FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures overlaying anti-N-methyl-D-aspartate receptor encephalitis: A case report.

RATIONALE: FLAIR-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is a rare clinical phenotype of anti-MOG; immunoglobulin G-associated disease is often misdiagnosed as viral encephalitis in the early stages. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis caused by antibodies targeting the GluN1 subunit of the NMDAR. The coexistence of anti-NMDAR encephalitis and FLAMES is very rare. PATIENT CONCERNS: A 20-year-old female patient initially presented with seizures accompanied by daytime sleepiness. DIAGNOSES: Magnetic resonance imaging revealed FLAIR-hyperintense lesions in unilateral cerebral cortex. NMDAR antibodies was positive in the cerebrospinal fluid and MOG antibodies in the serum. INTERVENTIONS: Steroid therapy was administrated. OUTCOMES: The symptoms completely relieved. At 6-month follow-up, the patient's condition remained stable. Magnetic resonance imaging showed no abnormalities in the unilateral cerebral cortex. CONCLUSION: When a patient with anti-NMDAR encephalitis or FLAMES is encountered in clinical practice, the coexistence of these diseases with double-positive anti-NMDAR and MOG antibodies should be considered and adopt appropriate evaluation and treatment.

Effect of inactivated COVID-19 vaccines on seizure frequency in patients with epilepsy: A multicenter, prospective study.

Objectives: Several COVID-19 vaccines list "uncontrolled epilepsy" as a contraindication for vaccination. This consequently restricts vaccination against COVID-19 in patients with epilepsy (PWE). However, there is no strong evidence that COVID-19 vaccination can exacerbate conditions in PWE. This study aims to determine the impact of COVID-19 vaccination on PWE. Methods: PWE were prospectively recruited from 25 epilepsy centers. We recorded the seizure frequency at three time periods (one month before the first vaccination and one month after the first and second vaccinations). A generalized linear mixed-effects model (GLMM) was used for analysis, and the adjusted incidence rate ratio (AIRR) with 95% CI was presented and interpreted accordingly. Results: Overall, 859 PWE were included in the analysis. Thirty-one (3.6%) and 35 (4.1%) patients were found to have increased seizure frequency after the two doses, respectively. Age had an interaction with time. The seizure frequency in adults decreased by 81% after the first dose (AIRR=0.19, 95% CI:0.11-0.34) and 85% after the second dose (AIRR=0.16, 95% CI:0.08-0.30). In juveniles (<18), it was 25% (AIRR=0.75, 95% CI:0.42-1.34) and 51% (AIRR=0.49, 95% CI:0.25-0.95), respectively. Interval between the last seizure before vaccination and the first dose of vaccination (ILSFV) had a significant effect on seizure frequency after vaccination. Seizure frequency in PWE with hereditary epilepsy after vaccination was significantly higher than that in PWE with unknown etiology (AIRR=1.95, 95% CI: 1.17-3.24). Two hundred and seventeen (25.3%) patients experienced non-epileptic but not serious adverse reactions. Discussion: The inactivated COVID-19 vaccine does not significantly increase seizure frequency in PWE. The limitations of vaccination in PWE should focus on aspects other than control status. Juvenile PWE should be of greater concern after vaccination because they have lower safety. Finally, PWE should not reduce the dosage of anti-seizure medication during the peri-vaccination period.

Amyloid and tau positive mild cognitive impairment: clinical and biomarker characteristics of dementia progression.

