Severe Neurological Impairment Research Articles

Single-nucleus transcriptomic mapping of blast-induced traumatic brain injury in mice hippocampus

As a significant type of traumatic brain injury (TBI), blast-induced traumatic brain injury (bTBI) frequently results in severe neurological and psychological impairments. Due to its unique mechanistic and clinical features, bTBI presents diagnostic and therapeutic challenges compared to other TBI forms. The hippocampus, an important site for secondary injury of bTBI, serves as a key niche for neural regeneration and repair post-injury, and is closely associated with the neurological outcomes of bTBI patients. Nonetheless, the pathophysiological alterations of hippocampus underpinning bTBI remain enigmatic, and a corresponding transcriptomic dataset for research reference is yet to be established. In this investigation, the single-nucleus RNA sequencing (snRNA-seq) technique was employed to sequence individual hippocampal nuclei of mice from bTBI and sham group. Upon stringent quality control, gene expression data from 17,278 nuclei were obtained, with the dataset’s reliability substantiated through various analytical methods. This dataset holds considerable potential for exploring secondary hippocampal injury and neurogenesis mechanisms following bTBI, with important reference value for the identification of specific diagnostic and therapeutic targets for bTBI.

Paediatric Palliative Care in a Reference Centre of Inherited Metabolic Diseases.

Paediatric palliative care (PPC) has a significant role in improving the quality of life of children with life-limiting or life-threatening illnesses, diminishing symptom burden, and providing holistic support to patients and families. Inherited metabolic diseases (IMD) are a group of heterogeneous diseases that often present with severe neurologic impairment, needing lifelong care and challenging symptom management. Our aim was to characterize the cohort of patients with IMD followed by the paediatric palliative care team (PPCT) and to describe the provision of care provided. The descriptive analysis of demographic, clinical, and care delivery data of a cohort of paediatric patients was carried out with a confirmed diagnosis of IMD, followed in a Reference Centre, in the care of PPCT between 2018 and 2023. Thirteen (10%) of a total of 134 patients in the care of PPCT had a confirmed diagnosis of an IMD: 6 mitochondrial, 3 peroxisomal, 3 lysosomal, and 1 pterin metabolism disorder. The median age at referral was 9 years (0-18), the median duration of care was 2 years [2-4], median number of home visits in the last year was 2 [1-4], and median number of outpatient consults was 4 [2 -8]. Twelve patients (92%) had no autonomy in their activities of daily living. Neurologic (100%), gastrointestinal (92%), and respiratory (69%) symptoms were the main focus of care. All patients were polymedicated (5 or more different drugs). Nine (69%) had percutaneous gastrostomy and 2 (15%) had noninvasive ventilation. Median hospital admissions before and after starting care by PPCT were 4 and 1. Moreover, three patients died and one was at home. Mitochondrial, lysosomal, and peroxisomal disorders are complex multisystemic diseases that very often have no treatment intended to cure. These patients have a heavy symptom burden and frequent intercurrences. Addressing these symptoms is challenging, but PPC has proven to reduce hospital admissions with consequent improvement in quality of life. In the future, PPC should be available for all children and families with life-threatening conditions.

Knowledge, and attitudes of patient’s primary caregiver towards decompressive hemicraniectomy

Background: Decompressive hemicraniectomy (DHC) is a surgical procedure in which a substantial piece of the cranium is removed to reduce intracranial pressure. DHC improves mortality. Although the surgical procedure may be lifesaving, many survivors suffer from a severe neurological impairment, which the patients and primary caregivers have to deal with afterward. This study’s purpose is to understand better the primary caregiver’s perception regarding the burden of the outcome of DHC. Methods: This was a descriptive, prospective study that included all primary caregivers of patients who had previously undergone DHC between the years 2019 to 2022 at Jose R. Reyes Memorial Medical Center. A total of 48 primary caregivers were included in the study. Results: Most primary caregivers have adequate knowledge of the pros and cons of the surgery, but few individuals demonstrated insufficient knowledge. Moreover, the primary caregivers also acknowledged the reality of the patient’s surgery, including the demand for the caregiver’s time and other negative effects. Conclusion: There is still a need to comprehensively orient the patient’s primary caregivers on the benefits and risks of DHC to ensure they know what to expect prior to the surgery. Also, fear of the negative outcomes of the surgery, family concerns, and finances were the main hindrances why other primary caregivers may opt out of the surgery.

