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1.  Surgery and Neurodevelopmental Outcome of Very Low Birth Weight Infants 
JAMA pediatrics  2014;168(8):746-754.
IMPORTANCE
Reduced death and neurodevelopmental impairment among infants is a goal of perinatal medicine.
OBJECTIVE
To assess the association between surgery during the initial hospitalization and death or neurodevelopmental impairment of very low birth weight infants.
DESIGN
Retrospective cohort analysis of patients enrolled in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database from 1998–2009 and evaluated at 18–22 months’ corrected age.
SETTING
22 academic neonatal intensive care units.
PARTICIPANTS
Inclusion criteria were: birth weight 401–1500 g; survival to 12 hours; available for follow-up. Some conditions were excluded. 12 111 infants were included in analyses, 87% of those eligible.
EXPOSURES
Surgical procedures; surgery also classified by expected anesthesia type as major (general anesthesia) or minor surgery (non-general anesthesia).
MAIN OUTCOME MEASURES
Multivariable logistic regression analyses planned a priori were performed for the primary outcome of death or neurodevelopmental impairment and for the secondary outcome of neurodevelopmental impairment among survivors. Multivariable linear regression analyses were performed as planned for the adjusted means of Bayley Scales of Infant Development, Second Edition, Mental Developmental Index and Psychomotor Developmental Index for patients born before 2006.
RESULTS
There were 2186 major, 784 minor and 9141 no surgery patients. The risk-adjusted odds ratio of death or neurodevelopmental impairment for all surgery patients compared with those who had no surgery was 1.29 (95% confidence interval 1.08–1.55). For patients who had major surgery compared with those who had no surgery the risk-adjusted odds ratio of death or neurodevelopmental impairment was 1.52 (95% confidence interval 1.24–1.87). Patients classified as having minor surgery had no increased adjusted risk. Among survivors who had major surgery compared with those who had no surgery the adjusted odds ratio for neurodevelopmental impairment was 1.56 (95% confidence interval 1.26–1.93) and the adjusted mean Mental Developmental Index and mean Psychomotor Developmental Index values were lower.
CONCLUSIONS AND RELEVANCE
Major surgery in very low birth weight infants is independently associated with a greater than 50% increased risk of death or neurodevelopmental impairment and of neurodevelopmental impairment at 18–22 months’ corrected age. The role of general anesthesia is implicated but remains unproven.
doi:10.1001/jamapediatrics.2014.307
PMCID: PMC4142429  PMID: 24934607
2.  Respiratory Outcomes of the Surfactant Positive Pressure and Oximetry Randomized Trial 
The Journal of pediatrics  2014;165(2):240-249.e4.
Objective
To explore the early childhood pulmonary outcomes of infants who participated in the NICHD SUPPORT Trial, using a factorial design that randomized extremely preterm infants to lower vs. higher oxygen saturation targets and delivery room CPAP vs. intubation/surfactant, found no significant difference in the primary composite outcome of death or BPD.
Study design
The Breathing Outcomes Study, a prospective secondary to SUPPORT, assessed respiratory morbidity at 6 month intervals from hospital discharge to 18–22 months corrected age (CA). Two pre-specified primary outcomes, wheezing more than twice per week during the worst 2 week period and cough longer than 3 days without a cold were compared between each randomized intervention.
Results
One or more interviews were completed for 918 of 922 eligible infants. The incidence of wheezing and cough were 47.9% and 31.0%, respectively, and did not differ between study arms of either randomized intervention. Infants randomized to lower vs. higher oxygen saturation targets had similar risks of death or respiratory morbidities (except for croup, treatment with oxygen or diuretics at home). Infants randomized to CPAP vs. intubation/surfactant had fewer episodes of wheezing without a cold (28.9% vs. 36.5%, p<0.05), respiratory illnesses diagnosed by a doctor (47.7% vs. 55.2%, p<0.05) and physician or emergency room visits for breathing problems (68.0% vs. 72.9%, p<0.05) by 18–22 months CA.
