Individualized Prediction of Drug Resistance in People with Post-Stroke Epilepsy: A Retrospective Study.

BACKGROUND: The study aimed to develop a model and build a nomogram to predict the probability of drug resistance in people with post-stroke epilepsy (PSE). METHODS: Subjects with epilepsy secondary to ischemic stroke or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of drug-resistant epilepsy defined according to International League Against Epilepsy criteria. RESULTS: One hundred and sixty-four subjects with PSE were included and 32 (19.5%) were found to be drug-resistant. Five variables were identified as independent predictors of drug resistance and were included in the nomogram: age at stroke onset (odds ratio (OR): 0.941, 95% confidence interval (CI) 0.907-0.977), intracerebral hemorrhage (OR: 6.292, 95% CI 1.957-20.233), severe stroke (OR: 4.727, 95% CI 1.573-14.203), latency of PSE (>12 months, reference; 7-12 months, OR: 4.509, 95% CI 1.335-15.228; 0-6 months, OR: 99.099, 95% CI 14.873-660.272), and status epilepticus at epilepsy onset (OR: 14.127, 95% CI 2.540-78.564). The area under the receiver operating characteristic curve of the nomogram was 0.893 (95% CI: 0.832-0.956). CONCLUSIONS: Great variability exists in the risk of drug resistance in people with PSE. A nomogram based on a set of readily available clinical variables may represent a practical tool for an individualized prediction of drug-resistant PSE.

Liver fibrosis-4 score predicts outcome of patients with ischemic stroke undergoing intravenous thrombolysis.

Some evidence suggests a possible influence of liver disease on stroke prognosis. We investigated the association between fibrosis-4 (FIB-4) score, a marker of liver disease, and the 3-month outcome in patients with ischemic stroke undergoing intravenous thrombolysis. We also evaluated the rate of symptomatic intracranial hemorrhage after thrombolysis. In this prospective cohort study, we enrolled consecutive patients with ischemic stroke treated with thrombolysis who had a 3-month follow-up. The FIB-4 score was calculated and the validated cut-off values were used to indicate high/low risk of advanced liver fibrosis. The primary outcome was 3-month poor prognosis estimated as a modified Rankin scale score ≥3. Of the 264 included patients, 131 (49.62%) had a 3-month mRS ≥3, with a significantly higher FIB-4 score, compared to those with a mRS <3 score (adjp <0.001). When adjusted for possible confounders by multivariate logistic regression, FIB-4 score remained a significant predictor of poor outcome (OR 1.894, p = 0.011), along with history of atrial fibrillation (OR 3.488, p = 0.017), admission NIHSS score (OR 1.305, p < 0.001), and low values of hemoglobin (OR 0.730, p < 0.001). Mechanical thrombectomy had a favorable effect on patients' outcome (OR 0.201, p = 0.005). The risk of poor 3-month outcome was significantly higher among the 32 patients (12.1%) with high risk of severe fibrosis (p = 0.007). FIB-4 score values were also related to symptomatic intracranial hemorrhage (p = 0.004), specifically among patients with high probability of advanced hepatic fibrosis (p = 0.037). FIB-4 score can be considered as a promising independent predictor of poor prognosis in patients with acute ischemic stroke undergoing intravenous thrombolysis.

Withdrawal of antiseizure medications - for whom, when, and how?

INTRODUCTION: Epilepsy is a chronic disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. Most patients can achieve complete seizure control (seizure freedom) with antiseizure medications (ASMs). In some of them, the withdrawal of ASMs can be considered. Guidance is required to identify patients in whom drug discontinuation can be safely attempted and to inform when and how ASM withdrawal can be done. AREAS COVERED: In this perspective, the authors discuss the evidence on ASM withdrawal in epilepsy patients who are seizure-free and provide some suggestions on how to do it effectively in clinical practice, minimizing the risk of seizure recurrence. EXPERT OPINION: The decision of discontinuing ASMs in epilepsy patients should rely on an accurate estimate of seizure recurrence risk. Whenever possible, such a risk should be assessed on an individual basis. The decision should also consider the psychosocial and personal consequences of seizure relapse. No robust evidence is available on the safest tapering regimen.

The EEG pen-on-paper sound: History and recent advances.