Morphine versus hydromorphone in pediatrics: a narrative review of latest indications and optimal use in neonates and children.

The management of pain in pediatrics is multimodal and includes non-pharmacologic and pharmacologic approaches. Opioids, and particularly morphine and hydromorphone, are frequently used to treat moderate-to-severe pain. The goals of this review are to describe the pharmacological characteristics of both drugs, to cover the latest evidence of their respective indications, and to promote their safe use in pediatrics. Morphine is the most studied opioid in children and is known to be safe and effective. Morphine and hydromorphone can be used to manage acute pain and are usually avoided when treating chronic non-cancer pain. Current evidence suggests that both opioids have a similar efficacy and adverse effect profile. Hydromorphone has not been studied in neonates but in some centers, it has been used instead of morphine for certain patients. In palliative care, the use of opioids is often indicated and their benefits extend beyond analgesia; indications include treatment of central neuropathic pain in children with severe neurologic impairment and treatment of respiratory distress in the imminently dying patients. The longstanding belief that the use of well-titrated opioids hastens death should be abandoned as robust evidence has shown the opposite. With the current opioid crisis, a responsible use of opioids should be promoted, including limiting the opioid prescription to the patient's anticipated needs, optimizing a multimodal analgesic plan including the use of non-pharmacological measures and non-opioid medications, and providing information on safe storage and disposal to patients and families. More data is needed to better guide the use of morphine and hydromorphone in children.

Biochemical and cellular studies of three human 3-phosphoglycerate dehydrogenase variants responsible for pathological reduced L-serine levels.

In the brain, the non-essential amino acid L-serine is produced through the phosphorylated pathway (PP) starting from the glycolytic intermediate 3-phosphoglycerate: among the different roles played by this amino acid, it can be converted into D-serine and glycine, the two main co-agonists of NMDA receptors. In humans, the enzymes of the PP, namely phosphoglycerate dehydrogenase (hPHGDH, which catalyzes the first and rate-limiting step of this pathway), 3-phosphoserine aminotransferase, and 3-phosphoserine phosphatase are likely organized in the cytosol as a metabolic assembly (a "serinosome"). The hPHGDH deficiency is a pathological condition biochemically characterized by reduced levels of L-serine in plasma and cerebrospinal fluid and clinically identified by severe neurological impairment. Here, three single-point variants responsible for hPHGDH deficiency and Neu-Laxova syndrome have been studied. Their biochemical characterization shows that V261M, V425M, and V490M substitutions alter either the kinetic (both maximal activity and Km for 3-phosphoglycerate in the physiological direction) and the structural properties (secondary, tertiary, and quaternary structure, favoring aggregation) of hPHGDH. All the three variants have been successfully ectopically expressed in U251 cells, thus the pathological effect is not due to hindered expression level. At the cellular level, mistargeting and aggregation phenomena have been observed in cells transiently expressing the pathological protein variants, as well as a reduced L-serine cellular level. Previous studies demonstrated that the pharmacological supplementation of L-serine in hPHGDH deficiencies could ameliorate some of the related symptoms: our results now suggest the use of additional and alternative therapeutic approaches.

Impact of treatment on blood-brain barrier impairment in Wilson's disease.

