Efficacy and Safety Assessment of Rivaroxaban for the Treatment of Cerebral Venous Sinus Thrombosis in a Chinese Population.

We aimed to investigate the efficacy and safety of rivaroxaban for acute and long-term management of cerebral venous sinus thrombosis (CVST). This study reviewed CVST-diagnosed patients admitted to the First Affiliated Hospital of Guangxi Medical University from January 2015 to December 2020. The primary outcome was a composite of recurrent thrombosis or major bleeding events. The secondary efficacy outcomes included a disease recovery time (DRT) presenting the time from admission to the endpoint as recovery (the modified Rankin scale [mRS] score [0-1]) within 30 and 90 days, and length of hospital stay (LHS). Patients treated with rivaroxaban (38) and warfarin (45) were enrolled in the final analysis. The primary outcome had no significant difference (5.3% vs 11.1%, P = .576) between the 2 groups. The secondary efficacy outcome regarding the median 30-d DRT was 17 days (95% confidence interval [CI], 14.6-19.4) in the rivaroxaban group, compared with 26.0 days (95% CI, 16.8-35.2) in the warfarin group (hazard ratio, 1.806; 95% CI, 1.051-3.103; log-rank P = .026). Two groups have a significant difference in LHS (P = .041). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability (admission mRS score [2-3]) treated with rivaroxaban recovered faster than those with warfarin (log-rank P < .05). Patients with cerebral edema, intracerebral hemorrhage, and mild/moderate disability treated with rivaroxaban had a shorter recovery time than those treated with warfarin within 1 month from admission, indicating that rivaroxaban a promising convenient therapy for CVST, helping them speedily restore social functions.

Light-Emitting Diode (LED) Therapy Attenuates Neurotoxicity of Methanol-Induced Memory Impairment and Apoptosis in The Hippocampus.

BACKGROUND & OBJECTIVE: The adolescent brain has a higher vulnerability to alcoholinduced neurotoxicity, compared to adult's brain. Most studies have investigated the effect of ethanol consumption on the body, however, methanol consumption, which peaked in the last years, is still poorly explored. METHOD: In this study, we investigated the effects of methanol neurotoxicity on memory function and pathological outcomes in the hippocampus of adolescent rats and examined the efficacy of Light- Emitting Diode (LED) therapy. Methanol induced neurotoxic rats showed a significant decrease in the latency period, in comparison to controls, which was significantly improved in LED treated rats at 7, 14 and 28 days, indicating recovery of memory function. In addition, methanol neurotoxicity in hippocampus caused a significant increase in cell death (caspase3+ cells) and cell edema at 7 and 28 days, which were significantly decreased by LED therapy. Furthermore, the number of glial fibrillary acid protein astrocytes was significantly lower in methanol rats, compared to controls, whereas LED treatment caused their significant increase. Finally, methanol neurotoxicity caused a significant decrease in the number of brain-derived neurotrophic factor (BDNF+) cells, but also circulating serum BDNF, at 7 and 28 days, compared to controls, which were significantly increased by LED therapy. Importantly, LED significantly increased the number of Ki-67+ cells and BDNF levels in the serum and hypothalamus in control-LED rats, compared to controls without LED therapy. CONCLUSION: In conclusion, chronic methanol administration caused severe memory impairments and several pathological outcomes in the hippocampus of adolescent rats which were improved by LED therapy.

A Callosal Catastrophe: Toxic Leukoencephalopathy Associated with Thermogenic Weight Loss Supplement Use.

