Acute Central Nervous System Disease Research Articles

The Potentials of Melatonin in the Prevention and Treatment of Bacterial Meningitis Disease.

Bacterial meningitis (BM) is an acute infectious central nervous system (CNS) disease worldwide, occurring with 50% of the survivors left with a long-term serious sequela. Acute bacterial meningitis is more prevalent in resource-poor than resource-rich areas. The pathogenesis of BM involves complex mechanisms that are related to bacterial survival and multiplication in the bloodstream, increased permeability of blood–brain barrier (BBB), oxidative stress, and excessive inflammatory response in CNS. Considering drug-resistant bacteria increases the difficulty of meningitis treatment and the vaccine also has been limited to several serotypes, and the morbidity rate of BM still is very high. With recent development in neurology, there is promising progress for drug supplements of effectively preventing and treating BM. Several in vivo and in vitro studies have elaborated on understanding the significant mechanism of melatonin on BM. Melatonin is mainly secreted in the pineal gland and can cross the BBB. Melatonin and its metabolite have been reported as effective antioxidants and anti-inflammation, which are potentially useful as prevention and treatment therapy of BM. In bacterial meningitis, melatonin can play multiple protection effects in BM through various mechanisms, including immune response, antibacterial ability, the protection of BBB integrity, free radical scavenging, anti-inflammation, signaling pathways, and gut microbiome. This manuscript summarizes the major neuroprotective mechanisms of melatonin and explores the potential prevention and treatment approaches aimed at reducing morbidity and alleviating nerve injury of BM.

Regulation of PGE2 Pathway During Cerebral Ischemia Reperfusion Injury in Rat.

Stroke is an acute central nervous system disease with high morbidity and mortality rate. Cerebral ischemia reperfusion (I/R) injury is easily induced during the development or treatment of stroke and subsequently leads to more serious brain damage. Prostaglandin E2 (PGE2) is one of the most important inflammatory mediators in the brain and contributes to both physiological and pathophysiological functions. It may be upregulated and subsequently plays a key role in cerebral ischemia reperfusion injury. The synthesis and degradation of PGE2 is an extremely complex process, with multiple key stages and molecules. However, there are few comprehensive and systematic studies conducted to investigate the synthesis and degradation of PGE2 during cerebral I/R injury, which is what we want to demonstrate. In this study, qRT-PCR and immunoblotting demonstrated that the key enzymes in PGE2 synthesis, including COX-1, COX-2, mPGES-1 and mPGES-2, were upregulated during cerebral I/R injury, but 15-PGDH, the main PGE2 degradation enzyme, was downregulated. In addition, two of PGE2 receptors, EP3 and EP4, were also increased. Meanwhile, immunohistochemistry demonstrated the localization of these molecules in ischemic areas, including cortex, striatum and hippocampus, and reflected their expression patterns in different regions. Combining the results of PCR, Western blotting and immunohistochemistry, we can determine where the increase or decrease of these molecules occurs. Overall, these results further indicate a possible pathway that mediates enhanced production of PGE2, and thus that may impact production of inflammatory cytokines including IL-1β and TNF-α during cerebral I/R injury.

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease.

Acute central nervous system (CNS) disease is very common and with high mortality. Many basic studies have confirmed the molecular mechanism of early brain injury (EBI) after acute CNS disease. Neuron death and dysfunction are important reasons for the neurological dysfunction in patients with acute CNS disease. Ferroptosis is a nonapoptotic form of cell death, the classical characteristic of which is based on the iron-dependent accumulation of toxic lipid reactive oxygen species. Previous studies have indicated that this mechanism is critical in the cell death events observed in many diseases, including cancer, tumor resistance, Alzheimer’s disease, Parkinson’s disease, stroke, and intracerebral hemorrhage (ICH). Ferroptosis may also play a very important role in EBI after acute CNS disease. Unresolved issues include the relationship between ferroptosis and other forms of cell death after acute CNS disease, the specific molecular mechanisms of EBI, the strategies to activate or inhibit ferroptosis to achieve desirable attenuation of EBI, and the need to find new molecular markers of ferroptosis that can be used to detect and study this process in vivo after acute CNS disease.

