Adverse Neurological Outcomes Research Articles

A - 49 The Role of the Tuberous Sclerosis Associated Neuropsychiatric Disorders Checklist in Pediatric Neuropsychological Assessment: a Case Study

Abstract Objective The Tuberous Sclerosis Associated Neuropsychiatric Disorders (TAND) checklist is a screening tool developed to assist in clarifying behavioral, psychiatric, neuropsychological, and psychosocial manifestations experienced by individuals with Tuberous Sclerosis Complex (TSC). TSC is a multisystem disorder, impacting 1 in 6000 children annually, caused by mutations in the TSC1/TSC2 genes that results in tumor growth throughout the body associated with widespread adverse medical and neurological outcomes including cognition. We present the use of the TAND checklist in a child referred for cognitive evaluation in the context of TSC to explore its potential use within neuropsychological assessment. Method Eleven-year-old female with TSC, referred by neurology, was seen for outpatient neuropsychological evaluation. Comprehensive neuropsychological testing and completion of the TAND checklist with parent were completed. Results Evaluation revealed variable cognitive performances with strengths in fluid reasoning and relative weakness in working memory. Academic performances were low average with weakness in reading. Overall slowed and disrupted processing impacted performance across domains. TAND checklist helped elucidate parental report about cognitive and psychological difficulties. Conclusions This eleven-year-old girl’s profile was variable across domains, consistent with research findings that TSC is a multisystemic disorder presenting in widespread dysfunction. Implementing the TAND checklist was helpful in efficiently eliciting symptomology across domains from parent collateral informant, demonstrating its augmentative value to comprehensive neuropsychological assessment in children with TSC. This is an important next step in validating the TAND checklist in neuropsychological settings.

B - 30 Influence of Military Blast Exposure on Subjective Post-Concussion Symptom Reporting

Abstract Objective Repeated subconcussive blast exposure associated with explosive breaching, mortars, and shoulder-fired artillery weapons is commonly seen in the military/veteran population and has been found to contribute to adverse neurological outcomes; however, the extent is not fully understood. The aim of this study was to assess the effects of blast exposure during military or other training exercises on neurobehavioral symptom endorsement. Method Cross-sectional data from 48 nonclinical post-deployment Operation Enduring Freedom/Operation Iraqi Freedom veterans prospectively-recruited for a study examining posttraumatic stress and cognitive correlates at an urban VA Medical Center were examined (M age = 36.02; SD = 6.12; M years of education = 14.94; SD = 1.84). The sample was 96% male, 41% White, 39% Black, 4% Asian, and 16% Other. The Neurobehavioral Symptom Inventory (NSI) was used to assess self-reported vestibular, somatosensory, cognitive, and affective post-concussion symptoms, and the Boston Assessment of Traumatic Brain Injury-Lifetime semi-structured clinical interview assessed military-related blast exposure. Results There was a significant difference in neurobehavioral symptoms based on blast exposure, F(4,43) = 3.49, p = 0.015; Wilk’s Λ = 0.755, partial η2 = 0.25. Follow-up analyses showed that veterans with history of blast exposure endorsed significantly higher levels of somatosensory (F(1,47) = 7.69, p = 0.008, η2 = 0.143); affective (F(1,47) = 12.66, p < 0.001, η2 = 0.216); cognitive (F(1,47) = 5.97, p = 0.018, η2 = 0.115); and vestibular (F(1,47) = 7.21, p = 0.010, η2 = 0.136) post-concussive symptoms on the NSI compared to those without history of military blast exposure. Conclusion Veterans with blast exposure during military service reported significantly greater levels of post-concussion symptoms. This demonstrates the need to assess history of blast exposure, implement prevention measures through safeguards and decreased exposure when possible, and establish treatment modalities to improve outcomes.