BACKGROUND: The use of weight loss drugs and dietary supplements is common, but safety profiles for these drugs are largely unknown. Reports of toxicity have been published, and the use of these agents should be considered in clinical differential diagnoses. METHODS: We report the case of a patient with toxic leukoencephalopathy and hyponatremia associated with oral consumption of a thermogenic dietary supplement and essential oils. RESULTS: A 30-year-old woman presented after 2 days of headache, blurred vision, photophobia, vomiting, and hand spasms. She was taking a thermogenic dietary supplement daily for 6 months as well as a number of essential oils. Examination revealed mild right sided ataxia and diffuse hyperreflexia. Neuroimaging demonstrated bilaterally symmetric T2 hyperintensities of the corpus callosum and periventricular white matter. Approximately 18 h after admission she became unresponsive with brief extensor posturing and urinary incontinence. She partially recovered, but 1 h later became unresponsive with dilated nonreactive pupils and extensor posturing (central herniation syndrome). She was intubated, hyperventilated, and given hyperosmotic therapy. Emergent imaging showed diffuse cerebral edema. Intracranial pressure was elevated but normalized with treatment; she regained consciousness the following day. She was extubated one day later and discharged on hospital day 5. She was seen 2 months later with no further symptoms and a normal neurologic examination. CONCLUSIONS: The pathophysiology of this patient's hyponatremia and toxic leukoencephalopathy is unknown. However, physicians must be aware of the association between thermogenic dietary supplements and toxic leukoencephalopathy. Vigilance for life-threatening complications including hyponatremia and cerebral edema is critical.

A neurotoxic alcohol exposure paradigm does not induce hepatic encephalopathy.

Alcohol abuse is associated with neurological dysfunction, brain morphological deficits and frank neurotoxicity. Although these disruptions may be a secondary effect due to hepatic encephalopathy, no clear evidence of causality is available. This study examined whether a 72h period of alcohol intoxication known to induce physical dependence, followed by a single withdrawal, was sufficient to induce signs of hepatic encephalopathy in male and female mice. Animals were continuously intoxicated via alcohol vapor inhalation, a procedure previously shown to induce significant neurotoxicity in female mice. At peak synchronized withdrawal (8h following the end of alcohol exposure), blood samples were taken and levels of several liver-regulated markers and brain swelling were characterized. Glutathione levels were also determined in the medial frontal cortex (mFC) and hippocampus. Results revealed elevated levels of cholesterol, albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and decreased levels of blood urea nitrogen and total bilirubin in alcohol-exposed male and female groups compared to controls. Brain water weight was not affected by alcohol exposure, though males tended to have slightly more water weight overall. Alcohol exposure led to reductions in tissue levels of glutathione in both the hippocampus and mFC which may indicate increased oxidative stress. Combined, these results suggest that hepatic encephalopathy does not appear to play a significant role in the neurotoxicity observed following alcohol exposure in this model.

Thrombin preconditioning reduces iron-induced brain swelling and brain atrophy.

Cerebral preconditioning with a low dose of thrombin attenuates brain edema induced by intracerebral hemorrhage (ICH), a large dose of thrombin or iron. This study examined whether or not thrombin preconditioning (TPC) reduces neuronal death and brain atrophy caused by iron. The right hippocampus of rats was pretreated with or without thrombin, and iron was then injected into the same location 3 days later. Rats were killed at 1 day or 7 days after iron injection, and the brains were used for histology. We found that TPC reduced neuronal death and brain swelling in the hippocampus 1 day after iron injection, and hippocampal atrophy 7 days later. Western blots showed that thrombin activates p44/42 mitogen-activated protein kinase (p44/42 MAPK) and 70-kDa ribosomal protein S6 kinase (p70 S6K). Our results indicate that TPC reduction of iron-induced neuronal death may be through the p44/42 MAPK /p70 S6K signal transduction pathway.

HMGB1 inhibitor glycyrrhizin attenuates intracerebral hemorrhage-induced injury in rats.