The electroencephalogram (EEG) is one of the most useful technologies for brain research and clinical neurology, characterized by non-invasiveness and high time resolution. The acquired traces are visibly displayed, but various studies investigate the translation of brain waves in sound (i.e., a process called sonification). Several articles have been published since 1934 about the sonification of EEG traces, in the attempt to identify the "brain-sound." However, for a long time this sonification technique was not used for clinical purposes. The analog EEG was in fact already equipped with an auditory output, although rarely mentioned in scientific papers: the pen-on-paper noise made by the writer unit. EEG technologists often relied on the sound that pens made on paper to facilitate the diagnosis. This article provides a sample of analog video-EEG recordings with audio support representing the strengths of a combined visual-and-auditory detection of different types of seizures. The purpose of the present article is to illustrate how the analog EEG "sounded," as well as to highlight the advantages of this pen-writing noise. It was considered so useful that early digital EEG devices could be equipped with special software to duplicate it digitally. Even in the present days, the sonification can be considered as an attempt to modify the EEG practice using auditory neurofeedback with applications in therapeutic interventions, cognitive improvement, and basic research.

Impact of Dimethylfumarate on Sleep in Multiple Sclerosis Patients: An Actigraphic Study.

BACKGROUND: Sleep disorders in multiple sclerosis (MS) patients are common. Dimethylfumarate is an oral disease-modifying drug (DMT), whose impact on sleep is unknown. OBJECTIVE: The aim of this study was to characterize actigraphic patterns in MS patients treated with dimethylfumarate. METHODS: Twenty relapsing-remitting MS patients with low to a mild disability, aged 20-50y, treated with dimethylfumarate for more than 6 months, were enrolled. All subjects had no history of sleep disorders. Actigraphy was used to study sleep patterns during a seven-day period. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Twenty healthy subjects served as controls. RESULTS: Our results showed statistically significant differences between some actigraphic patterns in MS patients treated with dimethylfumarate and healthy subjects, but the values for patients were still within normal limits. PSQI score was higher in MS patients compared to controls. CONCLUSION: Our findings suggest that dimethylfumarate, an oral DMT with a favourable benefit-risk profile, does not strongly alter sleep patterns in MS patients with low to mild disability and with no history of sleep disorders. Actigraphy is a simple diagnostic tool, able to support an objective measure of sleep parameters. The simplicity of application may allow considering its use for a screening of sleep disorders in MS patients.

Neutrophil-to-Lymphocyte Ratio Predicts Early Neurological Deterioration after Endovascular Treatment in Patients with Ischemic Stroke.

The worsening of neurological status that occurs early after acute ischemic stroke (AIS) remains a serious issue, and the inflammatory response plays a key role in stroke pathobiology. Recently, endovascular treatment (EVT) has revolutionized the management and outcome of patients with AIS due to either extracranial carotid disease or intracranial disease. The neutrophil-to-lymphocyte ratio (NLR) represents an easily available inflammatory biomarker. The aim of the study was to assess the relationship between the NLR at admission and the occurrence of early neurological deterioration (END) in patients with AIS who underwent EVT. Patients with AIS and proximal arterial occlusion in the anterior circulation undergoing EVT were retrospectively identified. Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were collected from admission blood work to calculate the NLR. The study outcome was END defined as an increase in at least 4 points in NIHSS score or death between baseline and 24 h after the ischemic event. Patients included were 211, and END occurred in 30 (14.2%). Patients with older age (OR = 1.07, 95% CI: 1.02−1.13), higher serum glucose (OR = 1.01, 95% CI: 1.01−1.02), and higher NLR (OR = 1.011, 95% CI: 1.04−1.18) had an increased risk of END. The best predictive cut-off value of NLR was 6.4, and END occurred in 24.1% and 3.9% of the patients with NLR ≥ 6.4 and <6.4, respectively (p < 0.001). In patients with AIS undergoing EVT, higher NLR values predicted a higher risk of END. Biomarkers able to identify inflammatory mechanisms might identify novel treatment targets and enhance proof-of-concept trials of immunomodulation in stroke.

Latency of poststroke epilepsy can predict drug resistance.

BACKGROUND AND PURPOSE: The progressive nature of epileptogenesis raises the question of whether the latent period may already carry information about the characteristics of the subsequent epilepsy. This study aimed to explore whether the time from stroke to epilepsy onset was related to the risk of drug resistance in patients with poststroke epilepsy (PSE). METHODS: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. Study outcome was the occurrence of drug resistance defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules to achieve sustained seizure freedom. RESULTS: One hundred fifty-nine patients with PSE and a median follow-up of 5 (interquartile range [IQR] = 3-9) years were included. In the study cohort, 29 (18.2%) participants were drug resistant. The median length of the time interval between stroke and PSE onset was 13 (IQR = 7-15) months in drug-resistant patients and 19 (IQR = 14-42) months (p < 0.001) in patients with seizure control. According to multivariable regression analysis, the time from stroke to PSE was an independent predictor of drug resistance (p < 0.001). The risk of drug resistance was highest when the onset of PSE occurred within the first months from stroke and decreased progressively with a steeper decline over the first 12 months. CONCLUSIONS: Substantial variability may exist in the pathways leading to PSE and distinguish patients with a variable risk of drug resistance.