Core cell cycle machinery is crucially involved in both life and death of post-mitotic neurons.

A persistent dogma in neuroscience supported the idea that terminally differentiated neurons permanently withdraw from the cell cycle. However, since the late 1990s, several studies have shown that cell cycle proteins are expressed in post-mitotic neurons under physiological conditions, indicating that the cell cycle machinery is not restricted to proliferating cells. Moreover, many studies have highlighted a clear link between cell cycle-related proteins and neurological disorders, particularly relating to apoptosis-induced neuronal death. Indeed, cell cycle-related proteins can be upregulated or overactivated in post-mitotic neurons in case of acute or degenerative central nervous system disease. Given the considerable lack of effective treatments for age-related neurological disorders, new therapeutic approaches targeting the cell cycle machinery might thus be considered. This review aims at summarizing current knowledge about the role of the cell cycle machinery in post-mitotic neurons in healthy and pathological conditions.

Emerging Pharmacological Treatments for Cerebral Edema: Evidence from Clinical Studies.

Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trials.

Neuron specific enolase as a marker of seizure related neuronal injury

Backgroundand purpose: Neuron specific enolase (NSE) is an established biomarker of neuronal damage. It is not clear how much seizures contribute to the neuronal damage, morbidity or mortality in critically ill neurology patients. The aim of this study is to determine the impact of seizures on neuronal injury in critically ill neurology patients by using neuron specific enolase as a biomarker. Material and methodsForty patients with clinical evidence of acute central nervous system disease associated with seizures were included as critically ill neurology patients with seizures [CINPS] (age in years 38.8 ± 17.54, mean ± SD; 22 males) and 43 age and sex-matched acute central nervous system disease without seizures were recruited as critically ill neurology patients [CINP] (age in years 37.84 ± 17.38 years mean ± SD; 24 males) The serum NSE assays were performed in CINPS (within 24 h of last seizure) and in CINP using an enzyme immunoassay kit. ResultsThe level of serum neuron specific enolase was significantly higher in CINP with seizures compared to those without seizures. The length of ICU stay was more prolonged in those with seizures. There was a close correlation between the NSE levels and frequency of seizures. There was no significant difference in the mortality between both the groups. ConclusionsNSE a marker of neuronal injury was elevated in patients with acute central nervous system diseases. It is significantly higher in patients with seizures in comparison to those without seizures. This warrants further studies to document aggressive treatment of seizures in acute neurologically ill patients can reduce neuronal damage.

Procoagulant activity of bovine neutrophils incubated with conditioned media or extracellular vesicles from Histophilus somni stimulated bovine brain endothelial cells

Histophilus somni is a Gram negative coccobacillus that causes respiratory, reproductive and central nervous system disease in cattle. The hallmark of H. somni infection is diffuse vasculitis and intravascular thrombosis that can lead to an acute central nervous system disease known as thrombotic meningoencephalitis (TME). Because neutrophils are major players in the pathophysiology of septic meningitis, we sought to determine their role in H. somni-induced fibrin clot formation in vitro. Bovine brain endothelial cells (TBBE cells) were exposed to H. somni cells at a 1:25 ratio, respectively. Conditioned media (CM) were collected after a 6 h incubation at 37 °C with 5% CO2, and then incubated with bovine peripheral blood polymorphonuclear neutrophils (PMNs). Following incubation, fibrin clot formation and tissue factor activity were assessed by a re-calcified plasma clotting assay. We found greater tissue factor activity in cell lysates and CM from H. somni-stimulated TBBE cells than unstimulated control TBBE cells. In addition, PMNs exposed to CM or extracellular vesicles from H. somni-stimulated TBBE cells expressed von Willenbrand factor, exhibited increased fibrin clot formation, and displayed greater tissue factor activity than PMNs exposed to CM or extracellular vesicles from unstimulated control TBBE cells. These results suggest that bovine PMNs might acquire extracellular vesicles from endothelial cells that leads to thrombus formation in bovine brain microvasculature and contribute to the process that characterizes TME.

