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ELife Jan 2023TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo...
TRPM3 is a temperature- and neurosteroid-sensitive plasma membrane cation channel expressed in a variety of neuronal and non-neuronal cells. Recently, rare de novo variants in were identified in individuals with developmental and epileptic encephalopathy, but the link between TRPM3 activity and neuronal disease remains poorly understood. We previously reported that two disease-associated variants in TRPM3 lead to a gain of channel function . Here, we report a further 10 patients carrying one of seven additional heterozygous missense variants. These patients present with a broad spectrum of neurodevelopmental symptoms, including global developmental delay, intellectual disability, epilepsy, musculo-skeletal anomalies, and altered pain perception. We describe a cerebellar phenotype with ataxia or severe hypotonia, nystagmus, and cerebellar atrophy in more than half of the patients. All disease-associated variants exhibited a robust gain-of-function phenotype, characterized by increased basal activity leading to cellular calcium overload and by enhanced responses to the neurosteroid ligand pregnenolone sulfate when co-expressed with wild-type TRPM3 in mammalian cells. The antiseizure medication primidone, a known TRPM3 antagonist, reduced the increased basal activity of all mutant channels. These findings establish gain-of-function of TRPM3 as the cause of a spectrum of autosomal dominant neurodevelopmental disorders with frequent cerebellar involvement in humans and provide support for the evaluation of TRPM3 antagonists as a potential therapy.
Topics: Animals; Humans; Gain of Function Mutation; Neurosteroids; Neurodevelopmental Disorders; Epilepsy; Ion Channels; TRPM Cation Channels; Mammals
PubMed: 36648066
DOI: 10.7554/eLife.81032 -
Epilepsy Research Jul 2020Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam... (Review)
Review
Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes. The favorable pharmacokinetic profile of brivaracetam and lack of clinically relevant drug-drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment, and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug-drug interaction. Few agents have been reported to affect the pharmacokinetics of brivaracetam. The strong enzyme-inducing AEDs carbamazepine, phenytoin and phenobarbital/primidone have been shown to moderately lower brivaracetam plasma concentrations, with no adjustment of brivaracetam dose needed. Dose adjustment should be considered when brivaracetam is coadministered with the more potent CYP inducer, rifampin. Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John's wort. In summary, brivaracetam (50-200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug-drug interactions.
Topics: Anticonvulsants; Brain; Carbamazepine; Drug Interactions; Humans; Pyrrolidinones; Seizures
PubMed: 32361205
DOI: 10.1016/j.eplepsyres.2020.106327 -
CNS Drugs Aug 2023Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with...
BACKGROUND
Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown.
OBJECTIVE
The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients.
METHODS
We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment.
RESULTS
Patients had a mean valproate intravenous loading dose of 34.5 mg/kg and a mean maintenance dose of 15.3 mg/kg/d (1078 mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p = 0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone).
CONCLUSION
Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.
Topics: Adult; Humans; Anticonvulsants; Brain Diseases; Hyperammonemia; Status Epilepticus; Valproic Acid
PubMed: 37466895
DOI: 10.1007/s40263-023-01024-5 -
Progress in Neuro-psychopharmacology &... Jun 2023Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a...
OBJECTIVE
Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a series of matrices from combined samples of pregnant/breastfeeding women treated with anticonvulsants or lithium.
METHODS
We conducted a systematic literature search in PubMed/EMBASE for studies with concentrations of anticonvulsants/lithium from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal concentrations. When data from multiple studies were available, we calculated combined penetration ratios, weighting studies' mean by study size.
RESULTS
Ninety-one eligible studies for brivaracetam, carbamazepine, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, lithium, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproate, vigabatrin and zonisamide were identified. For amniotic fluid, the highest penetration ratios were estimated for levetiracetam (mean 3.56, range 1.27-5.85, n = 2) and lowest for valproate (mean 0.11, range 0.02-1.02, n = 57). For umbilical cord plasma, oxcarbazepine had the highest ratio (mean 1.59, range 0.11-4.33, n = 12) with clonazepam having the lowest (mean 0.55, range 0.52-0.59, n = 2). For breast milk, the highest ratios were observed for oxcarbazepine (mean 3.75, range 0.5-7.0, n = 2), whereas the lowest were observed for valproate (mean 0.04, range 0.01-0.22, n = 121).