Thrombin activates immunocompetent microglia and increases release of inflammatory cytokines under intracerebral hemorrhage (ICH) insults. Also, thrombin injection into the striatum evokes acute necrosis and delayed apoptosis of neurons. A nucleoprotein high-mobility group box 1 (HMGB1) that is released from necrotic cells has been suggested to behave like a cytokine and cause over-facilitation of immune functions. Here we examined the effect of glycyrrhizin, known as an inhibitor of HMGB1, on thrombin-induced injury in rat cortico-striatal slice cultures and in vivo rat ICH model. In slice cultures, thrombin-induced a drastic increase in propidium iodide fluorescence indicating necrotic cell death in the cortical region, and robust shrinkage of the striatal tissue. Glycyrrhizin (10-100 µM) attenuated thrombin-induced cortical injury in a concentration-dependent manner. The protective effect of glycyrrhizin was not mediated by glucocorticoid receptors or modulation of nitric oxide production, but was reversed by exogenous HMGB1 application. The injury induced by a high concentration of HMGB1 was suppressed by glycyrrhizin. In vivo, unilateral injection of type IV collagenase into rat striatum induced ICH associated with brain edema formation, contralateral paralysis and neuron death. Once daily intraperitoneal administration of glycyrrhizin attenuated ICH-induced edema in both the cortex and the basal ganglia, and improved behavioral performance of rats in forelimb placing. Moreover, glycyrrhizin partially but significantly ameliorated ICH-induced neuron loss inside hematoma. These findings suggest that an HMGB1 inhibitor glycyrrhizin is a potential candidate for a remedy for ICH.

Aggravation of seizure-associated microvascular injuries by ibuprofen may involve multiple pathways.

PURPOSE: Recently we reported that intrathalamic microinjection of carbachol triggers generalized convulsive seizures (GCS) followed by severe inflammatory response including edema, microhemorrhages, and subsequent degeneration of amygdaloallocortical area. Our further observations of increased expression of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1ß immunoreactivity (IR) confirmed the inflammatory nature of the brain damage following GCS. In the presented experiments, we addressed possible effects of a nonspecific cyclooxygenase (COX) inhibitor (ibuprofen), in the development of inflammatory response following thalamic-induced GCS. METHODS: In male Wistar rats, intrathalamic microinjection of carbachol (55 nm, 100 nl) within 2 h induced three to four episodes of GCS of an average duration of 57 s, each which led to the development of edema associated with microhemorrhages at 72 h and changes in expression of TNF-α/IL-1ß IR in the amygdaloallocortical area as revealed by immunohistochemistry at 24 h. RESULTS: Ibuprofen when administered intraperitoneally 30 min after the episode of GCS dramatically increased edema and microhemorrhages. It also increased expression of TNF-α/IL-1ß in microvessels and decreased IL-1ß IR in microglia/macrophages. CONCLUSIONS: Experiments suggest that in our model, inhibition of COX pathway early after GCS may increase rather than reduce the inflammatory consequences of GCS, suggesting that COX products may have a negative feedback effect on the development of edema by modifying the expression of "proinflammatory" cytokines. There is also a possibility that ibuprofen may exert its action through other than COX-associated pathways.

Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury.

Recent studies have reported that estrogen and progesterone have a neuroprotective effect after traumatic brain injury (TBI); however, the mechanism(s) for this effect have not yet been elucidated. The aim of the present study was to investigate the role of sex steroid hormones on changes in brain edema, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) after TBI in ovariectomized (OVX) rats. In this study, 50 female rats were divided into 5 groups: control (intact), sham, and 3 TBI groups consisting of vehicle, estrogen (1 mg/kg), and progesterone (8 mg/kg). TBI was induced by the Marmarou method, and the hormones were injected i.p. 30 min after TBI. ICP was measured in the spinal cord, and CPP was calculated by subtracting the mean arterial pressure (MAP) from ICP. The results revealed that brain water content after TBI was lower (p < 0.001) in the estrogen and progesterone groups than in the vehicle group. After trauma, ICP was significantly higher in TBI rats (p < 0.001). The ICP in the estrogen and progesterone groups decreased at 4 and 24 h after TBI compared with vehicle (p < 0.001 and p < 0.05, respectively). The CPP in the estrogen and progesterone groups increased after 24 h compared with vehicle (p < 0.001). Also after TBI, the neurological score (veterinary coma scale) was significantly higher than vehicle at 1 h (p < 0.01) and 24 h (p < 0.001) in the group treated with estrogen. In conclusion, pharmacological doses of estrogen and progesterone improved ICP, CPP, and neurological scores after TBI in OVX rats, which implies that these hormones play a neuroprotective role in TBI.