Conclusion
Treatment with early CPAP rather than intubation/surfactant is associated with less respiratory morbidity by 18–22 months CA. Longitudinal assessment of pulmonary morbidity is necessary to fully evaluate the potential benefits of respiratory interventions for neonates.
doi:10.1016/j.jpeds.2014.02.054
PMCID: PMC4111960  PMID: 24725582
Bronchopulmonary Dysplasia; Infant, Newborn; Infant, Low Birth Weight; Infant, Extremely Low Birth Weight; Infant, Premature; Infant, Extremely Low Gestational Age; Infant mortality; Respiratory morbidity; Intensive care, neonatal; Hospital Readmission; Oximetry; Randomized controlled trial; Retinopathy of prematurity (ROP); Continuous Positive Airway Pressure; Intubation, endotracheal; Pulmonary surfactants/therapeutic use; Oxygen inhalation therapy/methods; Oxygen administration & dosage; Follow-up studies
3.  Causes and Timing of Death in Extremely Premature Infants from 2000 through 2011 
The New England journal of medicine  2015;372(4):331-340.
BACKGROUND
Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.
METHODS
We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.
RESULTS
The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008–2011 period (P = 0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008–2011 than in 2000–2003 and 2004–2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P = 0.002). Similarly, in 2008–2011, as compared with 2000–2003, there were decreases in deaths attributed to immaturity (P = 0.05) and deaths complicated by infection (P = 0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P = 0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.
CONCLUSIONS
We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis–related deaths increased. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1403489
PMCID: PMC4349362  PMID: 25607427
4.  Meningoceles in Idiopathic Intracranial Hypertension 
OBJECTIVE
MRI abnormalities have been described in patients with increased intracranial pressure (ICP), including in those with idiopathic intracranial hypertension (IIH). Spontaneous cerebral spinal fluid (CSF)-filled outpouchings of the dura (meningoceles), and secondary CSF leaks can occur from elevated ICP in patients with IIH, however, few studies have evaluated these findings. Our objective was to evaluate the frequency of spontaneous intracranial meningoceles among IIH patients and determine their association with visual outcome.
SUBJECTS AND METHODS
We performed a retrospective case-control study of consecutive IIH patients between 2000 and 2011 who underwent MRI including T2-weighted imaging. Demographics, presenting symptoms, CSF opening pressure, and visual outcome were collected for the first and last evaluations. Controls included patients without headache or visual complaints with normal brain MRIs. Stratified analysis was used to control for potential confounding by age, gender, race, and body mass index.
RESULTS
We included 79 IIH patients and 76 controls. Meningoceles were found in 11% of IIH patients versus 0% of controls (p<0.003). Prominent Meckel’s caves without frank meningoceles were found in 9% of IIH patients versus 0% of controls (p<0.003). Among IIH patients, the presence of meningocele or prominent Meckel’s caves was not associated with demographics, symptoms, degree of papilledema, CSF opening pressure, visual acuity, or visual field defect severity.
CONCLUSION
Meningoceles are significantly more common in IIH patients than in controls, and can be considered an additional imaging sign for IIH. Meningoceles are not, however, associated with decreased CSF opening pressure or better visual outcome in IIH.
doi:10.2214/AJR.13.10874
PMCID: PMC4041691  PMID: 24555598
5.  Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 
Pediatrics  2014;133(2):226-235.
OBJECTIVE:
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.
METHODS:
Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.
RESULTS:
Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.
CONCLUSIONS:
In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.
doi:10.1542/peds.2013-1702
PMCID: PMC3904274  PMID: 24446439
trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm infants
6.  Chorioamnionitis and Early Childhood Outcomes among Extremely Low-Gestational-Age Neonates 
JAMA pediatrics  2014;168(2):137-147.
Importance
Chorioamnionitis is strongly linked to preterm birth and to neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18-22 month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates.
Objective
To compare the neonatal and neurodevelopmental outcomes of three groups of extremely-low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis.
Design
Longitudinal observational study.
Setting
Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.
Participants
2390 extremely preterm infants born <27 weeks' gestational age between January 1, 2006 and December 31, 2008 with placental histopathology and 18-22 months' corrected age follow-up data were eligible.
Main exposure
Chorioamnionitis
Main Outcome Measures
Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant Development, 3rd-Edition) and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth.