Our study assessed changes in concentrations of serum markers for brain damage and blood-brain barrier (BBB) dysfunction in untreated and treated Wilson's disease (WD) patients, and examined correlations between these changes and neurological impairment. These results hold the potential to determine BBB impairment and neurological advancement in WD to develop the most effective treatment for patients with severe neurological deterioration. The study groups included 171 patients with WD (77 with hepatic and 94 with neurological manifestations), treated either for up to 5 or 15 years, and 88 healthy controls. Serum concentrations of intercellular adhesion molecule 1 (ICAM1), P-selectin, matrix metallopeptidase 9 (MMP9), glial fibrillary acidic protein (GFAP), and S100 calcium-binding protein B (S100B) were measured before and during anti-copper treatment. The Unified Wilson's disease Rating Scale (UWDRS) was used to assess neurological advancement. ICAM1 concentrations were elevated before and during anti-copper treatment compared to controls (p < 0.01), but therapy led to substantial decreases both in patients with hepatic (p < 0.01) and in patients with neurological manifestations (p < < 0.05). P-selectin concentrations remained elevated before and during treatment (p < 0.05) regardless of the treatment duration and disease form. MMP9 concentrations before treatment were lower (p < 0.05), but reached control levels during treatment. GFAP concentrations were significantly elevated only in untreated patients with neurological symptoms in the longer-treated group compared to controls (p < 0.05). A significant reduction during treatment was observed only in the shorter-treated neurological group (p < 0.05). No substantial changes were observed in S100B. Only ICAM1 concentrations positively correlated (r = 0.27, p < 0.001) with the UWDRS. Our results provide evidence of endothelial activation in WD. However, inconclusive GFAP results, and no increase in S100B, do not allow us to conclude whether the reactive gliosis is not prominent or alternatively whether the BBB is disrupted. Elevated ICAM1 concentrations and their correlation with neurological advancement indicate BBB impairment. A decrease in ICAM1 during treatment suggests that the inflammatory process is reduced, and the BBB partially repaired. Decreased MMP9 concentrations may be the result of active liver fibrosis and higher copper concentrations. Elevated P-selectin concentrations indicate a systemic inflammatory process.

Nutritional Management in Children and Adolescents with Severe Neurological Impairment-Who Cares? A Web-Based Survey Among Pediatric Specialists in Germany.

Nutritional management of children and adolescents with severe neurological impairment (SNI) is challenging. A web-based survey was distributed to identify the present situation and the knowledge of the involved medical professionals in Germany. The survey was created with LimeSurvey, and access data were distributed by several medical societies. Eighty-three questions covered four topics: "general information," "gastro- and jejunostomy procedure," "handling of gastrostomies and feeding tubes," and "nutritional management and follow-up of children and adolescents with SNI." A descriptive analysis was performed with Microsoft Excel. A total of 156 participated (65 completed and 91 partially), 27% being pediatric gastroenterologists, 23% pediatric neurologists, and 10% pediatric surgeons. The most common indications for gastrostomy and tube feeding were oropharyngeal dysfunction and failure to thrive. Many patients were still underweight after some months of enteral feeding. The procedure of gastrostomy and handling recommendations varied broadly. Frequently, standard operating procedures (SOPs) and written local guidelines did not exist, and there was a considerable request for training. Only 53% of participants were aware of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition position paper published in 2017, even fewer (38%) followed the guidelines. The recommended measures to assess a nutritional status were often not respected. Nutritional management of children and adolescents with SNI in Germany is still strongly deficient. Despite the international guideline of 2017, few colleagues are aware of and adhere to the recommendations. This could be improved by interdisciplinary teaching and evaluation of the reasons for noncompliance. The procedure of gastrostomy and the patients' follow-up vary widely. Therefore, modified SOPs should be developed.

Multifocal cerebral haemorrhage in two dogs with erythrocytosis

AbstractAn 8‐month‐old, female toy poodle and a 5‐year‐3‐month‐old, male, neutered Bernese Mountain dog presented with acute onset, progressive neurological deficits. Neurological examination findings were consistent with multifocal forebrain, brainstem and potential C1–C5 spinal cord segment involvement in both dogs. The toy poodle had a packed cell volume of 85% on presentation, and rapidly deteriorated to cardiopulmonary arrest. Postmortem examination revealed multifocal leptomeningeal, white and grey matter haemorrhage. Femoral bone marrow analysis revealed 95%:5% haematopoietic:fat ratio (reference value: 80%:20%). The Bernese Mountain dog had an initial packed cell volume of 81%. Magnetic resonance imaging of the head identified multifocal cerebral haemorrhage. The erythrocytosis was believed to be secondary to marked bilateral nephropathy. Following two phlebotomies, the packed cell volume decreased to 78%. However, the dog deteriorated and had a cardiopulmonary arrest. We report two clinical cases in which erythrocytosis was the cause of rapid and severe neurological deterioration.

Hyperbaric Oxygen and Outcomes Following the Brain Injury: A Systematic Review.