Blood-brain barrier breakdown and repair by Src after thrombin-induced injury.

OBJECTIVE: Thrombin mediates the life-threatening cerebral edema that occurs after intracerebral hemorrhage. Therefore, we examined the mechanisms of thrombin-induced injury to the blood-brain barrier (BBB) and subsequent mechanisms of BBB repair. METHODS: Intracerebroventricular injection of thrombin (20U) was used to model intraventricular hemorrhage in adult rats. RESULTS: Thrombin reduced brain microvascular endothelial cell (BMVEC) and perivascular astrocyte immunoreactivity-indicating either cell injury or death-and functionally disrupted the BBB as measured by increased water content and extravasation of sodium fluorescein and Evans blue dyes 24 hours later. Administration of nonspecific Src family kinase inhibitor (PP2) immediately after thrombin injections blocked brain edema and BBB disruption. At 7 to 14 days after thrombin injections, newborn endothelial cells and astrocytes were observed around cerebral vessels at the time when BBB permeability and cerebral water content resolved. Delayed administration of PP2 on days 2 through 6 after thrombin injections prevented resolution of the edema and abnormal BBB permeability. INTERPRETATION: Thrombin, via its protease-activated receptors, is postulated to activate Src kinase phosphorylation of molecules that acutely injure the BBB and produce edema. Thus, acute administration of Src antagonists blocks edema. In contrast, Src blockade for 2 to 6 days after thrombin injections is postulated to prevent resolution of edema and abnormal BBB permeability in part because Src kinase proto-oncogene members stimulate proliferation of newborn BMVECs and perivascular astrocytes in the neurovascular niche that repair the damaged BBB. Thus, Src kinases not only mediate acute BBB injury but also mediate chronic BBB repair after thrombin-induced injury.

Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats.

Intracerebral hemorrhage (ICH) is a devastating stroke with no clinically proven treatment. Deferoxamine (DFX), an iron chelator, is a promising therapy that lessens edema, mitigates peri-hematoma cell death, and improves behavioral recovery after whole-blood-induced ICH in rodents. In this model, blood is directly injected into the brain, usually into the striatum. This mimics many but not all clinical features of ICH (e.g., there is no spontaneous bleed). Thus, we tested whether DFX improves outcome after collagenase-induced striatal ICH in rats. In the first experiment, 3- and 7-day DFX regimens (100 mg/kg twice per day starting 6 h after ICH), similar to those shown effective in the whole-blood model, were compared to saline treatment. Functional recovery was evaluated from 3 to 28 days with several behavioral tests. Except for one instance, DFX failed to lessen ICH-induced behavioral impairments and it did not lessen brain injury, which averaged 43.5 mm(3) at a 28-day survival. In the second experiment, 3 days of DFX treatment were given starting 0 or 6 h after collagenase infusion. Striatal edema occurred, but it was not affected by either DFX treatment (vs. saline treatment). Therefore, in contrast to studies using the whole-blood model, DFX treatment did not improve outcome in the collagenase model. Our findings, when compared to others, suggest that there are critical differences between these ICH models. Perhaps, the current clinical work with DFX will help identify the more clinically predictive model for future neuroprotection studies.

Opening of the blood-brain barrier during isoflurane anaesthesia.

In order to produce its desired effect, anaesthesia acts upon neuronal elements by modifying membrane conductances and transmitter interactions. The effect of higher doses of isoflurane, widely used in clinical settings, on the permeability of the blood-brain barrier (BBB) is meanwhile ignored. In this study we investigated the integrity of the BBB during various levels of isoflurane anaesthesia (1% and 3%) in cats by monitoring the extravasation of Evans blue. Simultaneously we measured the electroencephalogram (EEG), with particular emphasis on its direct current (DC) component. High doses of anaesthetic (3%) broke down the BBB in the cortex and thalamus, while milder doses (1%) only opened the BBB in the thalamus. The fluorescent signal of Evans blue was visible over an extravascular length of 23 mum in the cortex and 25 mum in the thalamus, similar to the diffusion of the same dye when the BBB was disrupted with mannitol. The opening of the BBB was associated with (i) a positive DC shift in the EEG measured on the scalp and (ii) an evaluated increase in cerebral volume of 2-2.8%. The opening of the BBB by high doses of isoflurane brings into discussion hitherto unexplored effects of anaesthesia on the brain. The electrophysiological correlate provided by the DC component of the EEG constitutes a promising option for the assessment of the BBB integrity during human anaesthesia.