Continuous EEG Monitoring in a Consecutive Patient Cohort with Sepsis and Delirium.

Delirium is common during sepsis, although under-recognized. We aimed to assess the value of continuous electroencephalography (cEEG) to aid in the diagnosis of delirium in septic patients. We prospectively evaluated 102 consecutive patients in a medical intensive care unit (ICU), who had sepsis or septic shock, without evidence of acute primary central nervous system disease. We initiated cEEG recording immediately after identification. The median cEEG time per patient was 44h (interquartile range 21-99h). A total of 6723h of cEEG recordings were examined. The Confusion Assessment Method for the ICU (CAM-ICU) was administered six times daily to identify delirium. We analyzed the correlation between cEEG and delirium using 1252 two-minute EEG sequences recorded simultaneously with the CAM-ICU scorings. Of the 102 included patients, 66 (65%) had at least one delirium episode during their ICU stay, 30 (29%) remained delirium-free, and 6 (6%) were not assessable due to deep sedation or coma. The absence of delirium was independently associated with preserved high-frequency beta activity (> 13Hz) (P < 10-7) and cEEG reactivity (P < 0.001). Delirium was associated with preponderance of low-frequency cEEG activity and absence of high-frequency cEEG activity. Sporadic periodic cEEG discharges occurred in 15 patients, 13 of whom were delirious. No patient showed clinical or electrographic evidence of non-convulsive status epilepticus. Our findings indicate that cEEG can help distinguish septic patients with delirium from non-delirious patients.

Cardiac disease in brain-heart disorders.

Abstract There are a number of acute central nervous system (CNS) disorders, which trigger an acute cardiac reaction (brain-heart disorders). Both the brain and the heart may be previously normal or affected by chronic hereditary or acquired disease. The most common of these acute CNS disorders include subarachanoid bleeding, epilepsy, ischaemic stroke, intracerebral bleeding, infectious meningitis/encephalitis, immune-encephalitis, posterior reversible encephalopathy syndrome, migraine, central sleep apnoea syndrome, restless leg syndrome, and traumatic brain injury. Affection of the heart caused by these CNS abnormalities includes takotsubo syndrome, arrhythmias, heart failure or systolic/diastolic dysfunction, myocardial infarction, arterial hypertension, or pulmonary hypertension of which takotsubo syndrome, arrhythmias, or heart failure are the most frequent. Arrhythmias triggered by acute CNS disease include supraventricular or ventricular arrhythmias, including sudden cardiac death. Cardiologists a...

Bacillus Cereus: A Leukemia-Specific, Neuroinvasive Pathogen?