Results
Neonates exposed to chorioamnionitis had a lower gestational age (GA) and had higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of gestational age in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological+clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (Adjusted OR 2.4, [1.3- 4.3] without GA; Adjusted OR 2.0, [1.1-3.6] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological+clinical chorioamnionitis (Adjusted OR 0.68, [0.52-0.89] without GA; 0.66, [0.49-0.89] with GA). Risk of behavioral problems did not differ statistically between groups.
Conclusions and Relevance
Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.
doi:10.1001/jamapediatrics.2013.4248
PMCID: PMC4219500  PMID: 24378638
chorioamnionitis; preterm; neurodevelopmental impairment; outcome
7.  Vascular damage in giant cell arteritis 
Autoimmunity  2009;42(7):596-604.
Immune-mediated damage to medium-sized arteries results in wall remodeling with intimal hyperplasia, luminal stenosis and tissue ischemia. In the case of the aorta, vasculitis may result in dissection, aneurysm or rupture. The response-to-injury program of the blood vessel is a concerted action between the immune system and wall-resident cells, involving the release of growth and angiogenic factors from macrophages and giant cells and the migration and hyperproliferation of vascular smooth muscle cells. Innate immune cells, specifically, dendritic cells (DC) positioned in the vessel wall, have been implicated in the earliest steps of vasculitis. Pathogen-derived molecular patterns are capable of activating vascular DC and initiating adaptive immune responses. The pattern of the emerging vessel wall inflammation is ultimately determined by the initial insult. Ligands to toll-like receptor (TLR) 4, such as lipopolysaccharides, facilitate the recruitment of CD4 T cells that invade deep into the wall and distribute in a panarteritic pattern. Conversely, ligands for TLR5 condition vascular DC to support perivasculitic infiltrates. In essence, both innate and adaptive immune reactions collaborate to render the arterial wall susceptible to inflammatory damage. Unique features of the tissue microenvironment, including specialized DC, shape the course of the inflammatory response. Differences in vascular damage pattern encountered in different patients may relate to distinct instigators of vasculitis.
doi:10.1080/08916930903002495
PMCID: PMC4271842  PMID: 19657775
8.  Nonmydriatic retinal photography in the evaluation of acute neurologic conditions 
Neurology: Clinical Practice  2013;3(6):527-531.
Summary
Ocular fundus examination is a fundamental component of the neurologic examination. Finding papilledema in headache patients or retinal arterial emboli in stroke patients can be extremely useful. Although examination of the ocular fundus with a direct ophthalmoscope is an important skill for all neurologists, it is rarely and unreliably performed. Nonmydriatic ocular fundus photography, which allows direct visualization of high-quality photographs of the ocular fundus, has been recently proposed for screening neurologic patients in urgent care settings such as emergency departments. This new technology has many potential applications in neurology, including e-transmission of images for remote interpretation.
doi:10.1212/01.CPJ.0000437089.75536.fd
PMCID: PMC3863976  PMID: 24353924
9.  Primary Spontaneous Cerebrospinal Fluid Leaks and Idiopathic Intracranial Hypertension 
Introduction
Idiopathic intracranial hypertension (IIH) is increasingly recognized as a cause of spontaneous cerebrospinal (CSF) leak in the ENT and neurosurgical literature. The diagnosis of IIH in patients with spontaneous CSF leaks is classically made a few weeks after surgical repair of the CSF leak when symptoms and signs of elevated intracranial pressure (ICP) appear.
Methods
Case reports and literature review. Two young obese women developed spontaneous CSF rhinorrhea related to an empty sella in one, and a cribriform plate encephalocele in the other. Both patients underwent surgical repair of the CSF leak. A few weeks later, they developed chronic headaches and bilateral papilledema. Lumbar punctures showed elevated CSF-opening pressures with normal CSF contents, with temporary improvement of headaches. A man with a three-year history of untreated IIH developed spontaneous CSF rhinorrhea. He experienced improvement of his headaches and papilledema after a CSF shunting procedure, and the rhinorrhea resolved after endoscopic repair of the leak.
Results
These cases and the literature review confirm a definite association between IIH and spontaneous CSF leak based on: 1) similar demographics; 2) increased ICP in some patients with spontaneous CSF leak after leak repair; 3) higher rate of leak recurrence in patients with raised ICP; 4) patients with intracranial hypertension secondary to tumors may develop CSF leak, confirming that raised ICP from other causes than IIH can cause CSF leak.
