Obstetric and neonatal outcomes, antiseizure medication profile, and seizure types in pregnant women in a vulnerability state from Brazil.

This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.

Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.

BACKGROUND: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. METHODS: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. RESULTS: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). CONCLUSIONS: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. TRIAL REGISTRATION: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.

A Retrospective Evaluation of Adjunctive Phenobarbital vs. Benzodiazepine Alone for the Treatment of Moderate Alcohol Withdrawal in the Emergency Department.

BACKGROUND: Phenobarbital has been used in the emergency department (ED) as both a primary and adjunctive medication for alcohol withdrawal, but previous studies evaluating its impact on patient outcomes are limited by heterogenous symptom severity. OBJECTIVES: We compared the clinical outcomes of ED patients with moderate alcohol withdrawal who received phenobarbital, with or without benzodiazepines, with patients who received benzodiazepine treatment alone. METHODS: This is a retrospective cohort study conducted at a single academic medical center utilizing chart review of ED patients with moderate alcohol withdrawal between 2015 and 2020. Patient encounters were classified into two treatment categories based on medication treatment: phenobarbital alone or in combination with benzodiazepines vs. benzodiazepines alone. Chi-square test or Fisher's exact was used to analyze categorical variables and the Student's t-test for continuous data. RESULTS: Among the 287 encounters that met inclusion criteria, 100 received phenobarbital, compared with 187 that received benzodiazepines alone. Patients who received phenobarbital were provided significantly more lorazepam equivalents. There was a significant difference in the percentage of patient encounters that required admission to the hospital in the phenobarbital cohort compared with the benzodiazepine cohort (75% vs. 43.3%, p < 0.001). However, there was no difference in admission level of care to the floor (51.2% vs. 52.0%), stepdown (33.8% vs. 28%), or intensive care unit (15% vs. 20%), respectively. CONCLUSIONS: Patients who received phenobarbital for moderate alcohol withdrawal were more likely to be admitted to the hospital, but there was no difference in admission level of care when compared with patients who received benzodiazepines alone. Patients who received phenobarbital were provided greater lorazepam equivalents in the ED.

High Doses of ANA12 Improve Phenobarbital Efficacy in a Model of Neonatal Post-Ischemic Seizures.

Phenobarbital (PB) remains the first-line medication for neonatal seizures. Yet, seizures in many newborns, particularly those associated with perinatal ischemia, are resistant to PB. Previous animal studies have shown that in postnatal day P7 mice pups with ischemic stroke induced by unilateral carotid ligation, the tyrosine receptor kinase B (TrkB) antagonist ANA12 (N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide, 5 mg/kg) improved the efficacy of PB in reducing seizure occurrence. To meet optimal standards of effectiveness, a wider range of ANA12 doses must be tested. Here, using the unilateral carotid ligation model, we tested the effectiveness of higher doses of ANA12 (10 and 20 mg/kg) on the ability of PB to reduce seizure burden, ameliorate cell death (assessed by Fluoro-Jade staining), and affect neurodevelopment (righting reflex, negative geotaxis test, open field test). We found that a single dose of ANA12 (10 or 20 mg/kg) given 1 h after unilateral carotid ligation in P7 pups reduced seizure burden and neocortical and striatal neuron death without impairing developmental reflexes. In conclusion, ANA12 at a range of doses (10-20 mg/kg) enhanced PB effectiveness for the treatment of perinatal ischemia-related seizures, suggesting that this agent might be a clinically safe and effective adjunctive agent for the treatment of pharmacoresistant neonatal seizures.

Correlation between serum galanin and neuron-specific enolase levels with EEG abnormalities in pediatric convulsive status epilepticus and the efficacy of triple drug therapy.

