Biochemical profile of human infant cerebrospinal fluid in intraventricular hemorrhage and post-hemorrhagic hydrocephalus of prematurity.

BACKGROUND: Intraventricular hemorrhage (IVH) and post-hemorrhagic hydrocephalus (PHH) have a complex pathophysiology involving inflammatory response, ventricular zone and cell-cell junction disruption, and choroid-plexus (ChP) hypersecretion. Increased cerebrospinal fluid (CSF) cytokines, extracellular matrix proteins, and blood metabolites have been noted in IVH/PHH, but osmolality and electrolyte disturbances have not been evaluated in human infants with these conditions. We hypothesized that CSF total protein, osmolality, electrolytes, and immune cells increase in PHH. METHODS: CSF samples were obtained from lumbar punctures of control infants and infants with IVH prior to the development of PHH and any neurosurgical intervention. Osmolality, total protein, and electrolytes were measured in 52 infants (18 controls, 10 low grade (LG) IVH, 13 high grade (HG) IVH, and 11 PHH). Serum electrolyte concentrations, and CSF and serum cell counts within 1-day of clinical sampling were obtained from clinical charts. Frontal occipital horn ratio (FOR) was measured for estimating the degree of ventriculomegaly. Dunn or Tukey's post-test ANOVA analysis were used for pair-wise comparisons. RESULTS: CSF osmolality, sodium, potassium, and chloride were elevated in PHH compared to control (p = 0.012 - < 0.0001), LGIVH (p = 0.023 - < 0.0001), and HGIVH (p = 0.015 - 0.0003), while magnesium and calcium levels were higher compared to control (p = 0.031) and LGIVH (p = 0.041). CSF total protein was higher in both HGIVH and PHH compared to control (p = 0.0009 and 0.0006 respectively) and LGIVH (p = 0.034 and 0.028 respectively). These differences were not reflected in serum electrolyte concentrations nor calculated osmolality across the groups. However, quantitatively, CSF sodium and chloride contributed 86% of CSF osmolality change between control and PHH; and CSF osmolality positively correlated with CSF sodium (r, p = 0.55,0.0015), potassium (r, p = 0.51,0.0041), chloride (r, p = 0.60,0.0004), but not total protein across the entire patient cohort. CSF total cells (p = 0.012), total nucleated cells (p = 0.0005), and percent monocyte (p = 0.016) were elevated in PHH compared to control. Serum white blood cell count increased in PHH compared to control (p = 0.042) but there were no differences in serum cell differential across groups. CSF total nucleated cells also positively correlated with CSF osmolality, sodium, potassium, and total protein (p = 0.025 - 0.0008) in the whole cohort. CONCLUSIONS: CSF osmolality increased in PHH, largely driven by electrolyte changes rather than protein levels. However, serum electrolytes levels were unchanged across groups. CSF osmolality and electrolyte changes were correlated with CSF total nucleated cells which were also increased in PHH, further suggesting PHH is a neuro-inflammatory condition.

Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity.

Globally, approximately 11% of all infants are born preterm, prior to 37 weeks' gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP.

Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity.

OBJECTIVE: Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH. STUDY DESIGN: Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson's partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores. RESULTS: CSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966). CONCLUSION: CSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity.

BACKGROUND: Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. OBJECTIVE: To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. METHODS: A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. RESULTS: APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. CONCLUSION: Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae.

Role of beta-2-microglobulin as a biomarker in very preterm and extremely preterm infants with CNS inflammation.

BACKGROUND: Premature infants are at risk for severe sepsis and meningitis, both infections associated with high mortality and morbidity. Cerebro-spinal fluid (CSF) culture is the gold standard method for meningitis diagnosis, but interpretation of biochemical parameters of CSF is essential at the moment of the analysis in order to start the appropriate treatment. The main objective of this study was to determine whether levels of CSF beta-2-microglobulin (B2M) were elevated in preterm infants with CNS infections or other inflammatory processes, and to establish if there were differences in B2M concentrations amongst various inflammatory settings (sepsis, meningitis, and progressive post-hemorrhagic ventricular dilatation (PHVD)). METHODS: This is a retrospective study of all very preterm and extremely preterm infants (< 32 weeks of gestation) admitted to our NICU between 2012 and 2017. All those who underwent a lumbar puncture during their stay as part of a sepsis work-up or PHVD were considered for inclusion. CSF biochemical parameters and B2M were tested in all of the patients. RESULTS: Fifty-nine patients were included in the study. In patients with CNS infections, the median value of B2M was 8.69 mg/L (3.92-18.5). B2M levels above 3.92 mg/L showed greater sensitivity and specificity than leukocyte levels in discriminating between patients with CNS infections or other inflammatory processes and those without CNS inflammation. CONCLUSIONS: In this population, CSF B2M proved to be an effective biomarker to discriminate between patients with CNS infections and other inflammatory processes and those without CNS inflammation.

Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus.

BACKGROUND: Neuroinflammation has been implicated in the pathophysiology of post-hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF). METHODS: Lumbar CSF levels of key cytokines (IL-1α, IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, TGF-ß1, IFN-γ) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined. RESULTS: Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1α, IL-4, IL-6, IL-12, TNF-α, CCL-3, CCL-19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1α, IL-1ß, IL-10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1ß and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils. CONCLUSIONS: Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH.

Lumbar Cerebrospinal Fluid Biomarkers of Posthemorrhagic Hydrocephalus of Prematurity: Amyloid Precursor Protein, Soluble Amyloid Precursor Protein α, and L1 Cell Adhesion Molecule.

BACKGROUND: Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with posthemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. OBJECTIVE: To explore the diagnostic ability of candidate CSF biomarkers for PHH. METHODS: Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPß, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. RESULTS: Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared with all other conditions (all P < .001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cut points of 699, 514, and 113 ng/mL yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. CONCLUSION: Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα, in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair.

Hydrocephalus in newborns: clinical conditions and primary surgical treatment.

BACKGROUND: Hydrocephalus is a state in which excessive accumulation of cerebrospinal fluid occurs in intracranial space as a result of disorders of its circulation hydrodynamics. OBJECTIVES: The aim of this study was to analyze the clinical conditions and primary surgical treatment of hydrocephalus in the newborns examined in the study. MATERIAL AND METHODS: The data was gathered using a retrospective analysis of the medical and nursing records of 57 newborns treated for hydrocephalus at the Department of Pediatric Surgery of the Dr. A. Jurasz University Hospital in Bydgoszcz, Poland. RESULTS: In the years 2008-2009 at the Department of Pediatric Surgery of Dr. A. Jurasz University Hospital in Bydgoszcz, 57 newborns were treated for hydrocephalus. In all patients (100% of the study group) regardless of sex, age, place of residence or etiology, the doctors used surgical therapy. CONCLUSIONS: There is a connection between selected causes of hydrocephalus in the study group and sociodemographic characteristics such as the place of residence or age. Sociodemographic data (sex, age, place of residence) have no effect on the treatment of hydrocephalus in newborns. In all cases of hydrocephalus in the study, the treatment used was implantation of a drainage system. Rickham reservoirs are more rarely implanted in full-term newborns than in premature ones, while ventricle-peritoneal valves are more frequently used in full-term newborns than in premature babies. Regardless of the reason for hydrocephalus formation, the treatment is based on surgical intervention and the most common drainage system used to correct the defect is the ventricle-peritoneal valve.

Lumbar puncture in the neonate: challenges in decision making and interpretation.

Multiple studies have provided normative ranges for cerebrospinal fluid (CSF) parameters in term and preterm infants and described changes with advancing postnatal age, as well as in special circumstances, such as traumatic lumbar puncture (LP), previous antibiotic administration, seizures, and concomitant infections at other sites. Although guidelines exist for the interpretation of CSF parameters in neonates, there appears to be no single combination of parameters that conclusively excludes meningitis. It remains important for clinicians to perform LPs early in the course of illness, ideally before the administration of antibiotic therapy. This review presents currently available literature on the indications for LP as well as guidelines for the interpretation of CSF parameters in neonates.

Biomarkers of brain damage in preterm infants.

OBJECTIVE: There is growing evidence on the usefulness of biomarkers in the early detection of preterm infants at risk for brain damage. However, among different tools Activin A, S100B protein and adrenomedullin assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more non-invasive techniques in order to fulfill the minimal handling in diagnostic and therapeutic strategy performance. MATERIALS AND METHODS: The concept of Unconventional Biological Fluid (UBF: urine and saliva) is becoming even stronger and regards the assessment in non-invasive biological fluids of biochemical markers involved in the cascade of events leading to brain damage. RESULTS: Activin A, S100B protein and adrenomedullin in UBF were increased in preterm newborns developing brain damage and/or ominous outcome. CONCLUSIONS: The present manuscript offers an update on the usefulness of Activin A, S100B protein an adrenomedullin in UBF as brain damage markers. The findings open a new cue on the use of these markers in daily neonatal intensive care unit (NICU) activities.

Evaluation of cerebrospinal fluid parameters in preterm infants with intraventricular reservoirs.