Brain edema and breakdown of the blood-brain barrier during methamphetamine intoxication: critical role of brain hyperthermia.

To clarify the role of brain temperature in permeability of the blood-brain barrier (BBB), rats were injected with methamphetamine (METH 9 mg/kg) at normal (23 degrees C) and warm (29 degrees C) environmental conditions and internal temperatures were monitored both centrally (nucleus accumbens, NAcc) and peripherally (skin and nonlocomotor muscle). Once NAcc temperatures peaked or reached 41.5 degrees C (a level suggesting possible lethality), animals were administered Evans blue dye (protein tracer that does not normally cross the BBB), rapidly anaesthetized, perfused and had their brains removed. All METH-treated animals showed brain and body hyperthermia associated with relative skin hypothermia, suggesting metabolic activation coupled with peripheral vasoconstriction. While METH-induced NAcc temperature elevation varied from 37.60 to 42.46 degrees C (or 1.2-5.1 degrees C above baseline), it was stronger at 29 degrees C (+4.13 degrees C) than 23 degrees C (+2.31 degrees C). Relative to control, METH-treated animals had significantly higher brain levels of water, Na(+), K(+) and Cl(-), suggesting brain edema, and intense immunostaining for albumin, indicating breakdown of the BBB. METH-treated animals also showed strong immunoreactivity for glial fibrillary acidic protein (GFAP), possibly suggesting acute abnormality or damage of astrocytes. METH-induced changes in brain water, albumin and GFAP correlated linearly with NAcc temperature (r = 0.93, 0.98 and 0.98, respectively), suggesting a key role of brain hyperthermia in BBB permeability, development of brain edema and subsequent functional and structural neural abnormalities. Therefore, along with a direct destructive action on neural cells and functions, brain hyperthermia, via breakdown of the BBB, may be crucial for both decompensation of brain functions and cell injury following acute METH intoxication, possibly contributing to neurodegeneration resulting from chronic drug use.

Neurointensive care management of raised intracranial pressure caused by severe valproic acid intoxication.

INTRODUCTION: We describe the neurointensive care (NIC) management of a patient with severe cerebral swelling and raised intracranial pressure (ICP) after severe sodium valproic acid (VPA) intoxication. A previously healthy 25-year old male with mild tonic-clonic epilepsy was found unconscious with serum VPA levels >10,000 micromol/l. The patient deteriorated to Glasgow Motor Scale score (GMS) 2 and a CT scan showed signs of raised ICP. Early ICP was elevated, >50 mm Hg, and continuous EEG monitoring showed isoelectric readings. METHODS: The patient was treated with an ICP-guided protocol including mild hyperventilation, normovolemia, head elevation and intermittent doses of mannitol. Due to refractory elevations of ICP, high-dose pentobarbital infusion was initiated, and ICP gradually normalised. RESULTS: There were several systemic complications including coagulopathy, hypocalcemia and pancreatitis. The patient remained in a depressed level of consciousness for 2 months but gradually recovered, showing a good recovery with minor subjective cognitive deficits by 6 months. CONCLUSION: We conclude that NIC may be an important treatment option in cases of severe intoxication causing cerebral swelling.

[Implication of dexamethasone adjunctive therapy after the onset of cerebral vasculitis in Streptococcus pneumoniae meningitis]. / Implication du traitement adjuvant par dexaméthasone dans la survenue d'une artérite septique cérébrale au cours d'une méningite à Streptococcus pneumoniae.