BACKGROUND: According to the amyloid, tau, neurodegeneration research framework classification, amyloid and tau positive (A+T+) mild cognitive impairment (MCI) individuals are defined as prodromal Alzheimer disease. This study was designed to compare the clinical and biomarker features between A+T+MCI individuals who progressed to progressive MCI (pMCI) and those who remained stable MCI (sMCI), and to identify relevant baseline clinical biomarker and features that could be used to predict progression to dementia within 2 years. METHODS: We stratified 197 A+T+MCI individuals into pMCI (n = 64) and sMCI (n = 133) over 2 years. Demographics and cognitive assessment scores, cerebrospinal fluid (CSF), and neuroimaging biomarkers (18F-florbetapir positron emission tomography mean standardized uptake value ratios [SUVR] and structural magnetic resonance imaging [MRI]) were compared between pMCI and sMCI at baseline, 12- and 24-month follow-up. Logistic regression models then were used to evaluate clinical baseline and biomarker features that predicted dementia progression in A+T+MCI. RESULTS: pMCI individuals had higher mean 18F-florbetapir SUVR, CSF total-tau (t-tau), and p-tau181P than those in sMCI individuals. pMCI individuals performed poorer in cognitive assessments, both global and domain specific (memory, executive, language, attention, and visuospatial skills) than sMCI. At baseline, there were significant differences in regions of interest of structural MRI between the two groups, including bilateral amygdala, hippocampus and entorhinal, bilateral inferior lateral ventricle, left superior and middle temporal, left posterior and caudal anterior cingulate (P < 0.05). Baseline CSF t-tau levels and cognitive scores of Montreal cognitive assessment, functional assessment questionnaire, and everyday cognition by the patient's study partner language domain could predict progression to dementia in A+T+MCI within 2 years. CONCLUSIONS: In future clinical trials, specific CSF and cognitive measures that predict dementia progression in A+T+MCI might be useful risk factors for assessing the risk of dementia progression.

Recovery of posterior communicating artery aneurysm induced oculomotor nerve palsy: a comparison between surgical clipping and endovascular embolization.

BACKGROUND: Oculomotor nerve palsy (ONP) is a common symptom of posterior communicating artery aneurysm (PcomAA) that can lead to impaired eye movement and pupil dilation. Currently, surgical clipping and endovascular embolization are the two most popular treatment methods for PcomAA-induced ONP; however, the recovery outcome between the two methods remains to be elucidated. METHODS: In the present study, we thoroughly compared the pretreatment factors and recovery outcome of the two treatments on 70 patients with PcomAA-induced ONP. The patients were separated into two groups based on the treatment that was received. Pretreatment factors, including age, sex, time period between ONP onset and treatment, ONP type, aneurysm diameter, status of subarachnoid hemorrhage and aneurysm rupture were recorded for each individual patient. Recovery outcome of the patients was assessed over a 12-month period. RESULTS: No significant differences were observed in any of the analyzed factors. Importantly, we revealed a significantly higher full recovery rate for the patients receiving the surgical clipping treatment than the ones that received the endovascular embolization treatment. In addition, we showed that patients' age was negatively correlated with the recovery extent in both treatment groups. CONCLUSIONS: The outcome of our study suggests that surgical clipping might be a better option to treat PcomAA-induced ONP.

Diphenyleneiodonium chloride synergizes with diazoxide to enhance protection against amyloid ß induced neurotoxicity.

We examined synergistic effects of inhibiting reactive oxygen species generated from the mitochondria and from nicotinamide adenine dinucleotide phosphate oxidase on neurotoxicity. Primary hippocampal neurons were exposed to amyloid ß, and the cells were treated with diazoxide or/and diphenyleneiodonium chloride. We found that the cell viability was decreased significantly after exposure to amyloid ß for 72 h with higer reactive oxygen species and malondialdehyde levels, higher caspase-3 and cleaved caspase-3 levels and lower B-cell lymphoma 2 (Bcl-2) level. Both diazoxide and diphenyleneiodonium increased cell viability by inhibiting the increase in reactive oxygen species and caspase-3 activity as well as the decrease in Bcl-2 induced by amyloid ß. The combination of diazoxide and diphenyleneiodonium exhibited better protective effects compared to a single treatment. In conclusion, the activation of a mitochondrial potassium channel in combination with the inhibitor of nicotinamide adenine dinucleotide phosphate oxidase exhibit synergistic protective effects against amyloid ß neurotoxicity.

Effects of epigallocatechin­3­gallate on iron metabolism in spinal cord motor neurons.