OBJECTIVE: Intraventricular reservoirs (IVRs) are used to drain cerebrospinal fluid (CSF) in neonates with post-hemorrhagic ventricular dilatation (PHVD). The objectives of this case-control study were to evaluate changes in CSF parameters in serial IVR taps and to compare CSF parameters in culture-positive and -negative specimens. STUDY DESIGN: Clinical and laboratory data from serial (up to 7) reservoir taps at 5- to 8-day intervals were collected on preterm neonates with PHVD and IVR insertion. RESULT: The median (range) gestational age and birth weight of our cohort (n=52) was 26 (23 to 33) weeks and 796 (450 to 1620) grams. Significant decreases in percentage of CSF neutrophils and protein were noted in later taps, compared with the first tap at insertion of IVR. Five (9.6%) infants had positive CSF cultures on 10 occasions. Compared with negative specimens (n=266), the mean (s.d.) proportion of neutrophils in CSF (55% (33) vs 26% (23)) was significantly higher and ratio of CSF to serum glucose significantly lower (0.19 (0.08) vs 0.29 (0.13)) in culture-positive specimens (n=10). The area under the curve was 0.82 (95% confidence interval (CI) 0.72 to 0.93) for CSF white blood cell (WBC) count, 0.79 (95% CI 0.68 to 0.90) for CSF protein and 0.75 (95% CI 0.56 to 0.95) for percentage of neutrophils. The sensitivities and specificities for diagnosis of infection was 90 and 63% for CSF WBC count > 42 mm(-3), 89 and 58% for CSF protein at > 250 mg dl(-1) and 80 and 67% for CSF neutrophil proportion >31.5%. CONCLUSION: CSF parameters from IVR taps, specifically proportion of neutrophils and proteins are higher at insertion and progressively normalize over time. Although they vary widely, CSF WBC, protein and neutrophil proportion using higher cut-off values have good sensitivity in the diagnosis of infection.

Biomarkers in neonatal posthemorrhagic hydrocephalus.

Posthemorrhagic hydrocephalus (PHH) is a rare but serious outcome among premature babies in the NICU, with consequences including mortality and severe neurodevelopmental disabilities. The causes of PHH are still not entirely understood, and its prevention and treatment are controversial. Various cerebrospinal fluid biomarkers have been studied in infants with PHH in order to recognize the causes, diagnose brain injury, and predict neurodevelopmental outcomes. This systematic review summarizes studies on biomarkers of extracellular matrix activity, fibrinolysis/coagulation, hypoxia/cell death, and inflammation in the cerebrospinal fluid of infants with PHH.

Predictive value of vascular endothelial growth factor in preterm neonates with intraventricular haemorrhage.

OBJECTIVE: Intraventricular haemorrhage (IVH) is a major problem in premature infants. Our objective is to assess the early predictive value of vascular endothelial growth factor (VEGF) for development of IVH and management of its squeal in preterm neonates. METHODS: We prospectively studied 150 preterm neonates (PT) less than 34 weeks gestation. Fifty of them completed the study. 30/50 developed IVH during follow up, and 20 did not. First 24 hours, and 3(rd) day serum samples were collected. Cerebrospinal fluid (CSF) samples were withdrawn for 10 IVH patients. RESULTS: Serum VEGF; both samples were increased in IVH compared to non-IVH group (P=0.001). PHVD-group (n=10) had higher VEGF in both samples than resolved IVH (P=0.004), (P=0.005). While, VEGF increased in the IVH group 2(nd) sample compared to 1(st) (P=0.000), it decreased in non-IVH group, P=0.033). Each 1 unit increase in 1(ST) VEGF increased the risk of occurrence of IVH by 1.6%. 3(rd) day VEGF at a cut-off value of 135 pg/ml is 96% sensitive and 100% specific to predict PHVD. Serum VEGF inversely correlated with TLC, pH, PO(2) and HCO(3), and positively correlated with PCo(2) and FiO(2). CONCLUSION: Serum VEGF predicts development of IVH and PHVD in PT neonates. Also, high CSF level of VEGF could predict the need for permanent shunt placement.

Analysis of the risk of shunt failure or infection related to cerebrospinal fluid cell count, protein level, and glucose levels in low-birth-weight premature infants with posthemorrhagic hydrocephalus.

