Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Proton therapy for re-irradiation of pediatric diffuse brain stem tumors

Currently, there is no cure for pediatric diffuse brain stem (BS) tumors. Radiotherapy, including proton therapy, is an important component of combination treatment for this cancer, especially in children with a complicated medical history. The article addresses the issues of therapy for pediatric BS tumors and reports the use of proton re-irradiation in a 9-year-old boy with unverified diffuse BS tumor. Proton re-irradiation is an effective treatment option that can sustain and improve the quality of life and prolong survival in children with diffuse BS tumors.

Age-at-Injury Determines the Extent of Long-Term Neuropathology and Microgliosis After a Diffuse Brain Injury in Male Rats

Traumatic brain injury (TBI) can occur at any age, from youth to the elderly, and its contribution to age-related neuropathology remains unknown. Few studies have investigated the relationship between age-at-injury and pathophysiology at a discrete biological age. In this study, we report the immunohistochemical analysis of naïve rat brains compared to those subjected to diffuse TBI by midline fluid percussion injury (mFPI) at post-natal day (PND) 17, PND35, 2-, 4-, or 6-months of age. All brains were collected when rats were 10-months of age (n = 6–7/group). Generalized linear mixed models were fitted to analyze binomial proportion and count data with R Studio. Amyloid precursor protein (APP) and neurofilament (SMI34, SMI32) neuronal pathology were counted in the corpus callosum (CC) and primary sensory barrel field (S1BF). Phosphorylated TAR DNA-binding protein 43 (pTDP-43) neuropathology was counted in the S1BF and hippocampus. There was a significantly greater extent of APP and SMI34 axonal pathology and pTDP-43 neuropathology following a TBI compared with naïves regardless of brain region or age-at-injury. However, age-at-injury did determine the extent of dendritic neurofilament (SMI32) pathology in the CC and S1BF where all brain-injured rats exhibited a greater extent of pathology compared with naïve. No significant differences were detected in the extent of astrocyte activation between brain-injured and naïve rats. Microglia counts were conducted in the S1BF, hippocampus, ventral posteromedial (VPM) nucleus, zona incerta, and posterior hypothalamic nucleus. There was a significantly greater proportion of deramified microglia, regardless of whether the TBI was recent or remote, but this only occurred in the S1BF and hippocampus. The proportion of microglia with colocalized CD68 and TREM2 in the S1BF was greater in all brain-injured rats compared with naïve, regardless of whether the TBI was recent or remote. Only rats with recent TBI exhibited a greater proportion of CD68-positive microglia compared with naive in the hippocampus and posterior hypothalamic nucleus. Whilst, only rats with a remote brain-injury displayed a greater proportion of microglia colocalized with TREM2 in the hippocampus. Thus, chronic alterations in neuronal and microglial characteristics are evident in the injured brain despite the recency of a diffuse brain injury.

Mild gray matter atrophy in patients with long-standing multiple sclerosis and favorable clinical course

The mechanisms responsible for the favorable clinical course in multiple sclerosis (MS) remain unclear. In this longitudinal study, we assessed whether magnetic resonance imaging (MRI)-based changes in focal and diffuse brain damage are associated with a long-term favorable MS diseases course. We found that global brain and gray matter (GM) atrophy changes were milder in MS patients with long-standing disease (⩾30 years from onset) and favorable (no/minimal disability) clinical course than in sex-age-matched disable MS patients, independently of lesions accumulation. Data showed that different trajectories of volume changes, as reflected by mild GM atrophy, may characterize patients with long-term favorable evolution.

Unfortunate Case of Hypoglycemia Induced Seizures Resulting in Anoxic Encephalopathy

Background: Severe hypoglycemia in patient with diabetes mellitus can manifest as seizures and coma, most commonly occurring after excessive insulin administration. Clinical Case: A 35-year-old woman with uncontrolled type 1 diabetes mellitus on basal-bolus insulin, complicated by gastroparesis, hypoglycemia unawareness, and frequent hypoglycemic episodes due to a tendency to give more than the recommended amount of insulin, who presented with seizures and diffuse brain edema as severe manifestations of profound hypoglycemia. Hemoglobin A1c was 7.3% but patient had wide variation in blood glucose (40- 300 mmol/L) on her glucometer. Patient had initially self-treated overnight hypoglycemic symptoms by drinking soda and then fell asleep without re-checking her blood sugar. She was then unresponsive in the morning. Patient’s husband reported that there was no glucagon at home since he used the last one and did not refill. On EMS arrival, patient had a blood glucose of 25, for which she received dextrose and glucagon with improvement of blood glucose but no change in mentation. En route to the hospital, patient developed tonic-clonic seizures and decerebrate posturing. She received Ativan and was intubated for airway protection. On exam, she had bilateral dilated sluggishly reactive pupils, eyes opened spontaneously but did not track, and limbs moved spontaneously but there was no purposeful movement. Initial CT head without contrast showed significant diffuse brain edema. Repeat MRI brain with and without contrast showed bilateral basal ganglia diffusion restriction with associated T2 and FLAIR hyperintense signal, suggestive of toxic-metabolic etiology including hypoglycemia. Video EEG showed findings consistent with anoxic encephalopathy. Patient received IV mannitol and IV dexamethasone for cerebral edema and Keppra for seizure prophylaxis, but was unable to be weaned from the ventilator and had to undergo tracheostomy and PEG tube placement, and was eventually discharged to inpatient rehabilitation. Conclusion: This case highlights the dangers of accidental overcorrection of high blood sugar with short-acting insulin and not appropriately treating hypoglycemia, which can lead to irreversible brain injury due to prolonged hypoglycemia. This unfortunate case highlights the importance of educating patients with diabetes mellitus on insulin how to appropriately manage low sugars to avoid such outcomes.