Hyperbaric oxygen therapy (HBO2) aims to address ischemia resulting from brain injury by subjecting patients to an atmosphere that dramatically raises the concentration of inspired oxygen (100% O2 at greater than 1 ATA). This results in elevated levels of oxygen in the plasma, which in turn boosts the delivery of oxygen for diffusion to the brain tissue. To study the efficacy of hyperbaric oxygen (HBO)-based modalities in brain injury. Preferred reporting items for systematic reviews protocol was applied to perform literature search regarding this analytical review. In our study, fifteen studies are included in this review, involving 1067 people. The mean age group of patients enrolled was 57.0±11.6 and the mean NIHSS score was 10.5±8.7, of which 21 participants had moderate to severe neurological impairment. The total number of HBO treatments was 8 to 70 times (28.3±17.9), at the end of the 6-month follow-up period. mRS (modified Rankin scale) ≤3 was found in 25 cases, of which 12 patients with high-grade aSAH recovered. Poor prognosis was prevalent in patients who experienced delayed cerebral ischemia, this was true for 22.7% of patients in this study. In 3 studies conducted by Rockswold, ICP (mm Hg) was significantly lower in the HBO2 group after the treatment than pretreatment. (p<0.05). 4 studies showed an improvement in GCS score after HBO2 therapy.One trial (Imai 2006) reported that three patients in the HBO group died due to pneumonia (two) and heart failure (one) and one patient died in the control group due to heart failure. Overall, it is relatively safe to use HBO in the treatment of brain-related haemorrhage, strokes, and injury as there were no major complications reported. This systematic review demonstrates that HBO2 has significant clinical potential in treatment of brain related haemorrhages, stroke and injury.

Long-term behavioural alterations in mice following transient cerebral ischemia

Ischemic stroke is one of the leading causes of disability and mortality worldwide. Acute and chronic post-stroke changes have variable effects on the functional outcomes of the disease. Therefore, it is imperative to identify what daily activities are altered after stroke and to what extent, keeping in mind that ischemic stroke patients often have long-term post-stroke complications. Translational studies in stroke have also been challenging due to inconsistent study design of animal experiments. The objective of this study was to clarify whether and to what extent mouse behaviour was altered during a 6 months period after cerebral stroke. Experimental stroke was induced in mice by intraluminal filament insertion into the middle cerebral artery (fMCAo). Neurological deficits, recovery rate, motor performance, and circadian activity were evaluated following ischemia. We observed severe neurological deficits, motor impairments, and delay in the recovery rate of mice during the first 14 days after fMCAo. Aberrant circadian activity and distorted space map were seen in fMCAo mice starting one month after ischemia, similarly to altered new and familiar cage activity and sucrose preference using the IntelliCage, and was still evident 60- and 180- days following stroke in the voluntary running wheel using the PhenoMaster system. A preference towards ipsilateral side turns was observed in fMCAo mice both acutely and chronically after the stroke induction. Overall, our study shows the importance of determining time-dependent differences in the long-term post-stroke recovery (over 180 days after fMCAo) using multiple behavioural assessments.

Spontaneously hypertensive rats can become hydrocephalic despite undisturbed secretion and drainage of cerebrospinal fluid

BackgroundHydrocephalus constitutes a complex neurological condition of heterogeneous origin characterized by excessive cerebrospinal fluid (CSF) accumulation within the brain ventricles. The condition may dangerously elevate the intracranial pressure (ICP) and cause severe neurological impairments. Pharmacotherapies are currently unavailable and treatment options remain limited to surgical CSF diversion, which follows from our incomplete understanding of the hydrocephalus pathogenesis. Here, we aimed to elucidate the molecular mechanisms underlying development of hydrocephalus in spontaneously hypertensive rats (SHRs), which develop non-obstructive hydrocephalus without the need for surgical induction.MethodsMagnetic resonance imaging was employed to delineate brain and CSF volumes in SHRs and control Wistar-Kyoto (WKY) rats. Brain water content was determined from wet and dry brain weights. CSF dynamics related to hydrocephalus formation in SHRs were explored in vivo by quantifying CSF production rates, ICP, and CSF outflow resistance. Associated choroid plexus alterations were elucidated with immunofluorescence, western blotting, and through use of an ex vivo radio-isotope flux assay.ResultsSHRs displayed brain water accumulation and enlarged lateral ventricles, in part compensated for by a smaller brain volume. The SHR choroid plexus demonstrated increased phosphorylation of the Na+/K+/2Cl− cotransporter NKCC1, a key contributor to choroid plexus CSF secretion. However, neither CSF production rate, ICP, nor CSF outflow resistance appeared elevated in SHRs when compared to WKY rats.ConclusionHydrocephalus development in SHRs does not associate with elevated ICP and does not require increased CSF secretion or inefficient CSF drainage. SHR hydrocephalus thus represents a type of hydrocephalus that is not life threatening and that occurs by unknown disturbances to the CSF dynamics.