OBJECTIVE: This study aimed to investigate the association between serum galanin (GAL) and neuron-specific enolase (NSE) levels in children with convulsive status epilepticus (CSE) and their relationship with abnormal electroencephalogram (EEG) patterns. Additionally, the study assessed the effectiveness of a combination therapy involving midazolam, diazepam, and phenobarbital in treating CSE. PATIENTS AND METHODS: The research involved 100 children diagnosed with CSE and included a control group of 50 healthy children. Serum GAL and NSE levels were measured, and EEGs were analyzed for abnormalities in the CSE group. Comparisons were made between the healthy control group and the CSE group, particularly within the first 24 hours after persistent seizures. The severity of EEG abnormalities was correlated with GAL and NSE levels. The treatment consisted of an observation group that received the triple therapy of midazolam, diazepam, and phenobarbital, while a control group received diazepam and phenobarbital. Clinical efficacy, symptom improvement, Status Epilepticus Severity Score (STESS), and adverse reactions were evaluated. RESULTS: The results indicated elevated levels of GAL and NSE in the CSE group, with higher levels noted within 24 hours after persistent seizures. Furthermore, a positive correlation was observed between the severity of EEG abnormalities and GAL and NSE levels. The group receiving the triple therapy demonstrated superior efficacy, faster resolution of seizures and fever, reduced STESS scores, and fewer adverse reactions than the control group. In conclusion, this study highlights the positive correlation between serum GAL and NSE levels and the severity of EEG abnormalities in pediatric CSE. The triple therapy approach is effective in treating CSE, leading to improved clinical symptoms, reduced brain damage, and enhanced safety. CONCLUSIONS: The study concludes that serum GAL and NSE levels in children with convulsive status epilepticus are positively correlated with the degree of EEG abnormalities. The combination therapy involving midazolam, diazepam, and phenobarbital is effective in treating children with convulsive status epilepticus, significantly improving clinical symptoms, reducing brain damage, and ensuring safety.

A retrospective study of the efficacy of zonisamide in controlling seizures in 57 cats.

BACKGROUND: Evidence-based recommendations for antiepileptic drug selection in cats beyond phenobarbital are limited, and additional studies are needed for cats where seizures remain inadequately controlled by administration of phenobarbital alone or for cats that cannot safely receive phenobarbital. OBJECTIVE: To compare seizure frequency in cats before and after oral administration of zonisamide and describe adverse clinical or clinicopathologic effects in this cohort. ANIMALS: Fifty-seven cats with a history of seizures. METHODS: Multicenter, retrospective study. Median number of seizures per month and number of seizure days per month were compared before and after administration of zonisamide in all cats, a subgroup of cats with idiopathic epilepsy (IE), and a subgroup of cats receiving zonisamide as sole therapy. Clinical and clinicopathologic adverse effect data were also reported. RESULTS: A median decrease of 1 (P = .001, 95% confidence interval (CI) [-1.0, -0.5]) seizure per month, and 1 (P = .003, 95% CI [-1.5, -0.2]) seizure days per month was found across all cats after oral administration of zonisamide. The subgroup with IE showed median decreases of 1 (P = .03, 95% CI [-2.0, -0.5]) and 2 (P = .01, 95% CI [-2.5, -1.0]), respectively. The most common clinical adverse effects were sedation (17%), ataxia (11%), hyporexia (17%), and emesis (5%). One cat developed mild nonregenerative anemia, 2 cats developed mild metabolic acidosis, and 6 cats showed mild increases in ALT and ALP. CONCLUSION: Zonisamide was well tolerated and efficacious in controlling seizure activity in most cats.

Long-term clinical course and treatment outcomes of individuals with Nodding Syndrome.

