Acupuncture on intrauterine growth restriction associated brain injury: case study including use of magnetic resonance imaging.

Brain injury due to intrauterine growth restriction (IUGR) is a thorny clinical problem that often leads to permanent neurological deficits such as cerebral palsy. Few practical therapies can treat an IUGR-associated brain injury. We employed acupuncture to treat a 6-month-old male patient with severe hypoxic-ischemic encephalopathy (HIE) due to IUGR, as confirmed by magnetic resonance imaging (MRI). Three courses of acupuncture treatment significantly improved some of the patient's clinical characteristics, such as his insensitive responsiveness and motor deficits, with remarkably reversed HIE features on MRI at 1-year of age. This case suggests that acupuncture is a potential treatment option for an IUGR-associated brain injury and warrants further investigation.

A novel scoring system (YASHMA) predicting brain injury in asphyxiated newborns.

BACKGROUND: Hypoxic-ischemic encephalopathy is a complication of adverse intrapartum events and birth asphyxia resulting in brain injury and mortality in late preterm and term newborns. OBJECTIVES: In this study, we aimed to predict brain damage on magnetic resonance imaging (MRI) with a new scoring system. METHODS: Yieldly And Scorable Holistic Measuring of Asphyxia (YASHMA) is generated for detection of brain injury in asphyxiated newborns. Total scores were calculated according to scores of birth weight, gestation weeks, APGAR scores at first and fifth minutes, aEEG patterns and epileptic status of patients. The major outcome of the scoring system was to determine correlation between poor scores and neonatal brain injury detected on MRI. RESULTS: In hypothermia group with brain injury, low gestational weeks and lowest APGAR scores, abnormal aEEG findings were statistically different from others. YASHMA scores were statistically significant with high sensitivity, specificity, AUC and 95% confidence interval values. CONCLUSIONS: YASHMA scoring system is feasible and can be suggestive for detecting brain injury in low-income countries.

Deep nuclei injury distribution in isolated "basal ganglia-thalamus" (BGT) versus combined "BGT and watershed" patterns of hypoxic-ischaemic injury (HII) in children with cerebral palsy.

AIM: To compare frequency and distribution of deep nuclei involvement in isolated basal ganglia and ventrolateral thalamus (BGT) versus combined BGT and watershed (BGT-WS) hypoxic-ischaemic injury (HII). MATERIALS AND METHODS: A retrospective review was undertaken of the magnetic resonance imaging (MRI) reports of children (0-18 years) with isolated BGT or combined BGT-WS HII. The location and extent of deep nuclear injuries were compared between groups using Fisher's exact test. RESULTS: Of 762 MRI reports, 435 (57%) had isolated BGT and 327 (43%) combined BGT-WS. Isolated BGT showed basal ganglia involvement in 85.1% (n=370) versus 49.8% (n=163) for combined BGT-WS (p<0.01). Sole putamen lesions were more common in isolated BGT (70.3%; 306) versus combined (19.3%; 63; p<0.01). Thalamic involvement was similar between isolated BGT (93.8%; 408) and combined BGT-WS (96.9%; 317; p>0.05). Sole ventrolateral nucleus involvement was more common in isolated BGT (66.6%; 291) while sole pulvinar lesions (25.1%; 82) and whole thalamus lesions (41.6%; 136) were more common in combined BGT-WS (p<0.01). Putamen and ventrolateral nucleus was the most frequent BGT lesion combination in isolated BGT (55.4%) but not in combined BGT-WS (8.6%; p<0.01). CONCLUSION: Variations in the frequency of deep nuclear lesions between groups may reflect different underlying pathogenetic mechanisms. Therefore, combined BGT-WS patterns may not necessarily indicate a superimposed profound on partial prolonged HII, as other causes such as neonatal hypoglycaemia may cause these.

Thalamus L-Sign: A Potential Biomarker of Neonatal Partial, Prolonged Hypoxic-Ischemic Brain Injury or Hypoglycemic Encephalopathy?

