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Cumulative effect of evidence-based practices on outcomes of preterm infants born at <29 weeks' gestational age.
Rizzolo, A, Shah, PS, Boucorian, I, Lemyre, B, Bertelle, V, Pelausa, E, St Hilaire, M, Dahlgren, L, Beltempo, M, ,
American journal of obstetrics and gynecology. 2020;(2):181.e1-181.e10
Abstract
BACKGROUND Extremely preterm infants born at <29 weeks' gestational age are at high risk of death or severe neurological injury. Several individual evidence-based practices have been associated with neuroprotection. OBJECTIVE The objective of the study was to investigate the cumulative effect of 4 evidence-based practices and their association with death and/or severe neurological injury among infants born at <29 weeks' gestational age. STUDY DESIGN Observational study of infants born at 230-286 weeks gestational age admitted to neonatal intensive care units participating in the Canadian Neonatal Network from 2015 through 2017. We evaluated 4 practices: antenatal corticosteroids, antenatal MgSO4 for neuroprotection, deferred cord clamping ≥30 seconds, and normothermia on admission. The effect of exposure to 1, 2, 3, and all 4 evidence-based practices compared with none on death and/or severe neurological injury was assessed using multivariable logistic regression models adjusted for patient characteristics. RESULTS Rate of death and/or severe neurological injury was 20% (873 of 4297) and varied based on exposure to evidence-based practices: none, 34% (54 of 157); 1, 27% (171 of 626); 2, 20% (295 of 1448); 3, 18% (263 of 1448); and all 4, 14% (90 of 618). Significantly lower odds of death and/or severe neurological injury were observed with exposure to antenatal corticosteroids (adjusted odds ratio, 0.52, 95% confidence interval, 0.40-0.69) and deferred cord clamping (adjusted odds ratio, 0.81, 95% confidence interval, 0.68-0.96) but not MgSO4 (adjusted odds ratio, 0.88, 95% confidence interval, 0.72-1.08) or normothermia (adjusted odds ratio, 0.96, 95% confidence interval, 0.79-1.16). Infants exposed to ≥2 evidence-based practices had significantly lower odds of death and/or severe neurological injury than those exposed to no evidence-based practices (adjusted odds ratio, 0.61, 95% confidence interval, 0.43-0.88). CONCLUSION Among infants born at <29 weeks' gestational age, exposure to at least 2 of the evidence-based practices assessed was associated with decreased odds of death and/or severe neurological injury.
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Incidence, Presentation, and Risk Factors for Sodium Valproate-Associated Hyperammonemia in Neurosurgical Patients: A Prospective, Observational Study.
Woo, PYM, Woo, AWY, Lam, SW, Ko, NMW, Ho, JWK, Chu, ACH, Kwan, MCL, Chan, Y, Wong, HT, Chan, KY
World neurosurgery. 2020;:e597-e604
Abstract
OBJECTIVE Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 μmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 μmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.
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Drug Exposure in Newborns: Effect of Selected Drugs Prescribed to Mothers During Pregnancy and Lactation.
Rentsch, KM
Therapeutic drug monitoring. 2020;(2):255-263
Abstract
The number of newborns exposed to therapeutic drugs during pregnancy is growing because of the increased use of drugs during pregnancy. In recent years, advances in our understanding of drug placental transfer have augmented the likelihood of a healthy baby in mothers with chronic diseases needing drug therapy. Globally, for example, more than 1.4 million pregnancies in 2015 have been burdened with antiretroviral drugs due to an increasing number of HIV-positive women treated with these drugs, particularly in low- and middle-income countries. In most cases, the fetus is exposed to much higher drug doses in utero than the newborn nursed by the mother. Drug transfer through the placenta takes place by passive diffusion, active transport, or facilitated transport, and drug concentrations in the fetal circulation may be comparable to that in the mother's blood concentration. The excretion of drugs into breastmilk predominantly occurs by passive diffusion, allowing only the non-protein-bound fraction of the blood drug concentration to penetrate. Drug agencies in the United States and Europe highly recommend performing clinical trials in pregnant or breastfeeding women. However, only a few drugs have reported statistically sound data in these patient groups. Most available results concerning pregnancy are obtained from observational studies after birth, assessing outcomes in the newborn or by measuring drug concentrations in the mother and umbilical cord blood. In the case of the lactation period, some studies have evaluated drug concentrations in breastmilk and blood of the mother and/or infant. In this review, exposure to antiretrovirals, immunosuppressants used after solid organ transplantation, and antiepileptics during pregnancy and lactation has been discussed in detail.
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Oxcarbazepine add-on for drug-resistant focal epilepsy.
