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OBJECT - There is little consensus regarding the indications for surgical CSF diversion (either with implanted temporizing devices [reservoir or subgaleal shunt] or shunt alone) in preterm infants with posthemorrhagic hydrocephalus. The authors determined clinical and neuroimaging factors associated with the use of surgical CSF diversion among neonates with intraventricular hemorrhage (IVH), and describe variations in practice patterns across 4 large pediatric centers.
METHODS - The use of implanted temporizing devices and conversion to permanent shunts was examined in a consecutive sample of 110 neonates surgically treated for IVH related to prematurity from the 4 clinical centers of the Hydrocephalus Clinical Research Network (HCRN). Clinical, neuroimaging, and so-called processes of care factors were analyzed.
RESULTS - Seventy-three (66%) of the patients underwent temporization procedures, including 50 ventricular reservoir and 23 subgaleal shunt placements. Center (p < 0.001), increasing ventricular size (p = 0.04), and bradycardia (p = 0.07) were associated with the use of an implanted temporizing device, whereas apnea, occipitofrontal circumference (OFC), and fontanel assessments were not. Implanted temporizing devices were converted to permanent shunts in 65 (89%) of the 73 neonates. Only a full fontanel (p < 0.001) and increased ventricular size (p = 0.002) were associated with conversion of the temporizing devices to permanent shunts, whereas center, OFCs, and clot characteristics were not.
CONCLUSIONS - Considerable center variability exists in neurosurgical approaches to temporization of IVH in prematurity within the HCRN; however, variation between centers is not seen with permanent shunting. Increasing ventricular size-rather than classic clinical findings such as increasing OFCs-represents the threshold for either temporization or shunting of CSF.
OBJECT - Because there is no gold standard for preoperative diagnosis of shunt failure, understanding the sensitivity, specificity, and predictive values of symptoms, signs, and diagnostic tests enables practitioners to make logical clinical decisions. Parents of children with shunts undergo educational instruction to enable them to recognize shunt failure. The authors prospectively investigated parental ability to recognize shunt failure.
METHODS - Data were prospectively collected on 205 consecutive encounters in 153 children with shunted hydrocephalus presenting to the emergency department or clinic, or as an inpatient consultation, to the Children's Hospital of Alabama between April and October 2010. Regardless of the complaint, all parents were asked if they believed the shunt was in failure. Six children were excluded from analysis because a parental response was lacking. Using the Shunt Design Trial definitions, shunt failure was diagnosed intraoperatively or ruled out if the child did not undergo shunt revision within 1 week of presentation. Sensitivity, specificity, predictive values, and accuracy were calculated using the parental response and shunt failure diagnosis. Secondarily, parents were compared based on their experience with shunt failure in their children; experienced parents were defined as having experienced at least 3 shunt failures. Post hoc analysis evaluated diagnostic test characteristics among hydrocephalus causes and compared parental recognition of shunt failure to head CT and shunt series diagnostic test characteristics. Parents also completed a standardized shunt failure survey regarding their shunt teaching education and symptom tracking.
RESULTS - Children enrolled were a mean age of 6.9 years old, 92 (46%) of the encounters were with male patients, and most patients were Caucasian (69%) and had undergone an average of 2.8 previous shunt revisions. Seventy-one children (36%) were diagnosed with shunt failure. Parental response diagnostic test characteristics were: positive predictive value (PPV) of 41%, negative predictive value (NPV) of 79%, sensitivity of 83%, specificity of 34%, and accuracy of 52% for shunt failure. Sixty-three parents were considered experienced and responded with a PPV of 29%, NPV of 92%, sensitivity of 94%, specificity of 23%, and accuracy of 41%. One hundred thirty-six parents were considered inexperienced and responded with a PPV of 48%, NPV of 75%, sensitivity of 80%, specificity of 41%, and accuracy of 57%. When statistically compared, experienced parents had significantly lower PPV (29% vs 48%, respectively; p = 0.035) and accuracy (41% vs 57%, respectively; p = 0.049) than inexperienced parents. On post hoc analysis, parental recognition of shunt failure was inferior to head CT and shunt series diagnostic tests with a lower specificity (20% vs 88%, respectively; p < 0.0005), PPV (44% vs 84%, respectively; p < 0.0005), NPV (61% vs 85%, respectively; p = 0.006), and accuracy (47% vs. 85%, respectively; p < 0.0005).
