Cerebellar peduncle damage in Langerhans cell histiocytosis-associated neurodegenerative disease revealed by diffusion tensor imaging.

PURPOSE: To confirm the hypothesis that brain white matter damage is involved in the pathogenesis and disease progression of Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND), we aimed to analyze pediatric patients with LCH using diffusion tensor imaging (DTI). METHODS: We enrolled 33 patients with LCH and obtained 33 DTI datasets. Using DTI-based tractography, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured in the cerebral and cerebellar white matter tracts. The participants were divided into three groups-non-ND, ND without clinical symptoms (r-ND), and ND with clinical symptoms (c-ND)-according to their clinical status during the examination with DTI. We compared the DTI parameters in white matter tracts were compared among the three groups. RESULTS: In the order of non-ND, r-ND, and c-ND groups, the FA in superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) significantly decreased, the ADC, AD, and RD of MCP, and the RD of SCP were significantly elevated (FA-SCP; p < 0.001, FA-MCP; p = 0.026, ADC-MCP; p < 0.001, AD-MCP; p = 0.002, RD-MCP; p = 0.003, and RD-SCP; p = 0.018). Furthermore, in the simple linear regression analysis, the FA, ADC, AD, and RD values in the MCP and the FA value in the SCP were significantly influenced by the presence of neurological symptoms and ND findings on MRI (all p < 0.001). CONCLUSION: In LCH-ND, we identified microstructural damage in the SCP and MCP. DTI parameters in these tracts may help monitor LCH-ND; therefore, future studies are required to validate these results in a large cohort.

The prediction of estimated cerebral perfusion pressure with trans-systolic time in preterm and term infants.

It is important to monitor cerebral perfusion in infants because hypo- and hyperperfusion can contribute to neurological injury. This study aimed to clarify the relationship between trans-systolic time (TST) and critical closing pressure (CrCP) or estimated cerebral perfusion pressure (CPPe) in neonates. Moreover, we aimed to determine the TST values in preterm and term infants with stable cerebral perfusion to clarify normative reference data. This multicentre prospective study included infants with arterial lines admitted to the neonatal intensive care units between December 2021 and August 2023. TST, CrCP, and CPPe were calculated using middle cerebral artery waveforms recorded using transcranial Doppler ultrasonography when clinicians collected arterial blood samples. Three hundred and sixty samples were obtained from 112 infants with a gestational age of 32 (interquartile range, 27-37) weeks and a birth weight of 1481 (956-2355) g. TST was positively correlated with CPPe (r = 0.60, p < 0.001), but not with CrCP (r = 0.08, p = 0.10). The normative reference values of TST in preterm and term infants without samples of hyper- or hypocapnia and/or hyper- or hypotension, which may affect cerebral perfusion, were as follows: ≤ 29 weeks, 0.12 (0.11-0.14) s; 30-36 weeks, 0.14 (0.12-0.15) s; and ≥ 37 weeks, 0.16 (0.14-0.17) s, respectively.  Conclusion: TST in neonates significantly correlated with CPPe, but not with CrCP. TST may be a good predictor of cerebral perfusion and potentially have wider clinical applications. What is Known: • Trans-systolic time (TST) is used in evaluating the effects of increased intracranial pressure on cerebral haemodynamics. However, little is known about the efficacy of TST in predicting neonatal cerebral perfusion pressure. What is New: • This study added evidence that TST correlated with estimated cerebral perfusion pressure, but not with critical closing pressure. Additionally, we showed the normative reference values of the TST in preterm and term infants.

Radiographic scores as a predictor of oxygenation index in very low-birthweight infants.