Accumulating evidence suggests that iron homeostasis is disordered in amyotrophic lateral sclerosis (ALS). In view of the promising performance of epigallocatechin­3­gallate (EGCG) in neuroprotection studies, the present study aimed to verify whether EGCG protects motor neurons in an ALS model, and whether it has any effects on iron metabolism using an ELISA and western blotting. The results demonstrated that EGCG decreased oxidative stress and protected motor neurons in the organotypic culture of the rat spinal cord. Furthermore, total iron levels increased significantly in the spinal cord following 3 weeks of treatment with threo­hydroxyaspartate. In addition, the expression of influx proteins (transferrin receptor and divalent metal­ion transporter 1) increased significantly. However, EGCG demonstrated no effect on total iron levels and the expression of influx proteins. In conclusion, EGCG leads to a decrease in oxidative stress levels, leading to motor neuron protection in the organotypic culture of a rat spinal cord; however, EGCG does not alter iron metabolism protein expression regulation.

Influence of negative lymph node in No 7 on survival of patients with middle thoracic esophageal squamous cell carcinoma.

BACKGROUND: The overall survival (OS) of patients with thoracic esophageal cancer is poor because of the high rate of lymph node metastases. However, recent studies found that the negative lymph node (LN) may also influence the patients' OS. The purpose of this study is to investigate which negative LN stations play a key role in OS prediction. METHOD: Our study included the retrospective records of 99 patients, who were identified with middle thoracic esophageal squamous cell cancer after esophagectomy. The maximum follow-up time was 6 years. Cox regression models were employed to determine the association between the negative LN and OS of patients. After applying Kaplan-Meier method to calculate OS of patients with positive and negative LNs, the log-rank tests were used to assess the difference between them. RESULT: The hazard ratio of the total number of negative LNs was 0.937 (P=0.001), and the length of tumor was 1.166 (P=0.038). Multivariate regression results showed that the numbers of positive LNs in No 3 and 7 stations and negative LNs in No 109 and 7 stations were significantly related to OS, and their P-values were 0.017, 0.001, 0.020, and 0.022, respectively. The OS of the patients who had positive and negative LNs in No 7 station was significantly different (P=0.028). CONCLUSION: No 7 is the most important among the negative LN stations which prolong OS. More attention should be paid to this area when making treatment plan for patients with no negative LNs identified in operation.

Association of the p22phox polymorphism C242T with the risk of late-onset Alzheimer's disease in a northern Han Chinese population.

The C242T polymorphism of the CYBA gene that encodes p22phox, a component of nicotinamide adenine dinucleotide phosphate oxidase, has been found to modulate reactive oxygen species (ROS) production. Oxidative stress is thought to play a pivotal role in the pathophysiology of Alzheimer's disease (AD), which is manifested as increased availability of ROS because of an imbalanced redox state. Therefore, the aim of this study was to investigate potential associations of the p22phox C242T polymorphism with the risk of late-onset AD (LOAD) in a northern Han Chinese population. Patients with LOAD (n = 276) and 320 control subjects were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes. No significant differences were found between LOAD and p22phox C242T polymorphism, but a significant association was obtained in the genotype and allele distributions of p22phox C242T between LOAD patients and controls in apolipoprotein E (ApoE) ϵ4 carriers. These results suggested that p22phox C242T polymorphism has a possible role in changing the genetic susceptibility to LOAD in ApoE ϵ4 carriers of this northern Han Chinese population.

Effects of diazoxide on Aß1-42-induced expression of the NR2B subunit in cultured cholinergic neurons.

The accumulation of amyloid-ß protein (Aß) is significant in the pathogenesis of Alzheimer's disease. Several previous studies indicate that the NR2B­containing N­methyl­D­aspartate receptors are critically involved in the Aß mediated disruption of neuronal function. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP­sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism by which DZ protects cholinergic neurons against Aß­induced cytotoxicity remains to be elucidated. The present study was designed to investigate the effects of DZ pretreatment against Aß1­42­induced expression of NR2B in order to gain novel insights into the neuroprotective mechanisms. Following exposure to Aß1­42 for 24 h, the expression of the NR2B subunit remained unchanged compared with the control group. However, a significant increase in the expression of the NR2B subunit was observed following treatment with Aß1­42 for 72 h (P<0.05); and the upregulation of the expression of the NR2B subunit was reversed by pretreatment with DZ (P<0.05). These results suggested that DZ may counteract Aß1­42­mediated cytotoxicity by alleviating the expression of NR2B.