CONCLUSIONS - The overall parental response had the greatest value in ruling out shunt failure, reflected in the high NPV, particularly in experienced parents. The head CT and shunt series provide more favorable diagnostic test characteristics than the parental response. Although educational interventions have decreased shunt-related deaths, parents have difficulty differentiating shunt failure from alternative diagnoses.
BACKGROUND - Suspected or complicated intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial agent with excellent activity against pathogens associated with intra-abdominal infections in this population. The purpose of this study was to determine the pharmacokinetics (PK) of meropenem in young infants as a basis for optimizing dosing and minimizing adverse events.
METHODS - Premature and term infants <91 days old hospitalized in 24 neonatal intensive care units were studied. Limited PK sampling was performed following single and multiple doses of meropenem 20 to 30 mg/kg of body weight every 8 to 12 hours based on postnatal and gestational age at birth. Population and individual patient (Bayesian) PK parameters were estimated using NONMEM.
RESULTS - In this study, 200 infants were enrolled and received the study drug. Of them, 188 infants with 780 plasma meropenem concentrations were analyzed. Their median (range) gestational age at birth and postnatal age at PK evaluation were 28 (23-40) weeks and 21 (1-92) days, respectively. In the final PK model, meropenem clearance was strongly associated with serum creatinine and postmenstrual age (clearance [L/h/kg] = 0.12*[(0.5/serum creatinine)**0.27]*[(postmenstrual age/32.7)**1.46]). Meropenem concentrations remained >4 μg/mL for 50% of the dose interval and >2 μg/mL for 75% of the dose interval in 96% and 92% of patients, respectively. The estimated penetration of meropenem into the cerebrospinal fluid was 70% (5-148).
CONCLUSIONS - Meropenem dosing strategies based on postnatal and gestational age achieved therapeutic drug exposure in almost all infants.
Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)- and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel (lambda(
)) and perpendicular (lambda(perpendicular)) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: lambda(
): 2.13 +/- 0.14 and 2.14 +/- 0.11 microm(2)/ms; lambda(perpendicular): 0.67 +/- 0.16 and 0.61 +/- 0.09 microm(2)/ms; MD: 1.15 +/- 0.15 and 1.12 +/- 0.08 microm(2)/ms; FA: 0.68 +/- 0.06 and 0.68 +/- 0.05; MTCSF: 0.52 +/- 0.05 and 0.50 +/- 0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression.
(c) 2009 John Wiley & Sons, Ltd.
During chronic viral infections, T cells are exhausted due to constant antigen exposure and are associated with enhanced programmed death 1 (PD-1) expression. Deficiencies in the PD-1/programmed death-ligand 1 (PD-L1) pathway are associated with autoimmune diseases, including those of the central nervous system (CNS). To understand the role of PD-1 expression in regulating T-cell immunity in the CNS during chronic infection, we characterized PD-1 expression in cerebrospinal fluid (CSF) and blood of individuals with chronic human immunodeficiency virus type 1 (HIV-1) infection. PD-1 expression was higher on HIV-specific CD8(+) T cells than on total CD8(+) T cells in both CSF and blood. PD-1 expression on CSF T cells correlated positively with CSF HIV-1 RNA and inversely with blood CD4(+) T-cell counts, suggesting that HIV-1 infection drives higher PD-1 expression on CSF T cells. However, in every HIV-positive individual, PD-1 expression was higher on T cells in CSF than on those in blood, despite HIV-1 RNA levels being lower. Among healthy HIV-negative controls, PD-1 expression was higher in CSF than in blood. Furthermore, frequencies of the senescence marker CD57 were lower on CSF T cells than on blood T cells, consistent with our prior observation of enhanced ex vivo functional capacity of CSF T cells. The higher PD-1 expression level on CSF T cells therefore does not reflect cellular exhaustion but may be a mechanism to downregulate immune-mediated tissue damage in the CNS. As inhibition of the PD-1/PD-L1 pathway is pursued as a therapeutic option for viral infections, potential effects of such a blockade on development of autoimmune responses in the CNS should be considered.
OBJECT - The purpose of this study was to define the incidence of permanent shunt placement and infection in patients who have undergone the 2 most commonly performed temporizing procedures for posthemorrhagic hydrocephalus (PHH) of prematurity: ventriculosubgaleal (VSG) shunt placement and ventricular reservoir placement for intermittent tapping.