BACKGROUND: Very low birthweight infants (VLBWIs) often undergo chest radiographic examinations without standardization or objectivity. This study aimed to assess the association of two radiographic scores, the Brixia and radiographic assessment of lung edema (RALE), with oxygenation index (OI) in ventilated VLBWIs and to determine the optimal cutoff values to predict hypoxic respiratory severity. METHODS: VLBWIs who received invasive respiratory support with arterial lines between January 2010 and October 2023 were enrolled in this study (n = 144). The correlation between the Brixia or RALE scores and OI was investigated. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff points of the two radiographic scores for predicting OI values (OI ≥5, ≥10, and ≥15). RESULTS: The enrolled infants had a median gestational age of 27 weeks (interquartile range [IQR], 25-28 weeks) and a median birthweight of 855 g (IQR, 684-1003 g). Radiographic scoring methods correlated with the OI (Brixia score: r = 0.79, p < 0.001; RALE score: r = 0.72, p < 0.001). The optimal cutoff points for predicting OI values were as follows: Brixia score: OI ≥5, 10; OI ≥10, 13; OI ≥15, 15; RALE score: OI ≥5, 22; OI ≥10, 31; and OI ≥15, 40. CONCLUSIONS: Brixia and RALE scores are useful predictive markers of the oxygenation status in intubated VLBWIs with stable hemodynamics. These scores are easy to use and promising tools for clinicians to identify patients with a higher risk of hypoxic respiratory failure.

Effectiveness of cardiac palliative surgery for trisomy 18 patients with increased pulmonary blood flow.

Congenital heart disease (CHD) is common among patients with trisomy 18 (T18), but cardiac surgery has been rarely indicated for T18 patients due to their short life span. Although the therapeutic effects of aggressive interventions were recently demonstrated for T18 patients, the subjects and factors examined varied, resulting in inconsistent findings. Therefore, the effects of cardiac surgery for T18 remain unclear. We herein investigated the outcomes of cardiac palliative surgery for CHD with increased pulmonary blood flow in T18 patients. 27 patients were examined: 13 (48.1%) underwent cardiac palliative surgery and 14 (51.9%) did not. Median survival times in the no-surgery and surgery groups were 223.0 days (95% confidence interval [CI]: 46-361 days) and 723.0 days (95% CI: 360-1447 days), respectively. The number of patients with pulmonary hypertension significantly differed between the two groups (5 of 14 in the no-surgery group and 0 in the surgery group). Five of 14 patients in the no-surgery group and 10 of 13 in the surgery group were discharged to home care (odds ratio: 10.8 [95% CI: 1.07-110.0]). Therefore, cardiac palliative surgery may be used to treat CHD with increased pulmonary blood flow in T18 patients.

Low-grade IVH in preterm infants causes cerebellar damage, motor, and cognitive impairment.

BACKGROUND: Few studies have examined the effect of low-grade intraventricular hemorrhage (IVH) on the white matter in the cerebellum and its association with neurodevelopment. We evaluated cerebellar white matter at term-equivalent age (TEA) in preterm infants with low-grade IVH. Furthermore, we assessed neurodevelopmental outcomes at 3 years of age to examine the influence of low-grade IVH on neurodevelopment. METHODS: Thirteen infants with low-grade IVH and 26 without IVH, born at <30 weeks' postmenstrual age (PMA), were enrolled in this study. Diffusion tensor imaging (DTI) parameters, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in the middle and superior cerebellar peduncles (SCP), were measured. Neurodevelopmental outcomes at three years of age were assessed and the correlation between DTI parameters and developmental quotient (DQ) was analyzed. RESULTS: Preterm infants with IVH showed lower FA values (P < 0.01) and higher ADC values (P < 0.05) in the SCP at TEA than the no-IVH group. Lower Postural-Motor and Cognitive-Adaptive DQ at 3 years of age were observed in the IVH compared to the no-IVH group. A significant correlation between the FA values in the SCP at TEA and the Posture-Motor DQ was observed at three years of age (P = 0.043, r = 0.50). CONCLUSIONS: These data suggest that low-grade IVH in preterm infants affects the SCP at TEA and that impaired cerebellar white matter correlates with poor motor development at three years of age.

Validity of stress assessment using heart-rate variability in newborns.