Bresnahan, R, Atim-Oluk, M, Marson, AG
The Cochrane database of systematic reviews. 2020;(3):CD012433
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Abstract
BACKGROUND Epilepsy is a common neurological disorder. In approximately 30% of epilepsy cases, seizures are uncontrolled by one antiepileptic drug (AED). These people require treatment with a combination of multiple AEDs and are described as having drug-resistant epilepsy. Oxcarbazepine is a keto-analogue of carbamazepine, an established AED, and can be used as an add-on treatment for drug-resistant epilepsy. OBJECTIVES To assess the efficacy and tolerability of oxcarbazepine as an add-on treatment for people with drug-resistant focal epilepsy. SEARCH METHODS The following databases were searched on 24 September 2018: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL); Medline (Ovid) 1946 to 21 September 2018; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Originally, we also searched SCOPUS as a substitute for Embase, but this is no longer necessary, because randomised and quasi-randomised controlled trials in Embase are now included in CENTRAL. SELECTION CRITERIA Randomised controlled trials with parallel-group or cross-over design, recruiting people of any age with drug-resistant focal epilepsy. We accepted any level of blinding and trials could be placebo- or active-controlled. DATA COLLECTION AND ANALYSIS In accordance with the methodological procedures expected by the Cochrane Collaboration, two review authors independently assessed trial eligibility before extracting data and assessing risk of bias. We assessed the primary outcomes: median percentage seizure reduction per 28 days; 50% or greater reduction in seizure frequency; and adverse effects including ataxia, hyponatraemia, and somnolence. We assessed the secondary outcomes: seizure freedom; treatment withdrawal; cognitive effects; and quality of life. We used an intention-to-treat population for all primary analyses. We present results as risk ratios (RR) with 95% confidence intervals (CI), with the exception of adverse effects which we present with 99% CI. MAIN RESULTS We identified six eligible studies, involving 1593 participants. We judged that three studies were at unclear risk of bias and three were at high risk of bias. Bias mainly arose from lack of methodological details and from high attrition rates. Participants were aged 1 month to 65 years, with a diagnosis of drug-resistant focal epilepsy. All studies were either placebo- or alternative-dose-controlled with parallel-group design. The treatment period varied from 9 days to 26 weeks. The median percentage seizure reduction per 28 days (3 studies; moderate-certainty evidence) ranged from 26% to 83.3% for participants randomised to experimental oxcarbazepine compared to 7.6% to 28.7% for participants randomised to control treatment. Oxcarbazepine may increase the responder rate for 50% or greater reduction in seizure frequency compared to control treatment (RR 1.80, 95% CI 1.27 to 2.56; random-effects model; 6 studies; low-certainty evidence). For seizure freedom, the RR was 2.86 (95% CI 1.19 to 6.87; random-effects model; 5 studies; low-certainty evidence), suggesting an advantageous effectiveness of oxcarbazepine over control treatment. Treatment with oxcarbazepine was associated with an increased treatment withdrawal rate compared to control (RR 1.75, 95% CI 1.44 to 2.13; fixed-effect model; 6 studies; moderate-certainty evidence). The largest oxcarbazepine dose used, 2400 mg/d, was associated with a higher treatment withdrawal rate (RR 2.38, 95% CI 1.92 to 2.94; fixed-effect model; 2 studies) compared to control, than 1200 mg/d (RR 1.54, 95% CI 1.21 to 1.95; fixed-effect model; 3 studies) or 600 mg/d oxcarbazepine (RR 0.79, 95% CI 0.55 to 1.15; fixed-effect model; 1 study). Treatment with oxcarbazepine was associated with an increased incidence of multiple adverse effects including: ataxia (RR 2.54, 99% CI 0.86 to 7.54; random-effects model; 5 studies; moderate-certainty evidence); and somnolence (RR 2.03, 99% CI 1.17 to 3.54; random-effects model; 6 studies; low-certainty evidence). Hyponatraemia occurred more frequently with oxcarbazepine treatment but not significantly so (RR 2.53, 99% CI 0.27 to 23.85; fixed-effect model; 6 studies; moderate-certainty evidence). AUTHORS' CONCLUSIONS Oxcarbazepine might be effective at reducing seizure frequency when used as an add-on for drug-resistant focal epilepsy. The efficacy outcomes - 50% or greater seizure reduction and seizure freedom - were derived from low-certainty evidence. We are, therefore, uncertain whether the estimated effect size is representative of the true effect. In contrast, the evidence for median percentage seizure reduction and treatment withdrawal were of moderate certainty: thus, we are fairly certain of the effect estimates' reliability. Overall, we are unsure of the true efficacy of oxcarbazepine, but have concerns about its tolerability.
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Therapeutic advances in Dravet syndrome: a targeted literature review.