Nodding Syndrome is a poorly understood epilepsy disorder in sub-Saharan Africa. The cause(s) of the disease, risk factors and long-term outcomes are unknown or controversial. The objectives of this study were to describe the long-term clinical course and treatment outcomes of individuals suffering from Nodding Syndrome. In addition, we aimed to provide a comprehensive characterization of the epileptological and social features of patients with Nodding Syndrome. From 11/2014 to 4/2015, we conducted a hospital-based, cross-sectional and observational study in Mahenge, Tanzania. Seventy-eight individuals (female:male ratio: 40:38, age at examination: 21.1 ± 6.39 (SD) years) have been enrolled, of whom 38 (49%) had also been examined in 2005 and in 2009. The 10-year clinical course analysis of this revisited subgroup revealed a calculated case fatality of 0.8-2.3%. Progressive physical or cognitive deterioration has not been observed in any of the 78 individuals and more than half of the people studied (38/69; 55%) managed to live and work independently. 14/78 individuals (18%) were seizure-free, (no head nodding, no other seizure types), 13 of whom were taking antiseizure medication. Phenytoin was more effective against head nodding seizures (14/19 (74%)) than monotherapy with other available antiseizure medication (phenobarbitone 12/25 (48%) and carbamazepine 7/22 (32%), p = 0.02, chi-square test). Our ten-year clinical outcome data show that Nodding Syndrome is not a fatal disease, however, the response to treatment is worse than in epilepsy patients in general. Phenytoin may be more effective than carbamazepine and phenobarbitone, but further studies are needed to confirm this observation.

Grading the level of evidence of neonatal pharmacotherapy: midazolam and phenobarbital as examples.

BACKGROUND: Many drugs are used off-label or unlicensed in neonates. This does not mean they are used without evidence or knowledge. We aimed to apply and evaluate the Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies (GAPPS) scoring system for the level of evidence of two commonly used anti-epileptic drugs. METHODS: Midazolam and phenobarbital as anti-epileptics were evaluated with a systematic literature search on neonatal pharmacokinetic (PK) and/or pharmacodynamic [PD, (amplitude-integrated) electroencephalography effect] studies. With the GAPPS system, two evaluators graded the current level of evidence. Inter-rater agreement was assessed for dosing evidence score (DES), quality of evidence (QoE), and strength of recommendation (REC). RESULTS: Seventy-two studies were included. DES scores 4 and 9 were most frequently used for PK, and scores 0 and 1 for PD. Inter-rater agreements on DES, QoE, and REC ranged from moderate to very good. A final REC was provided for all PK studies, but only for 25% (midazolam) and 33% (phenobarbital) of PD studies. CONCLUSIONS: There is a reasonable level of evidence concerning midazolam and phenobarbital PK in neonates, although using a predefined target without integrated PK/PD evaluation. Further research is needed on midazolam use in term neonates with therapeutic hypothermia, and phenobarbital treatment in preterms. IMPACT: There is a reasonable level of evidence concerning pharmacotherapy of midazolam and phenobarbital in neonates. Most evidence is however based on PK studies, using a predefined target level or concentration range without integrated, combined PK/PD evaluation. Using the GAPPS system, final strength of recommendation could be provided for all PK studies, but only for 25% (midazolam) to 33% (phenobarbital) of PD studies. Due to the limited PK observations of midazolam in term neonates with therapeutic hypothermia, and of phenobarbital in preterm neonates these subgroups can be identified for further research.

Cenobamate enhances the anticonvulsant effect of other antiseizure medications in the DBA/2 mouse model of reflex epilepsy.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na+ channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam.

