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A trial involving comatose survivors of cardiac arrest tested whether aggressively treating rhythmic and periodic EEG activity would improve neurologic outcomes. Despite suppression of abnormal EEG activity, the incidence of a poor neurologic outcome did not differ significantly from that with standard care, and mortality was high.

Each year, about 225 million persons have malaria, with some 781,000 associated deaths. In a preliminary report of a phase 3 trial in African children, the RTS,S/AS01 malaria vaccine had about 50% efficacy against incident malaria and 34% efficacy against severe disease. Each year, malaria occurs in approximately 225 million persons worldwide, and 781,000 persons, mostly African children, die from the disease. 1 During the past decade, the scale-up of malaria-control interventions has resulted in considerable reductions in morbidity and mortality associated with malaria in parts of Africa. 2 , 3 However, malaria continues to pose a major public health threat. A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa. 4 The RTS,S vaccine that targets the circumsporozoite protein and is given with an adjuvant system (AS01 or AS02) has . . .

Preclinical data suggest that the loop-diuretic bumetanide might be an effective treatment for neonatal seizures. We aimed to assess dose and feasibility of intravenous bumetanide as an add-on to phenobarbital for treatment of neonatal seizures. In this open-label, dose finding, and feasibility phase 1/2 trial, we recruited full-term infants younger than 48 h who had hypoxic ischaemic encephalopathy and electrographic seizures not responding to a loading-dose of phenobarbital from eight neonatal intensive care units across Europe. Newborn babies were allocated to receive an additional dose of phenobarbital and one of four bumetanide dose levels by use of a bivariate Bayesian sequential dose-escalation design to assess safety and efficacy. We assessed adverse events, pharmacokinetics, and seizure burden during 48 h continuous electroencephalogram (EEG) monitoring. The primary efficacy endpoint was a reduction in electrographic seizure burden of more than 80% without the need for rescue antiepileptic drugs in more than 50% of infants. The trial is registered with ClinicalTrials.gov, number NCT01434225. Between Sept 1, 2011, and Sept 28, 2013, we screened 30 infants who had electrographic seizures due to hypoxic ischaemic encephalopathy. 14 of these infants (10 boys) were included in the study (dose allocation: 0·05 mg/kg, n=4; 0·1 mg/kg, n=3; 0·2 mg/kg, n=6; 0·3 mg/kg, n=1). All babies received at least one dose of bumetanide with the second dose of phenobarbital; three were withdrawn for reasons unrelated to bumetanide, and one because of dehydration. All but one infant also received aminoglycosides. Five infants met EEG criteria for seizure reduction (one on 0·05 mg/kg, one on 0·1 mg/kg and three on 0·2 mg/kg), and only two did not need rescue antiepileptic drugs (ie, met rescue criteria; one on 0·05 mg/kg and one on 0·3 mg/kg). We recorded no short-term dose-limiting toxic effects, but three of 11 surviving infants had hearing impairment confirmed on auditory testing between 17 and 108 days of age. The most common non-serious adverse reactions were moderate dehydration in one, mild hypotension in seven, and mild to moderate electrolyte disturbances in 12 infants. The trial was stopped early because of serious adverse reactions and limited evidence for seizure reduction. Our findings suggest that bumetanide as an add-on to phenobarbital does not improve seizure control in newborn infants who have hypoxic ischaemic encephalopathy and might increase the risk of hearing loss, highlighting the risks associated with the off-label use of drugs in newborn infants before safety assessment in controlled trials. European Community's Seventh Framework Programme.

Background. The reported case-fatality rate associated with severe malaria varies widely. Whether age is an independent risk factor is uncertain. Methods. In a large, multicenter treatment trial conducted in Asia, the presenting manifestations and outcome of severe malaria were analyzed in relation to age. Results. Among 1050 patients with severe malaria, the mortality increased stepwise, from 6.1% in children (age, <10 years) to 36.5% in patients aged >50 years (P < .001). Compared with adults aged 21–50 years, the decreased risk of death among children (adjusted odds ratio, 0.06; 95% confidence interval, 0.01–0.23; P < .001) and the increased risk of death among patients aged 150 years (adjusted odds ratio, 1.88; 95% confidence interval, 1.01–3.52; P = .046) was independent of the variation in presenting manifestations. The incidence of anemia and convulsions decreased with age, whereas the incidence of hyperparasitemia, jaundice, and renal insufficiency increased with age. Coma and metabolic acidosis did not vary with age and were the strongest predictors of a fatal outcome. The number of severity signs at hospital admission also had a strong prognostic value. Conclusion. Presenting syndromes in severe malaria depend on age, although the incidence and the strong prognostic significance of coma and acidosis are similar at all ages. Age is an independent risk factor for a fatal outcome of the disease.