OBJECT: Premature, low-birth-weight infants with posthemorrhagic hydrocephalus have a high risk of shunt obstruction and infection. Established risk factors for shunt failure include grade of the hemorrhage and age at shunt insertion. There is anecdotal evidence that the amount of red blood cells or protein levels in the CSF may affect shunt performance. However, this has not been analyzed specifically for this cohort of high-risk patients. Therefore, the authors performed this study to examine whether any statistical relationship exists between the CSF constituents and the rate of shunt malfunction or infection in this population. METHODS: A retrospective cohort study was performed on premature infants born at Riley Hospital for Children from 2000 to 2009. Inclusion criteria were a CSF sample analyzed within 2 weeks prior to shunt insertion, low birth weight (< 1500 grams), prematurity (birth prior to 37 weeks estimated gestational age), and shunt insertion for posthemorrhagic hydrocephalus. Data points included the gestational age at birth and shunt insertion, weight at birth and shunt insertion, history of CNS infection prior to shunt insertion, shunt failure, shunt infection, and the levels of red blood cells, white blood cells, protein, and glucose in the CSF. Statistical analysis was performed to determine any association between shunt outcome and the CSF parameters. RESULTS: Fifty-eight patients met the study entry criteria. Ten patients (17.2%) had primary shunt failure within 3 months of insertion. Nine patients (15.5%) had shunt infection within 3 months. A previous CNS infection prior to shunt insertion was a statistical risk factor for shunt failure (p = 0.0290) but not for shunt infection. There was no statistical relationship between shunt malfunction or infection and the CSF levels of red blood cells, white blood cells, protein, or glucose before shunt insertion. CONCLUSIONS: Low-birth-weight premature infants with posthemorrhagic hydrocephalus have a high rate of shunt failure and infection. The authors did not find any association of shunt failure or infection with CSF cell count, protein level, or glucose level. Therefore, it may not be useful to base the timing of shunt insertion on CSF parameters.

Expression of soluble Fas in the cerebrospinal fluid of preterm infants with posthemorrhagic hydrocephalus and cystic white matter damage.

Perinatal brain damage may result in impaired neurological development in extremely preterm infants. The underlying pathophysiological mechanisms are complex, and biomarkers of prognostic value are not available. The aim of this study was to analyze soluble Fas (sFas) concentrations in the cerebrospinal fluid (CSF) representative for involvement of apoptotic processes in preterm infants developing posthemorrhagic hydrocephalus (PHHC) and to link them to white matter damage (WMD) diagnosed by cranial ultrasound. A total of 29 preterm infants with PHHC were included in the study; 17 of them had signs of cystic WMD (cWMD) on ultrasound examinations. CSF samples were obtained at first ventriculostomy, and results were compared to those of a reference group of 24 preterm and term infants without neurologic diseases. sFas concentrations were elevated in CSF samples of PHHC patients compared to the reference group. In patients with cWMD, sFas concentrations were significantly higher than in patients without cWMD. These results indicate that apoptosis via the Fas pathway is involved in the pathogenesis of cWMD in the context of PHHC, and that sFas in the CSF may serve as a marker of cWMD development.

Effect of delay in analysis on neonatal cerebrospinal fluid parameters.

OBJECTIVES: The effect of delayed analysis on cerebrospinal fluid (CSF) white blood cell (WBC) count and glucose has never been studied in neonates. DESIGN: Prospective cohort study. SETTING: Level III newborn unit. PATIENTS: Neonates undergoing lumbar puncture were enrolled after consent. CSF was analysed at baseline (30 minutes) for protein, WBC and glucose; and from the same sample for WBC and glucose after a lag of 2 h and 4 h after lumbar puncture. Those with traumatic/inadequate CSF were excluded. Subjects were classified in three groups (n = 20 each) based on baseline WBC count: no WBC, 1-30 WBC and >30 WBC/microl. Analysis was by repeated-measures ANOVA. RESULTS: There was a significant decline in mean (SD) CSF glucose from baseline to 2 h and 4 h (41.0 (19) to 38.3 (19) and 36.2 (20) mg/dl, respectively) and WBC count (36 (45) to 28.6 (38) and 23.8 (34) cells/microl, respectively; both p<0.001). CSF glucose and WBC declined in all three groups (p<0.001). High baseline CSF WBC (p<0.001) and protein (p<0.001) was associated with a more rapid decline in the levels of CSF WBC, but not glucose. True CSF parameters could be predicted from 4-h parameters: "baseline glucose 5.4 + 0.98 (4-h glucose)" (adjusted R(2) 97.2%, p<0.001) and "baseline WBC 1.3 (4-h WBC) +0.05 (protein)" (adjusted R(2) 98.8%, p<0.001). In group 3, a diagnosis of meningitis (based on pleocytosis) would be missed in 52.6% and 78.9% subjects at 2 h and 4 h, respectively. CONCLUSIONS: CSF WBC count and glucose decrease significantly with time. Reliance on WBC counts of delayed samples can result in underdiagnosis.