The prevalence of neonatal anemia in Al Baha, Saudi Arabia: A retrospective observational study

Abstract Background Neonatal anemia contributes to the global burden of anemia, a crucial public health concern. It is primarily associated with mild to severe neurological impairment, which may result in perinatal mortality and morbidity. This study aimed to determine the prevalence of anemia and its association with sex and age in newborns at Al-Baha, Saudi Arabia. A retrospective observational study was performed using the R-studio/r-base coding tool. The analysis included the mean, standard deviation, median, interquartile range, correlation matrix, and logistic regression. The overall prevalence of neonatal anemia was 25.36% (n = 140). The mean±SD of hemoglobin (Hgb) (g/dl) was significantly different between anemic and nonanemic neonates, with values of 9.36 ± 1.04 and 15.74 ± 3.35 (P &lt; 0.0001). The prevalence of neonatal anemia in males and females was 29.8% and 20.5%, respectively. Among males, the neonatal anemia Severity was 14.4% (mild anemia) and 6.1% (moderate anemia), while among females, it was 20.1% (mild anemia) and 9.7% (moderate anemia). In female neonates, the prevalence of microcytic, normocytic, and macrocytic anemia was 6.08%, 62.36%, and 31.56%, respectively. In contrast, the prevalence rate of microcytic, normocytic, and macrocytic anemia among male neonates, was 8.3%, 54.4%, and 29.07%, respectively. In females, only normocytic iron deficiency anemia was observed (55%), whereas the prevalence of normocytic iron deficiency anemia and microcytic iron deficiency anemia in males was 69% and 31%, respectively. Overall, iron deficiency anemia affected 65% of males. Compared with neonates aged 0-90 days, neonates aged 90-180 days have ~0.4 times more likelihood of developing neonatal anemia. Female sex is one of the risk factors associated with anemia. Further investigation and implementation of preventive measures are crucial to address the prevalence and severity of neonatal anemia.

Hip Dysplasia in Congenital Zika Syndrome: A 5 Year Follow-Up

Children with Congenital Zika Syndrome (CZS) usually have severe neurological impairment with extrapyramidal involvement mainly spastic quadriplegia, so we believe they would have the same spasticity-related abnormalities, such as high prevalence of hip subluxation, as children with other aetiologies of cerebral palsy (CP).

GABAergic neurons differentiated from BDNF- and Dlx2-modified neural stem cells restore disrupted neural circuits in brainstem stroke

BackgroundBrainstem stroke causes severe and persistent neurological impairment. Due to the limited spontaneous recovery and regeneration of the disrupted neural circuits, transplantation of exogenous neural stem cells (NSCs) was an alternative, while there were limitations for primitive NSCs.MethodsWe established a mouse model of brainstem stroke by injecting endothelin in the right pons. Brain-derived neurotrophic factor (BDNF)- and distal-less homeobox 2 (Dlx2)-modified NSCs were transplanted to treat brainstem stroke. Transsynaptic viral tracking, immunostaining, magnetic resonance imaging, behavioral testing, and whole-cell patch clamp recordings were applied to probe the pathophysiology and therapeutic prospects of BDNF- and Dlx2-modified NSCs.ResultsGABAergic neurons were predominantly lost after the brainstem stroke. No endogenous NSCs were generated in situ or migrated from the neurogenesis niches within the brainstem infarct region. Co-overexpressions of BDNF and Dlx2 not only promoted the survival of NSCs, but also boosted the differentiation of NSCs into GABAergic neurons. Results from transsynaptic virus tracking, immunostaining, and evidence from whole-cell patch clamping revealed the morphological and functional integration of the grafted BDNF- and Dlx2-modified NSCs-derived neurons with the host neural circuits. Neurological function was improved by transplantation of BDNF- and Dlx2-modified NSCs in brainstem stroke.ConclusionsThese findings demonstrated that BDNF- and Dlx2-modified NSCs differentiated into GABAergic neurons, integrated into and reconstituted the host neural networks, and alleviated the ischemic injury. It thus provided a potential therapeutic strategy for brainstem stroke.