Conclusions
CSF leak may occasionally keep IIH patients symptom-free; however, classic symptoms and signs of intracranial hypertension may develop after the CSF leak is repaired, exposing these patients to a high risk of recurrence of the leak unless an ICP-lowering intervention is performed.
doi:10.1097/WNO.0b013e318299c292
PMCID: PMC4040082  PMID: 24042170
papilledema; rhinorrhea; cerebrospinal fluid leak; idiopathic intracranial hypertension
10.  Teaching Ophthalmoscopy To Medical Students (The TOTeMS Study) 
American journal of ophthalmology  2013;156(5):1056-1061.e10.
Purpose
To determine medical student preferences for learning the ocular fundus examination and to assess their accuracy using different examination modalities.
Design
Prospective, randomized study of medical student education approaches.
Methods
First-year medical students received training in direct ophthalmoscopy using simulators and human volunteers. Students were randomized to receive vs. not receive specific training on interpreting fundus photographs prior to accuracy assessments. Students’ preferences for each of the three methods (direct ophthalmoscopy on simulators or human volunteers, or use of fundus photographs) and recognition of normal and abnormal fundus features were assessed.
Results
Of 138 first year medical students, 119 (86%) completed all required elements. For learning ophthalmoscopy, 85 (71%) preferred humans to simulators. For learning relevant features of the ocular fundus, 92 (77%) preferred photographs to ophthalmoscopy on simulators or humans. Accuracy of answers was better when interpreting fundus photographs than when performing ophthalmoscopy on simulators (p<0.001). Performance improved after specific teaching about assessing fundus photographs before testing (p=0.02). Examination of the ocular fundus was found easier and less frustrating when using photographs than when using ophthalmoscopy on simulators or humans. Eighty-four students (70%) said they would prefer to have fundus photographs instead of using the ophthalmoscope during upcoming clinical rotations.
Conclusions
Students preferred fundus photographs for both learning and examining the ocular fundus. Identification of ocular fundus features was more accurate on photographs compared to examination by direct ophthalmoscopy. In the future, the increasing availability of non-mydriatic ocular fundus photography may allow replacement of direct ophthalmoscopy in many clinical settings for non-ophthalmologists.
doi:10.1016/j.ajo.2013.06.022
PMCID: PMC3805733  PMID: 24041982
ophthalmoscopy; undergraduate medical education; fundus photography; non-mydriatic retinal camera
11.  Isolated Third, Fourth and Sixth Cranial Nerve Palsies From Presumed Microvascular Versus Other Causes: A Prospective Study 
Ophthalmology  2013;120(11):10.1016/j.ophtha.2013.04.009.
Purpose
To estimate the proportion of patients presenting with isolated third, fourth or sixth cranial nerve palsies of presumed microvascular origin versus other causes.
Design
Prospective, multi-center observational case series.
Participants
One hundred and nine patients, 50 years of age or older with acute isolated ocular motor nerve palsy.
Testing
Magnetic resonance imaging (MRI) of the brain
Main outcome measures
Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment.
Results
Among 109 patients enrolled in the study, there were 22 patients with cranial nerve III palsy, 25 patients with cranial nerve IV palsy and 62 patients with cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5 %, 95% confidence interval (CI): 10.7–24.6%). The presence of one or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke and smoking) was significantly associated with a presumed microvascular cause (p=0.003, Fisher’s exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes including midbrain infarction, neoplasms, inflammation, pituitary apoplexy and giant cell arteritis (GCA). Excluding patients with third cranial nerve palsies and those with GCA the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64).
Conclusions
In our series of patients with acute isolated ocular motor nerve palsies, substantial proportion of patients had other causes including neoplasm, GCA and brainstem infarction. Brain MRI and laboratory work–up has a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present or not.
doi:10.1016/j.ophtha.2013.04.009
PMCID: PMC3795864  PMID: 23747163
12.  Evaluating Retinopathy of Prematurity Screening Guidelines for 24-27 Week Gestational Age Infants 
Objective
To determine if current retinopathy of prematurity screening guidelines1 adequately identify treatable ROP in a contemporary cohort of extremely low gestation infants.
