/194; 95% CI, 15-26%; p=0.34). CMV was present in the CSF of 13% (n=26/205; 95% CI, 8-18%) of infants with PIH compared to 0.5% of infants with NPIH (n=1/194; 95% CI, 0-3%, p<0.0001). Interpretation: Our findings highlight that congenital and postnatal CMV prevalence is high in this African setting and the associated complications may be significant. Universal testing and longitudinal studies are critical to understand the burden infant CMV has in sub-Saharan African countries. Funding Statement: U.S. National Institutes of Health (N.I.H) Director’s Pioneer Award 5DP1HD086071 and NIH Director’s Transformative Award 1R01AI145057. Declaration of Interests: No conflict of interest reported. Ethics Approval Statement: For all participants, mothers had to be at least 18 years of age and able to give informed written consent in either English, Lumasaba, Lugwere, Luganda, Ateso or Runyankole. The study was performed with approval from the CCHU Institutional Review Board, the Mbarara University of Science and Technology Research Ethics Committee, the Pennsylvania State University Institutional Review Board, and with oversight from the Ugandan National Council on Science and Technology. Material Transfer Agreements and a US Centers for Disease Control permit were obtained for the proper transfer and importation of samples to the Pennsylvania State University.

Neuroendoscopic surgery in neonates \u2014 indication and results over a 10-year practice

PurposeNeuroendoscopic procedures for treatment of term and preterm newborn infants, such as endoscopic lavage for posthemorrhagic hydrocephalus, are gaining popularity despite sparse data. This single-institution report compiles all neuroendoscopic surgical procedures performed in neonates during a 10-year period.MethodsCharts and electronic records were reviewed of all consecutive newborns who underwent a neuroendoscopic procedure before reaching a postmenstrual age of 44 weeks between 09/2010 and 09/2020. Available documentation was reviewed regarding the performed neuroendoscopic procedure, course of disease, complications, and all re-operations throughout the first year of life.ResultsDuring the 10-year study period, 116 infants (median gestational age at birth: 29 1/7 weeks) underwent a total of 153 neuroendoscopic procedures (median postmenstrual age at surgery: 35 0/7 weeks). The most common indication at the time of the neuroendoscopic procedures (n = 153) was intraventricular hemorrhage (IVH, n = 119), intraventricular infection (n = 15), congenital malformation (n = 8), isolated 4th ventricle (n = 7), multiloculated hydrocephalus (n = 3), and tumor (n = 1). Thirty-eight of 116 children (32.8%) underwent 43 operative revisions after 153 neuroendoscopic procedure (28.1%). Observed complications requiring surgical revision were secondary infection (n = 11), CSF fistula (n = 9), shunt dysfunction (n = 8), failure of ETV (n = 6), among others. 72 children (62%) of 116 children required permanent CSF diversion via a shunt. The respective shunt rates per diagnosis were 47 of 80 (58.8%) for previously untreated IVH, 11 of 13 (84.6%) for intraventricular infection. Shunt survival rate for the first year of life was 74% for the whole cohort.ConclusionThe experience with this large cohort of neonates demonstrates the feasibility of neuroendoscopic technique for the treatment of posthemorrhagic or postinfectious hydrocephalus. Rate and type of complications after neuroendoscopic procedures were within the expected range. Assessing the potential long-term benefits of neuroendoscopic techniques has to await results of ongoing studies.

Surgical treatment of post-infectious hydrocephalus in infants.

The management of post-infective hydrocephalus in infants remains a challenging task for the pediatric neurosurgeon. The decision-making curve is often complex in that appropriate temporizing measures need to be implemented to properly clear any infection within the CSF before any decision can be made regarding a permanent solution. The etiology differs at varying stages of neonatal development, and the weight of the child, skin fragility, and relevant surgical treatment options are often important limiting factors. Deciding on the optimal treatment option involves assessing the etiology, age, and clinical and radiological features of the individual case and selecting the most appropriate surgical option.