Derivation, external and clinical validation of a deep learning approach for detecting intracranial hypertension

Increased intracranial pressure (ICP) ≥15 mmHg is associated with adverse neurological outcomes, but needs invasive intracranial monitoring. Using the publicly available MIMIC-III Waveform Database (2000–2013) from Boston, we developed an artificial intelligence-derived biomarker for elevated ICP (aICP) for adult patients. aICP uses routinely collected extracranial waveform data as input, reducing the need for invasive monitoring. We externally validated aICP with an independent dataset from the Mount Sinai Hospital (2020–2022) in New York City. The AUROC, accuracy, sensitivity, and specificity on the external validation dataset were 0.80 (95% CI, 0.80–0.80), 73.8% (95% CI, 72.0–75.6%), 73.5% (95% CI 72.5–74.5%), and 73.0% (95% CI, 72.0–74.0%), respectively. We also present an exploratory analysis showing aICP predictions are associated with clinical phenotypes. A ten-percentile increment was associated with brain malignancy (OR = 1.68; 95% CI, 1.09-2.60), intracerebral hemorrhage (OR = 1.18; 95% CI, 1.07–1.32), and craniotomy (OR = 1.43; 95% CI, 1.12–1.84; P < 0.05 for all).

Perfusion imaging for delayed cerebral ischemia detection in patients following ruptured aneurysmal subarachnoid hemorrhage: Interrater reliability assessment.

Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is associated with adverse neurological outcomes. Early and accurate diagnosis of DCI is crucial to prevent cerebral infarction. This study aimed to assess the diagnostic accuracy and interrater agreement of the visual assessment of neuroimaging perfusion maps to detect DCI in patients suspected of vasospasm after aSAH. In this case-control study, cases were adult aSAH patients with DCI who underwent magnetic resonance perfusion or computed tomography perfusion (CTP) imaging in the 24 h prior to digital subtraction angiography for vasospasm diagnosis. Controls were patients with dizziness and no aSAH on CTP imaging. Three independent raters, blinded to patients' clinical information, other neuroimaging studies, and angiographic results, visually assessed anonymized perfusion color maps to classify patients as either having DCI or not. Tmax delay was classified by symmetry into no delay, unilateral, or bilateral. Perfusion imaging of 54 patients with aSAH and 119 control patients without aSAH was assessed. Sensitivities for DCI diagnosis ranged from 0.65 to 0.78, and specificities ranged from 0.70 to 0.87, with interrater agreement ranging from 0.60 (moderate) to 0.68 (substantial). Visual assessment of perfusion color maps demonstrated moderate to substantial accuracy in diagnosing DCI in aSAH patients.

Arachnoid Cysts in Athletes with Sports-Related Concussion: A Case Series and Literature Review

BackgroundArachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature.Results432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1–9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome.ConclusionsAC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered.

Muscle growth and motor development in NICU graduates and infants at high-risk of adverse neurological outcome over the first year

Muscle growth and motor development in NICU graduates and infants at high-risk of adverse neurological outcome over the first year

The Role of Troponin Measured on Admission to the Emergency Department in Patients with Acute Ischemic Stroke to Predict Stroke Severity and Neurological Outcome

Objective: This study aims to investigate the prognostic value of cardiac troponin levels measured at admission to the emergency department (ED) for stroke severity assessed by the National Institutes of Health Stroke Scale (NIHSS) and neurological outcomes determined by Modified Rankin Scale (mRS) scores in patients diagnosed with acute ischemic stroke (AIS). Materials and Methods: Patients presenting to ED with a diagnosis of AIS confirmed by neuroimaging findings were included. Patients were divided into 2 groups based on troponin-I levels: elevated and normal. NIHSS during admission, 30-day all-cause mortality data, and 30-day mRS were examined. In comparisons between groups, categorical variables were evaluated with Chi-square and continuous variables were evaluated with the Mann-Whitney-U test. To determine the prognostic value of troponin with poor outcomes in stroke patients, diagnostic 2x2 tables were made. Results: The study was conducted with 200 patients. Troponin elevation was detected in 37, and mortality was significantly higher in this group. The sensitivity of troponin to predict mortality was 88.89%, and PLR (positive likelihood ratio) was 5.85 (3.89–8.79). The 30-day mRS scores were significantly higher in the elevated troponin group. NIHSS scores didn’t show a significant difference between groups. Conclusions: Troponin levels assessed at admission in AIS patients may be a prognostic marker for mortality and adverse neurological outcomes.

