Widespread Brain Injury Research Articles

Nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia.

COVID-19 is a multifaceted disease and respiratory failure is a common manifestation. Interestingly, several reports are suggesting that many patients with COVID-19 pneumonia seem to present less respiratory effort and experience less dyspnea when exposed to acute respiratory failure and hypoxemia, a phenomenon called “silent,” “happy,” or even “apathetic” hypoxemia. We present a personal view exploring potential pathways associated with this intriguing clinical feature. We also suggest that “nondyspnogenic acute hypoxemic respiratory failure” is a more accurate terminology to describe this clinical finding in COVID-19, as hypoxemia may not be the only trigger for dyspnea in patients with pneumonia associated with respiratory failure. Acute hypoxemic respiratory failure is a common clinical manifestation in patients with pneumonia caused by the new severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and is a marker of in-hospital mortality (1, 2). The autonomic nervous system orchestrates a complex respiratory and cardiovascular response during a hypoxemic stress. Besides the lung and cardiovascular manifestations documented in patients with the new coronavirus disease 2019 (COVID-19) (3), there is growing evidence suggesting that SARS-CoV-2 is a neurotropic virus and may invade the peripheral and central nervous system (CNS) by several routes, with widespread brain injury, including the respiratory and cardiovascular autonomic centers (4, 5). In clinical practice, acute hypoxemic respiratory syndromes, such as those caused by bacterial or viral pneumonia, are generally accompanied by dyspnea sensation (6–8). In a cohort of 395 patients with community-acquired pneumonia, 94% of those with severe pneumonia presented with dyspnea (7). Interestingly, several anecdotal reports are suggesting that patients with COVID-19 pneumonia have an atypical nondyspnogenic response to acute hypoxemic respiratory failure (9–11). Some argue that these patients present with less respiratory effort and experience less dyspnea even when exposed to critical hypoxemia, a phenomenon called “silent,” “happy,” or even “apathetic” hypoxemia (11–13). The term “silent hypoxemia” has been criticized because dyspnea is a complex and multifactorial symptom not only dependent on systemic hypoxemia (14). Previous studies in healthy humans suggest that hypoxemia per se is generally well tolerated and hypoxemia associated with acute respiratory failure may be only a marker of a more complex respiratory pathophysiology and not the determinant cause of dyspnea (15–17). Moreover, in controlled human experiments, respiratory effort is not necessarily associated with dyspnea sensation (18). Therefore, in this review, we prefer to use the term nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia to describe the apparently comfortable status of patients with COVID-19, despite marked acute hypoxemic respiratory failure (9, 10). Nondyspnogenic acute hypoxemic respiratory failure is not an expected feature in clinical practice when assisting patients with pneumonia. Conversely, nondyspnogenic respiratory failure is more common in chronic conditions, such as chronic pulmonary obstructive disease and pulmonary fibrosis, and can also be seen in high altitude sickness (19). The limited understanding of the complex mechanisms involved in dyspnea sensation and of the neuropathology associated with SARS-CoV-2 infection is a barrier to explain why patients with severe hypoxemia may present to the emergency department without any physical discomfort and almost asymptomatic. Two initial hypotheses have been speculated to explain the installation of nondyspnogenic acute hypoxemic respiratory failure in these circumstances: the association of iso/hypocapnia, preventing the uncomfortable feelings of air hunger (19); and the maintenance of pulmonary mechanics (total dead space, lung compliance, and resistance) in near-normal range in the first stages of respiratory failure, thus not increasing significantly the respiratory effort (19, 20). Although both mechanisms are biologically plausible, they fail to address why acute respiratory failure in COVID-19 pneumonia seems to be peculiarly undersensed by these patients. To integrate the current knowledge regarding SARS-CoV-2 infection with the peculiar nondyspnogenic acute hypoxemic respiratory failure in COVID-19 pneumonia, we hypothesize a different mechanism related to an early and complex interaction between SARS-CoV-2 infection and the peripheral and central nervous system disturbing the activation of brain regions responsible for dyspnea sensation during acute hypoxemic respiratory failure.

Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association.

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.

The effects of Mucuna pruriens extract on histopathological and biochemical features in the rat model of ischemia.

Stroke is considered to be one of the most important causes of death worldwide. Global ischemia causes widespread brain injury and infarctions in various regions of the brain. Oxidative stress can be considered an important factor in the development of tissue damage, which is caused because of arterial occlusion with subsequent reperfusion. Kapikacchu or Mucuna pruriens, commonly known as velvet bean, is well known for its aphrodisiac activities. It is also used in the treatment of snakebites, depressive neurosis, and Parkinson's disease. Although this plant has different pharmacological actions, its neuroprotective activity has received minimal attention. Thus, this study was carried out with the aim of evaluating the neuroprotective action of M. pruriens in bilateral carotid artery occlusion-induced global cerebral ischemia in Wistar rats. The carotid arteries of both sides were occluded for 30 min and reperfused to induce global cerebral ischemia. The methanolic plant extract was administered to the study animals for 10 days. The brains of the Wistar rats were isolated by decapitation and observed for histopathological and biochemical changes. Cerebral ischemia resulted in significant neurological damage in the brains of the rats that were not treated by M. pruriens. The group subjected to treatment by the M. pruriens extract showed significant protection against brain damage compared with the negative control group, which indicates the therapeutic potential of this plant in ischemia.

Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia.

Global ischemia following cardiac arrest is characterized by high mortality and significant neurological deficits in long-term survivors. Its mechanisms of neuronal cell death have only partially been elucidated. 12/15-lipoxygenase (12/15-LOX) is a major contributor to delayed neuronal cell death and vascular injury in experimental stroke, but a possible role in brain injury following global ischemia has to date not been investigated. Using a mouse bilateral occlusion model of transient global ischemia which produced surprisingly widespread injury to cortex, striatum, and hippocampus, we show here that 12/15-LOX is increased in a time-dependent manner in the vasculature and neurons of both cortex and hippocampus. Furthermore, 12/15-LOX co-localized with apoptosis-inducing factor (AIF), a mediator of non-caspase-related apoptosis in the cortex. In contrast, caspase-3 activation was more prevalent in the hippocampus. 12/15-lipoxygenase knockout mice were protected against global cerebral ischemia compared to wild-type mice, accompanied by reduced neurologic impairment. The lipoxygenase inhibitor LOXBlock-1 similarly reduced neuronal cell death both when pre-administered and when given at a therapeutically relevant time point 1h after onset of ischemia. These findings suggest a pivotal role for 12/15-LOX in both caspase-dependent and caspase-independent apoptotic pathways following global cerebral ischemia and suggest a novel therapeutic approach to reduce brain injury following cardiac arrest.

Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups

ObjectiveStatus Epilepticus (SE) is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. However, the role of SE in this injury is uncertain. Until now, we have lacked an animal model in which seizures result in neuronal injury in rodent models at ages below postnatal day 12 (P12) unless seizures are combined with inflammatory stressors. MethodsWe induced SE with high-dose lithium and pilocarpine in P7 rats, which are developmentally close to human neonates. Several EEG measures and O2 saturation were recorded during the 6h following initiation of SE. We assessed neuronal injury at 6 and 24h post-SE onset using Fluoro–Jade B staining (FJB) and caspase-3a immunoreactivity (IR). ResultsEEGs showed continuous polyspikes activity for 54.3±6.7min, while O2 saturation showed no significant hypoxemia. By 24h after SE onset, significant neuronal injury was observed in CA1/subiculum, CA3, dentate gyrus, thalamus, neocortex, amygdala, piriform cortex, lateral entorhinal cortex, hypothalamus, caudate putamen, globus pallidus, ventral pallidum, and nucleus accumbens. At 24h post-SE, caspase-3a IR was significantly increased in CA1/subiculum, thalamus, and neocortex compared to sham, and caspase-3a IR neurons had fragmented nuclei, suggesting that SE triggered an irreversible form of cell injury. SignificanceIn conclusion, we have developed a model of cholinergic SE in P7 rat pups, which combines high survival (69.9% survival at 24h) and widespread brain injury. These studies suggest that the immature brain is vulnerable to severe forms of SE.