A critical assessment of the current pharmacotherapy for the treatment of embolic strokes of undetermined source.

INTRODUCTION: 'Embolic stroke of undetermined source' (ESUS) is a term coined to identify non-lacunar stroke whose mechanism is likely to be embolic, and the source remains unidentified. The best antithrombotic treatment for preventing stroke recurrence in this population has not been delineated. AREAS COVERED: The authors summarize and critically appraise the currently available evidence about the antithrombotic treatment for preventing stroke recurrence in patients with ESUS. Randomized trials addressing this topic were identified through MEDLINE (accessed by PubMed, as of November 2021, week 4). EXPERT OPINION: Recent randomized trials have failed to demonstrate a significant benefit of direct oral anticoagulants over aspirin in reducing the recurrence of cerebral infarctions in unselected cohorts of patients with ESUS. The heterogeneity and often overlap of embolic sources may be possible explanations for the overall absence of a benefit of oral anticoagulants in ESUS as a single homogeneous entity. The results of these trials and their subgroup analyses have provided important cues to understand the pathophysiology of ESUS. They have, furthermore, increased in the interest in researchers in identifying distinct etiological phenotypes within this stroke population. There is a good rationale for ongoing and future investigations in order to tailor antithrombotic treatment according to individual features of patients with ESUS.

Inflammation markers in moderate and severe obstructive sleep apnea: the influence of sex.

PURPOSE: Obstructive sleep apnea (OSA) is the most prevalent sleep-related breathing disorder, with a negative impact on cardiovascular health. Different OSA symptoms and treatment response in males and females have been reported. The aim of this study was to investigate inflammatory markers in patients with OSA and the relationship of those markers to disease severity in male and female subjects. METHODS: We considered consecutive subjects referred to the outpatient Sleep Disorder Service of the Respiratory Medicine Department, San Marino Hospital. We included patients with a diagnosis of moderate or severe OSAS and an age range of 45-80 years. Concomitant inflammatory conditions were an exclusion criterion. A polygraphic study and a blood draw for inflammatory markers were performed for each subject. RESULTS: Of 110 subjects, 59 were males. Severe OSA affected 72 subjects. We analyzed data through a 4-level categorical variable according to sex and OSA severity (moderate OSA, males; severe OSA, males; moderate OSA, females; severe OSA, females), which showed significant differences for interleukin-6 (IL-6) and C-reactive protein (CRP) levels. A significant difference in IL-6 levels with a significant ascending trend (p = 0.045) from females with moderate OSAS to males with severe OSAS emerged in our pairwise comparison for estimated marginal means. Also, a significant trend (p = 0.0001) for CRP levels from males with moderate OSAS to females with severe OSAS was shown. CONCLUSIONS: OSA and inflammation are interconnected, and both are associated with vascular diseases. Sex-related differences in OSA phenotypes may help the clinicians aim for a more personalized approach.

Sex-Related Differences in Polygraphic Parameters in a Population of Patients with Obstructive Sleep Apnea Syndrome.

BACKGROUND: Sex-related differences in the prevalence and clinical presentation of Obstructive Sleep Apnea Syndrome (OSAS) have been widely documented. The aim of this study was to investigate the influence of patients' sex on polygraphic parameters with particular attention to sleep autonomic changes in a population of OSAS patients. METHODS: Sixty OSAS patients aged 55-65 years (30 men, 30 women) were enrolled. Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness with the Epworth Sleepiness Scale (ESS). The presence of respiratory events and autonomic changes during the night was investigated by polygraphy. RESULTS: Similar main cardiovascular risk factors prevalence was observed in both men and women. We observed a significant difference in PSQI (higher in women, p=0.0001) and ESS (higher in men, p=0.004) scores. Snoring (p=0.033), supine AHI (p=0.004), T90 (p=0.021), LO2 (p=0.0001), LF/HF ratio and LF (p=0.0001) were significantly higher in men. Sex differences in PSQI mean score and LF/HF ratio variability were preserved in all the subgroups of OSA severity. CONCLUSION: The influence of sex in modulating cardiovascular risk is a widely discussed topic. In our study, men showed more severe polygraphic parameters and an increase in LF/HF ratio compared to women. The results of our investigation suggest the relevance of delivering information about the different expressions of OSAS in men and women in order to improve diagnostic skills and in-depth prevention approaches.