BACKGROUND: The process of birth causes stress for neonates, but additional stressors for sick neonates are a matter of concern. As analysis of heart-rate variability (HRV), which reflects autonomic activity, has demonstrated that low-frequency (LF) activity reflects overall autonomic activity, high-frequency (HF) activity reflects parasympathetic activity, and the LF/HF ratio reflects sympathetic activity, HRV has been clinically applied as a non-invasive index of physical stress. In this study, we evaluated whether HRV is useful as a stress index for neonates by analyzing it in comparison with their salivary cortisol level. METHODS: We measured the salivary cortisol level and HRV in 12 healthy neonates and 37 neonates born during between 2014 and 2016 and admitted to the neonatal intensive care unit. These examinations were performed at birth and after approximately 1 week. The changes in parameters with time were examined. RESULTS: The LF and HF values in both groups exhibited significant negative correlations with the salivary cortisol level. In those admitted to the neonatal intensive care unit, the LF and HF values were correlated with gestational age and height. In the healthy neonates, a reduced salivary cortisol level and increase in the LF and HF values were observed approximately 1 week after birth compared with the values at birth, whereas the LF/HF ratio was not correlated with the salivary cortisol level and did not change over time. CONCLUSIONS: The LF and HF values were significantly correlated with the cortisol level, suggesting their usefulness as physiological indices of stress in clinical neonatal care.

De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly.

Although paternally expressed IGF2 is known to play a critical role in placental and body growth, only a single mutation has been found in IGF2. We identified, through whole-exome sequencing, a de novo IGF2 indel mutation leading to frameshift (NM_000612.5:c.110_117delinsAGGTAA, p.(Leu37Glnfs*31)) in a patient with Silver-Russell syndrome, ectrodactyly, undermasculinized genitalia, developmental delay, and placental hypoplasia. Furthermore, we demonstrated that the mutation resided on the paternal allele by sequencing the long PCR product harboring the mutation- and methylation-sensitive SmaI and SalI sites before and after SmaI/SalI digestion. The results, together with the previous findings in four cases from a single family with a paternally inherited IGF2 nonsense mutation and those in patients with variable H19 differentially methylated region epimutations leading to compromised IGF2 expression, suggest that the whole phenotype of this patient is explainable by the IGF2 mutation, and that phenotypic severity is primarily determined by the IGF2 expression level in target tissues.

Low-grade intraventricular hemorrhage disrupts cerebellar white matter in preterm infants: evidence from diffusion tensor imaging.

INTRODUCTION: Recent diffusion tensor imaging (DTI) studies have demonstrated that leakage of hemosiderin into cerebrospinal fluid (CSF), which is caused by high-grade intraventricular hemorrhage (IVH), can affect cerebellar development in preterm born infants. However, a direct effect of low-grade IVH on cerebellar development is unknown. Thus, we evaluated the cerebellar and cerebral white matter (WM) of preterm infants with low-grade IVH. METHODS: Using DTI tractography performed at term-equivalent age, we analyzed 42 infants who were born less than 30 weeks gestational age (GA) at birth (22 with low-grade IVH, 20 without). These infants were divided into two birth groups depending on GA, and we then compared the presence and absence of IVH which was diagnosed by cerebral ultrasound (CUS) within 10 days after birth or conventional magnetic resonance imaging (MRI) at term-equivalent age in each group. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), motor tract, and sensory tract were measured. RESULTS: In the SCP, preterm born infants with IVH had lower FA values compared with infants without IVH. In particular, younger preterm birth with IVH had lower FA values in the SCP and motor tract and higher ADC values in the MCP. CONCLUSION: Low-grade IVH impaired cerebellar and cerebral WM, especially in the SCP. Moreover, younger preterm infants exhibited greater disruptions to cerebellar WM and the motor tract than infants of older preterm birth.

Early manifestations of BPAN in a pediatric patient.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive brain disorders with several distinguishable subtypes. Recently, WDR45 mutations were reported in patients with ß-propeller protein-associated neurodegeneration (BPAN), characterized by early intellectual disability followed by delayed progressive motor and cognitive deterioration with onset in the second to third decade. BPAN has a distinct brain magnetic resonance imaging (MRI) pattern showing iron deposition in the globus pallidus and substantia nigra. To date, many of the BPAN patients have been diagnosed in adulthood. Here, we report on 6-year-old girl with BPAN diagnosed by whole exome sequencing. She showed Rett syndrome-like manifestations, a peculiar facial appearance and mildly elevated serum enzymes. Brain iron accumulation was detected by T2*-weighted MRI and T2-star weighted angiography (SWAN). This unique combination of clinical and neuroimaging features may be helpful for early diagnosis of BPAN.