BACKGROUND AND PURPOSE: Considerable overlap exists in the MR imaging features of hypoglycemic injury and hypoxic-ischemic brain injury, with similar predilections for the occipital and parietal lobes. In partial, prolonged hypoxia-ischemia, there is cortical destruction at the interarterial watershed zones, and in concomitant hypoglycemia and hypoxia-ischemia, an exaggerated final common pathway injury occurs. We interrogated secondary white matter tract-based thalamic injury as a tool to separate pure injuries in each group. MATERIALS AND METHODS: A retrospective observational study of the MRIs of 320 children with a history of hypoxia-ischemia and/or hypoglycemia was undertaken with 3 major subgroups: 1) watershed-type hypoxic-ischemic injury, 2) neonatal hypoglycemia, and 3) both perinatal hypoxia-ischemia and proved hypoglycemia. Cerebral and thalamic injuries were assessed, particularly hyperintensity of the posterolateral margin of the thalami. A modified Poisson regression model was used to assess factors associated with such thalamic injury. RESULTS: Parieto-occipital injuries occurred commonly in patients with hypoglycemia and/or hypoxia-ischemia. Eighty-five of 99 (86%) patients with partial, prolonged hypoxia-ischemia exhibited the thalamus L-sign. This sign was also observed in patients who had both hypoglycemia and hypoxia-ischemia, predominantly attributable to the latter. Notably, the risk of a thalamus L-sign injury was 2.79 times higher when both the parietal and occipital lobes were injured compared with when they were not involved (95% CI, 1.25-6.23; P = .012). The thalamus L-sign was not depicted in patients with pure hypoglycemia. CONCLUSIONS: We propose the thalamus L-sign as a biomarker of partial, prolonged hypoxia-ischemia, which is exaggerated in combined hypoglycemic/hypoxic-ischemic injury.

Hyperbaric oxygen therapy for hypoxic-ischemic encephalopathy in non-fatal drowning.

Paroxysmal autonomic instability syndrome with dystonia (PAISD) is a possible complication that worsens the prognosis of hypoxic-ischemic encephalopathy related to non-fatal drowning. There are case reports of hyperbaric oxygen (HBO2) therapy enhancing recovery in such cases. We report a case of a 5-year-old boy admitted to the Pediatric Intensive Care Unit after a non-fatal drowning. He was transferred under mechanical ventilation and sedation, with hemodynamic instability and hypothermia. On admission he had a Glasgow Coma Score of 6. On the fifth day of admission he presented episodes of dystonia with decerebration posture, diaphoresis, tachycardia and hypertension, sometimes with identified triggers, suggesting PAISD. The episodes were difficult to control; multiple drugs were needed. Electroencephalography showed diffuse slow wave activity, and cranioencephalic magnetic resonance imaging showed hypoxia-related lesions, suggesting hypoxic-ischemic encephalopathy. Early after admission the patient started physiotherapy combined with normobaric oxygen therapy. Subsequently he started HBO2 therapy at 2 atmospheres, with a total of 66 sessions. Dystonia progressively subsided, with gradual discontinuation of therapy. He also showed improvement in spasticity, non-verbal communication and cephalic control. This case highlights the diagnostic and therapeutic challenges of PAISD and the potential benefit of HBO2 therapy, even in the subacute phase, in recovery of hypoxic-ischemic encephalopathy.

Objective and Clinically Feasible Analysis of Diffusion MRI Data can Help Predict Dystonia After Neonatal Brain Injury.

BACKGROUND: Dystonia in cerebral palsy is debilitating but underdiagnosed precluding targeted treatment that is most effective if instituted early. Deep gray matter injury is associated with dystonic cerebral palsy but is difficult to quantify. Objective and clinically feasible identification of injury preceding dystonia could help determine the children at the highest risk for developing dystonia and thus facilitate early dystonia detection. METHODS: We examined brain magnetic resonance images from four- to five-day-old neonates after therapeutic hypothermia for hypoxic-ischemic encephalopathy at a tertiary care center. Apparent diffusion coefficient values in the striatum and thalamus were determined using a web-based viewer integrated with the electronic medical record (IBM iConnect Access). The notes of specialists in neonatal neurology, pediatric movement disorders, and pediatric cerebral palsy (physicians most familiar with motor phenotyping after neonatal brain injury) were screened for all subjects through age of five years for motor phenotype documentation. RESULTS: Striatal and thalamic apparent diffusion coefficient values significantly predicted dystonia with receiver operator characteristic areas under the curve of 0.862 (P = 0.0004) and 0.838 (P = 0.001), respectively (n = 50 subjects). Striatal apparent diffusion coefficient values less than 1.014 × 10-3 mm2/s provided 100% specificity and 70% sensitivity for dystonia. Thalamic apparent diffusion coefficient values less than 0.973 × 10-3 mm2/s provided 100% specificity and 80% sensitivity for dystonia. CONCLUSIONS: Lower striatal and thalamic apparent diffusion coefficient values predicted dystonia in four- to five-day-old neonates who underwent therapeutic hypothermia for hypoxic ischemic encephalopathy. Objective and clinically feasible neonatal brain imaging assessment could help increase vigilance for dystonia in cerebral palsy.

