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Frontiers in Neurology 2023Neonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been...
INTRODUCTION
Neonatal hypoxia is a common cause of early-life seizures. Both hypoxia-induced seizures (HS), and the drugs used to treat them (e.g., phenobarbital, PB), have been reported to have long-lasting impacts on brain development. For example, in neonatal rodents, HS reduces hippocampal long-term potentiation (LTP), while PB exposure disrupts GABAergic synaptic maturation in the hippocampus. Prior studies have examined the impact of HS and drug treatment separately, but in the clinic, PB is unlikely to be given to neonates without seizures, and neonates with seizures are very likely to receive PB. To address this gap, we assessed the combined and separate impacts of neonatal HS and PB treatment on the development of hippocampal LTP.
METHODS
Male and female postnatal day (P)7 rat pups were subjected to graded global hypoxia (or normoxia as a control) and treated with either PB (or vehicle as a control). On P13-14 (P13+) or P29-37 (P29+), we recorded LTP of the Schaffer collaterals into CA1 pyramidal layer in acute hippocampal slices. We compared responses to theta burst stimulation (TBS) and tetanization induction protocols.
RESULTS
Under the TBS induction protocol, female rats showed an LTP impairment caused by HS, which appeared only at P29+. This impairment was delayed compared to male rats. While LTP in HS males was impaired at P13+, it normalized by P29+. Under the tetanization protocol, hypoxia produced larger LTP in males compared to female rats. PB injection, under TBS, did not exacerbate the effects of hypoxia. However, with the tetanization protocol, PB - on the background of HS - compensated for these effects, returning LTP to control levels.
DISCUSSION
These results point to different susceptibility to hypoxia as a function of sex and age, and a non-detrimental effect of PB when administered after hypoxic seizures.
PubMed: 38073649
DOI: 10.3389/fneur.2023.1295934 -
Molecules (Basel, Switzerland) Nov 2023The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection...
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
Topics: Humans; Anticonvulsants; Chromatography, High Pressure Liquid; Drug Monitoring; Carbamazepine; Oxcarbazepine
PubMed: 38067559
DOI: 10.3390/molecules28237830 -
PloS One 2023Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous...
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants.
MATERIALS AND METHODS
The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001.
RESULTS
After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs.
CONCLUSIONS
PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.
Topics: Animals; Male; Rats; Anticonvulsants; Diazepam; Pentylenetetrazole; Phenobarbital; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Seizures; Sildenafil Citrate; Tadalafil
PubMed: 38033148
DOI: 10.1371/journal.pone.0294754 -
ACS Omega Nov 2023In medicine, barbiturates are a class of depressive medications used as hypnotics, anticonvulsants, and anxiolytics. For the treatment of specific forms of epilepsy and...
In medicine, barbiturates are a class of depressive medications used as hypnotics, anticonvulsants, and anxiolytics. For the treatment of specific forms of epilepsy and seizures in young children in underdeveloped countries, the World Health Organization recommends phenobarbital (PBAR), a barbiturate drug. This review describes the fabrication and characterization of a paper-based analytical apparatus for phenobarbital detection that is straightforward, affordable, portable, and disposable. All of the solid-state ion-selective electrodes (ISEs) for PBAR as well as a Ag/AgCl reference electrode were constructed and optimized on a nonconductive paper substrate. Using carbon nanotube ink, the sensors were made to function as an ion-to-electron transducer and to make the paper conductive. A suitable polymeric membrane is drop-cast onto the surface of the carbon ink orifice. The pyrido-tetrapeptide and pyrido-hexapeptide derivatives, which were recently synthesized, functioned as distinct ionophores in the PBAR-membrane sensor, enabling its detection. With a detection limit of 5.0 × 10 M, the manufactured analytical device demonstrated a Nernstian response to PBAR anions in 50 mM phosphate buffer, pH 8.5, over a linear range of 1.0 × 10 to 1.0 × 10 M. The PBAR-based sensors showed quick (less than 5 s) response times for PBAR ion detection. The modified separate solution method was utilized to evaluate the selectivity pattern of these novel ionophores with respect to PBAR ions in comparison to other common anions. The analytical instrument that was exhibited on paper had good precision both within and between days. The suggested technology assisted in the detection of trace amounts of PBAR in real pharmaceutical samples. A comparison was made between the data acquired using the HPLC reference method and the information obtained by the recommended potentiometric approach. The described paper-based analytical device may be a good choice for point-of-care PBAR determination because it is cheap and easy to find and can self-pump (especially when combined with potentiometric detection).