The brain injury after pentetrazole kindling in adenosine A1 receptor knock-out mice

Objective To evaluate the neuroprotective function of adenosine A1 receptor ( A1R)by observing the dynamic change of brain injury after pentetrazole kindling in adenosine A1R knock-out (KO) mice. Methods The animals were divided into three groups: wild type group, KO group and control group. For each animal, 4 parts of the brain (cortex, cerebellum, hippocampus and brainstem) were chosen. The latent period of kindling was calculated. The dynamic change of the ultrastructure in neurocytes during pentetrazole kindling was examined by a transmission electron microscope at different time points (2 h, 7 day, 1 month). Results The average latent period in KO group was (2. 38 ± 1.66) days,showing statistically significant difference in comparison with the wild type group (P <0. 01 ). Morphologically, there was widespread brain injury in KO mice at the 2nd h after kindling, especially in the mitochondria. Over time, the injury was gradually aggravated. However, in wild type group, the mitochondrial injury mainly in hippocampus and temporal lobe was found at the 7th day after kindling. At the 1st month, the injury still focused on temporal lobe. Conclusion Adenosine A1R acts strong neuroprotective function.This receptor can reduce the damage of the ultrastructures during pentetrazole kindling. Key words: Adenosine A1 receptor; Ultrastructure; Mitochondrion injury; Neuroprotective function

Postnatal cerebral infection leading to hemiplegic cerebral palsy: Clinical description of 13 children in Stockholm, Sweden

Purpose. The aim of this research was to estimate the prevalence of postnatal cerebral infection leading to hemiplegic cerebral palsy (CP) in Stockholm County and to describe the motor impairments, associated impairments and involvement of the non hemiplegic side.Method. Children with hemiplegic CP subsequent to a cerebral infection in the perinatal period up to the age of seven years were identified. The assessments of child psychologists and speech therapists and EEG-studies, CT-scan or MRI of the brain were extracted from the children's files. Thirteen children, with a mean age of 9.5 years, participated. The prevalence was 0.03/1000.Results. Nine children suffered from mental retardation, seven took antiepileptic drugs and six had bilateral radiological anomalies. The non-hemiplegic side was involved in six of the children.Conclusion. Cerebral infection at an early age can cause hemiplegic CP with a high frequency of associated impairments and with involvement of the non-hemiplegic side. The infectious origin probably gives rise to a more widespread brain injury.

Fetal brain monitoring: Future applications

Future application of fetal brain monitoring is explored by selecting and analysing articles for information on types of brain damage that can be monitored, where in the brain this can be done, how long after the risk exposure, and with what method of investigation. A limited number of--mainly--case histories reported that early (cell death and oedema) and late (gliosis) effects of brain damage can be demonstrated before birth with multiplanar ultrasound and magnetic resonance imaging, and that hypoxic ischaemic injury or infection can induce local or widespread brain injury, occurring as transient or longer-lasting changes in age-related predilection areas for which normal features are known. The antenatal role of risk factors inducing abnormal brain development can be studied longitudinally with ultrasound and magnetic resonance imaging. A multidisciplinary approach will facilitate the introduction of various techniques with adequate know-how of underlying processes, to evaluate the predictive value on neurological outcome and prevent premature introduction into clinical application.

Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity

We examined the effects of methamphetamine (METH) on monoaminergic (i.e. dopamine and serotonin) axonal markers and glial cell activation in the rat brain. Our findings indicate that the loss of dopamine transporters (DAT), serotonin transporters (5-HTT), vesicular monoamine transporter type-2 (VMAT-2) and glial cell activation induced by METH in the striatum and in the central gray are consistent with a degenerative process. Our novel finding of METH effects on monoaminergic neurons in the central gray may have important implications on METH-induced hyperthermia. In other brain regions examined, DAT and 5-HTT deficits after METH administration were present in the absence of lasting changes in VMAT-2 levels or glial cell activation. Brain regions exhibiting protracted deficits in DAT and/or 5-HTT and VMAT-2 levels also expressed increased levels of [ 3H]-R-PK11195 binding to peripheral benzodiazepine receptors, a quantitative marker of glial cell activation. Immunohistochemical assessment of microglia and astrocytes confirmed the PBR results. Microglia activation was more pronounced than astrocytosis in affected regions in most METH-exposed brains with the exception of a small number of rats that were most severely affected by METH based on loss of body weight. In these rats, both microglia and astrocytes were highly activated and expressed a distinct regional pattern suggestive of widespread brain injury. The reason for the pattern of glial cell activation in this group of rats is not currently known but it may be associated with METH-induced hyperthermia. In summary, our findings suggest two neurotoxic endpoints in the brain of METH-exposed animals. Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration. However, the DAT and 5-HTT deficits in brain regions lacking a deficit in VMAT-2 and glial cell activation may reflect drug-induced modulation of these plasma membrane proteins.

Calpastatin Is Up-regulated in Response to Hypoxia and Is a Suicide Substrate to Calpain after Neonatal Cerebral Hypoxia-Ischemia

In a model of cerebral hypoxia-ischemia in the immature rat, widespread brain injury is produced in the ipsilateral hemisphere, whereas the contralateral hemisphere is left undamaged. Previously, we found that calpains were equally translocated to cellular membranes (a prerequisite for protease activation) in the ipsilateral and contralateral hemispheres. However, activation, as judged by degradation of fodrin, occurred only in the ipsilateral hemisphere. In this study we demonstrate that calpastatin, the specific, endogenous inhibitor protein to calpain, is up-regulated in response to hypoxia and may be responsible for the halted calpain activation in the contralateral hemisphere. Concomitantly, extensive degradation of calpastatin occurred in the ipsilateral hemisphere, as demonstrated by the appearance of a membrane-bound 50-kDa calpastatin breakdown product. The calpastatin breakdown product accumulated in the synaptosomal fraction, displaying a peak 24 h post-insult, but was not detectable in the cytosolic fraction. The degradation of calpastatin was blocked by administration of CX295, a calpain inhibitor, indicating that calpastatin acts as a suicide substrate to calpain during hypoxia-ischemia. In summary, calpastatin was up-regulated in areas that remain undamaged and degraded in areas where excessive activation of calpains and infarction occurs.

Post-traumatic intention tremor--clinical features and CT findings.

Eight patients with post-traumatic intention tremor were reported. Intention tremor developed in the young as a late complication of severe head injury (Glasgow Coma Scale was below 8 in all cases) and impaired their functional outcome. This state was treatable with medication or by stereotactic thalamotomy. Neurologically, all the patients lapsed into coma immediately after the injury and many patients manifested clinical signs of a midbrain lesion in the chronic stage. The characteristic CT (computed tomography) findings in the acute stage were a high density area in the midbrain, accompanied by diffuse cerebral swelling or intraventricular hemorrhage, and in the chronic stage, brain atrophy or ventricular enlargement were the most prominent CT findings. These characteristics, indicating diffuse brain damage in addition to midbrain injury, may suggest the presence of shearing injury. The midbrain damage is consistent with the classical hypothesis that the damage to the Dentate-Rubro-thalamic system accounts for the occurrence of intention tremor. Furthermore, the presence of diffuse brain damage suggests that a more widespread brain injury may participate in its development.