Study Design
Data from the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial were used. Inborn infants 24 0/7 to 27 6/7 weeks gestational age with consent prior to delivery were enrolled in 2005-2009. Severe retinopathy of prematurity (Type 1 retinopathy of prematurity or treatment with laser, cryotherapy, or bevacizumab) or death was the primary outcome for the randomized trial. Examinations followed then current American Academy of Pediatrics (AAP) screening recommendations, beginning by 31-33 weeks postmenstrual age.2,3
Results
1316 infants were enrolled in the trial. 997 of the 1121 who survived to first eye exam had final retinopathy of prematurity outcome determined. 137 (14% of 997) met criteria for severe retinopathy of prematurity and 128 (93%) of those had sufficient data (without missing or delayed exams) to determine age of onset of severe retinopathy of prematurity. Postmenstrual age at onset was 32.1 to 53.1 wks. In this referral center cohort, 1.4% (14/997) developed severe retinopathy of prematurity after discharge.
Conclusion
Our contemporary data support the 2013 AAP screening guidelines for ROP for infants 24 0/7 to 27 6/7 weeks gestational age.1 Some infants do not meet treatment criteria until after discharge home. Post-discharge follow-up of infants who are still at risk for severe ROP is crucial for timely detection and treatment.
doi:10.1038/jp.2014.12
PMCID: PMC3969774  PMID: 24503911
extremely premature infant
13.  Evolving blood pressure dynamics for extremely preterm infants 
Objective
To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants.
Study Design
Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 hours.
Results
A cohort of 367 infants had 18,709 ABP measurements recorded. ABP decreased for the first three hours, reached a nadir at 4 – 5 hours, then increased at an average rate of 0.2 mmHg / hour. The rise in ABP from hour 4 – 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135), or dopamine (n=92). GA specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA.
Conclusion
Arterial blood pressure increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.
doi:10.1038/jp.2014.6
PMCID: PMC3982788  PMID: 24503912
Antihypotensive therapy; fluid bolus; dopamine
14.  A prospective photographic study of the ocular fundus in obstructive sleep apnea 
Background
The prevalence of optic nerve and retinal vascular changes within the obstructive sleep apnea (OSA) population are not well known, although it has been postulated that optic nerve ischemic changes and findings related to elevated intracranial pressure may be more common in OSA patients. We prospectively evaluated the ocular fundus in unselected patients undergoing overnight diagnostic polysomnography (PSG).
Methods
Demographic data, past medical/ocular history and non-mydriatic fundus photographs were prospectively collected in patients undergoing polysomnography at our institution and reviewed for the presence of optic disc edema for which our study was appropriately powered a priori. Retinal vascular changes were also evaluated. OSA was defined using measures of both sleep disordered breathing and hypoxia.
Results
Of 250 patients evaluated in the sleep center, fundus photographs were performed on 215 patients, among whom 127 patients (59%) had an apnea/hypopnea index (AHI) ≥15 events per hour, including 36 with severe OSA. Those with AHI<15 served as the comparison group. None of the patients had optic disc edema (95%CI:0-3%). There was no difference in rates of glaucomatous appearance or pallor of the optic disc among the groups. Retinal arteriolar changes were more common in severe OSA patients (OR: 1.09 per 5 unit increase in AHI, 95%CI: 1.02-1.16; p=0.01), even after controlling for mean arterial blood pressure.
Conclusions
We did not find an increased prevalence of optic disc edema or other optic neuropathies in our OSA population. However, retinal vascular changes were more common in patients with severe OSA, independent of blood pressure.
doi:10.1097/WNO.0b013e318290194f
PMCID: PMC3750087  PMID: 23736744
sleep apnea; optic nerve; retina; neuro-ophthalmology
15.  Outcomes of extremely preterm infants following severe intracranial hemorrhage 
Objective
Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH.
Study design
Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: i) unilateral vs. bilateral ICH; and ii) presence vs. absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI).
Results
Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI.
Conclusions
Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.
doi:10.1038/jp.2013.162
PMCID: PMC4143234  PMID: 24370654
intraventricular hemorrhage; neurodevelopmental impairment; extremely low birth weight; cranial ultrasound
16.  Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial 
The New England journal of medicine  2012;367(26):2495-2504.
