A Randomized Trial for the Treatment of Refractory Status Epilepticus

Background: Refractory status epilepticus (RSE) has a mortality of 16-39%; coma induction is advocated for its management, but no comparative study has been performed. We aimed to assess the effectiveness (RSE control, adverse events) of the first course of propofol versus barbiturates in the treatment of RSE. Methods: In this randomized, single blind, multi-center trial studying adults with RSE not due to cerebral anoxia, medications were titrated toward EEG burst-suppression for 36-48h and then progressively weaned. The primary endpoint was the proportion of patients with RSE controlled after a first course of study medication; secondary endpoints included tolerability measures. Results: The trial was terminated after 3years, with only 24 patients recruited of the 150 needed; 14 subjects received propofol, 9 barbiturates. The primary endpoint was reached in 43% in the propofol versus 22% in the barbiturates arm (P=0.40). Mortality (43 vs. 34%; P=1.00) and return to baseline clinical conditions at 3months (36 vs. 44%; P=1.00) were similar. While infections and arterial hypotension did not differ between groups, barbiturate use was associated with a significantly longer mechanical ventilation (P=0.03). A non-fatal propofol infusion syndrome was detected in one patient, while one subject died of bowel ischemia after barbiturates. Discussion: Although undersampled, this trial shows significantly longer mechanical ventilation with barbiturates and the occurrence of severe treatment-related complications in both arms. We describe practical issues necessary for the success of future studies needed to improve the current unsatisfactory state of evidenc

Methods of Assessing Frailty in the Critically Ill: A Systematic Review of the Current Literature.

INTRODUCTION As new treatments have become established, more frail pre-ICU patients are being admitted to intensive care units (ICUs); this is creating new challenges to provide adequate care and to ensure that resources are allocated in an ethical and economical manner. This systematic review evaluates the current standard for assessing frailty on the ICU, including methods of assessment, time point of measurements, and cut-offs. METHODS A systematic search was conducted on MEDLINE, Clinical Trials, Cochrane Library, and Embase. Randomized and non-randomized controlled studies were included that evaluated diagnostic tools and ICU outcomes for frailty. Exclusion criteria were the following: studies without baseline assessment of frailty on ICU admission, studies in paediatric patients or pregnant women, and studies that targeted very narrow populations of ICU patients. Eligible articles were included until January 31, 2021. Methodological quality was assessed using the Newcastle-Ottawa Scale. No meta-analysis was performed, due to heterogeneity. RESULTS N = 57 articles (253,376 patients) were included using 19 different methods to assess frailty or a surrogate. Frailty on ICU admission was most frequently detected using the Clinical Frailty Scale (CFS) (n = 35, 60.3%), the Frailty Index (n = 5, 8.6%), and Fried's frailty phenotype (n = 6, 10.3%). N = 22 (37.9%) studies assessed functional status. Cut-offs, time points, and manner of baseline assessment of frailty on ICU admission varied widely. Frailty on ICU admission was associated with short- and long-term mortality, functional and cognitive impairment, increased health care dependency, and impaired quality of life post-ICU discharge. CONCLUSIONS Frailty assessment on the ICU is heterogeneous with respect to methods, cut-offs, and time points. The CFS may best reflect frailty in the ICU. Frailty assessments should be harmonized and performed routinely in the critically ill

Theta burst stimulation over premotor cortex in Parkinson's disease: an explorative study on manual dexterity.

Dorsal pre-motor cortex (PMd) is thought to play a role in fine motor control. The aim of the present study was to investigate whether inhibitory or excitatory stimulation of PMd would have an impact on manual dexterity in Parkinson's disease (PD). Fifteen patients with PD participated in this study. High resolution structural MRI was used for neuro-navigated TBS. Participants were targeted with one train of TBS in three experimental sessions: sham stimulation over vertex, continuous TBS (cTBS) over PMd and intermittent TBS (iTBS) over PMd, respectively. Dexterity was measured by a coin rotation task (CRT), which is a valid measure to detect limb kinetic apraxia (LKA). Neither cTBS or iTBS significantly interfered with CRT. Post hoc sub-analysis in a group of PD patients (n = 5) with stronger baseline impairment, indicating LKA, revealed further deterioration of dexterous performance for the cTBS condition (p = 0.04). This sham controlled pilot study demonstrates that TBS over PMd does not significantly interfere with dexterity in PD. However, patients with dexterous impairment qualifying for LKA may be more susceptible to TBS

Theta burst stimulation reduces disability during the activities of daily living in spatial neglect

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviou

Theta burst stimulation reduces disability during the activities of daily living in spatial neglect