METHODS - The 4 centers of the Hydrocephalus Clinical Research Network participated in a retrospective chart review of infants with PHH who underwent treatment at each institution between 2001 and 2006. Patients were included if they had received a diagnosis of Grade 3 or 4 intraventricular hemorrhage, weighed < 1500 g at birth, and had received surgical intervention. The authors determined the incidence of conversion from a temporizing device to a permanent shunt, the incidence of CSF infection during temporization, and the 6-month CSF infection rate after permanent shunt placement.
RESULTS - Thirty-one (86%) of 36 patients who received VSG shunts and 61 (69%) of 88 patients who received ventricular reservoirs received permanent CSF diversion with a shunt (p = 0.05). Five patients (14%) in the VSG shunt group had CSF infections during temporization, compared with 11 patients (13%) in the ventricular reservoir group (p = 0.83). The 6-month incidence of permanent shunt infection in the VSG shunt group was 16% (5 of 31), compared with 12% (7 of 61) in the reservoir placement group (p = 0.65). For the first 6 months after permanent shunt placement, infants with no preceding temporizing procedure had an infection rate of 5% (1 of 20 infants) and those who had undergone a temporizing procedure had an infection rate of 13% (12 of 92; p = 0.45).
CONCLUSIONS - The use of intermittent tapping of ventricular reservoirs in this population appears to lead to a lower incidence of permanent shunt placement than the use of VSG shunts. The incidence of infection during temporization and for the initial 6 months after conversion appears comparable for both groups. The apparent difference identified in this pilot study requires confirmation in a more rigorous study.
During untreated human immunodeficiency virus type 1 (HIV-1) infection, virus-specific CD8(+) T cells partially control HIV replication in peripheral lymphoid tissues, but host mechanisms of HIV control in the central nervous system (CNS) are incompletely understood. We characterized HIV-specific CD8(+) T cells in cerebrospinal fluid (CSF) and peripheral blood among seven HIV-positive antiretroviral therapy-naïve subjects. All had grossly normal brain magnetic resonance imaging and spectroscopy and normal neuropsychometric testing. Frequencies of epitope-specific CD8(+) T cells by direct tetramer staining were on average 2.4-fold higher in CSF than in blood (P = 0.0004), while HIV RNA concentrations were lower. Cells from CSF were readily expanded ex vivo and responded to a broader range of HIV-specific human leukocyte antigen class I restricted optimal peptides than did expanded cells from blood. HIV-specific CD8(+) T cells, in contrast to total CD8(+) T cells, in CSF and blood were at comparable maturation states, as assessed by CD45RO and CCR7 staining. The strong relationship between higher T-cell frequencies and lower levels of viral antigen in CSF could be the result of increased migration to and/or preferential expansion of HIV-specific T cells within the CNS. This suggests an important role for HIV-specific CD8(+) T cells in control of intrathecal viral replication.
INTRODUCTION - The authors previously conducted a retrospective study regarding deaths from CSF shunt failure to identify circumstances surrounding shunt malfunction-related deaths in children in the modern era.
MATERIALS AND METHODS - Using the same methodology, we conducted a follow-up study to determine whether recent policy and procedural changes instituted since the time of the first study had effected a change in the mortality rate of our shunted patient population.
RESULTS - Thirty-nine original patient records (of patients seen at Children's Hospital who died with the diagnosis of hydrocephalus between 1998 and 2004) were identified and reviewed for inclusion into the study. Only four (10.3%) were found to have died directly as a result of shunt malfunction.
CONCLUSIONS - Our rate of shunt malfunction death has decreased over time. It is reasonable to attribute part of this decline to continued improvements in diagnostic and therapeutic techniques and to the use of surveillance scans to identify asymptomatic patients with shunt failure. However, we believe the majority of this decline is due to two additional factors: (1) increased nursing staff and (2) effective patient/family education.
Protein profiling using mass spectrometry may be useful in identifying previously unknown protein markers in human immunodeficiency virus (HIV) dementia and provide insight into disease pathogenesis. Six samples of matched cerebrospinal (CSF) and blood serum from patients with no, mild, and moderate dementia were prepped for biomarker screening by the Ciphergen system. Chips were analyzed in the matrix-assisted laser desorption/ionization (MALDI) mass spectrometer at low mass (700 to 20,000 Da) and at higher mass (5000 to 100,000 Da). In both serum and CSF samples, differences in protein intensity appeared to correlate with degree of dementia. This preliminary study suggests that protein markers of HIV dementia may be detected by MALDI mass spectrometry.