BACKGROUND
Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses.
METHODS
Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age.
RESULTS
The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046).
CONCLUSIONS
We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.)
doi:10.1056/NEJMoa1208506
PMCID: PMC4140695  PMID: 23268664
17.  Association of MRI Findings and Visual Outcome in Idiopathic Intracranial Hypertension 
OBJECTIVE
Patients with idiopathic intracranial hypertension (IIH) have elevated intracranial pressure (ICP) without identifiable cause. The clinical course is variable, resulting in irreversible vision loss in some, and a benign course in others. While MRI findings have been described in IIH, their association with visual outcome has not been evaluated.
MATERIALS AND METHODS
46 patients with IIH underwent funduscopic evaluation, visual field testing, lumbar puncture with opening pressure (OP) measurement, and MRI. Patients were stratified into: Group 1: no vision loss (n=28), Group 2: some vision loss (n=10), and Group 3: severe vision loss (n=8). MRI findings in the orbits, pituitary gland, and optic canals, and frequency of skull base cephaloceles and transverse sinus stenosis (TSS) were assessed blinded to the patients’ visual outcome. Demographic, clinical, and MRI findings were evaluated for association with visual outcome.
RESULTS
Patients in group 3 (worst visual outcome) were significantly younger (P=0.03) and had higher OP (P=0.04) than the other groups. There were no significant differences in gender, race, or body mass index. Despite worse visual outcomes and sometimes fulminant vision loss, there were no differences in the frequency of orbital MRI findings, TSS, or in optic canal diameter and pituitary appearance among the three groups. Group 3 had significantly lower cephalocele frequency than the other groups (P=0.04).
CONCLUSION
While MRI findings may suggest elevated ICP and the diagnosis of IIH, they are not predictive of visual outcome in IIH.
doi:10.2214/AJR.12.9638
PMCID: PMC4048553  PMID: 23883223
18.  Does bilateral transverse cerebral venous sinus stenosis exist in patients without increased intracranial pressure? 
Clinical neurology and neurosurgery  2012;115(8):1215-1219.
Objective
Transverse cerebral venous sinus stenosis (TSS) is common among patients with idiopathic intracranial hypertension. TSS likely also exists among individuals with normal ICP but the prevalence is unclear. The goal of this study was to identify patients with incidental TSS and normal ICP and describe their characteristics.
Methods
Among 240 adult patients who underwent brain magnetic resonance imaging (MRI) with magnetic resonance venography (MRV) with contrast at our institution between September 2009 and September 2011, 44 had isolated TSS without further substantial imaging abnormality. Medical records were reviewed for symptoms of increased ICP, papilledema, cerebrospinal fluid (CSF) constituents and opening pressure (OP), and reason for brain imaging. Of these, 37 were excluded for confirmed or possible idiopathic intracranial hypertension. Of the remainder,5 had CSF-OP ≤25 cmH2O without papilledema, and 2 did not have measured ICP, but had no papilledema or symptoms of increased ICP. Imaging was re-interpreted to assess for signs suggestive of elevated ICP and to characterize the TSS further.
Results
All patients were women (mean age: 41, mean BMI: 37.1). CSF contents were normal, but OPs were at the upper limit of normal (22 – 25 cmH2O). Indications for MRI/MRV included query pituitary abnormality (1), migraine (4), and anomalous-appearing optic nerves (2). All had bilateral TSS. Six had short TSS and an empty sella; one had long TSS and no empty sella; one had flattening of the posterior sclera; two had prominence of peri-optic nerve CSF.
Conclusion
Asymptomatic bilateral TSS exists in patients with ICP ≤25 cmH2O, but is likely uncommon. CSF-OP was at the upper limit of normal in our patients, who also had other radiologic signs suggestive (but not specific) of chronically-raised ICP. Findings of bilateral TSS on imaging should prompt funduscopic examination for papilledema.
doi:10.1016/j.clineuro.2012.11.004
PMCID: PMC3610812  PMID: 23219404
transverse cerebral venous sinus stenosis; magnetic resonance venography; intracranial pressure; intracranial venous sinus anatomy; empty sella; flattening of the posterior sclera; peri-optic nerve cerebrospinal fluid
19.  Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants 
Pediatrics  2013;132(1):e175-e184.