BackgroundBacillus cereus has been associated with central nervous system (CNS) infections in immunocompromised patients.1 We report 5 cases of neuroinvasive B.cereus infections (4 fatal) in patients with acute myelogenous leukemia (AML) at Brigham and Women’s Hospital (BWH) in Boston from May 2013 to February 2014.MethodsClinical Investigation: Cases were defined as patients with positive blood or CNS cultures for B.cereus and/or positive PCR tests from CNS specimens and radiological evidence of acute CNS disease >48 hours after admission. Infection control practices were observed. A case-control analysis of medications and exposures was conducted; odds ratios and p-values were calculated via Fisher’s exact test.Genomic Analysis: Genomic DNA was extracted from patient-derived and environmental B. cereus isolates. Sequencing libraries were prepared and paired-end whole genome sequencing (WGS) was performed. Sequencing reads were computationally assembled using several existing tools (SPAdes, AllPaths-LG, VELVET, and Newbler). Draft genome annotation was performed using RAST and Prodigal. All single copy core genes were aligned using MUSCLE and a phylogenetic tree was generated using FastTree and RAxML.ResultsClinical Investigation: All 5 cases were AML patients who received chemotherapy. All had neutropenic fevers early in their course that resolved with empiric antibiotics. Fever recurred > 1 week into hospitalization (median onset 17 days, range 9-20) with headaches, neurological changes, and abnormal CNS imaging. Three had documented B. cereus bacteremia with bacilli identified on CNS pathological stains; two had positive CNS cultures. Four patients expired. Autopsies were notable for intestinal ulcers with Gram-positive bacilli in 2 patients.No infection control breaches were observed. Of 43 environmental samples, 4 tested positive for B.cereus, including a kitchen cart where bananas were stored, the shelf of a blanket warmer, and an air sample near a construction site. On case-control analysis, no medications were associated with cases. The only significant food exposures were bananas (OR 9.3, p=0.04) and cranberry juice (OR 9.6, p=0.04).Genomic Analysis:WGS data was obtained for all B. cereus isolates from BWH (n=4) and swabs of environmental screening efforts from BWH (n=4). Two patient isolates (7299 and 6254) were taken forward for pilot analysis. A comparison of various computational assembly tools demonstrated that the SPAdes assembler exhibited superior performance. SPAdes was thus used for draft genome assembly for the remaining isolates. Phylogenetic analysis of isolates 7299 and 6254 revealed that the organisms were genetically distinct from one another (Fig. 1). Genomic analysis and multilocus sequence typing (performed by WGS and independently by PCR amplification/Sanger sequencing) confirmed that all strains were genetically distinct from one another, and suggested that the environmental strains were relatively divergent from the pathogenic strains studied.ConclusionsNeuroinvasive B.cereus infection should be suspected in febrile AML patients with acute neurological symptoms, even those with negative blood cultures.The clinical investigation suggests the outbreak may have been attributable to gastrointestinal inoculation, possibly secondary to bananas. Of note, the B. cereus strain cultured from the suspected banana source was not identical to the pathogenic strains. Multiple changes in practice were instituted as a consequence of this outbreak including enhanced environmental cleanings, temporary modification of empiric antibiotic recommendations for recurrent neutropenic fever (vancomycin, cefepime, and ciprofloxacin) and the placement of all AML patients on diets that excluded fresh fruits, vegetables, and rice. Six months have elapsed since the last case.WGS demonstrated that the case series was not the result of a single, hyper-virulent B. cereus organism. Rather, the infections appear to have been attributable to distinct B. cereus strains that fall into two distinct genotypic clusters. Ongoing comparative microbial genomic and biological efforts are underway and have identified candidate bacterial and host factors that may induce heightened virulence in this patient population.1. Inoue et al. Leukemia & lymphoma. 2010;51(5):860-9. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Protective role of TNF-α, IL-10 and IL-2 in mice infected with the Oshima strain of Tick-borne encephalitis virus.

Tick-borne encephalitis virus (TBEV) causes acute central nervous system disease. Here, we investigated the roles of the TNF-α, IL-10 and other cytokines in appropriate KO mice following infection with Oshima and Sofjin strains of TBEV. Following infection with the Oshima strain, mortality rates were significantly increased in TNF-α KO and IL-10 KO mice compared with wild type (WT) mice. These results suggested that TNF-α and IL-10 play protective roles against fatal infection due to Oshima strain infection. However, viral loads and proinflammatory cytokine levels in the brain of TNF-α KO andIL-10 KO mice were not significantly different compared with those of WT mice. On the other hand, all WT, TNF-α KO and IL-10 KO mice died following infection with Sofjin strain. Interestingly, Sofjin-infected mice did not exhibit an up-regulated mRNA level of IL-2 in the spleen in all groups of mice, whereas Oshima-infected mice showed significantly increased level of IL-2 compared with mock-infected mice. From these results, we suggest that TNF-α, IL-10 and IL-2 are key factors for disease remission from fatal encephalitis due to infection with Oshima strain of TBEV.

Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.

The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

Busulfan, Melphalan, and Thiotepa Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) of Pediatric Patients with Acute Leukemia and Central Nervous System (CNS) Disease

Busulfan, Melphalan, and Thiotepa Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) of Pediatric Patients with Acute Leukemia and Central Nervous System (CNS) Disease

Pathologic potential of variant clones of the oshima strain of far-eastern subtype tick-borne encephalitis virus.

Tick-borne encephalitis virus (TBEV) is a zoonotic agent that causes acute central nervous system (CNS) disease in humans. We previously suggested that immune response in addition to CNS infection contribute to mouse mortality following TBEV infection. However, we did not examine the influence of virus variants in the previous study. Therefore, in this study, we investigated the biological and pathologic potentials of the variant clones in the TBEV Oshima strain. We isolated eight variant clones from the stock virus of the Oshima 5-10. These variants exhibited different plaque morphologies in BHK cells and pathogenic potentials in mice. Full sequences of viral genomes revealed that each of the variant clones except one had specific combinations of nucleotide and amino acid changes at certain positions different from the parent strain. We also showed that an amino acid substitution of Glu122→Gly in the E protein could have affected virus infection and replication in vivo, as well as the attenuated pathogenicity in mice. These data confirm the presence of virus variants or quasispecies from the parent strain. Further elucidation of the effect of each variant clone on immune responses such as the T-cell response is an important priority in the development of an effective vaccine and treatment strategies for tick-borne encephalitis.

TNF-α Acts as an Immunoregulator in the Mouse Brain by Reducing the Incidence of Severe Disease Following Japanese Encephalitis Virus Infection

Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.

Development of simple and rapid assay to detect viral RNA of tick-borne encephalitis virus by reverse transcription-loop-mediated isothermal amplification

BackgroundTick-borne encephalitis virus (TBEV) is a causative agent of acute central nervous system disease in humans. It has three subtypes, far eastern (FE), Siberian (Sib) and European (Eu) subtypes, which are distributed over a wide area of Europe and Asia. The objective of this study was to develop a simple and rapid assay for the detection of TBEV RNA by using reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) method that can differentiate the three subtypes of TBEV and can be used for clinical diagnosis and epidemiological study.MethodsPrimers for TBEV-specific and subtype-specific RT-LAMP assay were designed to target the consensus sequence in NS1 of all subtypes and the consensus sequence in the E gene of each subtype, respectiveluy. In vitro transcribed RNA of Oshima strain that belongs to FE subtype was serially diluted and used to examine the sensitivity of the assay. Cross-reactivity of subtype-specific RT-LAMP assay was tested by using the RNA of Oshima and Sofjin (FE), IR-99 (Sib) and Hochosterwitz (Eu) strains. RNA extracted from the mixtures of TBEV and ticks, and of TBEV and human blood, and the mouse tissues infected with TBEV, were evaluated in the assay. Positive amplification was observed by real-time monitoring of turbidity and by visual detection of color change.ResultsThe sensitivity of TBEV-specific RT-LAMP assay was 102 copies of target RNA per reaction volume. FE-specific RT-LAMP assay amplified viral genes of Oshima and Sofjin strains but not of IR-99 and Hochosterwitz strains, and of Japanese encephalitis virus. RT-LAMP assay for Sib and for Eu specifically amplified viral genes of IR-99 and Hochosterwitz strains, respectively. We also showed that tick or human blood extract did not inhibit the amplification of viral gene during the assay. Furthermore, we confirmed that the TBEV RT-LAMP could detect virus RNA from peripheral and central nervous system tissues of laboratory mice infected with TBEV.ConclusionTBEV RT-LAMP assay offers a sensitive, specific, rapid and easy-to-handle method for the detection of TBEV RNA in tick samples and this may be applied in the clinical samples collected from TBE-suspected patients.