Strzelczyk, A, Schubert-Bast, S
Expert review of neurotherapeutics. 2020;(10):1065-1079
Abstract
INTRODUCTION Dravet syndrome (DS), a prototypic developmental and genetic epileptic encephalopathy (DEE), is characterized by an early onset of treatment-refractory seizures, together with impairments in motor control, behavior, and cognition. Even with multiple conventional anti-epileptic drugs, seizures remain poorly controlled, and there has been a considerable unmet need for effective and tolerable treatments. AREAS COVERED This targeted literature review aims to highlight recent changes to the therapeutic landscape for DS by summarizing the most up-to-date, evidence-based research, including pivotal data from the clinical development of stiripentol, cannabidiol, and fenfluramine, which are important milestones for DS treatment, together with the latest findings of other pharmacotherapies in development. In phase III, double-blind, placebo-controlled randomized controlled trials stiripentol, cannabidiol, and fenfluramine have shown clinically relevant reductions in convulsive seizure frequency, and are generally well tolerated. Stiripentol was associated with responder rates (greater than 50% reduction in convulsive seizure frequency) of 67%-71%, when added to valproic acid and clobazam; cannabidiol was associated with responder rates of 43%-49% (48%-63% in conjunction with clobazam), and fenfluramine of 54%-68% across studies. Therapies in development include soticlestat, ataluren, verapamil, and clemizole, with strategies to treat the underlying cause of DS, including gene therapy and antisense oligonucleotides beginning to emerge from preclinical studies. EXPERT OPINION Despite the challenges of drug development in rare diseases, this is an exciting time for the treatment of DS, with the promise of new efficacious and well-tolerated therapies, which may pave the way for treatment advances in other DEEs.
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Dose-Ranging Effect of Adjunctive Oral Cannabidiol vs Placebo on Convulsive Seizure Frequency in Dravet Syndrome: A Randomized Clinical Trial.
Miller, I, Scheffer, IE, Gunning, B, Sanchez-Carpintero, R, Gil-Nagel, A, Perry, MS, Saneto, RP, Checketts, D, Dunayevich, E, Knappertz, V, et al
JAMA neurology. 2020;(5):613-621
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Abstract
IMPORTANCE Clinical evidence supports effectiveness of cannabidiol for treatment-resistant seizures in Dravet syndrome, but this trial is the first to evaluate the 10-mg/kg/d dose. OBJECTIVE To evaluate the efficacy and safety of a pharmaceutical formulation of cannabidiol, 10 and 20 mg/kg/d, vs placebo for adjunctive treatment of convulsive seizures in patients with Dravet syndrome. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, randomized clinical trial (GWPCARE2) recruited patients from April 13, 2015, to November 10, 2017, with follow-up completed on April 9, 2018. Of 285 patients screened from 38 centers in the United States, Spain, Poland, the Netherlands, Australia, and Israel, 86 were excluded, and 199 were randomized. Patients were aged 2 to 18 years with a confirmed diagnosis of Dravet syndrome and at least 4 convulsive seizures during the 4-week baseline period while receiving at least 1 antiepileptic drug. Data were analyzed from November 16 (date of unblinding) to December 13 (date of final outputs), 2018, based on intention to treat and per protocol. INTERVENTIONS Patients received cannabidiol oral solution at a dose of 10 or 20 mg/kg per day (CBD10 and CBD20 groups, respectively) or matched placebo in 2 equally divided doses for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were blinded to group assignment. MAIN OUTCOMES AND MEASURES The primary outcome was change from baseline in convulsive seizure frequency during the treatment period. Secondary outcomes included change in all seizure frequency, proportion with at least a 50% reduction in convulsive seizure activity, and change in Caregiver Global Impression of Change score. RESULTS Of 198 eligible patients (mean [SD] age, 9.3 [4.4] years; 104 female [52.5%]), 66 were randomized to the CBD10 group, 67 to the CBD20 group, and 65 to the placebo group, and 190 completed treatment. The percentage reduction from baseline in convulsive seizure frequency was 48.7% for CBD10 group and 45.7% for the CBD20 group vs 26.9% for the placebo group; the percentage reduction from placebo was 29.8% (95% CI, 8.4%-46.2%; P = .01) for CBD10 group and 25.7% (95% CI, 2.9%-43.2%; P = .03) for the CBD20 group. The most common adverse events were decreased appetite, diarrhea, somnolence, pyrexia, and fatigue. Five patients in the CBD20 group discontinued owing to adverse events. Elevated liver transaminase levels occurred more frequently in the CBD20 (n = 13) than the CBD10 (n = 3) group, with all affected patients given concomitant valproate sodium. CONCLUSIONS AND RELEVANCE Adjunctive cannabidiol at doses of 10 and 20 mg/kg/d led to similar clinically relevant reductions in convulsive seizure frequency with a better safety and tolerability profile for the 10-mg/kg/d dose in children with treatment-resistant Dravet syndrome. Dose increases of cannabidiol to greater than 10 mg/kg/d should be tailored to individual efficacy and safety. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02224703.