Cerebrospinal fluid drainage in posthaemorrhagic ventricular dilatation leads to improvement in amplitude-integrated electroencephalographic activity.

AIM: Progressive posthaemorrhagic ventricular dilatation (PHVD) may induce abnormal amplitude-integrated electroencephalographic (aEEG) activity prior to clinical deterioration or significant cerebral ultrasound changes. These abnormalities might be ameliorated with cerebrospinal fluid (CSF) drainage. The aims of this study were to investigate the occurrence of aEEG-abnormalities with progressive PHVD in relation to clinical and cerebral ultrasound changes and to evaluate whether CSF drainage results in aEEG improvement. METHODS: aEEG and cerebral ultrasound scans were performed in 12 infants with PHVD, before and after CSF drainage, until normalization of aEEG occurred. RESULTS: aEEG was abnormal with progressive PHVD in all patients. Concurrently, 60% of the patients were clinically stable without deterioration in ultrasonographic cerebral abnormalities. Post drainage, continuous pattern was restored in all but one patient, whereas the frequency of discontinuous pattern decreased in nine patients and burst-suppression pattern decreased in all but one patient. Low-voltage pattern was only observed in one patient who suffered severe grade IV IVH and died one week after EVD placement. Sleep-wake cycling matured in 75%. CONCLUSION: These findings demonstrate the impact of CSF drainage on compromised aEEG-activity associated with PHVD. aEEG changes indicative of impaired cerebral function were apparent before clinical deterioration or major ultrasound changes. These changes were reversible with CSF drainage. aEEG should therefore be used in addition to clinical observation and ultrasound when monitoring PHVD.

Meningitis in preterm neonates: importance of cerebrospinal fluid parameters.

Cerebrospinal fluid parameters are of great importance in diagnosing meningitis, but normal values for preterm neonates are based on small, single-center studies. We sought to determine current values for preterm neonate cerebrospinal fluid parameters and assess the association of cerebrospinal fluid parameters with culture proven meningitis. We performed a cohort study of the first lumbar puncture from 4632 neonates < 34 weeks' gestation performed in the years 1997 to 2004 at 150 neonatal intensive care units managed by the Pediatrix Medical Group. We identified 95 cases of meningitis from the 4632 lumbar punctures. The area under the receiver operating characteristic curves for white blood cell count, glucose, and protein were 0.80, 0.63, and 0.72, respectively, for prediction of culture-proven meningitis. Cerebrospinal fluid parameters used to diagnose meningitis in the absence of dependable cerebrospinal fluid cultures are unreliable. Caution should be employed when interpreting cerebrospinal fluid parameters in the premature neonate.

Cerebrospinal fluid compartmental pharmacokinetics of amikacin in neonates.

To describe and investigate the covariate effects of cerebrospinal fluid (CSF) amikacin pharmacokinetics in neonates, CSF samples were prospectively collected from neonates in whom amikacin had been initiated before a diagnostic lumbar puncture was performed. CSF analysis (amikacin concentration, white blood count [WBC], glucose content, and protein concentration) and amikacin therapeutic drug monitoring results (peak and trough concentrations) in serum were recorded. Correlations (Spearman rank) between the CSF amikacin concentration and the CSF WBC and glucose and protein concentration were investigated. There were 44 CSF amikacin concentrations and 83 serum samples available from 43 neonates (mean postmenstrual age, 36 weeks [range, 26 to 41 weeks]; mean weight, 2.43 kg [range, 0.87 to 3.86 kg]). The median time interval between initiation of amikacin administration and CSF sampling was 25 h (range, 2.5 to 93.7 h). The median amikacin concentration in the CSF was 1.08 mg/liter (range, 0.34 to 2.65 mg/liter), and the mean trough and peak amikacin concentrations in serum were 3.8 +/- 2.5 mg/liter and 35.7 +/- 5.9 mg/liter, respectively. A correlation between CSF amikacin and CSF protein contents (P < 0.01, r = 0.41, 95% confidence interval = 0.13 to 0.63) but not between CSF WBC and CSF glucose was documented. A two-compartment (central and CSF) linear disposition model was used to estimate population pharmacokinetics. The half time for equilibration (T(eq)) between serum and CSF compartments was used as a measure of blood-brain barrier permeability. The T(eq) was 7.58 h (coefficient of variation [CV] = 49.1%) with a partition coefficient of 0.103 (CV = 26.4%). There was no relationship between the T(eq) and CSF WBC, CSF glucose content, or CSF protein content.