OBJECTIVE:
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
METHODS:
We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and ≥25 weeks.
RESULTS:
Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs ≥25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants ≥25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates.
CONCLUSIONS:
Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks’ GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA ≥25 weeks these differences account for only a small part of the variation in mortality.
doi:10.1542/peds.2012-3707
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
20.  Ten-Year Review of Major Birth Defects in VLBW Infants 
Pediatrics  2013;132(1):49-61.
OBJECTIVE:
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
METHODS:
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
RESULTS:
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
CONCLUSIONS:
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
doi:10.1542/peds.2012-3111
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
21.  Obstructive sleep apnea in idiopathic intracranial hypertension: comparison with matched population data 
Journal of neurology  2013;260(7):1748-1751.
Patients with idiopathic intracranial hypertension (IIH) frequently have coexisting obstructive sleep apnea (OSA). We aimed to determine if the prevalence and severity of OSA is greater in patients with IIH than would be expected given their other risk factors for OSA. We included 24 patients (20 women, 4 men) with newly-diagnosed IIH who had undergone overnight polysomnography. We calculated the expected apnea-hypopnea index (AHI) for each patient, based on their age, sex, race, body mass index (BMI), and menopausal status, using a model derived from 1741 randomly-sampled members of the general population who had undergone overnight polysomnography. We compared the AHI values obtained from polysomnography with those predicted by the model using a paired t-test. Our study had 80% power to detect a 10 unit change in mean AHI at α=0.05. Eight patients (33.3%; 6 women, 2 men) had OSA by polysomnography. AHIs from polysomnography were not significantly different from those predicted by the model (mean difference 3.5, 95% CI: −3.0–9.9, p=0.28). We conclude that the prevalence and severity of OSA in IIH patients is no greater than would be expected for their age, sex, race, BMI, and menopausal status. It remains unclear if the presence or treatment of OSA influences the clinical course of IIH.
doi:10.1007/s00415-013-6858-6
PMCID: PMC3707935  PMID: 23412355
Idiopathic intracranial hypertension; Papilledema; Obstructive sleep apnea; Intracranial pressure
22.  Diagnostic accuracy and use of non-mydriatic ocular fundus photography by emergency department physicians: Phase II of the FOTO-ED study 
Annals of emergency medicine  2013;62(1):28-33.e1.
Objective
During the first phase of the FOTO-ED Study, 13% (44/350;95%CI:9–17%) of patients had an ocular fundus finding, such as papilledema, relevant to their emergency department (ED) management found by non-mydriatic ocular fundus photography reviewed by neuro-opthalmologists. All of these findings were missed by ED physicians (EPs), who only examined 14% of enrolled patients by direct ophthalmoscopy. In the present study, we evaluated the sensitivity of non-mydriatic ocular fundus photography, an alternative to direct ophthalmoscopy, for relevant findings when photographs were made available for use by EPs during routine clinical care.
Methods
354 patients presenting to our ED with headache, focal neurologic deficit, visual change, or diastolic blood pressure ≥120 mmHg had non-mydriatic fundus photography obtained (Kowa nonmyd-alpha-D). Photographs were placed on the electronic medical record for EPs review. Identification of relevant findings on photographs by EPs was compared to a reference standard of neuro-ophthalmologist review.
Results
EPs reviewed photographs of 239 patients (68%). 35 patients (10%;95%CI:7–13%) had relevant findings identified by neuro-ophthalmologist review (6 disc edema, 6 grade III/IV hypertensive retinopathy, 7 isolated hemorrhages, 15 optic disc pallor, and 1 retinal vascular occlusion). EPs identified 16/35 relevant findings (sensitivity:46%;95%CI:29–63%), and also identified 289/319 normal findings (specificity:96%; 95%CI:87–94%). EPs reported that photographs were helpful for 125 patients (35%).
Conclusions
EPs used non-mydriatic fundus photographs more frequently than they perform direct ophthalmoscopy, and their detection of relevant abnormalities improved. Ocular fundus photography often assisted ED care even when normal. Non-mydriatic ocular fundus photography offers a promising alternative to direct ophthalmoscopy.
doi:10.1016/j.annemergmed.2013.01.010
PMCID: PMC3722897  PMID: 23433654
23.  Outcomes of Small for Gestational Age Infants < 27 Weeks’ Gestation 
The Journal of pediatrics  2013;163(1):55-60.e1-3.