Anatomical and Radiological Findings of Abnormal Calcified Structures within and around the Foramen Transversarium and Its Clinical Implications.

The foramen transversarium is a vital anatomical structure found in the cervical vertebrae of the spine. Typically, it serves as a passageway for important neurovascular structures, including the vertebral artery and vein, as well as the vertebral nerve. However, abnormal calcification or ossification of soft tissues in and around this area can lead to various clinical implications. Understanding the presence and implications of abnormal ossified structures in and around the foramen transversarium is crucial for clinicians involved in the diagnosis and management of cervical spine disorders. Accordingly, this present study was designed to evaluate the abnormal ossified structures anatomically and radiologically within and around the foramen transversarium. This study was conducted on 182 (26 sets of cervical vertebrae) dried human cervical vertebrae obtained from the respective departments of anatomy and on 190 (95 males and 95 females) adult patients who visited the radiology department for neck-related problems such as stiff neck, neck/shoulder pain, dizziness, vertigo, imbalance, visual disturbances, and cognitive impairment. Among 182 examined cervical vertebrae, unilateral complete accessory foramen transversarium was found in 23 vertebrae (12.63%), bilateral complete in 19 (10.44%), bilateral incomplete in 6 (3.29%), unilateral complete double in 4 (2.19%), and unilateral complete absence of foramen transversarium in 3 (1.64%). Stenosis due to aberrant osteophytes was noted in 9 vertebrae (4.9%). Out of 190 patients, three males presented with cervical kyphosis, severe spinal canal stenosis, and spinal cord compression due to ossification of the posterior longitudinal ligament and osteophyte complexes at C3-C6, with the most significant compression at C5-C6. A thorough understanding of abnormal ossifications in and around the foramen transversarium is crucial for the management of cervical spine disorders; imaging modalities such as X-ray, computed tomography, and magnetic resonance imaging are crucial for recognizing and intervening in these cases, which is essential to prevent adverse neurological outcomes associated with vertebral artery involvement.

H7N7 viral infection elicits pronounced, sex-specific neuroinflammatory responses in vitro.

Influenza A virus (IAV) infection can increase the risk of neuroinflammation, and subsequent neurodegenerative diseases. Certain IAV strains, such as avian H7N7 subtype, possess neurotropic properties, enabling them to directly invade the brain parenchyma and infect neurons and glia cells. Host sex significantly influences the severity of IAV infections. Studies indicate that females of the reproductive age exhibit stronger innate and adaptive immune responses to IAVs compared to males. This heightened immune response correlates with increased morbidity and mortality, and potential neuronal damage in females. Understanding the sex-specific neurotropism of IAV and associated mechanisms leading to adverse neurological outcomes is essential. Our study reveals that primary hippocampal cultures from female mice show heightened interferon-β and pro-inflammatory chemokine secretion following neurotropic IAV infection. We observed sex-specific differences in microglia activation: both sexes showed a transition into a hyper-ramified state, but only male-derived microglia exhibited an increase in amoeboid-shaped cells. These disparities extended to alterations in neuronal morphology. Neurons derived from female mice displayed increased spine density within 24 h post-infection, while no significant change was observed in male cultures. This aligns with sex-specific differences in microglial synaptic pruning. Data suggest that amoeboid-shaped microglia preferentially target postsynaptic terminals, potentially reducing neuronal hyperexcitability. Conversely, hyper-ramified microglia may focus on presynaptic terminals, potentially limiting viral spread. In conclusion, our findings underscore the utility of primary hippocampal cultures, incorporating microglia, as an effective model to study sex-specific, virus-induced effects on brain-resident cells.