Comparison of phenobarbital monotherapy to a benzodiazepine-based regimen for management of alcohol withdrawal syndrome in trauma patients.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is associated with increased morbidity and mortality in the trauma population. Benzodiazepines (BZDs) are standard of care for AWS; however, given the risk of delirium with BZDs and reports of BZD-refractory withdrawal, phenobarbital (PHB) has emerged as an alternative therapy for AWS. Safety and efficacy studies of PHB for AWS in trauma patients are lacking. Our aim was to compare a BZD versus PHB protocol in the management of AWS in trauma patients. METHODS: We performed a retrospective cohort study at a level 1 trauma center of patients at risk for AWS managed with either a BZD or a low-dose oral PHB regimen. Patients were excluded if they were taking BZDs or barbiturates before admission, received propofol or dexmedetomidine before initiation of the study drug, presented with delirium tremens or seizures, or died or discharged within 24 hours of presentation. The primary outcome was complicated AWS (seizures or alcohol withdrawal delirium/delirium tremens). Secondary outcomes included uncomplicated AWS; therapy escalation; oversedation; delirium-, intensive care unit-, and ventilator-free days; and length of stay. RESULTS: A total of 411 patients were identified; 118 received BZD, and 293 received PHB. The odds of developing complicated AWS with PHB versus BZD-based therapy were not statistically significant (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.21-1.39); however, patients receiving PHB were less likely to develop uncomplicated AWS (OR, 0.08; 95% CI, 0.04-0.14) and less likely to require escalation of therapy (OR, 0.45; 95% CI, 0.24-0.84). The PHB group had a length of stay 3.1 days shorter than the BZD group ( p = 0.002). There was no difference in intensive care unit-, ventilator-, or delirium-free days. CONCLUSION: A PHB-based protocol for the management of AWS is a safe and effective alternative to BZD-based regimens in trauma patients. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Facial dysmorphology in children exposed in pregnancy to anticonvulsant medications correlates with deficits in IQ.

Some children exposed at conception to the antiepileptic drugs (AEDs) phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) have changes in their midface and fingers. It has been suggested that the anticonvulsant-exposed child with these subtle changes in facial features (the "anticonvulsant face") has a greater likelihood of having deficits in IQ in comparison with children exposed to the same anticonvulsants who do not have these features. 115 AED-exposed children (40, PHT; 34, PB; and 41, CBZ) between 6.5 and 16 years of age and 111 unexposed children matched by sex, race, and year in school were evaluated. The evaluations were (WISC-III), physical examination with measurements of facial features and digits and photographs. The AED-exposed children had cephalometric radiographs, but not the unexposed. Each parent had a similar examination of face and hands plus tests of intelligence. These AED-exposed children showed an increased frequency of a short nose and anteverted nares, features of the "anticonvulsant face." Lateral skull radiographs showed a decrease in the angle between the anterior cranial base and nasal bone, which produces anteverted nares. Mean IQs were significantly lower on one or more IQ measures for the children with these facial features. Shortening of the distal phalanges and small fingernails correlated with the presence of a short nose in that child. The findings in 115 children exposed at conception to either phenytoin, phenobarbital, or carbamazepine, as monotherapy, confirmed the hypothesis that those with a short nose and anteverted nares had a lower IQ than exposed children without those features.

Extreme Symptom Burden for Patients With COVID-19 at the End of Life; Extrapolation of Knowledge Gained to Achieve Sustained Comfort and Dignity for all Patients in Their Last Days of Life1.

BACKGROUND: We describe two complex cases in the setting of COVID-19 at the End of Life, to enhance learning for all patients. CASE PRESENTATION: Maintenance of sustained comfort in two cases required multiple drugs, specifically selected for symptoms that necessitated three separate pumps delivering continuous 24-hour subcutaneous infusion. CASE MANAGEMENT: Management of sustained comfort included opioid, midazolam, anti-secretory, diclofenac for intractable temperature, phenobarbital for extreme agitation, in one, where seizure activity was present, while insomnia, was a prominent feature of another. Management of Akatasia was also required. CASE OUTCOME: Attention to each individual patient's rapidly evolving symptoms, during the dying phase, with a thorough differential diagnosis, wa s vitally important in the context of a 'Good Death'. This was achieved in both cases, reflected by evidence at the bedside of comfort and a minimum need for 'as required' drugs in the last days of life. CONCLUSIONS: COVID-19 being a new illness, we need to prospectively study the symptom burden/clustering at End of Life and learn from management of this new disease for other illnesses also. Further research is required to develop protocols on; when does Midazolam dose reach tolerance and when should an alternative drug such as phenobarbital for sustained Gamma-Aminobutyric Acid effects be initiated; examine the optimal approach to sustained temperature control; be cognisant of extrapyramidal side effects of drugs used at End of Life and consider looking at a lack of need for 'as required' drugs in the last days of life as an outcome measure of sustained comfort.