The prognosis of brain magnetic resonance imaging injury pattern for outcomes of hypothermia-treated infants.

Magnetic resonance imaging (MRI) can be a tool that allows the observation of structural injury patterns after cooling. The aim of this study was to determine the early pattern of brain injury in the MRIs of infants with hypoxic ischemic encephalopathy (HIE) after cooling and to search for any clinical factors related to abnormal MRI findings.The study retrospectively recruited 118 infants who were treated with therapeutic hypothermia (TH) between 2013 and 2016.Forty-three patients had normal brain MRI, and 75 had abnormal brain MRI findings. The TH-treated infants with abnormal brain MRI readings showed significantly more clinical seizures and the use of additional antiepileptic drugs (AEDs) than the normal MRI group. As a long-term outcome, more lesions in the basal ganglia and thalamus, posterior limb of internal capsule, or severe white matter lesions were associated with abnormal neurodevelopmental outcomes at 18 to 24 months of age.A higher frequency of clinical seizures and AED use were related to abnormal brain injury on MRI. A significant risk for poor long-term outcomes was found in the abnormal brain MRI group.

Neonatal Vitamin D Status Is Associated with the Severity of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy: A Pilot Study.

OBJECTIVE: The primary aim of this study was to evaluate the association between 25-hydroxyvitamin D (25OHD) concentration at birth and the short-term outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). Our secondary aim was to evaluate the effect of postnatal vitamin D supplementation on outcomes in the perinatal period after hypoxic injury. STUDY DESIGN: This retrospective cohort study included all infants ≥35 weeks gestation admitted to a regional level IV neonatal intensive care unit and diagnosed with moderate or severe HIE. Spearman correlation coefficients were used to evaluate associations between clinical outcomes including standardized brain magnetic resonance imaging (MRI) scores and either 25OHD concentrations in the first 48 hours of life or total vitamin D supplementation. RESULT: A total of 43 infants met inclusion criteria; 22 had 25OHD concentrations drawn within the first 48 hours. There was a significant inverse association between 25OHD concentration and brain injury on MRI (p = 0.017). There was a trend toward decreased ventilator days in infants receiving higher doses of vitamin D in the first week of life (p = 0.062), but there was no association between vitamin D dosing and MRI injury. CONCLUSION: These results support an association between lower vitamin-D levels and early adverse outcomes in HIE, including radiographic severity of brain injury.

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury.

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (1H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA ( r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score ( p = 0.04), thalamic Lac/NAA ( p = 0.04) and neurodevelopmental outcome at one year ( p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study.

BACKGROUND: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy. METHODS: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4-14 days after birth. Clinical neurodevelopmental tests were done 18-24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711. FINDINGS: Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5-10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20-25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94-1·00]; sensitivity 100% [74-100]; specificity 97% [90-100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65-0·78) and 0·60 (0·53-0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65-0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60-0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75-0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76-0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76-0·87). MRS metabolite peak-area ratios (n=160) of NAA-creatine (<1·29) had an AUC of 0·79 (0·72-0·85), of NAA-choline had an AUC of 0·74 (0·66-0·80), and of lactate-NAA (>0·22) had an AUC of 0·94 (0·89-0·97). INTERPRETATION: Thalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration. FUNDING: National Institute for Health Research UK.