DISCUSSION
We observed substantial variability between anticonvulsants and lithium regarding their ability to enter fetal/newborn circulation. Assessing concentrations of anticonvulsants and lithium in maternal samples can provide a surrogate of fetal/infant exposure, although patterns of concentration-dependent effects for maternal/neonatal safety are lacking.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Amniotic Fluid; Anticonvulsants; Fetal Blood; Lithium; Maternal-Fetal Exchange; Milk, Human
PubMed: 36805301
DOI: 10.1016/j.pnpbp.2023.110733 -
Signal Transduction and Targeted Therapy Dec 2023Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to...
Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1 mice and ALS patients. SOD1 mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Biomarkers; Interleukin-8; Mice, Transgenic; Motor Neurons; Neurodegenerative Diseases; Primidone; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 38086800
DOI: 10.1038/s41392-023-01713-z -
Cureus May 2024Essential tremors (ETs) commonly manifest as involuntary shaking of the hands that disrupt daily activities. These tremors involve the central motor network of the... (Review)
Review
Essential tremors (ETs) commonly manifest as involuntary shaking of the hands that disrupt daily activities. These tremors involve the central motor network of the cerebellum, thalamus, and cortical networks, leading to different clinical phenotypes. The goal of this review was to establish evidence-based recommendations for effective care and simplify decisions for those dealing with ET. For this narrative literature review, we conducted a thorough search using core keywords such as "essential tremor" and "therapy." From the 27 selected articles, relevant data were presented regarding pathophysiology, medications, and other treatment options, with necessary supplemental data such as side effects and use cases. This paper examines treatments for ET, including commonly prescribed medications such as propranolol and primidone; invasive treatments such as deep brain stimulation, focused ultrasound thalamotomy, transcranial magnetic stimulation, and some surgical methods; and non-invasive methods such as the neuromodulation technique of transcutaneous afferent patterned stimulation. Overall, this study presents a synthesized understanding of the currently available modalities for managing ETs. It is intended to guide care providers in choosing the best possible method to contain symptoms.
PubMed: 38826876
DOI: 10.7759/cureus.59451 -
Revista de Neurologia Jul 2019In clinical practice, it is common to find cases of epileptic women being treated with antiepileptic drugs (AEDs) whom we have to advise on the compatibility of these... (Review)
Review
INTRODUCTION
In clinical practice, it is common to find cases of epileptic women being treated with antiepileptic drugs (AEDs) whom we have to advise on the compatibility of these AEDs with breastfeeding.
AIMS
In order to offer correct guidance, we must be well informed about the pharmacokinetic characteristics of the different AEDs, in addition to being aware of the clinical experience in this regard. This review stems from the paucity of information on this topic.
DEVELOPMENT
The World Health Organisation recommends that breastfeeding should be the norm for all women, even in epileptic mothers that are taking AEDs, who must always be given special attention in order to watch for the appearance of adverse effects in the infant, and always avoiding sudden weaning in order to avoid withdrawal symptoms.
CONCLUSIONS
Very few AEDs are incompatible with breastfeeding. The decision to breastfeed should take into account not only the AED, but also its number, dose, serum levels, transmission and elimination rates in the infant, and the conditions of the newborn infant. Ethosuximide and felbamate are probably high risk and incompatible with breastfeeding. Lamotrigine, phenobarbital, pregabalin, primidone, tiagabine, eslicarbazepine, brivaracetam, perampanel, zonisamide, lacosamide or the sporadic use of benzodiazepines in low doses are considered quite safe, with a low risk for breastfeeding. The other AEDs present a very low risk for breastfeeding.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Humans; Infant, Newborn
PubMed: 31287150
DOI: 10.33588/rn.6902.2019037 -
The Lancet Regional Health. Europe Mar 2024The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs)...
BACKGROUND
The short- and long-term consequences of restricted fetal growth cause considerable concern, and how prenatal exposure to different antiseizure medications (ASMs) affects fetal growth remains uncertain.
METHODS
This was a population-based cohort study of liveborn singleton children born in Denmark, Finland, Iceland, Norway, and Sweden from 1996 to 2017. Prenatal exposure was defined as maternal filling of prescriptions for ASM during pregnancy registered in national prescription registries and primary outcomes were adjusted odds ratios (aORs) of microcephaly or being born small for gestational age.