The Usefulness of Continuous Respiratory Sound Monitoring for the Detection of Pulmonary Atelectasis in a Ventilated Extremely Low Birth Weight Infant.

The assessment of auscultation using a stethoscope is unsuitable for continuous monitoring. Therefore, we developed a novel acoustic monitoring system that continuously, objectively, and visually evaluates respiratory sounds. In this report, we assess the usefulness of our revised system in a ventilated extremely low birth weight infant (ELBWI) for the diagnosis of pulmonary atelectasis and evaluation of treatment by lung lavage. A female infant was born at 24 weeks of age with a birth weight of 636 g after emergency cesarean section. The patient received invasive mechanical ventilation immediately after birth in our neonatal (NICU). After obtaining informed consent, we monitored her respiratory status using the respiratory-sound monitoring system by attaching a sound collection sensor to the right anterior chest wall. On day 26, lung-sound spectrograms showed that the breath sounds were attenuated simultaneously as hypoxemia progressed. Finally, chest radiography confirmed the diagnosis as pulmonary atelectasis. To relieve atelectasis, surfactant lavage was performed, after which the lung-sound spectrograms returned to normal. Hypoxemia and chest radiographic findings improved significantly. On day 138, the patient was discharged from the NICU without complications. The continuous respiratory-sound monitoring system enabled the visual, quantitative, and noninvasive detection of acute regional lung abnormalities at the bedside. We, therefore, believe that this system can resolve several problems associated with neonatal respiratory management and save lives.

Effects of chemotherapy on the brain in childhood: diffusion tensor imaging of subtle white matter damage.

INTRODUCTION: With reducing mortality in children with hematological malignancies, the survivors' quality of life regarding development of chronic neurological disturbances is important. We aimed to determine whether chemotherapy affects white matter (WM). METHODS: Using brain diffusion tensor imaging, we evaluated 17 patients (15 with acute lymphoblastic leukemia, 2 with non-Hodgkin's lymphoma; 9 male, 8 female; age, 1.6-13 years) before and after chemotherapy. We measured the quantitative values of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) at the regions of interest (ROIs) such as periventricular WM, corona radiata, posterior limb of the internal capsule, and corpus callosum. We assessed sensorimotor and callosal tracts by tractography. RESULTS: Reduction in FA and increase in ADC were significant at the ROIs of the left and right anterior periventricular WM and corona radiata and at the tract passing through the genu. A significant reduction in FA with a nonsignificant increase in ADC was seen at the ROI of the genu and at the tracts passing through the body and isthmus. CONCLUSION: Chemotherapy in children with hematological malignancies predominantly affects the frontal WM. This finding might indicate a negative effect of chemotherapy on neurological development in children with hematological malignancies.

Thyroid hypogenesis is associated with a novel AKT3 germline variant that causes megalencephaly and cortical malformation.

The molecular mechanisms involved in thyroid organogenesis have not been fully elucidated. We report a patient with a de novo germline AKT3 variant, NM_005465.7:c.233A > G, p.(Gln78Arg), who presented with congenital hypothyroidism in addition to typical AKT3-related brain disorders. The report of this patient contributes to delineating the associated yet uncertain endocrine complications of this AKT3 disease-causing variant.

Development of corpus callosum in preterm infants is affected by the prematurity: in vivo assessment of diffusion tensor imaging at term-equivalent age.