PubMed: 38027332
DOI: 10.1021/acsomega.3c03977 -
Brain : a Journal of Neurology Dec 2023STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end...
STXBP1-related disorders are among the most common genetic epilepsies and neurodevelopmental disorders. However, the longitudinal epilepsy course and developmental end points, have not yet been described in detail, which is a critical prerequisite for clinical trial readiness. Here, we assessed 1281 cumulative patient-years of seizure and developmental histories in 162 individuals with STXBP1-related disorders and established a natural history framework. STXBP1-related disorders are characterized by a dynamic pattern of seizures in the first year of life and high variability in neurodevelopmental trajectories in early childhood. Epilepsy onset differed across seizure types, with 90% cumulative onset for infantile spasms by 6 months and focal-onset seizures by 27 months of life. Epilepsy histories diverged between variant subgroups in the first 2 years of life, when individuals with protein-truncating variants and deletions in STXBP1 (n = 39) were more likely to have infantile spasms between 5 and 6 months followed by seizure remission, while individuals with missense variants (n = 30) had an increased risk for focal seizures and ongoing seizures after the first year. Developmental outcomes were mapped using milestone acquisition data in addition to standardized assessments including the Gross Motor Function Measure-66 Item Set and the Grasping and Visual-Motor Integration subsets of the Peabody Developmental Motor Scales. Quantification of end points revealed high variability during the first 5 years of life, with emerging stratification between clinical subgroups. An earlier epilepsy onset was associated with lower developmental abilities, most prominently when assessing gross motor development and expressive communication. We found that individuals with neonatal seizures or early infantile seizures followed by seizure offset by 12 months of life had more predictable seizure trajectories in early to late childhood compared to individuals with more severe seizure presentations, including individuals with refractory epilepsy throughout the first year. Characterization of anti-seizure medication response revealed age-dependent response over time, with phenobarbital, levetiracetam, topiramate and adrenocorticotropic hormone effective in reducing seizures in the first year of life, while clobazam and the ketogenic diet were effective in long-term seizure management. Virtual clinical trials using seizure frequency as the primary outcome resulted in wide range of trial success probabilities across the age span, with the highest probability in early childhood between 1 year and 3.5 years. In summary, we delineated epilepsy and developmental trajectories in STXBP1-related disorders using standardized measures, providing a foundation to interpret future therapeutic strategies and inform rational trial design.
Topics: Infant, Newborn; Child; Child, Preschool; Humans; Infant; Anticonvulsants; Spasms, Infantile; Epilepsy; Topiramate; Seizures; Munc18 Proteins
PubMed: 38015929
DOI: 10.1093/brain/awad287 -
CNS Drugs Nov 2023Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The...
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.
Topics: Humans; Child; Adult; Female; Middle Aged; Aged; Aged, 80 and over; Male; Anticonvulsants; Phenytoin; Midazolam; Levetiracetam; Valproic Acid; Propofol; Lacosamide; Hospitals, University; Status Epilepticus; Phenobarbital; Benzodiazepines; Medical Records
PubMed: 37979095
DOI: 10.1007/s40263-023-01049-w -
JAMA Network Open Nov 2023Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) frequently experience seizures, which are associated with adverse outcomes.... (Observational Study)
Observational Study
IMPORTANCE
Neonates with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) frequently experience seizures, which are associated with adverse outcomes. Efforts to rapidly identify seizures and reduce seizure burden may positively change neurologic and neurodevelopmental outcomes.