Fixed-Dose Phenobarbital Versus As-Needed Benzodiazepines for the Management of Alcohol Withdrawal in Acute Care General Internal Medicine.

OBJECTIVES: The management of patients at risk of severe alcohol withdrawal is challenging because conventional treatment with as-needed benzodiazepines may be ineffective. We created a fixed-dose phenobarbital protocol and compared patient outcomes using this protocol with an as-needed benzodiazepine protocol. METHODS: Patients admitted from the emergency department (ED) to General Medicine from January 1 to June 30, 2022 and treated for alcohol withdrawal with a novel phenobarbital protocol were compared with all of the patients admitted from the ED to General Medicine from January 1 to June 30, 2018, and treated with as-needed benzodiazepines. The primary outcome was a composite of intensive care unit (ICU) transfer or mortality. Secondary outcomes included mortality, ICU transfer, seizure, length of stay, excess sedation, delirium, against medical advice discharge, 30-day re-admission, 30-day ED reevaluation, and antipsychotic use. RESULTS: There were 54 patients in the phenobarbital group and 197 in the benzodiazepine group. The phenobarbital group was less medically complex but had more risk factors for severe withdrawal. There was no difference in the primary outcome, although there was a trend toward benefit in the phenobarbital group (3.7 vs 8.1%, P = 0.26), and there was a lower incidence of delirium in the phenobarbital cohort (0 vs 8.6%, P = 0.03). Secondary outcome trends favored phenobarbital, with lower mortality, ICU transfer, seizure, oversedation, against medical advice discharge, and 30-day re-admissions. A subgroup analysis accounting for differences in patient populations in the primary analysis found similar results. CONCLUSIONS: Phenobarbital is as safe and effective as benzodiazepine-based protocols for the treatment of high-risk alcohol withdrawal, with lower rates of delirium.

Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.

BACKGROUND AND OBJECTIVES: Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials. METHODS: The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly. RESULTS: This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021. CONCLUSION: Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.

Evaluation of phenobarbital dosing strategies for hospitalized patients with alcohol withdrawal syndrome.

OBJECTIVE: Alcohol remains the fourth­leading preventable cause of death in the U.S. The objective of this study was to compare the incidence of phenobarbital (PHB)-resistant withdrawal and determine risk factors for PHB-resistant alcohol withdrawal syndrome (AWS). METHODS: This retrospective cohort study included adults admitted to an academic center with AWS who received PHB as part of an institution-specific treatment protocol. The primary outcome was incidence of AWS resistant to initial protocolized PHB load across two cohorts (standard-dose, 10 mg/kg vs. low-dose, 6 mg/kg). RESULTS: Among 176 included patients, there was no difference in the incidence of PHB-resistant AWS based on initial PHB load [low-dose load, 21 (18.3%) vs. standard-dose load, 12 (19.7%), p = 0.82]. There were also no differences in observed PHB-related ADEs between the groups. Total benzodiazepine dose received (mg) in the 24 h prior to initial PHB load was the only risk factor significantly associated with AWS resistant to initial protocolized PHB load [adjusted OR 1.79 (95% CI 1.24, 2.60)]. PHB-resistant withdrawal occurred in 33 (18.8%) patients with a median cumulative PHB dose of approximately 20 mg/kg during hospitalization. CONCLUSION(S): There were no differences in the incidence of PHB-resistant AWS or PHB-related ADEs based on initial PHB loading dose.

[Neonatal abstinence syndrome due to kratom]. / Neonataal abstinentiesyndroom door kratom.