The relationship between neurological function trajectory, assessed by repeated NIHSS measurement, and long-term cardiovascular events, recurrent stroke, and mortality after ischemic stroke.

Clinically significant changes in neurological deficits frequently occur after stroke onset, reflecting further neurological injury or neurological improvement. However, the National Institutes of Health Stroke Scale (NIHSS) score is only evaluated once in most studies, usually at stroke onset. Utilizing repeated measures of NIHSS scores to identify different trajectories of neurological function may be more informative and provide more useful predictive information. We determined the association of neurological function trajectories with long-term clinical outcomes after ischemic stroke. A total of 4025 participants with ischemic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke were included. Patients were recruited from 26 hospitals across China between August 2009 and May 2013. A group-based trajectory model was used to identify distinct neurological function trajectories, as measured by NIHSS at admission, 14 days or hospital discharge, and 3 months. Study outcomes were cardiovascular events, recurrent stroke, and all-cause mortality during 3-24 months after ischemic stroke onset. Cox proportional hazards models were used to examine the associations of neurological function trajectories with outcomes. We identified three distinct subgroups of NIHSS trajectories: persistent severe (persistent high NIHSS scores during the 3-month follow-up), moderate (NIHSS scores started at around 5 and gradually reduced), and mild (NIHSS scores always below 2). The three trajectory groups had different clinical profiles and different risk of stroke outcomes at 24-month follow-up. Compared to the mild trajectory group, patients in the persistent severe trajectory group had a higher risk of cardiovascular events (multivariable-adjusted hazard ratios (95% confidence intervals) = 1.77 (1.10-2.86)), recurrent stroke (1.82 (1.10-3.00)), and all-cause mortality (5.64 (3.37-9.43)). Those with moderate trajectory had an intermediate risk: 1.45 (1.03-2.04) for cardiovascular events and 1.52 (1.06-2.19) for recurrent stroke. Longitudinal neurological function trajectories derived from repeated NIHSS measurements during the first 3 months after stroke provide additional predictive information and are associated with long-term clinical outcomes. The trajectories characterized by persistent severe and moderate neurological impairment were associated with increased risk of subsequent cardiovascular events.

Clinical Profile, Corticosteroid Usage and Predictors of Mortality in Near-hanging Patients: A Five-year, Single-center Retrospective Study.

Hanging is the most common method of suicide in India. When near-hanging patients reach the hospital for treatment, their neurological outcome ranges from full recovery to severe neurological impairment or death. This study looked at the clinical profile, usage of corticosteroids and predictors of mortality in near-hanging patients. This retrospective study was conducted from May 2017 to April 2022. Demographic, clinical, and treatment details were collected from case records. Neurological outcome at discharge was assessed using the Glasgow Outcome Scale (GOS). The study involved 323 patients, 60% of men with a median (interquartile range) age of 30 (20-39). At the time of admission, the Glasgow Coma Scale (GCS) ≤8 in 110 (34%) patients, hypotension was present in 43 (13.3%) of patients, and 21 (6.5%) had hanging-induced cardiac arrest. About 101 patients required intensive care unit care. Corticosteroid therapy was given to 219 patients (67.8%) as part of anti-cerebral edema measures. Good neurological recovery was found (GOS-5) in 84.2% of patients, and the death rate (GOS-1) was 9.3%. Univariate logistic regression showed that usage of corticosteroids is significantly associated with poor survival (p < 0.02, odds ratio 4.7). In the multivariable logistic regression analysis, GCS ≤8, hypotension, need for intensive care, hanging-induced cardiac arrest, aspiration pneumonia, and severe cerebral edema were found to be significantly associated with mortality. The majority of near-hanging patients had a good neurological recovery. Corticosteroids were used in two-thirds of the study population. There were multiple variables associated with mortality. Ramadoss R, Sekar D, Rameesh M, Saibaba J, Raman D. Clinical Profile, Corticosteroid Usage and Predictors of Mortality in Near-hanging Patients: A Five-year, Single-center Retrospective Study. Indian J Crit Care Med 2023;27(6):403-410.

Clinical, radiological, therapeutic and prognostic differences between MOG-seropositive and MOG-seronegative pediatric acute disseminated encephalomyelitis patients: a retrospective cohort study.