ETV and choroid plexus coagulation: a critical analysis

Objective: To analyze the current medical literature regarding the addition of choroid plexus coagulation (CPC) to an endoscopic third ventriculostomy (ETV), with the aim of improving its efficacy. The historical background and rationale for these procedures are also presented. Methods: A Pubmed search using MeSH terms “choroid plexus coagulation” and “endoscopic third ventriculostomy” was performed in October 2020, retrieving 107 papers. A summary of the findings of these articles is provided, with a particular emphasis on the ones with higher scientific evidence levels (two systematic reviews with meta-analyses and three prospective studies with large case series). The following questions should be answered: “Does CPC add to the success rate of ETV, and in comparison, with shunts?” “Which clinical and surgical factors contribute to positive results of CPC / ETV?” And “Does CPC add morbidity / mortality to endoscopic surgery?” Results/Discussion: There is significant evidence to support that CPC adds up to the success rates of ETV; this is particularly true in the context of the so-called “communicating hydrocephalus”, especially for patients with post-infectious and post-hemorrhagic hydrocephalus. Nevertheless, patients with “obstructive” etiologies also benefit from CPC + ETV. Pooled success was estimated at around 63%, and successful results as measured by shunt-free rates ranged from 49% to 75%. The highest benefit was observed in patients above 6 months of age. Other factors that might have an influence in success rates include extent of cauterization and, understandably, the use of flexible endoscopes, that allow for coagulating greater amounts of choroid plexus. Morbidity rates were not affected and remained similar to ETV and other neuroendoscopic procedures alone (around 1% overall). Conclusion: The addition of CPC to an ETV can be quite beneficial and improve its success rate; this combination is certainly useful to avoid shunts. Nevertheless, patient selection and a thorough knowledge of the surgical indications and techniques is still required to achieve satisfactory results.

Predictor of a permanent shunt after treatment of external ventricular draining in pediatric postinfective hydrocephalus-a retrospective cohort study.

To assess the therapeutic efficacy of external ventricular draining (EVD) and to predict the need for permanent shunts in infants with postinfective hydrocephalus (PIHC). This is a retrospective study of infants diagnosed with PIHC and treated by EVD between January 2013 and December 2017 at the Children's Hospital of Fudan University. Clinical, laboratory, and imaging data were collected and analyzed to identify independent risk factors by logistic regression analyses. The predictor was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. In total, 48 patients were identified, and 31 cases (64.5%) had a permanent shunt. EVD was effective in accelerating cerebrospinal fluid purification. In the permanent shunt group, the duration of EVD was significantly longer (28.5 ± 5.2 vs 14.9 ± 3.0 P < 0.05) and the frontal and occipital horn ratio (FOHR) at 7-10 days after EVD was significantly higher (0.57 ± 0.01 vs 0.48 ± 0.01 P < 0.001). The FOHR at 7-10 days after EVD predicts the need for a permanent shunt with an area under the ROC curve of 0.818. EVD was effective for purification of CSF, whereas a permanent shunt was needed for more than half of the patients. The FOHR at 7-10 days after EVD may be a strong predictor for a permanent shunt.

Post-Infective Hydrocephalus

Post-infective hydrocephalus (PIH) arises as a complication of any CNS infection, and can be either communicating or noncommunicating. The aim of this article is to study the various causes of PIH and its pathophysiology and treatment. The literature was searched for articles describing the causes of PIH. Common causes of PIH are CNS tuberculosis (TB), neurocysticercosis, and perinatal or neonatal infection. TBM is most likely to result in hydrocephalus out of all these manifestations of CNS TB, and hydrocephalus is more likely to occur early in the course, typically 4-6 weeks after the onset of TBM, and is more common among children as compared to adults. A trial of medical management (antitubercular therapy, steroids, and decongestants) can be given to patients with communicating hydrocephalus. Ventriculoperitoneal shunt is the most employed method of CSF diversion in these patients. Though traditionally considered contraindicated, many recent studies have found ETV to be a reasonable option in patients with PIH. HCP in patients with neurocysticercosis can be associated with intraventricular cysts and racemose cysts in the basal subarachnoid cisterns. Surgical intervention is required either for cyst removal or CSF diversion. Endoscopic approaches can be used to remove the intraventricular cysts, which takes care of the HCP. PIH in infants can result either from antenatal infections (TORCH infections) or postnatal infections such as meningitis. Management of PIH can be challenging. Management has to be individualized.