Objective
To determine whether small for gestational age (SGA) infants <27 weeks gestation is associated with mortality, morbidity, growth and neurodevelopmental impairment at 18–22 months’ corrected age (CA).
Study design
This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network’s Generic Database and Follow-up Studies. Infants born at <27 weeks’ gestation from January 2006 to July 2008 were included. SGA was defined as birth weight <10th percentile for gestational age by the Olsen growth curves. Infants with birth weight ≥10th percentile for gestational age were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes and neurodevelopmental data were compared between the groups. Neurodevelopmental impairment was defined as any of the following: cognitive score <70 on BSID III, moderate or severe cerebral palsy, bilateral hearing loss (+/− amplification) or blindness (vision <20/200). Logistic regression analysis evaluated the association between SGA status and death or neurodevelopmental impairment.
Results
There were 385 SGA and 2586 non-SGA infants. Compared with the non-SGA group, mothers of SGA infants were more likely to have higher level of education, prenatal care, cesarean delivery, pregnancy-induced hypertension and antenatal corticosteroid exposure. SGA infants were more likely to have postnatal growth failure, a higher mortality and to have received prolonged mechanical ventilation and postnatal steroids. SGA status was associated with higher odds of death or neurodevelopmental impairment [OR 3.91 (95% CI: 2.91–5.25), P<0.001].
Conclusion
SGA status among infants <27 weeks’ gestation was associated with an increased risk for postnatal steroid use, mortality, growth failure and neurodevelopmental impairment at 18–22 months’ CA.
doi:10.1016/j.jpeds.2012.12.097
PMCID: PMC3947828  PMID: 23415614
extremely preterm infants; neurodevelopmental follow-up
24.  Late-Onset Sepsis in Very Low Birth Weight Infants from Singleton and Multiple Gestation Births 
The Journal of pediatrics  2013;162(6):1120-1124.e1.
Objectives
To describe and compare incidence of late-onset sepsis (LOS) and demographic and clinical characteristics associated with LOS in very low birth weight (VLBW) infants from singleton and multiple births and to examine the heritability in susceptibility to LOS among VLBW twins by comparing same-sex with unlike-sex twin pairs.
Study design
We studied infants with birth weight 401–1500 grams cared for at clinical centers of the NICHD Neonatal Research Network 2002–2008. Only the first episode of LOS was examined. Stepwise logistic regression models were fitted separately for singleton and multiple pregnancies to examine the maternal and neonatal factors associated with LOS. LOS due to only gram-negative bacteria among singleton and multiple pregnancies was also examined in separate models. The heritability of LOS was estimated by examining concordance of LOS between twins from same-sex and unlike-sex pairs.
Results
LOS occurred in 25.0% (3797/15,178) of singleton and 22.6% (1196/5294) of multiple VLBW infants. Coagulase-negative staphylococci were the most common infecting organisms, accounting for 53.2% of all LOS episodes in singletons and 49.2% in multiples. E. coli and Klebsiella species were the most commonly isolated gram-negative organisms, and Candida albicans was the most commonly isolated fungus. Concordance of LOS was not significantly different between same-sex and unlike-sex twin pairs.
Conclusions
LOS remains a common problem in VLBW infants. The incidence of LOS is similar for singleton and multiple infants. Similar concordance of LOS in same-sex and unlike-sex twin pairs provided no evidence that susceptibility to LOS among VLBW infants is genetically determined.
doi:10.1016/j.jpeds.2012.11.089
PMCID: PMC3633723  PMID: 23324523
Heredity; preterm infants; twins
25.  Use of Antihypotensive Therapies in Extremely Preterm Infants 
Pediatrics  2013;131(6):e1865-e1873.
OBJECTIVE:
To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.
METHODS:
Prospective observational study of infants 230/7 to 266/7 weeks’ gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.
RESULTS:
Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.
CONCLUSIONS:
Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.
doi:10.1542/peds.2012-2779
PMCID: PMC3666108  PMID: 23650301
extremely preterm infant; antihypotensive therapy; blood pressure; hypotension

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