Systemic Inflammatory Response Index and Futile Recanalization in Patients with Ischemic Stroke Undergoing Endovascular Treatment.

Futile recanalization remains a significant challenge for endovascular treatment (EVT) of acute ischemic stroke (AIS). The inflammatory response that occurs after cerebral infarct plays a central role in stroke pathobiology that can influence the outcome of a recanalization procedure. The aim of this study was to evaluate the relationship between the systemic inflammatory response index (SIRI) and futile recanalization in patients with AIS. We retrospectively identified consecutive patients with ischemic stroke due to proximal arterial occlusion in the anterior circulation, who were treated with EVT and achieved near-complete or complete recanalization. Absolute neutrophil count (ANC), absolute monocyte count (AMC), and absolute lymphocyte count (ALC) were collected from admission blood work to calculate SIRI as ANC × AMC/ALC. The study outcome was futile recanalization, defined as poor functional status [modified Rankin scale (mRS) score ≥ 3] at 3 months despite complete or near-complete recanalization. A total of 184 patients were included. Futile recanalization was observed in 110 (59.8%) patients. Older patients (odds ratio (OR) = 1.07, 95% confidence interval (CI): 1.04-1.10, p < 0.001), higher admission National Institutes of Health stroke scale score (OR = 1.10, 95% CI: 1.02-1.19, p = 0.013), and higher admission SIRI (OR = 1.08, 95% CI: 1.01-1.17, p = 0.028) increased the risk of the poor outcome at 3 months despite complete or near-complete recanalization.

Predictors of Pharmaco-Resistance in Patients with Post-Stroke Epilepsy.

OBJECTIVES: The study aimed to explore the clinical predictors of pharmaco-resistance in patients with post-stroke epilepsy (PSE). METHODS: Patients with epilepsy secondary to cerebral infarct or spontaneous intracerebral hemorrhage were included. The study outcome was the occurrence of pharmaco-resistance defined as the failure of adequate trials of two tolerated and appropriately chosen and used antiseizure medication schedules, whether as monotherapies or in combination, to achieve sustained seizure freedom. RESULTS: One-hundred and fifty-nine patients with PSE and a median follow-up of 5 (3-9) years were included. The mean age of the patients at stroke onset was 56.7 (14.9) years, and 104 (65.4%) were males. In the study cohort, 29 participants were pharmaco-resistant. Age at stroke onset [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.93-0.99; p = 0.044], history of intracerebral hemorrhage (OR 2.95, 95% CI 1.06-8.24; p = 0.039), severe stroke (OR 5.43, 95% CI 1.82-16.16; p = 0.002), status epilepticus as initial presentation of PSE (OR 7.90, 1.66-37.55; p = 0.009), and focal to bilateral tonic-clonic seizures (OR 3.19, 95% CI 1.16-8.79; p = 0.025) were independent predictors of treatment refractoriness. CONCLUSIONS: Pharmaco-resistance developed in approximately 20% of patients with PSE and was associated with younger age at stroke onset, stroke type and severity, status epilepticus occurrence, and seizure types.

Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity.

Doxorubicin is the most effective single agent in the treatment of non-Hodgkin's lymphoma (NHL). Its use is limited because of the cardiac toxicity primarily in elderly patients (pts) and in pts with history of cardiac disease. Liposomal doxorubicin has been proven to reduce cardiotoxicity. The aim of this retrospective study was the use of nonpeghylated liposomal doxorubicin (NPLD) in term of efficacy, response rate and incidence of cardiac events. We retrospectively collected the experience of 33 Hematological Italian Centers in using NPLD. Nine hundred and forty-six consecutive pts treated with R-COMP (doxorubicin was substituted with NPLD, Myocet) were collected. Median age was 74 years, the reasons for use of NPLD were: age (466 pts), cardiac disease (298 pts), uncontrolled hypertension (126 pts), other reasons (56 pts). According to clinicians' evaluation, 49.9% of pts would not have used standard doxorubicin for different situations (age, cardiomyopathy, previous use of doxorubicin, and uncontrolled hypertension). Overall 687 pts (72.6%) obtained a complete remission (CR). About 5% (n = 51) of subjects developed major cardiotoxic events including heart failure (N = 31), ischemic heart disease (N = 16), acute heart attack (N = 3), and acute pulmonary oedema (N = 1). After a median follow-up of 32 months, 651 pts were alive and the overall survival (OS) was 72%. After a median observation period of 23 months disease free survival (DFS) was 58%. Either in univariate or in multivariate analysis OS and DFS were not significantly affected by age or cardiac disease. Our findings strongly support that including R-COMP is effective and safe when the population is at high risk of cardiac events and negatively selected. Moreover, the use of this NPLD permitted that about half of our population had the opportunity to receive the best available treatment.