BACKGROUND: Kratom (Mitragyna speciosa) is a herbal product obtained from the tropical tree family 'Rubiaceae'. Kratom is available without prescription in several formulations. The active component mitragynine acts in high dose as a mu-opioid agonist. It is misconceived to be a safe alternative to conventional opioid drugs for the treatment of chronic pain. Therefore, maternal use of Kratom is not without risks as opioid use during pregnancy is associated with Neonatal Abstinence Syndrome (NAS). CASE DESCRIPTION: In this case report we describe a term neonate with severe NAS as a result of daily Kratom ingestion by the mother during pregnancy. Presence of mitragynine was confirmed in serum of the neonate. NAS was successfully treated with oral phenobarbital. CONCLUSION: Maternal Kratom use during pregnancy can cause severe NAS via in utero exposure. Physicians should be aware of the possible maternal use of Kratom in the case of a neonate with NAS. NAS as a result of maternal Kratom use can be effectively treated with oral phenobarbital.

Anti-seizure medications for neonates with seizures.

BACKGROUND: Newborn infants are more prone to seizures than older children and adults. The neuronal injury caused by seizures in neonates often results in long-term neurodevelopmental sequelae. There are several options for anti-seizure medications (ASMs) in neonates. However, the ideal choice of first-, second- and third-line ASM is still unclear. Further, many other aspects of seizure management such as whether ASMs should be initiated for only-electrographic seizures and how long to continue the ASM once seizure control is achieved are elusive. OBJECTIVES: 1. To assess whether any ASM is more or less effective than an alternative ASM (both ASMs used as first-, second- or third-line treatment) in achieving seizure control and improving neurodevelopmental outcomes in neonates with seizures. We analysed EEG-confirmed seizures and clinically-diagnosed seizures separately. 2. To assess maintenance therapy with ASM versus no maintenance therapy after achieving seizure control. We analysed EEG-confirmed seizures and clinically-diagnosed seizures separately. 3. To assess treatment of both clinical and electrographic seizures versus treatment of clinical seizures alone in neonates. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL, Epistemonikos and three databases in May 2022 and June 2023. These searches were not limited other than by study design to trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that included neonates with EEG-confirmed or clinically diagnosed seizures and compared (1) any ASM versus an alternative ASM, (2) maintenance therapy with ASM versus no maintenance therapy, and (3) treatment of clinical or EEG seizures versus treatment of clinical seizures alone. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility, risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence interval (CI). We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 18 trials (1342 infants) in this review. Phenobarbital versus levetiracetam as first-line ASM in EEG-confirmed neonatal seizures (one trial) Phenobarbital is probably more effective than levetiracetam in achieving seizure control after first loading dose (RR 2.32, 95% CI 1.63 to 3.30; 106 participants; moderate-certainty evidence), and after maximal loading dose (RR 2.83, 95% CI 1.78 to 4.50; 106 participants; moderate-certainty evidence). However, we are uncertain about the effect of phenobarbital when compared to levetiracetam on mortality before discharge (RR 0.30, 95% CI 0.04 to 2.52; 106 participants; very low-certainty evidence), requirement of mechanical ventilation (RR 1.21, 95% CI 0.76 to 1.91; 106 participants; very low-certainty evidence), sedation/drowsiness (RR 1.74, 95% CI 0.68 to 4.44; 106 participants; very low-certainty evidence) and epilepsy post-discharge (RR 0.92, 95% CI 0.48 to 1.76; 106 participants; very low-certainty evidence). The trial did not report on mortality or neurodevelopmental disability at 18 to 24 months. Phenobarbital versus phenytoin as first-line ASM in EEG-confirmed neonatal seizures (one trial) We are uncertain about the effect of phenobarbital versus phenytoin on achieving seizure control after maximal loading dose of ASM (RR 0.97, 95% CI 0.54 to 1.72; 59 participants; very low-certainty evidence). The trial did not report on mortality or neurodevelopmental disability at 18 to 24 months. Maintenance therapy with ASM versus no maintenance therapy in clinically diagnosed neonatal seizures (two trials) We are uncertain about the effect of short-term maintenance therapy with ASM versus no maintenance therapy during the hospital stay (but discontinued before discharge) on the risk of repeat seizures before hospital discharge (RR 0.76, 95% CI 0.56 to 1.01; 373 participants; very low-certainty evidence). Maintenance therapy with ASM compared to no maintenance therapy may have little or no effect on mortality before discharge (RR 0.69, 95% CI 0.39 to 1.22; 373 participants; low-certainty evidence), mortality at 18 to 24 months (RR 0.94, 95% CI 0.34 to 2.61; 111 participants; low-certainty evidence), neurodevelopmental disability at 18 to 24 months (RR 0.89, 95% CI 0.13 to 6.12; 108 participants; low-certainty evidence) and epilepsy post-discharge (RR 3.18, 95% CI 0.69 to 14.72; 126 participants; low-certainty evidence). Treatment of both clinical and electrographic seizures versus treatment of clinical seizures alone in neonates (two trials) Treatment of both clinical and electrographic seizures when compared to treating clinical seizures alone may have little or no effect on seizure burden during hospitalisation (MD -1871.16, 95% CI -4525.05 to 782.73; 68 participants; low-certainty evidence), mortality before discharge (RR 0.59, 95% CI 0.28 to 1.27; 68 participants; low-certainty evidence) and epilepsy post-discharge (RR 0.75, 95% CI 0.12 to 4.73; 35 participants; low-certainty evidence). The trials did not report on mortality or neurodevelopmental disability at 18 to 24 months. We report data from the most important comparisons here; readers are directed to Results and Summary of Findings tables for all comparisons. AUTHORS' CONCLUSIONS: Phenobarbital as a first-line ASM is probably more effective than levetiracetam in achieving seizure control after the first loading dose and after the maximal loading dose of ASM (moderate-certainty evidence). Phenobarbital + bumetanide may have little or no difference in achieving seizure control when compared to phenobarbital alone (low-certainty evidence). Limited data and very low-certainty evidence preclude us from drawing any reasonable conclusion on the effect of using one ASM versus another on other short- and long-term outcomes. In neonates who achieve seizure control after the first loading dose of phenobarbital, maintenance therapy compared to no maintenance ASM may have little or no effect on all-cause mortality before discharge, mortality by 18 to 24 months, neurodevelopmental disability by 18 to 24 months and epilepsy post-discharge (low-certainty evidence). In neonates with hypoxic-ischaemic encephalopathy, treatment of both clinical and electrographic seizures when compared to treating clinical seizures alone may have little or no effect on seizure burden during hospitalisation, all-cause mortality before discharge and epilepsy post-discharge (low-certainty evidence). All findings of this review apply only to term and late preterm neonates. We need well-designed RCTs for each of the three objectives of this review to improve the precision of the results. These RCTs should use EEG to diagnose seizures and should be adequately powered to assess long-term neurodevelopmental outcomes. We need separate RCTs evaluating the choice of ASM in preterm infants.