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(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research.
Formato, M, Crescente, G, Scognamiglio, M, Fiorentino, A, Pecoraro, MT, Piccolella, S, Catauro, M, Pacifico, S
Molecules (Basel, Switzerland). 2020;(11)
Abstract
Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).
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Anticonvulsant mechanisms of the ketogenic diet and caloric restriction.
Rudy, L, Carmen, R, Daniel, R, Artemio, R, Moisés, RO
Epilepsy research. 2020;:106499
Abstract
Many treatments have been proposed to control epileptic seizures, such as the ketogenic diet and caloric restriction. However, seizure control has not yet been improved completely in all patients. Probably, due to the lack of understanding regarding this neurological disorder pathogenesis or pathophysiology, including its molecular approach. Currently, there is not much information about the molecular processes and genes involved, and their relation to the possible beneficial effects of diet therapy on epilepsy. The ketogenic diet and caloric restriction are implicated in potential anti-seizure mechanisms related to the gut microbiome, metabolic pathways, hormones and neurotransmitters, mitochondria improvement, a role in inflammation, and oxidative stress, among others. In this review, we pretend to describe the molecular mechanism and the possible genes involved in the different ketogenic diet and caloric restriction mechanisms of action described to decrease neural excitability and, therefore, epileptic seizures, especially when conventional treatment is not enough to achieve control of epilepsy.
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Levetiracetam as preventive treatment in adults with migraine: an up-to-date systematic review and quantitative meta-analysis.
Tsaousi, G, Pourzitaki, C, Siafis, S, Kyrgidis, A, Grosomanidis, V, Kouvelas, D, Papazisis, G
European journal of clinical pharmacology. 2020;(2):161-174
Abstract
PURPOSE The aim of this systematic review was to evaluate current evidence on the efficacy and safety of levetiracetam as migraine prophylaxis in adult patients suffering from migraine attacks. METHODS PubMed, Scopus, Cochrane Central Register of Controlled Trials, and International Web of Science were searched (last search in August 2018) for studies investigating levetiracetam for migraine prophylaxis in adults. Both randomized and non-randomized trials were eligible. Efficacy was the primary outcome, but tolerability was also investigated. The study is registered on PROSPERO, number CRD42018088900. RESULTS Nine studies, enrolling 215 patients, were included. Levetiracetam decreased the frequency of attacks with headache in all studies, with a pooled mean difference of -3.02 (95% CI: -4.59 to -1.45; I2 = 0%), -4.65(-7 to -2.3; I2 = 0%), and -5.71 (-8.60 to -2.82; I2 = 0%) at 1, 3, and 6 months compared with baseline. Three randomized controlled trials were included, and levetiracetam was superior to placebo in two but was inferior to sodium valproate in reducing headache frequency. Similar results were found in the other indices of efficacy, and levetiracetam was generally well tolerated. CONCLUSION Levetiracetam may be a relatively safe and efficacious treatment for the prophylaxis of migraine based on limited evidence, most from uncontrolled studies. Further evidence from randomized controlled trials is necessary.
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Medical management of status epilepticus: Emergency room to intensive care unit.
Crawshaw, AA, Cock, HR
Seizure. 2020;:145-152
Abstract
In convulsive status epilepticus (SE), achieving seizure control within the first 1-2 hours after onset is a significant determinant of outcome. Treatment is also more likely to work and be cost effective the earlier it is given. Initial first aid measures should be accompanied by establishing intravenous access if possible and administering thiamine and glucose if required. Calling for help will support efficient management, and also the potential for video-recording the events. This can be done as a best interests investigation to inform later management, provided adequate steps to protect data are taken. There is high quality evidence supporting the use of benzodiazepines for initial treatment. Midazolam (buccal, intranasal or intramuscular) has the most evidence where there is no intravenous access, with the practical advantages of administration outweighing the slightly slower onset of action. Either lorazepam or diazepam are suitable IV agents. Speed of administration and adequate initial dosing are probably more important than choice of drug. Although only phenytoin (and its prodrug fosphenytoin) and phenobarbitone are licensed for established SE, a now considerable body of evidence and international consensus supports the utility of both levetiracetam and valproate as options in established status. Both also have the advantage of being well tolerated as maintenance treatment, and possibly a lower risk of serious adverse events. Two adequately powered randomized open studies in children have recently reported, supporting the use of levetiracetam as an alterantive to phenytoin. The results of a large double blind study also including valproate are also imminent, and together likely to change practice in benzodiazepine-resistant SE.