Callosal injury in preterm infants is a key factor affecting neurodevelopmental outcome. We investigated the characteristics of corpus callosum (CC) in preterm infants without apparent white matter lesions. We studied 58 preterm infants divided into three groups of 23-25, 26-29, and 30-33 wk GA. Diffusion tensor imaging (DTI) was obtained at term-equivalent age. The CC was parcellated into the genu, body, isthmus, and splenium. We measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of each CC subdivision using tractography and manual region of interest analysis. The cross-sectional areas were also measured. At the isthmus and splenium in the 23-25 GA group, the FA was significantly lower and the size was also significantly reduced. Furthermore, the FA and cross-sectional areas in the posterior CC decreased linearly with decreasing GA. There were no differences in FA and cross-sectional areas in other CC subdivisions, and no differences in ADC in any CC subdivisions, among the GA groups. We demonstrated that preterm infants without apparent white matter lesions affect development of the posterior CC depending on the degree of prematurity.

A Case of Fetal Tachycardia after Electroconvulsive Therapy: A Possible Effect of Maternal Hypoxia and Uterine Contractions.

Electroconvulsive therapy (ECT) is considered to be an effective and safe treatment for depression in pregnant women in that it avoids the risk of psychotropic pharmacotherapy. However, clinicians should be cautious about the adverse effects in the fetus, such as fetal cardiac arrhythmia. Most of the previous studies have demonstrated a reduction in fetal heart rate associated with ECT. However, we encountered a case of fetal tachycardia after maternal ECT-induced convulsions. The patient was a woman who was 30 weeks' pregnant and had severe depression; fetal tachycardia (180-200 bpm) occurred immediately after the electrical stimulation and lasted for more than 30 minutes. The fetal tachycardia might have been caused by maternal hypoxia and uterine contractions. To our knowledge, this is the first report of fetal tachycardia as an adverse effect of ECT. Prolonged fetal tachycardia may cause fetal heart failure. Therefore, oxygenation during convulsions and careful fetal cardiac monitoring are essential when administering ECT in pregnancy.

Cerebellar peduncle injury predicts motor impairments in preterm infants: A quantitative tractography study at term-equivalent age.

PURPOSE: Cerebellar injury is well established as an important finding in preterm infants with cerebral palsy (CP). In this study, we investigated associations between injury to the cerebellar peduncles and motor impairments in preterm infants using quantitative tractography at term-equivalent age, which represents an early phase before the onset of motor impairments. METHODS: We studied 64 preterm infants who were born at <33 weeks gestational age. These infants were divided into three groups: CP, Non-CP (defined as infants with periventricular leukomalacia but having normal motor function), and a Normal group. Diffusion tensor imaging was performed at term-equivalent age and motor function was assessed no earlier than a corrected age of 2 years. Using tractography, we measured fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the superior cerebellar peduncles (SCP) and middle cerebellar peduncles (MCP), as well as the motor/sensory tracts. RESULTS: The infants in the CP group had significantly lower FA of the SCP and sensory tract than those in the other groups. There was no significant difference in FA and ADC of the motor tract among the three groups. Severity of CP had a significant correlation with FA of the MCP, but not with the FA of other white matter tracts. CONCLUSION: Our results suggested that the infants with CP had injuries of the ascending tracts (e.g. the SCP and sensory tract), and that additional MCP injury might increase the severity of CP. Quantitative tractography assessment at term-equivalent age may be useful for screening preterm infants for prediction of future motor impairments.

Luteolin attenuates interleukin-6-mediated astrogliosis in human iPSC-derived neural aggregates: A candidate preventive substance for maternal immune activation-induced abnormalities.

Maternal infection during pregnancy increases the risk of neurodevelopmental conditions such as autism spectrum disorders and schizophrenia in offspring. Several previous animal studies have indicated that maternal immune activation (MIA), rather than a specific pathogen, alters fetal brain development. Among them, prenatal exposure to interleukin-6 (IL-6) has been associated with behavioral and neuropathological abnormalities, though such findings remain to be elucidated in humans. We developed a human cell-based model of MIA by exposing human induced pluripotent stem cells (hiPSCs)-derived neural aggregates to IL-6 and investigated whether luteolin-a naturally occurring flavonoid found in edible plants-could prevent MIA-induced abnormalities. We generated neural aggregates from hiPSCs using the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) method, following which aggregates were cultured in suspension. We then exposed the aggregates to IL-6 (100ng/ml) for 24h at day 51. Transient IL-6 exposure significantly increased the area ratio of astrocytes (GFAP-positive area ratio) and decreased the area ratio of early-born neurons (TBR1-positive or CTIP2-positive area ratio) relative to controls. In addition, western blot analysis revealed that levels of phosphorylated STAT3 were significantly elevated in IL-6-exposed neural aggregates. Luteolin treatment inhibited STAT3 phosphorylation and counteracted IL-6-mediated increases of GFAP-positive cells and reductions of TBR1-positive and CTIP2-positive cells. Our observations suggest that the flavonoid luteolin may attenuate or prevent MIA-induced neural abnormalities. As we observed increased apoptosis at high concentrations of luteolin, further studies are required to determine the optimal intake dosage and duration for pregnant women.