Clinical value of serum neuron-specific enolase in sepsis-associated encephalopathy: a systematic review and meta-analysis

ObjectiveThis study aimed to investigate the serum levels of neuron-specific enolase (NSE) in sepsis-associated encephalopathy (SAE) and perform a meta-analysis to assess the diagnostic and prognostic potential of serum NSE in SAE patients.MethodsWe searched English and Chinese databases for studies related to SAE that reported serum NSE levels until November 2023. We extracted information from these studies including the first author and year of publication, the number of samples, the gender and age of patients, the collection time of blood samples in patients, the assay method of serum NSE, the study methods, and the levels of serum NSE with units of ng/mL. The quality assessment of diagnostic accuracy studies 2 (QUADAS-2) tool was used to evaluate the study quality. A meta-analysis was performed using Review Manager version 5.3, employing either a random effects model or a fixed effects model.ResultsA total of 17 studies were included in the final meta-analysis, including 682 SAE patients and 946 NE patients. The meta-analysis demonstrated significantly higher serum NSE levels in SAE patients compared to NE patients (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23–10.34), irrespective of the method used for serum NSE detection (Z = 6.15, P < 0.001, mean difference [MD] = 7.75, 95%CI 5.28–10.22) and the study methods (Z = 5.97, P < 0.001, MD = 7.79, 95%CI 5.23–10.34). Furthermore, sepsis patients with a favorable outcome showed significantly lower levels of serum NSE compared to those with an unfavorable outcome (death or adverse neurological outcomes) (Z = 5.44, P < 0.001, MD = − 5.34, 95%CI − 7.26–3.42).ConclusionThe Serum level of NSE in SAE patients was significantly higher than that in septic patients without encephalopathy. The higher the serum NSE level in SAE patients, the higher their mortality rate and incidence of adverse neurological outcomes.

Efficacy analysis of mechanical thrombectomy combined with prolonged mild hypothermia in the treatment of acute middle cerebral artery occlusion: a single-center retrospective cohort study.

To determine the efficacy of mechanical thrombectomy combined with prolonged mild hypothermia compared with conventional treatment in managing acute middle cerebral artery occlusion, and to explore whether extending the duration of hypothermia can improve neurological function. From 2018 to June 2023, a retrospective analysis was conducted on 45 patients with acute middle cerebral artery occlusion treated at the NICU of Suzhou Kowloon Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. After thrombectomy, patients were admitted to the neurological intensive care unit (NICU) for targeted temperature management. Patients were divided into two groups: the mild hypothermia group (34.5-35.9°C) receiving 5-7 days of treatment, and the normothermia group (control group) whose body temperature was kept between 36 and 37.5°C using pharmacological and physical cooling methods. Baseline characteristics and temperature changes were compared between the two groups of patients. The primary outcome was the modified Rankin Scale (mRS) score at 3 month after surgery, and the secondary outcomes were related complications and mortality rate. Prognostic risk factors were investigated using both univariate and multivariate logistic regression analyses. Among 45 patients, 21 underwent prolonged mild hypothermia, and 24 received normothermia, with no significant differences in baseline characteristics between the two groups. The duration of mild hypothermia ranged from 5 to 7 days. The incidence of chills (33.3% vs. 8.3%, p = 0.031) and constipation (57.1% vs. 20.8%, p = 0.028) was significantly higher in the mild hypothermia group compared with the control group. There was no significant difference in mortality rates between the mild hypothermia and the control group (4.76% vs. 8.33%, p = 1.000, OR = 1.75, 95% CI, 0.171-17.949). At 3 month, there was no significant difference in the modified mRS (0-3) score between the mild hypothermia and control groups (52.4% vs. 25%, p = 0.114, OR = 0.477, 95% CI, 0.214-1.066). Infarct core volume was an independent risk factor for adverse neurological outcomes. Prolonged mild hypothermia following mechanical thrombectomy had no severe complications and shows a trend to improve the prognosis of neurological function. The Infarct core volume on CTP was an independent risk factor for predicting neurological function.

Neonatal dysglycemia: a review of dysglycemia in relation to brain health and neurodevelopmental outcomes.

Neonatal dysglycemia has been a longstanding interest of research in neonatology. Adverse outcomes from hypoglycemia were recognized early but are still being characterized. Premature infants additionally introduced and led the reflection on the importance of neonatal hyperglycemia. Cohorts of infants following neonatal encephalopathy provided further information about the impacts of hypoglycemia and, more recently, highlighted hyperglycemia as a central concern for this population. Innovative studies exposed the challenges of management of neonatal glycemic levels with a "u-shape" relationship between dysglycemia and adverse neurological outcomes. Lately, glycemic lability has been recognized as a key factor in adverse neurodevelopmental outcomes. Research and new technologies, such as MRI and continuous glucose monitoring, offered novel insight into neonatal dysglycemia. Combining clinical, physiological, and epidemiological data allowed the foundation of safe operational definitions, including initiation of treatment, to delineate neonatal hypoglycemia as ≤47 mg/dL, and >150-180 mg/dL for neonatal hyperglycemia. However, questions remain about the appropriate management of neonatal dysglycemia to optimize neurodevelopmental outcomes. Research collaborations and clinical trials with long-term follow-up and advanced use of evolving technologies will be necessary to continue to progress the fascinating world of neonatal dysglycemia and neurodevelopment outcomes. IMPACT STATEMENT: Safe operational definitions guide the initiation of treatment of neonatal hypoglycemia and hyperglycemia. Innovative studies exposed the challenges of neonatal glycemia management with a "u-shaped" relationship between dysglycemia and adverse neurological outcomes. The importance of glycemic lability is also being recognized. However, questions remain about the optimal management of neonatal dysglycemia to optimize neurodevelopmental outcomes. Research collaborations and clinical trials with long-term follow-up and advanced use of evolving technologies will be necessary to progress the fascinating world of neonatal dysglycemia and neurodevelopment outcomes.

RADT-12. CLINICAL RELEVANCE OF RADIATION-INDUCED CAVERNOUS MALFORMATIONS

Abstract BACKGROUND Radiation-induced cavernous malformations (RICMs) are delayed complications of brain irradiation during childhood. The prevalence of cavernomas in the general population was found to be 0.5% in a large prospective study. However, the exact incidence of RICM in children and the mechanisms of the development of RICM remain largely unknown since the cumulative incidence of RICM is underreported. Recent systemic review revealed 113 children with RICM after treatment of brain tumors and leukemias. 67% were asymptomatic and 21% showed signs of hemorrhage. In this review, the average dose of radiation was 50Gy and the mean time to detection was 9.2 years. METHODS We conducted a retrospective review of RICM in children who underwent total body irradiation (TBI) for bone marrow transplant. Our study goals were to better understand the incidence and patterns of RICMs and to develop a risk stratification for monitoring. Between 9/2000-1/2023, 161 patients underwent TBI. Of 47 patients who had post-transplant brain MR imaging done, 15 patients had MRIs available for review. RESULTS Of 15 reviewed MRIs, 11 (73.3%) had RICMs identified. 6 cases had &amp;gt;5 small (&amp;lt;3mm) RICMs. Most RICMs were in the frontal lobes. MRIs were obtained an average of 64 months from TBI. Radiation doses ranged from 200-2760cGy with an average of 1144cGy. There was 1 case of microhemorrhage due to RICM. None of our patients deceased as a result of their RICM. CONCLUSIONS Our cohort showed a high incidence (73.3%) of RICM despite low doses of radiation. Due to their typically small size and lack of clinical symptoms, RICM is often underreported. Although the outcome of cavernous malformation is favorable, it is important to understand the incidence and risk of adverse neurologic outcomes posed by RICMs. By performing regular surveillance, complications related to RICMs may be intervened with preventative procedures such as microsurgery.