OBJECTIVE
To describe the onset, treatment, and evolution of seizures in a large cohort of newborns with HIE during TH assisted by a telehealth model and remote neuromonitoring approach.
DESIGN, SETTING, AND PARTICIPANTS
This was a prospective, observational, multicenter cohort study performed between July 2017 and December 2021 in 32 hospitals in Brazil. Participants were newborns with HIE meeting eligibility criteria and receiving TH. Data were analyzed from November 2022 to April 2023.
EXPOSURE
Infants with HIE receiving TH were remotely monitored with 3-channel amplitude-integrated electroencephalography (aEEG) including raw tracing and video imaging, and bedside clinicians received assistance from trained neonatologists and neurologists.
MAIN OUTCOMES AND MEASURES
Data on modified Sarnat examination, presence, timing and seizure type, aEEG background activity, sleep-wake cycling, and antiepileptic drugs used were collected. Descriptive statistical analysis was used with independent t test, χ2, Mann-Whitney test, and post hoc analyses applied for associations.
RESULTS
A total of 872 cooled newborns were enrolled; the median (IQR) gestational age was 39 (38-40) weeks, 518 (59.4%) were male, and 59 (6.8%) were classified as having mild encephalopathy by modified Sarnat examination, 504 (57.8%) as moderate, and 180 (20.6%) as severe. Electrographic seizures were identified in 296 newborns (33.9%), being only electrographic in 213 (71.9%) and clinical followed by electroclinical uncoupling in 50 (16.9%). Early abnormal background activity had a significant association with seizures. Infants with flat trace had the highest rate of seizures (58 infants [68.2%]) and the greatest association with the incidence of seizures (odds ratio [OR], 12.90; 95% CI, 7.57-22.22) compared with continuous normal voltage. The absence of sleep-wake cycling was also associated with a higher occurrence of seizures (OR, 2.22; 95% CI, 1.67-2.96). Seizure onset was most frequent between 6 and 24 hours of life (181 infants [61.1%]); however, seizure occurred in 34 infants (11.5%) during rewarming. A single antiepileptic drug controlled seizures in 192 infants (64.9%). The first line antiepileptic drug was phenobarbital in 294 (99.3%).
CONCLUSIONS AND RELEVANCE
In this cohort study of newborns with HIE treated with TH, electrographic seizure activity occurred in 296 infants (33.9%) and was predominantly electrographic. Seizure control was obtained with a single antiepileptic drug in 192 infants (64.9%). These findings suggest neonatal neurocritical care can be delivered at remote limited resource hospitals due to innovations in technology and telehealth.
Topics: Infant, Newborn; Infant; Male; Humans; Female; Anticonvulsants; Cohort Studies; Hypoxia-Ischemia, Brain; Prospective Studies; Seizures; Hypothermia, Induced
PubMed: 37966836
DOI: 10.1001/jamanetworkopen.2023.43429 -
Revista de Neurologia Nov 2023Given the immaturity of the newborn, neonatal seizures are a diagnostic challenge. Most of them are secondary to an acute event. A small percentage constitute the onset... (Observational Study)
Observational Study
INTRODUCTION
Given the immaturity of the newborn, neonatal seizures are a diagnostic challenge. Most of them are secondary to an acute event. A small percentage constitute the onset of epilepsy.
AIMS
The aim was to analyse neonates with a diagnosis of seizures admitted to a tertiary hospital between November 2009 and May 2021, and their subsequent progression to epilepsy.
MATERIAL AND METHODS
A retrospective observational study was carried out using the hospital database. Information was collected on neonates with a discharge diagnosis of 'seizures' or 'moderate or severe hypoxic-ischaemic encephalopathy'. Different variables were analysed: aetiology of the seizures, type, persistence over time, treatment and electroclinical correlates.