Association of insulin receptor H1085H C>T, insulin receptor substrate 1 G972R and insulin receptor substrate 2 1057G/A polymorphisms with refractory temporal lobe epilepsy in Han Chinese.

PURPOSE: Insulin/insulin receptor (INSR) signaling plays diverse roles in the central nervous system, including regulation of blood glucose, synaptic plasticity, dendritic growth, modulation of electrophysiological activity, proliferation of astrocytes and neuronal apoptosis. Interestingly, many of these and/or related processes represent biological mechanisms associated with temporal lobe epilepsy (TLE). Thus, insulin signaling may play a role in the development of TLE and its therapeutic responses. We hypothesized that functional polymorphisms in the insulin pathway genes INSR, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with the therapeutic responses of TLE. Therefore, in this study we analyzed the association of three single nucleotide polymorphisms (SNPs) showing a risk for TLE drug resistance using a hospital-based case-control design. METHOD: Two hundred and one patients with refractory TLE and one hundred and seventy-five drug-responsive TLE patients were recruited for the study. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the genotypes of INSR His1085His, IRS1 G972R and IRS2 1057G/A. RESULTS: No significant differences between refractory and drug-responsive TLE patients were observed for the IRS1 G972R and IRS2 1057G/A polymorphisms (P>0.05), but a significant association was found for the INSR His1085His polymorphism for both genotypes (P=0.035) and alleles (P=0.011). IRS2 1057G/A combined with the INSR His 1085 His polymorphism increased the odds ratio of drug resistance in TLE (P=0.011, OR=2.263, 95% CI: 1.208-4.239). CONCLUSION: These results suggest that a genetic variation in the insulin signaling pathway genes may affect the therapeutic response of TLE.

Diazoxide pretreatment prevents Aß1-42 induced oxidative stress in cholinergic neurons via alleviating NOX2 expression.

The aggregation and accumulation of amyloid-ß (Aß) plays a significant role in the pathogenesis of Alzheimer's disease. Aß is known to increase free radical production in neuronal cells, leading to oxidative stress and cell death. Diazoxide (DZ), a highly selective drug capable of opening mitochondrial ATP-sensitive potassium channels, has neuroprotective effects against neuronal cell death. However, the mechanism through which DZ protects cholinergic neurons against Aß-induced oxidative injury is still unclear. The present study was designed to investigate the effects of DZ pretreatment against Aß1-42 induced oxidative damage and cytotoxicity. Through measures of DZ effects on Aß1-42 induced cellular damage, reactive oxygen species (ROS) and MDA generation and expressions of gp91phox and p47phox in cholinergic neurons, new insights into the neuroprotective mechanisms can be derived. Aß1-42 significantly decreased 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide levels and increased ROS and MDA production; all effects were attenuated by pretreatment with DZ or diphenyleneiodonium chloride (a NOX2 inhibitor). Pretreatment with DZ also attenuated the upregulation of NOX2 subunits (gp91phox and p47phox) induced by Aß1-42. Since NOX2 is one of the main sources of free radicals, these results suggest that DZ can counteract Aß1-42 induced oxidative stress and associated cell death by reducing the level of ROS and MDA, in part, by alleviating NOX2 expression.

Diazoxide preconditioning antagonizes cytotoxicity induced by epileptic seizures.

Diazoxide, an activator of mitochondrial ATP-sensitive potassium channels, can protect neurons and astrocytes against oxidative stress and apoptosis. In this study, we established a cellular model of epilepsy by culturing hippocampal neurons in magnesium-free medium, and used this to investigate effects of diazoxide preconditioning on the expression of inwardly rectifying potassium channel (Kir) subunits of the ATP-sensitive potassium. We found that neuronal viability was significantly reduced in the epileptic cells, whereas it was enhanced by diazoxide preconditioning. Double immunofluorescence and western blot showed a significant increase in the expression of Kir6.1 and Kir6.2 in epileptic cells, especially at 72 hours after seizures. Diazoxide pretreatment completely reversed this effect at 24 hours after seizures. In addition, Kir6.1 expression was significantly upregulated compared with Kir6.2 in hippocampal neurons after seizures. These findings indicate that diazoxide pretreatment may counteract epileptiform discharge-induced cytotoxicity by suppressing the expression of Kir subunits.

Diazoxide reverses the enhanced expression of KATP subunits in cholinergic neurons caused by exposure to Aß1₋42.

The ATP-sensitive potassium channel (KATP) play a crucial role in coupling metabolic energy to the cell membrane potential, ß-amyloid peptide (Aß) neurotoxicity has been associated with cellular oxidative stress and metabolic impairment. Whether there is an interaction between KATP and Aß or not? The expression of KATP subunits was to be investigated after the cultured primary rat basal forebrain cholinergic neurons being exposed to Aß1₋42. The subunits of KATP: Kir6.1, Kir6.2, SUR1 and SUR2 expressing change was observed by double Immunofluorescence and immunoblotting in cultured cholinergic neurons from different groups: treatment with Aß1₋42 (group Aß1₋42), pretreatment with diazoxide and then exposure to Aß1₋42 (group diazoxide + Aß1₋42), and the control (group control). The results showed that in response to the treatment with Aß1₋42 (2 µmol/L) for 24 h, the expression of Kir6.1 and SUR2 were significantly up-regulated, while this change can be partly reversed by pretreatment with diazoxide (1 mmol/L) for 1 h. There were significant increases in all KATP subunits expression levels after exposure to Aß1₋42 for 72 h. However, the up-regulation of Kir6.1, Kir6.2 and SUR2 except SUR1 can be partly reversed by pretreatment with diazoxide (1 mmol/L) for 1 h. It is concluded that exposure to Aß1₋42 for different time (24 and 72 h) induced differential regulation of KATP subunits expression in cultured primary rat basal forebrain cholinergic neurons. The change in composition of KATP may contribute to the dysfunction of KATP and membrane excitability disturbance. The effect of diazoxide on KATP subunits expression may explain, in part, the resistance of diazoxide to the toxicity of Aß1₋42.

Effects of Abeta1-42 on the subunits of KATP expression in cultured primary rat basal forebrain neurons.

ATP-sensitive potassium channels (KATP) play a crucial role in coupling metabolic energy to the membrane potential of cells, thereby functioning as cellular "metabolic sensors." Recent evidence has showed a connection between the amyloid neurotoxic cascade and metabolic impairment. With regard to their neuroprotection in other neuronal preparations, KATP channels may mediate a potential neuroprotective role in Alzheimer's disease (AD). To investigate the effects of Abeta1-42 on the subunits of KATP expression in cultured primary rat basal forebrain cholinergic neurons, primary rat basal forebrain neurons were cultured and evaluated. The subunits of KATP: Kir6.1, Kir6.2, SUR1 and SUR2 expressing changes were observed by double immunofluorescence and immunoblotting when the neurons were exposed to Abeta1-42(2 microM) for different time (0, 24, 72 h). We found a significant increase in the expression of Kir6.1 and SUR2 in the cultured neurons being exposed to Abeta1-42 for 24 h, while Kir6.2 and SUR1 showed no significant change. However, after being treated with Abeta1-42 for 72 h, the expression of the four subunits was all increased significantly compared with the control. These findings suggest that being exposed to Abeta1-42 for different time (24 and 72 h) induces differential regulations of KATP subunits expression in cultured primary rat basal forebrain cholinergic neurons. The change in composition of KATP may contribute to resist the toxicity of Abeta1-42.