A Pilot Study Investigating the Use of Serum Glial Fibrillary Acidic Protein to Monitor Changes in Brain White Matter Integrity After Repetitive Head Hits During a Single Collegiate Football Game.

Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurological outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after nonconcussive RHHs during a single sporting contest, raising the possibility that they could be used in real time to monitor the brain's early response to repeated asymptomatic head hits. To test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 min (T2) after a single collegiate football game in 30 athletes. Glial fibrillary acidic protein (GFAP) changes were correlated with three measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 h before (T1) to 48 h after (T3) the game. To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5 ± 1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs. 91.95 pg/mL, p = 0.008) and from T0 to T2 (mean 79.69 vs. 99.21 pg/mL, p < 0.001). WM integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% confidence interval [CI]: -2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus and with increased MD in the right fornix (r-values ranged from 0.59 to 0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69 to 0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurological response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Owing to the small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.

Assessing mean corpuscular volume as a screening tool for gestational vitamin B12 deficiency based on NHANES.

Vitamin B12 can lead to neurological deficits. We assessed whether the mean corpuscular volume (MCV) could be a sufficiently sensitive measurement for abnormal serum methylmalonic Acid (MMA) and total plasma homocysteine (tHCY) (biomarkers of vitamin B12 or folate deficiency) and if so, at what cutoff value. A total of 26,397 participants (12,730 males and 13,667 females) were included in the analysis. Weighted analysis was performed using NHANES data to calculate crude/adjusted associations between MCV-MMA/tHCY, using linear regression. Unadjusted odds ratios (OR) 95% CIs were estimated from logistic regression models. Receiver Operating Curve and the Youden Index were used to identify the MCV level that most accurately distinguished those with abnormal MMA and tHCY (dependent variables) from those without. A positive and significant correlation between MCV-MMA/tHCY was found in the general population between ages 18-85, 0.95 (95% C.I. 0.75-1.17) and 2.61 (95% C.I. 2.15-3.08). In pregnant women, for every unit increase in MCV there was a 19% increase in odds of abnormal MMA, OR 1.19 (95% C.I. 1.08-1.31), p=0.001 and the Area Under the Curve for MCV as a test for abnormal MMA was 78%. An MCV cutoff of 93.1 correctly identified abnormal MMA in pregnant women with 81% sensitivity and 77% specificity. In the general population the MCV test performed poorly in identifying abnormal MMA/tHCY. MCV is an inexpensive measurement that may be useful to screen asymptomatic pregnant women for vitamin B12 abnormalities. This may have a significant impact on reducing adverse neurological outcomes in their children.

Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology.

Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing-remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro. In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.

Optimization of the betamethasone and dexamethasone dosing regimen during pregnancy: a combined placenta perfusion and pregnancy physiologically based pharmacokinetic modeling approach