Anticonvulsant effects of isopimpinellin and its interactions with classic antiseizure medications and borneol in the mouse tonic-clonic seizure model: an isobolographic transformation.

BACKGROUND: Overwhelming evidence indicates that some naturally occurring coumarins and terpenes are widely used in folk medicine due to their various therapeutic effects affecting the brain. Antiseizure medications (ASMs) are the principal treatment option for epilepsy patients, although some novel strategies based on naturally occurring substances are intensively investigated. This study was aimed at determining the influence of isopimpinellin (ISOP-a coumarin) when administered either separately or in combination with borneol (BOR-a monoterpenoid), on the antiseizure potencies of four classic ASMs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and valproate (VPA)) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MATERIALS: Tonic-clonic seizures were evoked experimentally in mice after systemic (ip) administration of the respective doses of ISOP, BOR, and classic ASMs. Interactions for two-drug (ISOP + a classic ASM) and three-drug (ISOP + BOR + a classic ASM) mixtures were assessed isobolographically in the mouse MES model. RESULTS: ISOP (administered alone) had no impact on the anticonvulsant potencies of four classic ASMs. Due to the isobolographic transformation of data, the combination of ISOP + VPA exerted an antagonistic interaction, whereas the two-drug mixtures of ISOP + CBZ, ISOP + PHT, and ISOP + PB produced additive interactions in the mouse MES model. The three-drug combinations of ISOP + BOR with CBZ and PHT produced additive interactions, while the three-drug combinations of ISOP + BOR with PB and VPA exerted synergistic interactions in the mouse MES model. CONCLUSIONS: The most intriguing interaction was that for ISOP + VPA, for which the addition of BOR evoked a transition from antagonism to synergy in the mouse MES model.