Evaluating a Targeted Bedside Measure of Cerebral Perfusion in a Nonhuman Primate Model of Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To compare ultrasound-derived resistive indices (RIs) obtained at the level of the thalamus via fast Doppler ultrasound with traditional anterior cerebral artery measures in a model of neonatal hypoxic-ischemic encephalopathy and to correlate each with clinical outcomes. METHODS: Nine nonhuman primate neonates underwent no umbilical cord occlusion (n = 3), umbilical cord occlusion without hypothermia (n = 3), or umbilical cord occlusion with hypothermia (n = 3). The RI was measured in the anterior cerebral artery and thalamus on days 0, 1, and 4 of life. Magnetic resonance imaging with spectroscopy was performed on day 4. RESULTS: Mean thalamus and anterior cerebral artery RI values in the first 36 hours of life were statistically different in neonates who died (+0.13; P = .019) or developed cerebral palsy (-0.08; P = .003). Thalamic RI values showed stronger associations with serum and spectroscopic lactate values than those in the anterior cerebral artery. The umbilical cord occlusion-with-hypothermia group showed a significant increase in the RI in the thalamus but not the anterior cerebral artery. CONCLUSIONS: Resistive index measurements in the thalamus may eventually supplement other bedside measures for predicting outcomes in the HIE population, but further studies need to differentiate the effect of hypothermia from illness severity on thalamic perfusion.

Injury of the Hypothalamus in Patients With Hypoxic-Ischemic Brain Injury: A Diffusion Tensor Imaging Study.

OBJECTIVES: The survival rate for hypoxic-ischemic brain injury (HI-BI) is less than 20%. Several brain regions, including the caudate, hippocampus, and hypothalamus, are vulnerable to HI-BI. Hypothalamus is involved in regulation of temperature, sleep-wakefulness cycle, emotional behavior, and memory function. Using diffusion tensor imaging, we examined injury of the hypothalamus in patients with HI-BI. METHODS: Twelve patients with HI-BI and 27 healthy control subjects were recruited. The region of interest was defined for the hypothalamus and the fractional anisotropy and apparent diffusion coefficient were measured. RESULTS: The fractional anisotropy value was significantly lower in the patient group compared with the control group (P < 0.05), whereas the apparent diffusion coefficient value was significantly higher compared with that of the control group (P < 0.05). In the individual analysis, 7 (58.3%) of 12 patients and 14 (58.3%) of 24 hemispheres showed a decrement or increment of more than two SDs in either fractional anisotropy or apparent diffusion coefficient values compared with the control group. CONCLUSIONS: Using diffusion tensor imaging, injury of the hypothalamus was demonstrated in patients with HI-BI. Our methodology and results of this study would be helpful in research on the hypothalamus in patients with HI-BI.

Biventricular function on early echocardiograms in neonatal hypoxic-ischaemic encephalopathy.

AIM: To compare early (<24 hours) echocardiograms (ECHOs) in infants with perinatal hypoxic-ischaemic encephalopathy (HIE) undergoing (i) therapeutic hypothermia (TH), (ii) normothermia and (iii) normal controls. METHODS: This was a single-centre retrospective review of clinical early ECHOs of term infants with moderate or severe HIE and controls (with a normal ECHO <72 hours of age). Right (RVO) and left ventricular output (LVO), RV and LV myocardial performance index (MPI), systolic to diastolic duration ratio (S/D) and eccentricity indices (EI) in systole and diastole were compared using ANOVA. RESULTS: Among infants with HIE (n = 56, 38 in the TH and 18 in normothermia groups), 14 (25%) infants died and 42 survived. Significantly elevated biventricular MPI, lower RVO and LVO and pulmonary hypertension (abnormal EI, higher RV S/D and bidirectional or right-to-left ductal shunt) were found in groups with HIE, compared to controls (n = 35). LV MPI was lower in HIE-TH, compared to the HIE-normothermia group. Infants with HIE who died (n = 14) had a significantly lower EId [0.77 (0.09) vs. 0.83 (0.08), p = 0.021] compared to survivors (n = 42). CONCLUSION: Infants with perinatal HIE have ventricular dysfunction; those who died had significantly lower EId than survivors; this association needs to be further validated.

Neuroprotective Treatments after Perinatal Hypoxic-Ischemic Brain Injury Evaluated with Magnetic Resonance Spectroscopy.