This study aimed to compare the clinical, radiological, therapeutic, and prognostic differences between pediatric patients showing acute disseminated encephalomyelitis (ADEM) with and without myelin oligodendrocyte glycoprotein (MOG) antibodies. We retrospectively collected all available data of children diagnosed with ADEM and tested for serum MOG antibodies at the Children's Hospital of Chongqing Medical University from January 2017 to May 2021. A total of 62 patients were included in our cohort, of which 35 were MOG-seropositive and 27 were MOG-seronegative. MOG-seropositive ADEM children presented with significantly lower rates of seizures (P = 0.038) and cranial nerve (III-XII) palsy (P = 0.003). Isolated leukocytosis in the blood was more common in ADEM children with MOG antibodies (P < 0.001). The two groups showed no significant differences in the distributions and extent of the MRI lesions as well as the appearance of typical/atypical magnetic resonance imaging (MRI) features. MOG-seropositive children were more likely to relapse (P = 0.017) despite having slower oral prednisolone tapering after acute treatments (P = 0.028). In scoring performed on the basis of two neurological function scoring systems, MOG-seropositive children showed milder neurological disability status at onset (P = 0.017 and 0.025, respectively) but showed no difference during follow-up. In summary, the differences in the clinical manifestations and auxiliary examination findings for MOG-seropositive and MOG-seronegative ADEM children lacked significance and specificity, making early identification difficult. MOG-seropositive children were more likely to relapse and showed slower steroid tapering. Moreover, MOG-seronegative children tended to have more severe neurological impairments at onset with no difference during follow-up.

Rescue of GM3 synthase deficiency by spatially controlled, rAAV-mediated ST3GAL5 delivery.

GM3 synthase deficiency (GM3SD) is an infantile-onset epileptic encephalopathy syndrome caused by biallelic loss-of-function mutations in ST3GAL5. Loss of ST3GAL5 activity in humans results in systemic ganglioside deficiency and severe neurological impairment. No disease-modifying treatment is currently available. Certain recombinant adeno-associated viruses (rAAVs) can cross the blood-brain barrier to induce widespread, long-term gene expression in the CNS and represent a promising therapeutic strategy. Here, we show that a first-generation rAAV-ST3GAL5 replacement vector using a ubiquitous promoter restored tissue ST3GAL5 expression and normalized cerebral gangliosides in patient-derived induced pluripotent stem cell neurons and brain tissue from St3gal5-KO mice but caused fatal hepatotoxicity when administered systemically. In contrast, a second-generation vector optimized for CNS-restricted ST3GAL5 expression, administered by either the intracerebroventricular or i.v. route at P1, allowed for safe and effective rescue of lethality and behavior impairment in symptomatic GM3SD mice up to a year. These results support further clinical development of ST3GAL5 gene therapy.

Affirming Perspectives About Quality-of-Life With Caregivers of Children With Severe Neurological Impairment

Affirming Perspectives About Quality-of-Life With Caregivers of Children With Severe Neurological Impairment

Exposure to Tetrabutylammonium Bromide Impairs Cranial Neural Crest Specification, Neurogenic Program, and Brain Morphogenesis.

Tetrabutylammonium bromide (TBAB) is a widely used industrial reagent and is commonly found in our aquatic ecosystem as an industrial byproduct. In humans, the ingestion of TBAB causes severe neurological impairments and disorders such as vertigo, hallucinations, and delirium. Yet, the extent of environmental risk and TBAB toxicity to human health is poorly understood. In this study, we aim to determine the developmental toxicity of TBAB using zebrafish embryos as a model and provide novel insights into the mechanism of action of such chemicals on neurodevelopment and the overall embryonic program. Our results show that exposure to TBAB results in impaired development of the brain, inner ear, and pharyngeal skeletal elements in the zebrafish embryo. TBAB treatment resulted in aberrations in the specification of the neural crest precursors, hindbrain segmentation, and otic neurogenesis. TBAB treatment also induced a surge in apoptosis in the head, tail, and trunk regions of the developing embryo. Long-term TBAB exposure resulted in cardiac edema and craniofacial defects. Further, in silico molecular docking analysis indicated that TBAB binds to AMPA receptors and modulates neural developmental genes such as olfactomedin and acetylcholinesterase in the embryonic brain. To summarize, our study highlights the novel effects of TBAB on embryonic brain formation and segmentation, ear morphogenesis, and craniofacial skeletal development.