FINDINGS
We identified 4,494,918 children (males: 51.3%, 2,306,991/4,494,918), including 38,714 (0.9%) children of mothers with epilepsy. In the overall population, prenatal monotherapy exposure with carbamazepine (aOR: 1.25 (95% CI: 1.12-1.40)), pregabalin (aOR: 1.16 (95% CI: 1.02-1.31)), oxcarbazepine (aOR: 1.48 (95% CI: 1.28-1.71)), clonazepam (aOR: 1.27 (95% CI: 1.10-1.48)), and topiramate (aOR: 1.48 (95% CI: 1.18-1.85)) was associated with risk of being born small for gestational age, and carbamazepine was associated with microcephaly (aOR: 1.43 (95% CI: 1.17-1.75)). In children of mothers with epilepsy, prenatal exposure to carbamazepine (aOR: 1.27 (95% CI: 1.11-1.47)), oxcarbazepine (aOR: 1.42 (95% CI: 1.18-1.70)), clonazepam (aOR: 1.40 (95% CI: 1.03-1.89)), and topiramate (aOR: 1.86 (95% CI: 1.36-2.54)) was associated with being born small for gestational age; carbamazepine, with microcephaly (aOR: 1.51 (95% CI: 1.17-1.95)). No associations with small for gestational age and microcephaly were identified after prenatal exposure to lamotrigine, valproate, gabapentin, levetiracetam, phenobarbital, acetazolamide, phenytoin, clobazam, primidone, zonisamide, vigabatrin, ethosuximide and lacosamide, but except for lamotrigine, valproate, gabapentin, and levetiracetam, numbers of exposed children were small.
INTERPRETATION
Prenatal exposure to carbamazepine, oxcarbazepine, clonazepam, and topiramate was associated with increased risk of being born small for gestational age in both the overall population and in children of women with epilepsy suggesting that prenatal exposure to these drugs is associated with fetal growth restriction.
FUNDING
The NordForsk Nordic Program on Health and Welfare (83539), the Independent Research Fund Denmark (1133-00026B), the Danish Epilepsy Association, the Central Denmark Region, the Novo Nordisk Foundation (NNF16OC0019126 and NNF22OC0075033), and the Lundbeck Foundation (R400-2022-1205).
PubMed: 38476755
DOI: 10.1016/j.lanepe.2024.100849 -
Journal of Clinical Neurology (Seoul,... Oct 2020Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and... (Review)
Review
Epilepsy is a common neurological disorder that is mainly treated using antiepileptic drugs. Several antiepileptic drugs such as phenobarbital, phenytoin, primidone, and ethosuximide were developed in the early 20th century. More than 10 types of antiepileptic drugs have been developed since the 1990s, and there are now more than 20 antiepileptic drugs in active clinical use. The choice of antiepileptic drugs is based on the clinical features of the seizure types, electroencephalogram findings, epileptic syndrome, and drug stability. Currently there are 19 antiepileptic drugs approved by the Korean Food and Drug Administration, 18 of which (with the exclusion of brivaracetam) are covered by the National Health Insurance Service in Korea. We reviewed the selection of antiepileptic drugs according to the classification of epileptic seizures.
PubMed: 33029959
DOI: 10.3988/jcn.2020.16.4.547 -
Seizure May 2022Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the... (Review)
Review
BACKGROUND
Recent position papers and guidelines encourage women with epilepsy (WWE) to exclusively breastfeed their infants because the benefits to their infants outweigh the potential adverse effects caused by exposure to antiseizure medications (ASMs).
OBJECTIVE
The objectives of this review were: to evaluate concentrations of ASMs in breastmilk of lactating WWE, qualitatively synthesize evidence that can be used to estimate theoretical doses as estimated daily intake (EDI) and relative infant dose (RID) of ASMs, and to evaluate potential risks to infants as a result of exposure to ASMs from breastmilk.
METHODS
This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42020223645. The databases: MEDLINE/PubMed, EMBASE, CINAHL/EBSCO, COCHRANE, SpringerLink, ScienceDirect, Summon, WHO International Clinical Trials Registry Platform, and SCOPUS were systematically searched. A qualitative synthesis was adopted in this study.
RESULTS
A total of 15 records were included in this systematic review. The included studies reported levels of 8 ASMs in the breastmilk of WWE. The highest RIDs of carbamazepine, lamotrigine, primidone, phenobarbital, gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%, 36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively. Breastfeeding might be limited or even discontinued when signs of excessive sedation/drowsiness and/or poor weight gain are evident on infants exposed to primidone and phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital.
CONCLUSIONS
Concentrations of ASMs can be detected in breastmilk of WWE and plasma/serum of infants exposed via breastmilk. Healthcare providers and WWE might use the findings of this study to make informed decisions on the safety of breastfeeding while taking ASMs.
Topics: Anticonvulsants; Breast Feeding; Epilepsy; Ethosuximide; Female; Humans; Infant; Lactation; Milk, Human; Phenobarbital; Primidone
PubMed: 35427849
DOI: 10.1016/j.seizure.2022.03.017