Early exit from neonatal therapeutic hypothermia: A single institution experience using MRI to guide decision-making.

BACKGROUND: To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit". METHODS: Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment. RESULTS: Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (p < 0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination. CONCLUSIONS: Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.

Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

BACKGROUND: The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside. OBJECTIVE: The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia. DESIGN/METHODS: In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1-2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram. RESULTS: Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r=0.88; p value=0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE. CONCLUSIONS: NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.

Passive cooling during transport of asphyxiated term newborns.

OBJECTIVE: To evaluate the efficacy and safety of passive cooling during transport of asphyxiated newborns. STUDY DESIGN: Retrospective medical record review of newborns with perinatal asphyxia transported for hypothermia between July 2007 and June 2010. RESULT: Of 43 newborns transported, 27 were passively cooled without significant adverse events. Twenty (74%) passively cooled newborns arrived with temperature between 32.5 and 34.5 °C. One newborn arrived with a temperature <32.5, and 6 (22%) had temperatures >34.5 °C. Time from birth to hypothermia was significantly shorter among passively cooled newborns compared with newborns not cooled (215 vs 327 min, P<0.01), even though time from birth to admission to Boston Children's Hospital was similar (252 vs 259 min, P=0.77). Time from birth to admission was the only significant predictor of increased time to reach target temperature (P=0.001). CONCLUSION: Exclusive passive cooling achieves significantly earlier initiation of effective hypothermia for asphyxiated newborns but should not delay transport for active cooling.

Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders.

BACKGROUND: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. PATIENTS: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. RESULTS: We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. CONCLUSIONS: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.

Time course of changes in diffusion-weighted magnetic resonance imaging in a case of neonatal encephalopathy with defined onset and duration of hypoxic-ischemic insult.

The onset and duration of hypoxic-ischemic (HI) insults rarely can be determined precisely in perinatal asphyxia. The need to establish the timing of HI insults will be critical for the successful application of evolving neuroprotective therapies that may be administered to the asphyxiated newborn. Diffusion-weighted magnetic resonance imaging has emerged as an imaging technique that can be used to identify HI brain injury before the detection of abnormalities by conventional magnetic resonance imaging. This case illustrates the early changes in diffusion-weighted and conventional magnetic resonance imaging studies and in quantitative values of the apparent diffusion coefficient in a unique case of neonatal asphyxia in which the onset and duration of the HI insult were known.hypoxia-ischemia, newborn brain, perinatal asphyxia, diffusion-weighted imaging, proton magnetic resonance spectroscopy.

Cerebral infarction in Menkes' disease.

Menkes' disease is an X-linked disorder caused by impaired intracellular transport of copper. Currently, no therapy effectively arrests the relentless neurodegeneration of Menkes' disease. Previous neuroimaging reports of patients with Menkes' disease describe a range of abnormalities, including intracranial vessel tortuosity and cerebral white matter changes. We report two infants with Menkes' disease who developed ischemic cerebrovascular disease early in infancy. Magnetic resonance studies, including diffusion-weighted imaging and proton magnetic resonance spectroscopy, demonstrated bilateral infarctions of deep gray matter nuclei, a finding not previously described in Menkes' disease. Potential mechanisms for these cerebrovascular lesions in Menkes' disease include the susceptibility to free radical attack and inadequate energy supply from oxidative phosphorylation. These infarctions may play an unrecognized but important role in the neurodegeneration of children with Menkes' disease. The development of effective therapeutic agents against this disease will require a more detailed understanding of such underlying mechanisms.

Noninvasive detection of changes in cerebral blood flow by near-infrared spectroscopy in a piglet model of hydrocephalus.

Formulation of rational interventions in infantile hydrocephalus is limited by the inability to monitor cerebral hemodynamics quantitatively, continuously, and noninvasively. Near-infrared spectroscopy (NIRS) measures changes in cerebral concentration of oxygenated and deoxygenated hemoglobin (HbO(2) and Hb); HbD is the derived difference between HbO(2) and Hb. Our previous work showed that HbD reflected cerebral blood flow (CBF) measured by radioactive microspheres in a piglet model of systemic hypotension. This study was designed to determine whether NIRS detected important changes in cerebral perfusion and oxygenation in a piglet model of hydrocephalus and whether changes in HbD accurately reflected changes in CBF. Acute hydrocephalus was produced in neonatal piglets by intraventricular infusion of "mock cerebrospinal fluid." Intracranial pressure (ICP) was maintained for several minutes at approximately 10, 20, and 30 mm Hg above the baseline ICP. CBF was measured in cerebral cortex, white matter, and basal ganglia at each ICP by radioactive microspheres. Changes in HbO(2) and Hb were measured continuously by NIRS. Cerebral perfusion pressure declined with increasing ICP, and this decline was accompanied by significant decreases in HbD measured by NIRS and CBF measured by radioactive microspheres. There was a strong correlation between changes in HbD and individual changes in CBF in cerebral cortex, white matter, and basal ganglia (all p < 0.0001). This study demonstrates that changes in HbD reflect changes in CBF over a wide range of ICP in a model of acute hydrocephalus. This reproducible and easily obtained measurement by NIRS could facilitate considerably decisions concerning therapeutic interventions.

New technologies in pediatric neurology. Near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) is a relatively new technology that offers the enormous advantage of making measurements in vivo of changes in cerebral hemodynamics and oxygenation. Because NIRS is noninvasive and portable, it can provide real-time measurements of these changes at the bedside. Thus NIRS is ideally suited to the study of many physiological and pathological processes affecting the brain, particularly in the infant or young child in the intensive care unit or operating room. This review outlines the basic principles, advantages, and limitations of the current state of NIRS technology. An emphasis is placed on the animal and clinical studies that are relevant to the field of child neurology, with an eye to the future evolution and potential applications of this promising technique.

Sonographic ventriculography: a new potential use for sonographic contrast agents in neonatal hydrocephalus.

BACKGROUND AND PURPOSE: Sonographic identification of communicating and noncommunicating forms of posthemorrhagic hydrocephalus can be difficult. This study evaluates the feasibility of using sonographic contrast agents to determine ventricular patency in a newborn animal model. METHODS: A craniotomy was performed and a catheter was placed under sonographic guidance into the lateral ventricle in five anesthetized newborn piglets. Sonograms were obtained before and after intraventricular injection of 0.01 mL of a sonographic contrast agent (Imagent, formulation AF0150; Alliance Pharmaceutical Corp, San Diego, CA) diluted in 1 mL normal saline, and images were assessed for presence and location of echogenic contrast material. RESULTS: Flow of contrast material was identifiable from the ipsilateral lateral ventricle into the contralateral lateral ventricle, and through the third and fourth ventricles into the basal cisterns during real-time sonography in every animal. Ventricular and cistern echogenicity remained increased for approximately 4 minutes after injection. CONCLUSION: Contrast-enhanced sonographic ventriculography has the potential to identify patency of CSF pathways in newborns with hydrocephalus and an indwelling ventricular catheter.