Longitudinal change in white matter in preterm infants without magnetic resonance imaging abnormalities: Assessment of serial diffusion tensor imaging and their relationship to neurodevelopmental outcomes.

PURPOSE: We used diffusion tensor imaging (DTI) to evaluate longitudinal changes in fractional anisotropy (FA) of white matter tracts in preterm infants without abnormal magnetic resonance imaging (MRI) findings. Imaging was conducted at term equivalent age (TEA) and 1year of corrected age. Furthermore, we assessed correlations between FA and neurodevelopmental outcomes at 3years of corrected age to investigate brain prematurity of preterm infants without MRI abnormalities. METHODS: Preterm infants underwent serial MRI at TEA and 1year of corrected age. Of these, 13 infants entered a retrospective study, undergoing neurodevelopmental assessment at 3years of corrected age. These infants were divided into two groups depending on gestational age (GA): <26weeks and ⩾26weeks. DTI-based tractography was performed to obtain the FA of the motor tract, sensory tract, superior cerebellar peduncle, middle cerebellar peduncle, and corpus callosum. FA was compared between two groups, and correlations between FA and neurodevelopmental outcomes were assessed. RESULTS: FA of the splenium at TEA was significantly different between the two groups divided according to GA. However, this difference was no longer observed at 1year of corrected age. There was no correlation between FA of the splenium at TEA and neurodevelopmental assessment scores at 3years of corrected age. CONCLUSIONS: At TEA, FA of the splenium was lower in younger GA infants without MRI abnormalities, but this may not affect subsequent neurodevelopmental outcomes.

Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects.

BACKGROUND: Silver-Russell syndrome (SRS) is a rare congenital disorder characterized by pre- and postnatal growth failure and dysmorphic features. Recently, pathogenic copy number variations (PCNVs) and imprinting defects other than hypomethylation of the H19-differentially methylated region (DMR) and maternal uniparental disomy chromosome 7 have been reported in patients with the SRS phenotype. This study aimed to clarify the frequency and clinical features of patients with SRS phenotype caused by PCNVs. METHODS: We performed array comparative genomic hybridization analysis using a catalog array for 54 patients satisfying the Netchine-Harbison clinical scoring system (NH-CSS) (SRS-compatible) and for 28 patients presenting with three NH-CSS items together with triangular face and/or fifth finger clinodactyly and/or brachydactyly (SRS-like) without abnormal methylation levels of 9 DMRs related to known imprinting disorders. We then investigated the clinical features of patients with PCNVs. RESULTS: Three of the 54 SRS-compatible patients (5.6%) and 2 of the 28 SRS-like patients (7.1%) had PCNVs. We detected 3.5 Mb deletion in 4p16.3, mosaic trisomy 18, and 3.77-4.00 Mb deletion in 19q13.11-12 in SRS-compatible patients, and 1.41-1.97 Mb deletion in 7q11.23 in both SRS-like patients. Congenital heart diseases (CHDs) were identified in two patients and moderate to severe global developmental delay was observed in four patients. CONCLUSIONS: Of the patients in our study, 5.6% of SRS-compatible and 7.1% of SRS-like patients had PCNVs. All PCNVs have been previously reported for genetic causes of contiguous deletion syndromes or mosaic trisomy 18. Our study suggests patients with PCNVs, who have a phenotype resembling SRS, show a high tendency towards CHDs and/or apparent developmental delay.