RESULTS
Of 165 patients, 55 presented neonatal seizures. As regards aetiology, 43 patients (78%) had seizures secondary to an acute event, of which 19 (34%) were hypoxic-ischaemic encephalopathies, and 22 (40%) had other acute disorders. Genetic alteration was found in six of them (11%). Thirteen patients (24%) progressed to subsequent epilepsy, of whom seven had symptomatic epilepsy, with a period of latency after the acute event in two patients. Six patients had neonatal epilepsy with unprovoked seizures. Twenty-two (62%) showed electroclinical correlates. All of the confirmed crises (100%) were focal. All the seizures were treated. The drug of choice was phenobarbital.
CONCLUSIONS
Diagnosis of neonatal seizures requires high clinical suspicion and electroclinical confirmation. Most of them progress favourably, but a percentage constitute the onset of epilepsy, the identification of which will determine their therapeutic management.
Topics: Infant, Newborn; Humans; Tertiary Care Centers; Epilepsy; Seizures; Affect; Hospitalization; Hypoxia-Ischemia, Brain
PubMed: 37962536
DOI: 10.33588/rn.7710.2023218 -
Indian Journal of Pharmacology 2023The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain...
Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin-sphingolipid pathway in an animal model of pharmacoresistant epilepsy.
BACKGROUND
The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats.
MATERIALS AND METHODS
PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury.
RESULTS
Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy.
CONCLUSION
The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.
Topics: Animals; Humans; Rats; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistant Epilepsy; Endothelins; Fingolimod Hydrochloride; Models, Animal; Nitric Oxide; Pentylenetetrazole; Seizures; Sphingolipids
PubMed: 37929409
DOI: 10.4103/ijp.ijp_100_23 -
BMC Pediatrics Nov 2023Empyema as a rare cause of respiratory distress in neonatal period has not yet been reported after Corona virus disease 2019 (COVID-19) and even rarely in the context of...
BACKGROUND
Empyema as a rare cause of respiratory distress in neonatal period has not yet been reported after Corona virus disease 2019 (COVID-19) and even rarely in the context of bacterial infections is age group.
CASE PRESENTATION
The first neonate of quadruplets, resulting from Cesarean-Section of a 30-year-old mother without a history of previous illness, born at 34 weeks of gestation with a birth weight of 1600 gram. All four newborns were hospitalized; while the first one underwent nasal continuous positive airway pressure (N-CPAP) with a positive end-expiratory pressure of 6 and fractional inspired oxygen of 0.6, due to respiratory distress, noting a respiratory score of five out of 12.She was resuscitated one hour later due to bradycardia and underwent ventilator support. She received a single dose of pulmonary surfactant, intravenous paracetamol, and phenobarbital due to respiratory distress syndrome, Pectus Ductus Arteriosus, and unilateral clonic movements, respectively. In the lack of positive blood culture, she extubated two days later and breast-feeding was started. On day eight, she underwent high flow nasal cannula. On day 12, she suddenly developed respiratory distress, mottling, and abdominal distension, leading to N-CPAP and re-evaluation. The nasopharyngeal sampling for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) real time Polymerase chain reaction and the blood culture for staphylococcus aurous became positive. A large volume pleural effusion including septa and loculation in right hemi-thorax on chest computerized tomography scan and ultrasound was seen, necessitating to thoracotomy, which was not possible due to her general condition. Remdesivir was started and antibiotics changed to a more broad-spectrum coverage. Chest tube was inserted and Alteplase was injected for three consecutive days with beneficial effects. She had no problem for six-month follow up.
CONCLUSION
This was a case of empyema thoracic in the context of SARS-CoV-2 and Staphylococcus arouses co-infection. In our experience, it can be treated by chest drainage and fibrinolysis in neonatal period.
Topics: Pregnancy; Female; Humans; Infant, Newborn; Adult; SARS-CoV-2; COVID-19; Fibrinolysis; Staphylococcus; Continuous Positive Airway Pressure; Empyema; Pleural Effusion; Respiratory Distress Syndrome; Dyspnea
PubMed: 37923992
DOI: 10.1186/s12887-023-04375-6