Prognostic Factors for Pediatric Acute Encephalopathy Associated with Severe Brain Edema

<b><i>Background and Objective:</i></b> Acute encephalopathy is a life-threatening brain dysfunction in children, often associated with a preceding infection and diffuse noninflammatory brain edema. At present, the role of decompressive craniectomy (DC) over the swollen area of the brain is unclear. The risk factors for predicting clinical deterioration also need clarification. <b><i>Methods:</i></b> A retrospective study of pediatric patients admitted between 2015 and 2019 with acute cerebral encephalopathy was carried out. Patients were classified according to: (1) the preceding pathogens, (2) the syndromic classification, and (3) the extent of brain edema. The syndromic classification is a relatively new classification of acute encephalopathy proposed in 2016 and divides patients into 3 groups: those with systemic inflammatory reactions or “cytokine storms” (group 1), those with status epilepticus but no cytokine storm (group 2), and others (group 3). Glasgow Outcome Scale (GOS) scores of 1–3 were defined as unfavorable, while a GOS score of 4 or 5 was defined as a favorable outcome in this study. DC was performed for select patients with life-threatening signs of brainstem compression. <b><i>Results:</i></b> Nineteen patients (mean age: 23.3 months) were included in the study, 8 (42.1%) of whom had an unfavorable outcome. There was no significant correlation between the types of pathogens and outcome. Unfavorable outcomes were observed in significantly more patients in group 1 (87.5%) than group 2 (14.3%) and group 3 (0%). There was a significant association between diffuse brain edema and unfavorable outcomes (72.7%). Neurosurgical DC was performed in 2 patients to alleviate life-threatening brainstem compression: one with a cytokine storm and diffuse bilateral brain edema, and the other with prolonged status epilepticus causing diffuse right-sided brain edema. The GOS score was 3 and 4, respectively. <b><i>Conclusion:</i></b> The risk factors for clinical deterioration in pediatric acute encephalopathy were evaluated based on a variety of classifications, including the new syndromic classification. Laboratory features of cytokine storms and radiological evidence of diffuse brain edema were associated with unfavorable outcomes. The role of surgical decompression is still controversial and should be assessed on a case-by-case basis.

The Association of Early Electrocardiographic Abnormalities With Brain Injury Severity and Outcome in Severe Traumatic Brain Injury

The aim of this study was to evaluate the frequency of electrocardiographic (ECG) abnormalities in the acute phase of severe traumatic brain injury (TBI) and the association with brain injury severity and outcome. In contrast to neurovascular diseases, sparse information is available on this issue. Data of adult patients with severe TBI admitted to the Intensive Care Unit (ICU) for intracranial pressure monitoring of a level-1 trauma center from 2002 till 2018 were analyzed. Patients with a cardiac history were excluded. An ECG recording was obtained within 24 h after ICU admission. Admission brain computerized tomography (CT)-scans were categorized by Marshall-criteria (diffuse vs. mass lesions) and for location of traumatic lesions. CT-characteristics and maximum Therapy Intensity Level (TILmax) were used as indicators for brain injury severity. We analyzed data of 198 patients, mean (SD) age of 40 ± 19 years, median GCS score 3 [interquartile range (IQR) 3–6], and 105 patients (53%) had thoracic injury. In-hospital mortality was 30%, with sudden death by cardiac arrest in four patients. The incidence of ECG abnormalities was 88% comprising ventricular repolarization disorders (57%) mostly with ST-segment abnormalities, conduction disorders (45%) mostly with QTc-prolongation, and arrhythmias (38%) mostly of supraventricular origin. More cardiac arrhythmias were observed with increased grading of diffuse brain injury (p = 0.042) or in patients treated with hyperosmolar therapy (TILmax) (65%, p = 0.022). No association was found between ECG abnormalities and location of brain lesions nor with thoracic injury. Multivariate analysis with baseline outcome predictors showed that cardiac arrhythmias were not independently associated with in-hospital mortality (p = 0.097). Only hypotension (p = 0.029) and diffuse brain injury (p = 0.017) were associated with in-hospital mortality. In conclusion, a high incidence of ECG abnormalities was observed in patients with severe TBI in the acute phase after injury. No association between ECG abnormalities and location of brain lesions or presence of thoracic injury was present. Cardiac arrhythmias were indicative for brain injury severity but not independently associated with in-hospital mortality. Therefore, our findings likely suggest that ECG abnormalities should be considered as cardiac mimicry representing the secondary effect of traumatic brain injury allowing for a more rationale use of neuroprotective measures.

Brain damage caused by chlorfenapyr poisoning: a case report and literature review

Introduction: Chlorfenapyr poisoning is uncommon, but fatal, and is often ignored. Chlorfenapyr inhibits ATP production in the mitochondrial of lipid-rich organs such as the brain. The initial symptoms of chlorfenapyr poisoning are not serious and are usually ignored; fever and unconsciousness are the main signs. Patients often die of brain damage, and survivors often present toxic leukoencephalopathy. Case report: We report a case of a 15-year-old female who swallowed 10 mL of 10%chlorfenapyr, and was subjected to gastric lavage one hour after ingestion. The patient felt no discomfort on the first and second day after lavage and went to school. On the third day, the patient complained of a headache and rested at home. On the fourth day, the patient still complained of headache, and the condition progressed to confusion and fever; therefore, the patient was admitted to the emergency room and underwent hemoperfusion. Cerebral CT revealed diffuse brain edema. The patient died on the fourth day because of central fever, brain hernia, and brain dysfunction. Conclusion: Chlorfenapyr poisoning is fatal, even in small doses. Patients suspected of chlorfenapyr poisoning should be closely observed and promptly treated by hemoperfusion.