BackgroundAntenatal betamethasone and dexamethasone are prescribed to women who are at high risk of premature birth to prevent neonatal respiratory distress syndrome. The current treatment regimens, effective to prevent neonatal RDS, may be suboptimal. Recently, concerns have been raised regarding possible adverse long-term neurological outcomes due to high fetal drug exposures. Data from non-human primates and sheep suggest maintaining a fetal plasma concentration above 1 ng/mL for 48 hours to retain efficacy, while avoiding undesirable high fetal plasma levels. ObjectiveWe aimed to re-evaluate the current betamethasone and dexamethasone dosing strategies to assess estimated fetal exposure and provide new dosing proposals that meet the efficacy target but avoid excessive peak exposures. Study designA pregnancy physiologically-based pharmacokinetic model was used to predict fetal drug exposures. To allow prediction of the extent of betamethasone and dexamethasone exposure in the fetus, placenta perfusion experiments were conducted to determine placental transfer. Placental transfer rates were integrated in the PBPK model to predict fetal exposure and model performance was verified using published maternal and fetal PK data. The verified pregnancy physiologically-based pharmacokinetic models were then used to simulate alternative dosing regimens to establish a model-informed dose. ResultsEx vivo data showed that both drugs extensively cross the placenta. For betamethasone 15.7 ± 1.7% and for dexamethasone 14.4 ± 1.5% of the initial maternal perfusate concentration reached the fetal circulations at the end of the 3-hour perfusion period. Pregnancy physiologically-based pharmacokinetic models that include these ex vivo-derived placental transfer rates, accurately predicted maternal and fetal exposures resulting from current dosing regimens. The dose simulations suggest that for betamethasone intramuscular a dose reduction from 2 dosages 11.4 mg, 24 hours apart, to 4 dosages 1.425 mg, 12 hours apart would avoid excessive peak exposures and still meet the fetal response threshold. For dexamethasone, the dose may be reduced from four times 6 mg every 12 hours to 8 times 1.5 mg every 6 hours. ConclusionA combined placenta perfusion and pregnancy physiologically-based pharmacokinetic modeling approach adequately predicted both maternal and fetal drug exposures of two antenatal corticosteroids. Strikingly, our PBPK simulations suggest that drug doses might be reduced drastically to still meet earlier proposed efficacy targets and minimize peak exposures. We propose the provided model-informed dosing regimens are used to support further discussion on an updated antenatal corticosteroid scheme and design of clinical trials to confirm the effectiveness and safety of lower doses.

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 μM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Brain magnetic resonance imaging review suggests unrecognised hypoglycaemia in childhood.

Neonatal and early-life hypoglycaemia, is a frequent finding but is often non-specific and asymptomatic, making detection and diagnosis challenging. Hypoglycaemia-induced cerebral injury can be identified by magnetic resonance imaging (MRI) changes in cerebral white matter, occipital lobes, and posterior parietotemporal regions. It is unknown if children may have hypoglycaemic brain injury secondary to unrecognised hypoglycaemia in early life. We have examined retrospective radiological findings of likely brain injury by neuroimaging to investigate the existence of previous missed hypoglycaemic events. Retrospective MRI data in children in a single tertiary centre, over a ten-year period was reviewed to identify potential cases of unrecognised early-life hypoglycaemia. A detailed search from an electronic radiology repository involved the term "hypoglycaemia'' from text-based reports. The initial report was used for those who required serial scanning. Images specific to relevant reports were further reviewed by a designated paediatric neuroradiologist to confirm likely hypoglycaemia induced brain injury. Medical records of those children were subsequently reviewed to assess if the hypoglycaemia had been diagnosed prior to imaging. A total of 107 MR imaging reports were identified for review, and 52 (48.5%) showed typical features strongly suggestive of hypoglycaemic brain injury. Medical note review confirmed no documented clinical information of hypoglycaemia prior to imaging in 22 (42%) patients, raising the likelihood of missed hypoglycaemic events resulting in brain injury. We have identified the existence of unrecognised childhood hypoglycaemia through neuroimaging review. This study highlights the need for heightened awareness of early life hypoglycaemia to prevent adverse neurological outcomes later in childhood.

Reversible Cerebral Vasoconstriction Syndrome in Children and Adolescents: A Case Series and Literature Review

Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical radiographic phenomenon characterized by thunderclap headaches and transient vasoconstriction of cerebral vessels, which typically resolve within 3 months of symptom onset. Although RCVS has been extensively studied in adults, research on this condition in pediatric populations is limited, likely due to its perceived rarity. This comprehensive review aims to bridge the knowledge gap by examining the clinical presentation, diagnostic methods, treatment strategies, and prognostic outcomes of pediatric RCVS cases, including two case reports contributed by the authors. This study demonstrates an inconclusive sex distribution of RCVS in children, attributed to the scarcity of comprehensive studies of this demographic. Additionally, we identified several predictors of adverse neurological outcomes in children with RCVS, including motor deficits, aphasia, hypertension, and renal disease. This study offers a thorough overview of RCVS in the pediatric population, providing valuable insights to inform future research in this area.