Effects of bumetanide on neonatal seizures: A systematic review of animal and human studies.

BACKGROUND: Bumetanide, an inhibitor of the sodium-potassium-chloride cotransporter-1, has been suggested as an adjunct to phenobarbital for treating neonatal seizures. METHODS: A systematic review of animal and human studies was conducted to evaluate the efficacy and safety of bumetanide for neonatal seizures. PubMed, Embase, CINAHL and Cochrane databases were searched in March 2023. RESULTS: 26 animal (rat or mice) studies describing 38 experiments (28 in-vivo and ten in-vitro) and two human studies (one RCT and one open-label dose-finding) were included. The study designs, methods to induce seizures, bumetanide dose, and outcome measures were heterogeneous, with only 4/38 experiments being in animal hypoxia/ischaemia models. Among 38 animal experiments, bumetanide was reported to have antiseizure effects in 21, pro-seizure in six and ineffective in 11. The two human studies (n = 57) did not show the benefits of bumetanide as an add-on agent to phenobarbital in their primary analyses, but one study reported benefit on post-hoc analysis. Overall, hearing impairment was detected in 5/37 surviving infants in the bumetanide group vs. 0/13 in controls. Four of the five infants with hearing impairment had received aminoglycosides concurrently. Other adverse effects reported were diuresis, mild-to-moderate dehydration, hypotension, and electrolyte disturbances. The studies did not report on long-term neurodevelopment. The certainty of the evidence was very low. CONCLUSION: Animal data suggest that bumetanide has inconsistent effects as an antiseizure medication in neonates. Data from human studies are scarce and raise some concerns regarding ototoxicity when given with aminoglycosides. Well conducted studies in animal models of hypoxic-ischaemic encephalopathy are urgently needed. Future RCTs, if conducted in human neonates, should have an adequate sample size, assess neurodevelopment, minimize using aminoglycosides, be transparent about the potential ototoxicity in the parent information sheet, conduct early hearing tests and have trial-stopping rules that include hearing impairment as an outcome.

Once-a-day oral treatment with phenobarbital in cats with presumptive idiopathic epilepsy.

OBJECTIVES: Phenobarbital (PB) q12h is the most common treatment recommendation for cats with recurrent epileptic seizures. Medicating cats may be challenging and result in decreased quality of life for both cat and owner. The aim of this retrospective study was to evaluate treatment with oral PB q24h in cats with presumptive idiopathic epilepsy. METHODS: Nine cats with presumptive idiopathic epilepsy, receiving oral PB q24h, were included in a retrospective descriptive study. RESULTS: Seizure remission was achieved in 88% (8/9) of the cats and good seizure control in 12% (1/9) of the cats, treated with a mean dose of oral PB of 2.6 mg/kg q24h (range 1.4-3.8 mg/kg). No cats required an increase of their PB frequency at any time during a mean follow-up period of 3.5 years (range 1.1-8.0 years). No cats displayed side effects or issues with compliance at the last recorded follow-up. CONCLUSIONS AND RELEVANCE: Once-a-day administration of PB for feline epilepsy was safe and resulted in satisfactory seizure control for the nine cats included in this study. The results of this study justify exploring this topic further in larger prospective studies.