Cytogenetic Profile of Patients With Acute Myeloid Leukemia and Central Nervous System Disease

Cytogenetic Profile of Patients With Acute Myeloid Leukemia and Central Nervous System Disease

Cytogenetic Profile of Patients With Acute Myeloid Leukemia and Central Nervous System Disease

Cytogenetic Profile of Patients With Acute Myeloid Leukemia and Central Nervous System Disease

Third-line antiepileptic therapy and outcome in status epilepticus

To characterize associations between antiepileptic drugs with sedating or anesthetic effects (third-line antiepileptic drugs) vs. other antiepileptic agents, and short-term outcomes, in status epilepticus. Furthermore, to evaluate the role of adverse hemodynamic and respiratory effects of these agents in status epilepticus treatment. Retrospective comparative analysis. Tertiary academic medical center with two emergency departments and two neurologic intensive care units. Adults admitted with a diagnosis of status epilepticus defined as seizures lasting continuously >5 mins, or for discrete periods in succession. None. Of 126 patients with 144 separate status epilepticus admissions, 57 were female (45%) with mean age 54.7 ± 15.7 yrs. Status epilepticus was convulsive in 132 cases (92%). Status epilepticus etiologies included subtherapeutic antiepileptic drugs (43%), alcohol or other nonantiepileptic drug (13%), and acute central nervous system disease (12%). Third-line antiepileptic drugs were administered in 47 cases (33%). Seventy-eight status epilepticus episodes (54%) had good outcomes (Glasgow Outcome Score = 1, 2) at the time of hospital discharge. On univariate analysis, poor outcome (Glasgow Outcome Score > 2) was associated with older age (mean 59.8 ± 15.5 vs. 50.5 ± 13.8 yrs, p < .001), acute central nervous system disease (21% vs. 4%, p = .001), mechanical ventilation (76% vs. 53%, p = .004), longer duration of ventilation (median 10 days [range 1-56] vs. 2 days [range 1-10], p < .001), treatment with vasopressors (35% vs. 5%, p < .001), and treatment with third-line antiepileptic drugs (51% vs. 17%, p < .001). Death was associated with acute central nervous system disease, prolonged ventilation, treatment with vasopressors, and treatment with third-line antiepileptic drugs. Predictors of poor outcome among all status epilepticus episodes were older age (odds ratio 1.06; 95% confidence interval 1.03-1.09; p < .001), treatment with third-line antiepileptic therapy (odds ratio 5.64; 95% confidence interval 2.31-13.75; p < .001), and first episode of status epilepticus (odds ratio 3.73; 95% confidence interval 1.38-10.10; p = .010). Among status epilepticus episodes treated by third-line antiepileptic drugs, predictors of poor outcome were older age (odds ratio, 1.09; 95% confidence interval 1.01-1.18; p = .038) and longer ventilation (odds ratio, 1.47; 95% confidence interval 1.08-2.00; p = .015). Predictors of mortality among all status epilepticus episodes were treatment with third-line antiepileptic drugs (odds ratio, 12.08; 95% confidence interval 2.30-63.39; p = .003) and older age (odds ratio, 1.06; 95% confidence interval 1.00-1.12; p = .045). Third-line antiepileptic drug therapies with sedating or anesthetic effects predicted poor outcome and death in status epilepticus. Hypotension requiring vasopressor therapy and duration of mechanical ventilation induced by these agents may be contributing factors, especially when pentobarbital is used. These findings may inform decision making on drug therapy in status epilepticus and help develop safer and more effective treatment strategies to improve outcome.

Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages

Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic paralytic central nervous system disease, in which most rats spontaneously recover from paralysis. EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein. EAE is mediated by CD4+ Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells. Recently, it was established that classically activated macrophages (M1 phenotype) play an important role in the initiation of EAE, while alternatively activated macrophages (M2 phenotype) contribute to spontaneous recovery from rat EAE. This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages.