Arterial spin labeling image findings in the acute phase in paediatric patients with acute encephalopathy with biphasic seizures and late reduced diffusion.

Introduction: Diagnosing acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) after the first seizure (early seizure/seizures, ES/ESs) is challenging because a reduced apparent diffusion coefficient (ADC) in the cortical or subcortical white matter, often described as having a "bright-tree appearance (BTA)," is usually not observed until secondary seizures (late seizures, LSs) occur. Previous studies have reported hypoperfusion on arterial spin labeling (ASL) within 24 h after ES/ESs in patients with AESD and hyperperfusion within 24 h after LS onset. This study aimed to investigate cerebral blood flow in the hyperacute phase (between ES/ESs and LSs) using ASL in patients with AESD. Methods: Eight ASL images were acquired in six patients with AESD admitted to our hospital from October 2021 to October 2022. ASL findings in the hyperacute phase were investigated and video-electroencephalogram findings obtained around ASL image acquisition in the hyperacute phase were evaluated. Results: Four ASL images were obtained for three patients before LS onset, with three images showing hyperperfusion areas and one image showing hypoperfusion areas. These hyperperfuion regions coincided with BTA on subsequent images of these patients.In one patient, the first ASL image was obtained in the late hyperacute phase and revealed hyperperfusion areas with a slightly abnormal change on diffusion-weighted image (DWI), which were not accompanied by ADC abnormalities. The second ASL image obtained 51 h after the first ASL, and before LS onset revealed more prominent hyperperfusion areas than the first ASL image, which were accompanied by BTA. In another patient, the ASL image obtained 82 h after ES revealed hyperperfusion areas without abnormal change on DWI or ADC. Conclusion: This study revealed that two patients exhibited hyperperfusion regions and another patient exhibited hypoperfusion regions among three patients who underwent ASL imaging during the period from 24 h after ES/ESs to LSs in patients with LSs or cooling initiation in patients without LSs due to early anaesthesia induction (late hyperacute phase). Further prospective studies on cerebral blood flow are required to explore the relationship among the timing of image acquisition, the presence of electrographic seizures, and ASL findings in patients with AESD.

Truncal Instability and Titubation in Patients With Acute Encephalopathy With Reduced Subcortical Diffusion.

The present retrospective study aimed to investigate the presence of truncal instability or titubation after the first seizure and second phase in patients with acute encephalopathy with reduced subcortical diffusion (AED). Of the 15 patients with AED who were admitted to our hospital for 3 years and 2 months and had reached developmental milestones for sitting before disease onset, six experienced moderate-to-severe truncal instability while sitting after the first seizure. These patients had a significantly longer first seizure duration and significantly lower GCS scores 12-24 h after the first seizure, as well as significantly higher Tada score and Creatinine and blood glucose levels than those with mild or no truncal instability while in a seated position after the first seizure. Three 1-year-old children with bilateral frontal lobe lesions, particularly in the bilateral prefrontal lobe regions, demonstrated truncal titubation, which has not previously been reported as a clinical feature of AED. Tada score reported to be a predictor of AED prognosis and truncal instability in the sitting position after the first seizure may represent disease severity, but not the specific lesions. Conversely, truncal titubation might be suggestive of bilateral frontal lobe lesions, particularly in patients without severe instability. Further studies on the role of bilateral prefrontal lobe lesions to truncal titubation in patients with AED using more objective evaluation methods, such as stabilometry, are necessary.

Case Report: Rituximab Improved Epileptic Spasms and EEG Abnormalities in an Infant With West Syndrome and Anti-NMDAR Encephalitis Associated With APECED.

Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder caused by a mutation in the autoimmune regulator gene. Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy typically exhibit hypoparathyroidism, adrenocortical failure, and chronic mucocutaneous candidiasis. There are only a few case reports of autoimmune encephalitis during autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, but not as an initial manifestation. Furthermore, there are no reports of patients with infantile spasms/West syndrome with autoimmune encephalitis, partly because the median age for paediatric patients with anti-N-methyl-D-aspartate receptor encephalitis, which is the most frequent and best characterised in paediatric autoimmune encephalitides, is 13-14 years. Herein, we present a case of a 3-month-old infant with autoimmune encephalitis as an initial manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy who later developed infantile spasms/West syndrome. Case Presentation: A 3-month-old girl was admitted to our hospital with a fever, involuntary movements in all four limbs, and right-side facial palsy. Acute central nervous system demyelination diseases were suspected from neuroimaging findings and the presence of the cerebrospinal fluid oligoclonal band. She did not respond to multiple methylprednisolone pulse therapies and later developed infantile spasms/West syndrome and diabetes mellitus. Rituximab, a chimeric mouse/human monoclonal antibody directed against human CD20 which depletes B cells, was initially administered as a treatment for autoimmune encephalitis. Unexpectedly, this treatment resulted in complete spasm cessation and resolution of hypsarrhythmia. The patient eventually showed severely delayed developmental milestones, and her electroencephalography findings showed periodic generalised slow spike-and-wave pattern. Conclusions: Despite the limited ability to extrapolate findings from a single case, rituximab's effects may suggest that B cells play a crucial role in infantile spasms/West syndrome mechanisms; use of rituximab as an aetiology-specific treatment for infantile spasms/West syndrome patients with autoimmune encephalitis or its effectiveness for infantile spasms/West syndrome patients with other underlying mechanisms warrants further investigation.

Determinants of outcomes for acute encephalopathy with reduced subcortical diffusion.

Acute encephalopathy with reduced subcortical diffusion (AED), characterised by seizure onset and widespread reduced apparent diffusion coefficient in the cortex/subcortical white matter, is one of the most common acute encephalopathies in children in East Asia. This 14-year single-centre retrospective study on 34 patients with AED showed that therapeutic hypothermia was used for patients with more severe consciousness disturbance after the first seizure or second phase initiation, extrapolating from neonatal hypoxic encephalopathy and adult post-cardiac arrest syndrome. The basal ganglia/thalamus lesions and the Tada score were the poor outcome determinants in the multivariate analysis. The correlation between the worse outcomes and the duration from the first seizure to the initiation of therapeutic hypothermia was observed only in the patients with AED cooled before the second phase. This correlation was not observed in the overall AED population. There was a moderate negative association between the worse outcomes and the duration between the first seizure and the second phase. Therefore, the basal ganglia/thalamus lesions and the Tada score were the outcome determinants for patients with AED. Further investigation is required to examine the efficacy of therapeutic hypothermia in this population while considering the timing of the therapeutic hypothermia initiation and the second phase.

Brain stem infarction in a 6-year-old boy with Down syndrome.

Infarct locations in children with arterial ischemic stroke have primarily been reported to be lobar or in the basal ganglia, and those in patients with Down syndrome (DS) and antiphospholipid syndrome (APS) are typically wide and multiple. No solitary brain stem infarctions have ever been reported in children with DS until now. Here, we report a case of brain stem infarction in a 6-year-old boy with DS who had no cardiac, renal, or intestinal complications. He exhibited ataxic gait and medial longitudinal fasciculus (MLF) symptoms at first presentation. Neuroimaging revealed a localized and isolated lesion in the midbrain. Although he did not satisfy the diagnostic criteria of APS, he showed persistently elevated levels of anticardiolipin antibody (21 U/mL; normal value <10 U/mL). Although he had the risks of a multiple vascular systems disorder, DS, and persistently elevated levels of antiphospholipid antibodies, his lesion was not similar to any of the previously reported cerebral infarctions in DS or in APS. To our knowledge, this is the first report of limited solitary brain stem infarction in a child with DS.

Fulminant acute disseminated encephalomyelitis in children.

Acute disseminated encephalomyelitis (ADEM) is a typically monophasic inflammatory demyelinating disease of the central nervous system with a favorable outcome. However, 2% of ADEM involves acute hemorrhagic leukoencephalitis (AHLE), which is a fulminant and hyperacute variant of ADEM with a poor outcome and high mortality. There are limited case reports of fulminant ADEM including AHLE in children. Herein, we report two pediatric cases of fulminant ADEM. Both cases had a rapid deterioration of consciousness, repetitive seizures, and brain edema on neuroimaging, in addition to atypical neuroradiological findings on magnetic resonance imaging (MRI), a reversible splenial lesion in case 1, and bilateral frontal and occipital cortical lesions in case 2. Both cases were treated with early high-dose methyl-prednisolone and immunoglobulin, while therapeutic hypothermia was also initiated in case 2 after the patient exhibited a decerebrate posture and irregular breathing pattern. Both cases had a favorable outcome. Further case reports on pediatric fulminant ADEM are required to clarify the various clinical types, and to examine the efficacy of various treatment modalities for fulminant ADEM and AHLE in children.

Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia.

The selective α2-adrenoreceptor agonist dexmedetomidine has shown neuroprotective, analgesic, anti-inflammatory, and sympatholytic properties that may be beneficial in neonatal encephalopathy (NE). As therapeutic hypothermia is only partially effective, adjunct therapies are needed to optimize outcomes. The aim was to assess whether hypothermia + dexmedetomidine treatment augments neuroprotection compared to routine treatment (hypothermia + fentanyl sedation) in a piglet model of NE using magnetic resonance spectroscopy (MRS) biomarkers, which predict outcomes in babies with NE, and immunohistochemistry. After hypoxia-ischaemia (HI), 20 large White male piglets were randomized to: (i) hypothermia + fentanyl with cooling to 33.5°C from 2 to 26 h, or (ii) hypothermia + dexmedetomidine (a loading dose of 2 µg/kg at 10 min followed by 0.028 µg/kg/h for 48 h). Whole-brain phosphorus-31 and regional proton MRS biomarkers were assessed at baseline, 24, and 48 h after HI. At 48 h, cell death was evaluated over 7 brain regions by means of transferase-mediated d-UTP nick end labeling (TUNEL). Dexmedetomidine plasma levels were mainly within the target sedative range of 1 µg/L. In the hypothermia + dexmedetomidine group, there were 6 cardiac arrests (3 fatal) versus 2 (non-fatal) in the hypothermia + fentanyl group. The hypothermia + dexmedetomidine group required more saline (p = 0.005) to maintain blood pressure. Thalamic and white-matter lactate/N-acetylaspartate did not differ between groups (p = 0.66 and p = 0.21, respectively); the whole-brain nucleotide triphosphate/exchangeable phosphate pool was similar (p = 0.73) over 48 h. Cell death (TUNEL-positive cells/mm2) was higher in the hypothermia + dexmedetomidine group than in the hypothermia + fentanyl group (mean 5.1 vs. 2.3, difference 2.8 [95% CI 0.6-4.9], p = 0.036). Hypothermia + dexmedetomidine treatment was associated with adverse cardiovascular events, even within the recommended clinical sedative plasma level; these may have been exacerbated by an interaction with either isoflurane or low body temperature. Hypothermia + dexmedetomidine treatment was neurotoxic following HI in our piglet NE model, suggesting that caution is vital if dexmedetomidine is combined with cooling following NE.

Surgery increases cell death and induces changes in gene expression compared with anesthesia alone in the developing piglet brain.

In a range of animal species, exposure of the brain to general anaesthesia without surgery during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex but include an increase in brain cell death. In humans, attempts to link adverse cognitive development to infantile anaesthesia exposure have yielded ambiguous results. One caveat that may influence the interpretation of human studies is that infants are not exposed to general anaesthesia without surgery, raising the possibility that surgery itself, may contribute to adverse cognitive development. Using piglets, we investigated whether a minor surgical procedure increases cell death and disrupts neuro-developmental and cognitively salient gene transcription in the neonatal brain. We randomly assigned neonatal male piglets to a group who received 6h of 2% isoflurane anaesthesia or a group who received an identical anaesthesia plus 15 mins of surgery designed to replicate an inguinal hernia repair. Compared to anesthesia alone, surgery-induced significant increases in cell death in eight areas of the brain. Using RNAseq data derived from all 12 piglets per group we also identified significant changes in the expression of 181 gene transcripts induced by surgery in the cingulate cortex, pathway analysis of these changes suggests that surgery influences the thrombin, aldosterone, axonal guidance, B cell, ERK-5, eNOS and GABAA signalling pathways. This suggests a number of novel mechanisms by which surgery may influence neural and cognitive development independently or synergistically with the effects of anaesthesia.

Isoflurane Exposure Induces Cell Death, Microglial Activation and Modifies the Expression of Genes Supporting Neurodevelopment and Cognitive Function in the Male Newborn Piglet Brain.

Exposure of the brain to general anesthesia during early infancy may adversely affect its neural and cognitive development. The mechanisms mediating this are complex, incompletely understood and may be sexually dimorphic, but include developmentally inappropriate apoptosis, inflammation and a disruption to cognitively salient gene expression. We investigated the effects of a 6h isoflurane exposure on cell death, microglial activation and gene expression in the male neonatal piglet brain. Piglets (n = 6) were randomised to: (i) naive controls or (ii) 6h isoflurane. Cell death (TUNEL and caspase-3) and microglial activation were recorded in 7 brain regions. Changes in gene expression (microarray and qPCR) were assessed in the cingulate cortex. Electroencephalography (EEG) was recorded throughout. Isoflurane anesthesia induced significant increases in cell death in the cingulate and insular cortices, caudate nucleus, thalamus, putamen, internal capsule, periventricular white matter and hippocampus. Dying cells included both neurons and oligodendrocytes. Significantly, microglial activation was observed in the insula, pyriform, hippocampus, internal capsule, caudate and thalamus. Isoflurane induced significant disruption to the expression of 79 gene transcripts, of these 26 are important for the control of transcription and 23 are important for the mediation of neural plasticity, memory formation and recall. Our observations confirm that isoflurane increases apoptosis and inflammatory responses in the neonatal piglet brain but also suggests novel additional mechanisms by which isoflurane may induce adverse neural and cognitive development by disrupting the expression of genes mediating activity dependent development of neural circuits, the predictive adaptive responses of the brain, memory formation and recall.

Acute encephalopathy with biphasic seizures and late reduced diffusion associated with staphylococcal toxic shock syndrome caused by burns.

We report a case of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) associated with toxic shock syndrome caused by burns. A one-year-old girl was admitted to our hospital for treatment of severe burns. On day 3, she exhibited a fever, generalized rash and multiple organ failure. She was diagnosed with toxic shock syndrome after burns. She had seizures with fever twice on the same day, followed by secondary seizures on day 8 and transient deterioration of the gross motor functions involved in sitting alone and rolling over. On day 9, MRI diffusion-weighted images showed bright tree appearance (BTA). We conclude that she developed AESD.

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter.

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC - with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter.

Inhaled 45-50% argon augments hypothermic brain protection in a piglet model of perinatal asphyxia.

Cooling to 33.5°C in babies with neonatal encephalopathy significantly reduces death and disability, however additional therapies are needed to maximize brain protection. Following hypoxia-ischemia we assessed whether inhaled 45-50% Argon from 2-26h augmented hypothermia neuroprotection in a neonatal piglet model, using MRS and aEEG, which predict outcome in babies with neonatal encephalopathy, and immunohistochemistry. Following cerebral hypoxia-ischemia, 20 Newborn male Large White piglets<40h were randomized to: (i) Cooling (33°C) from 2-26h (n=10); or (ii) Cooling and inhaled 45-50% Argon (Cooling+Argon) from 2-26h (n=8). Whole-brain phosphorus-31 and regional proton MRS were acquired at baseline, 24 and 48h after hypoxia-ischemia. EEG was monitored. At 48h after hypoxia-ischemia, cell death (TUNEL) was evaluated over 7 brain regions. There were no differences in body weight, duration of hypoxia-ischemia or insult severity; throughout the study there were no differences in heart rate, arterial blood pressure, blood biochemistry and inotrope support. Two piglets in the Cooling+Argon group were excluded. Comparing Cooling+Argon with Cooling there was preservation of whole-brain MRS ATP and PCr/Pi at 48h after hypoxia-ischemia (p<0.001 for both) and lower (1)H MRS lactate/N acetyl aspartate in white (p=0.03 and 0.04) but not gray matter at 24 and 48h. EEG background recovery was faster (p<0.01) with Cooling+Argon. An overall difference between average cell-death of Cooling versus Cooling+Argon was observed (p<0.01); estimated cells per mm(2) were 23.9 points lower (95% C.I. 7.3-40.5) for the Cooling+Argon versus Cooling. Inhaled 45-50% Argon from 2-26h augmented hypothermic protection at 48h after hypoxia-ischemia shown by improved brain energy metabolism on MRS, faster EEG recovery and reduced cell death on TUNEL. Argon may provide a cheap and practical therapy to augment cooling for neonatal encephalopathy.

Investigation of cerebral autoregulation in the newborn piglet during anaesthesia and surgery.

The relationship between cerebral autoregulation (CA) and the neurotoxic effects of anaesthesia with and without surgery is investigated. Newborn piglets were randomly assigned to receive either 6 h of anaesthesia (isoflurane) or the same with an additional hour of minor surgery. The effect of the spontaneous changes in mean arterial blood pressure (MABP) on the cerebral haemodynamics (oxy- and deoxy-haemoglobin, HbO2 and Hb) was measured using transverse broadband near-infrared spectroscopy (NIRS). A marker for impaired CA, concordance between MABP and intravascular oxygenation (HbD = HbO2 - Hb) in the ultra-low frequency domain (0.0018-0.0083 Hz), was assessed using coherence analysis. Presence of CA impairment was not significant but found to increase with surgical exacerbation. The impairment did not correlate with histological outcome (presence of cell death, apoptosis and microglial activation in the brain).