Few adverse effects have been reported with adjunctive dexamethasone treatment in pneumococcal meningitis. Nevertheless, we report a case of cerebral vasculitis. A 49-year-old man was admitted for fever and altered mental status. Lumbar puncture revealed a high inflammatory response and Streptococcus pneumoniae was identified by culture. Antibacterial therapy and adjunctive dexamethasone treatment were initiated as recommended. The immediate outcome was favorable but due to the onset of focal cerebral abnormalities, a CT scan was performed on the ninth day showing cerebral vasculitis. The patient died on the thirteenth day despite antibacterial therapy and resuscitation. In our case, a secondary neurological worsening appeared when adjunctive dexamethasone treatment was stopped suggesting a rebound effect. Observation of similar cases may lead to modifying adjunctive dexamethasone treatment protocol in bacterial meningitis.

NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort.

Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of affective disorders. Hyperforin, a constituent of St. John's wort, is known to modulate the release and re-uptake of various neurotransmitters, an action that likely underlies its antidepressive activity. We now report that hyperforin also has N-methyl-D-aspartate (NMDA)-antagonistic effects. Hyperforin (10 microM) was found to inhibit the NMDA-induced calcium influx into cortical neurons. In rat hippocampal slices, hyperforin inhibited the NMDA-receptor-mediated release of choline from phospholipids. Hyperforin also antagonized the increase of water content in freshly isolated hippocampal slices, and it counteracted, at 3 and 10 microM, the increase of water content induced by NMDA. Hyperforin was inactive, however, in two in vivo models of brain edema formation, middle cerebral artery occlusion and water intoxication in mice. In conclusion, hyperforin has NMDA-receptor-antagonistic and potential neuroprotective effects in vitro. This effect may contribute to the therapeutic effectiveness of St. John's wort extracts in some situations, for example, for relapse prevention in alcoholism.

Valproate-induced hyperammonemic encephalopathy.

Valproate-induced hyperammonemic encephalopathy (VHE) is an unusual complication characterized by a decreasing level of consciousness, focal neurological deficits, cognitive slowing, vomiting, drowsiness, and lethargy. We have thoroughly reviewed the predisposing factors and their screening, the biochemical and physiopathological mechanisms involved, the different treatments described, and those that are being investigated. Etiopathogenesis is not completely understood, although hyperammonemia has been postulated as the main cause of the clinical syndrome. The increase in serum ammonium level is due to several mechanisms, the most important one appearing to be the inhibition of carbamoylphosphate synthetase-I, the enzyme that begins the urea cycle. Polytherapy with several drugs, such as phenobarbital and topiramate, seems to contribute to hyperammonemia. Hyperammonemia leads to an increase in the glutamine level in the brain, which produces astrocyte swelling and cerebral edema. There are several studies that suggest that treatment with supplements of carnitine can lead to an early favorable clinical response due to the probable carnitine deficiency induced by a valproate (VPA) treatment. Development of the progressive confusional syndrome, associated with an increase in seizure frequency after VPA treatment onset, obliges us to rule out VHE by screening for blood ammonium levels and the existence of urea cycle enzyme deficiency, such as ornithine carbamoyltransferase deficiency. Electroencephalography (EEG) is characterized by signs of severe encephalopathy with continuous generalized slowing, a predominance of theta and delta activity, occasional bursts of frontal intermittent rhythmic delta activity, and triphasic waves. These EEG findings, as well as clinical manifestations and hyperammonemia, tend to normalize after VPA withdrawal.

[Haemodialysis, L-carnitine therapy and valproic acid overdose]. / Epuration extrarénale, supplémentation en L-carnitine et intoxication à l'acide valproïque.

We report the case of a severe valproic acid poisoning in a 36-year-old man. In front of a high serum concentration of valproic acid at the admission, haemodialysis was initiated to decrease serum valproic acid concentration. A L-carnitine therapy (50 mg/kg per day) was also started. A cerebral oedema appeared at the third day, but the patient recovered without any sequela.