Perinatal hypoxic-ischemic brain injury is a major health problem. Adjuvant treatments that improve the neuroprotective effect of the current treatment, therapeutic hypothermia, are urgently needed. The growing knowledge about the complex pathophysiology of hypoxia-ischemia (HI) has led to the discovery of several important targets for neuroprotection. Early interventions should focus on the preservation of energy metabolism, the reduction of glutamate excitotoxicity and oxidative stress, the maintenance of calcium homeostasis, and the prevention of apoptosis. Delayed interventions should promote injury repair. The multiple metabolic changes following HI as well as the metabolic effects of potential treatments can be observed noninvasively by magnetic resonance spectroscopy (MRS). This mini-review provides an overview of the neuroprotective pharmacological agents that have been evaluated with 1H/31P/13C MRS. A better understanding of how these agents influence cerebral metabolism and the use of relevant translational MRS biomarkers can guide future clinical trials.

Intestinal ultrasonography in infants with moderate or severe hypoxic-ischemic encephalopathy receiving hypothermia.

BACKGROUND: Infants with hypoxic-ischemic encephalopathy (HIE) may develop multiorgan dysfunction, but assessment of intestinal involvement is imprecise and based on nonspecific clinical signs that may occur several days later. Ultrasound imaging has been described as a helpful tool in assessing intestinal involvement in many gastrointestinal disorders. OBJECTIVE: Describe abdominal ultrasonography findings in infants receiving therapeutic hypothermia and investigate its association with the severity of the hypoxic-ischemic insult and death. MATERIALS AND METHODS: Studies were performed within the first 36 h of life to assess intestinal appearance (normal bowel, bowel wall echogenicity and thickness, and sloughed mucosa), free fluid, peristalsis and intramural perfusion. These findings were compared between infants with moderate and severe encephalopathy. Ultrasound findings were also categorized in three major groups and compared with markers of severity of the hypoxic-ischemic insult and with mortality. RESULTS: Nineteen infants with moderate and 9 with severe HIE at admission were studied (17.7 ± 9.5 h of life). Major ultrasonography findings were increased bowel wall echogenicity (78%), free fluid (75%), decreased or absent peristalsis (50%) and sloughing of the intestinal mucosa (21%). Abnormal intestinal findings such as increased bowel wall echogenicity in all quadrants and presence of sloughed mucosa were associated with more severe hypoxic-ischemic insult. All 12 patients with normal bowel appearance or increased bowel wall echogenicity restricted to only one quadrant survived, whereas 7/15 (47%) patients with increased bowel wall echogenicity in all four quadrants died during hospitalization. The presence of sloughed mucosa was associated with increased mortality (P < 0.001). CONCLUSION: In infants receiving therapeutic hypothermia, a high prevalence of intestinal involvement was noted by using ultrasonographic assessment. An association between intestinal findings and severity of hypoxic-ischemic insult was observed. The presence of sloughed mucosa is a potential ultrasonographic sign of severity.

[Hypoxic injury of all deep nuclei of the brain--a case report from computed tomography]. / Hypoxischer Schaden aller tiefen Kerngebiete des Gehirns--ein Fallbericht aus der Computertomographie.

Though being inferior to magnetic resonance imaging, computed tomography (CT) of the brain is the most frequently applied imaging modality in the diagnostic workup of acute cerebral Ischaemia. We report on a case of a comatose 53-year-old man who was brought to the emergency room after cardiopulmonary resuscitation. The CT of the brain showed a diffuse brain oedema with an explicit hypodense demarcation of all deep nuclei.

Hypoxic-ischemic encephalopathy with cystic brain stem necroses and thalamic calcifications in a preterm twin.

A severe and rare ischemic brain lesion in a preterm twin boy is reported. The boy was born after two weeks of anhydramnios and amnionic infection at 24 weeks of gestation. Following a difficult Caesarean section and prolonged umbilical cord compression he developed prenatal acidosis with an umbilical cord pH of 6.96. At the age of 7 h, heart rate variability narrowed due to severely disturbed brain stem function and the patient developed clinical signs of hypoxic-ischemic encephalopathy. Sonography demonstrated extensive symmetrical brain stem and basal ganglia lesions. After a prolonged comatose and apneic state, death occurred at the age of 25 days. Autopsy confirmed columnar bilateral cavitation of basal ganglia, diencephalon, brain stem and spinal gray matter, as well as focal calcifications in the palladium, thalamus, and brain stem. The findings highly resemble those observed after experimental or clinical cardiac arrest.