Background Seizures are common in patients with brain tumors, impacting daily life and healthcare burden. In contemporary neuro-oncology practice, levetiracetam is the most commonly prescribed anti-seizure medication (ASM). Although the practice is widely variable, levetiracetam is usually used for 2–3 years following surgery to prevent further seizures. However, the incidence of seizures post antitumoral treatment is relatively low, and the duration of use is not well defined. To address this knowledge gap, the current randomized controlled non-inferiority trial will be conducted comparing a shorter regimen of levetiracetam with the standard long-term schedule. Methods and analysis Patients with newly diagnosed primary brain tumors (brain metastasis excluded) in the supratentorial compartment with a prior history of seizure will be eligible for the study. Adults (> 18 years), within 1 year from surgery, and controlled on levetiracetam monotherapy for 6 months will be randomized in a 1:1 ratio to either standard arm (long course: additional 2 years levetiracetam) or experimental arm (short course: tapered of levetiracetam and stopped). Stratification factors include tumor location, seizure type, histology, grade, and adjuvant therapy. The primary endpoint is 2-year seizure-free survival (SFS); secondary endpoints include seizure impact, quality of life, progression-free survival (PFS), and overall survival (OS). Assuming a 2-year SFS rate of 80%, a total of 431 patients (167 events) will be needed to prove the non-inferiority of the experimental arm (non-inferiority margin of 8%, α = 0.05, power = 80%). Considering an attrition rate of 40% (25% accounting for death and 15% lost to follow-up), the final sample size is 604. Discussion The trial will provide level 1 evidence on the optimal duration of ASM use in primary brain tumors with a history of seizures. If short-term ASM use is non-inferior, it will reduce drug utilization, lower neurotoxicity, improve quality of life, and optimize resource usage. Ethics and dissemination The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. Registration Registered with CTRI/2024/06/069498, Clinicaltrials.gov: NCT06442748.

Improved glycemic control reduces complications in type 1 diabetes, but tight control of glucose is associated with more hypoglycemic episodes. The long-term effect of recurrent hypoglycemic events on cognitive function is not known. In this 18-year follow-up of patients enrolled in the Diabetes Control and Complications Trial, relatively high rates of severe hypoglycemic events were not associated with worse cognitive outcomes. In this 18-year follow-up of patients with type 1 diabetes, relatively high rates of severe hypoglycemic events were not associated with worse cognitive outcomes. Over time, improving glycemic control decreases the risk of microvascular, peripheral neuropathic, and macrovascular complications of type 1 diabetes. 1 – 4 However, it is unclear whether type 1 diabetes and its treatment have substantial effects on the structure and function of the central nervous system. 5 – 8 The widespread use of intensive therapies designed to achieve glycemic control near the nondiabetic range and the attendant increased risk of severe hypoglycemia 9 have elevated concern about the effects of hypoglycemia on the central nervous system. The Diabetes Control and Complications Trial (DCCT) incorporated a comprehensive battery of cognitive tests to evaluate the effect of . . .

Background The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. Methods/Design The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants’ views of the intervention and factors that acted as facilitators and barriers to participation. Discussion This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. Trial registration Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT02325544

Background Early seizures after craniotomy are significant perioperative complications that can adversely impact patient outcomes. Despite current guidelines advising against the routine use of antiseizure drugs for seizure after craniotomy prevention due to limited efficacy data, many clinicians continue prescribing them. This discrepancy highlights the need for robust evidence to guide clinical practice. This multi-center, randomized clinical trial was designed to investigate the efficacy of perampanel in preventing early seizures after craniotomy. Method This multi-center, open-label, randomized clinical trial will be conducted across five hospitals in Nagoya, Japan, from February 2024 to December 2026. A total of 142 seizure-naive patients with supratentorial brain tumors will be recruited and randomized (1:1) into the treatment and control groups. The treatment group will receive 2 mg of perampanel starting 2 days preoperatively and continuing for 28 days postoperatively, while the control group will receive no antiseizure drugs. The primary outcome is the incidence of seizures within 28 days after craniotomy. Secondary outcomes are length of hospital and intensive care unit stays and postoperative complications. Discussion This study addresses the critical need for evidence-based recommendations regarding antiseizure drug use for preventing early seizures after craniotomy. As the first multi-center, randomized trial evaluating perampanel’s efficacy in this setting, the findings may significantly influence clinical guidelines and perioperative practices. Trial registration This trial was registered with the Japan Registry of Clinical Trials (approval number: jRCTs041230117) on December 18, 2023, a member of the Primary Registry Network of the World Health Organization’s International Clinical Trials Registry Platform.

Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1·0–1·85 mmol/L or 1·25–2·5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with Clinicaltrials.gov, number NCT00004730. Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference −7 to 14; p=0·70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI −10·5 to −2; p=0·007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

Background Anti-epileptic drugs are commonly used for seizure prophylaxis after neurological injury. We performed a study comparing intravenous (IV) levetiracetam (LEV) to IV phenytoin (PHT) for seizure prophylaxis after neurological injury. Methods In this prospective, single-center, randomized, single-blinded comparative trial of LEV versus PHT (2:1 ratio) in patients with severe traumatic brain injury (sTBI) or subarachnoid hemorrhage (NCT00618436) patients received IV load with either LEV or fosphenytoin followed by standard IV doses of LEV or PHT. Doses were adjusted to maintain therapeutic serum PHT concentrations or if patients had seizures. Continuous EEG (cEEG) monitoring was performed for the initial 72 h; outcome data were collected. Results A total of 52 patients were randomized (LEV = 34; PHT = 18); 89% with sTBI. When controlling for baseline severity, LEV patients experienced better long-term outcomes than those on PHT; the Disability Rating Scale score was lower at 3 months ( P  = 0.042) and the Glasgow Outcomes Scale score was higher at 6 months ( P  = 0.039). There were no differences between groups in seizure occurrence during cEEG (LEV 5/34 vs. PHT 3/18; P  = 1.0) or at 6 months (LEV 1/20 vs. PHT 0/14; P  = 1.0), mortality (LEV 14/34 vs. PHT 4/18; P  = 0.227). There were no differences in side effects between groups (all P  > 0.15) except for a lower frequency of worsened neurological status ( P  = 0.024), and gastrointestinal problems ( P  = 0.043) in LEV-treated patients. Conclusions This study of LEV versus PHT for seizure prevention in the NSICU showed improved long-term outcomes of LEV-treated patients vis-à-vis PHT-treated patients. LEV appears to be an alternative to PHT for seizure prophylaxis in this setting.