Detection of cAMP and of PKA activity in Saccharomyces cerevisiae single cells using Fluorescence Resonance Energy Transfer (FRET) probes.

In Saccharomyces cerevisiae the second messenger cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) play a central role in metabolism regulation, stress resistance and cell cycle progression. To monitor cAMP levels and PKA activity in vivo in single S. cerevisiae cells, we expressed an Epac-based FRET probe and a FRET-based A-kinase activity reporter, which were proven to be useful live-cell biosensors for cAMP levels and PKA activity in mammalian cells. Regarding detection of cAMP in single yeast cells, we show that in wild type strains the CFP/YFP fluorescence ratio increased immediately after glucose addition to derepressed cells, while no changes were observed when glucose was added to a strain that is not able to produce cAMP. In addition, we had evidence for damped oscillations in cAMP levels at least in SP1 strain. Regarding detection of PKA activity, we show that in wild type strains the FRET increased after glucose addition to derepressed cells, while no changes were observed when glucose was added to either a strain that is not able to produce cAMP or to a strain with absent PKA activity. Taken together these probes are useful to follow activation of the cAMP/PKA pathway in single yeast cells and for long times (up to one hour).

Nuclear Ras2-GTP controls invasive growth in Saccharomyces cerevisiae.

Using an eGFP-RBD3 probe, which specifically binds Ras-GTP, we recently showed that the fluorescent probe was localized to the plasma membrane and to the nucleus in wild type cells growing exponentially on glucose medium, indicating the presence of active Ras in these cellular compartments. To investigate the nuclear function of Ras-GTP, we generated a strain where Ras2 is fused to the nuclear export signal (NES) from the HIV virus, in order to exclude this protein from the nucleus. Our results show that nuclear active Ras2 is required for invasive growth development in haploid yeast, while the expression of the NES-Ras2 protein does not cause growth defects either on fermentable or non-fermentable carbon sources and does not influence protein kinase A (PKA) activity related phenotypes analysed. Moreover, we show that the cAMP/PKA pathway controls invasive growth influencing the localization of active Ras. In particular, we show that PKA activity plays a role in the localization of active Ras and influences the ability of the cells to invade the agar: high PKA activity leads to a predominant nuclear accumulation of active Ras and induces invasive growth, while low PKA activity leads to plasma membrane localization of active Ras and to a defective invasive growth phenotype.

Live-cell imaging of endogenous Ras-GTP shows predominant Ras activation at the plasma membrane and in the nucleus in Saccharomyces cerevisiae.

Ras proteins function as a point of convergence for different signalling pathways in eukaryotes and are involved in many cellular responses; their different subcellular locations could regulate distinct functions. To investigate the localization of active Ras in vivo in Saccharomyces cerevisiae, we expressed a probe consisting of a GFP fusion with a trimeric Ras binding domain of Raf1 (eGFP-RBD3), which binds Ras-GTP with a much higher affinity than Ras-GDP. Our results show that in wild type cells active Ras accumulates mainly at the plasma membrane and in the nucleus during growth on medium containing glucose, while it accumulates mainly in mitochondria in wild type glucose-starved cells and relocalizes to the plasma membrane and to the nucleus upon addition of this sugar. A similar pattern is observed in a strain deleted in the CYR1 gene indicating that the absence of adenylate cyclase does not impair the localization of Ras-GTP. Remarkably, in a gpa2Δ, but not in a gpr1Δ mutant, active Ras accumulates in internal membranes and mitochondria, both when cells are growing on glucose medium or are starved, indicating that Gpa2, but not Gpr1 is required for the recruitment of Ras-GTP at the plasma membrane and in the nucleus. Moreover, deletion of both HXK1 and HXK2 also causes a mitochondrial localization of the probe, which relocalizes to the plasma membrane and to the nucleus upon expression of HXK2 on a centromeric plasmid, suggesting that this kinase is involved in the proper localization of active Ras.