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Altered praxis network underlying limb kinetic apraxia in Parkinson's disease:an fMRI study

Parkinson's disease (PD) patients frequently suffer from dexterous deficits impeding activities of daily living. There is controversy whether impaired fine motor skill may stem from limb kinetic apraxia (LKA) rather than bradykinesia. Based on classical models of limb praxis LKA is thought to result when premotor transmission of time-space information of skilled movements to primary motor representations is interrupted. Therefore, using functional magnetic resonance imaging (fMRI) we tested the hypothesis that dexterous deficits in PD are associated with altered activity and connectivity in left parieto-premotor praxis network. Whole-brain analysis of fMRI activity during a task for LKA (coin rotation) showed increased activation of superior and inferior parietal lobule (SPL, IPL) and ventral premotor cortex (vPM) in PD patients compared to controls. For bradykinesia (assessed by finger tapping) a decreased fMRI activity could be detected in patients. Additionally, psychophysical interaction analysis showed increased functional connectivity between IPL and the posterior hippocampi in patients with PD. By contrast, functional connectivity to the right dorsolateral prefrontal cortex was decreased in patients with PD compared to controls.In conclusion, our data demonstrates that dexterous deficits in PD were associated with enhanced fMRI activation of the left praxis network upstream to primary motor areas, mirroring a neural correlate for the behavioral dissociation of LKA and bradykinesia. Furthermore, the findings suggest that patients recruit temporal areas of motor memory as an attempt to compensate for impaired motor skills. Finally, dysexecutive function may contribute to the deficit. Keywords: Coin rotation, Dexterity, Executive control, Functional connectivity, Hippocampu

Viral escape in the CNS with multidrug-resistant HIV-1

Introduction: HIV-1 viral escape in the cerebrospinal fluid (CSF) despite viral suppression in plasma is rare [1,2]. We describe the case of a 50-year-old HIV-1 infected patient who was diagnosed with HIV-1 in 1995. Antiretroviral therapy (ART) was started in 1998 with a CD4 T cell count of 71 cells/ìL and HIV-viremia of 46,000 copies/mL. ART with zidovudine (AZT), lamivudine (3TC) and efavirenz achieved full viral suppression. After the patient had interrupted ART for two years, treatment was re-introduced with tenofovir (TDF), emtricitabin (FTC) and ritonavir boosted atazanavir (ATVr). This regimen suppressed HIV-1 in plasma for nine years and CD4 cells stabilized around 600 cells/ìL. Since July 2013, the patient complained about severe gait ataxia and decreased concentration. Materials and Methods: Additionally to a neurological examination, two lumbar punctures, a cerebral MRI and a neuropsycological test were performed. HIV-1 viral load in plasma and in CSF was quantified using Cobas TaqMan HIV-1 version 2.0 (Cobas Ampliprep, Roche diagnostic, Basel, Switzerland) with a detection limit of 20 copies/mL. Drug resistance mutations in HIV-1 reverse transcriptase and protease were evaluated using bulk sequencing. Results: The CSF in January 2014 showed a pleocytosis with 75 cells/ìL (100% mononuclear) and 1,184 HIV-1 RNA copies/mL, while HIV-1 in plasma was below 20 copies/mL. The resistance testing of the CSF-HIV-1 RNA showed two NRTI resistance-associated mutations (M184V and K65R) and one NNRTI resistance-associated mutation (K103N). The cerebral MRI showed increased signal on T2-weighted images in the subcortical and periventricular white matter, in the basal ganglia and thalamus. Four months after ART intensification with AZT, 3TC, boosted darunavir and raltegravir, the pleocytosis in CSF cell count normalized to 1 cell/ìL and HIV viral load was suppressed. The neurological symptoms improved; however, equilibrium disturbances and impaired memory persisted. The neuro-psychological evaluation confirmed neurocognitive impairments in executive functions, attention, working and nonverbal memory, speed of information processing, visuospatial abilities and motor skills. Conclusions: HIV-1 infected patients with neurological complaints prompt further investigations of the CSF including measurement of HIV viral load and genotypic resistance testing since isolated replication of HIV with drug resistant variants can rarely occur despite viral suppression in plasma. Optimizing ART by using drugs with improved CNS penetration may achieve viral suppression in CSF with improvement of neurological symptoms

Interference with gesture production by theta burst stimulation over left inferior frontal cortex

The traditional view of a predominant inferior parietal representation of gestures has been recently challenged by neuroimaging studies demonstrating that gesture production and discrimination may critically depend on inferior frontal lobe function. The aim of the present work was therefore to investigate the effect of transient disruption of these brain sites by continuous theta burst stimulation (cTBS) on gesture production and recognition