Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.
- Klíčová slova
- CACNA1H, Calcium channel, Cav3.2 channel, Channelopathy, Encephalopathy, Epilepsy, Ion channels, Nav1.6 channel, SCN8A, Sodium channel,
- MeSH
- aktivační mutace MeSH
- bodová mutace MeSH
- duplikace genu MeSH
- epilepsie tonicko-klonická genetika MeSH
- gating iontového kanálu genetika fyziologie MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- missense mutace MeSH
- mnohočetné abnormality genetika MeSH
- napěťově řízený sodíkový kanál, typ 6 genetika fyziologie MeSH
- novorozenec MeSH
- refrakterní epilepsie genetika MeSH
- rodokmen MeSH
- skolióza genetika MeSH
- vápníkové kanály - typ T genetika fyziologie MeSH
- vývojové poruchy u dětí genetika MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CACNA1H protein, human MeSH Prohlížeč
- napěťově řízený sodíkový kanál, typ 6 MeSH
- SCN8A protein, human MeSH Prohlížeč
- vápníkové kanály - typ T MeSH
OBJECTIVES: The aim of the study was to evaluate the long-term efficacy and hospitalization rates in children with refractory focal epilepsy treated by vagus nerve stimulation. MATERIALS AND METHODS: We retrospectively analyzed 15 children with intractable focal epilepsy treated by vagus nerve stimulation (mean age of 14.6 ± 2.5 years at the time of implantation). We analyzed the treatment effectiveness at 1, 2, and 5 year follow-up visits. We counted the average number of urgent hospitalizations and number of days of urgent hospitalization per year for each patient before and after the VNS implantation. RESULTS: The mean seizure reduction was 42.5% at 1 year, 54.9% at 2 years, and 58.3% at 5 years. The number of responders was 7 (46.7%) at 1 year and 9 (60%) at both 2 and 5 years. The mean number of urgent hospitalizations per patient was 1.0 ± 0.6 per year preoperatively and 0.3 ± 0.5 per year post-operatively (P < 0.0001). The mean number of days of urgent hospitalization per patient was 9.3 ± 6.1 per year preoperatively and 1.3 ± 1.8 per year post-operatively ( < 0.0001). CONCLUSIONS: Vagus nerve stimulation is an effective method of treating children with refractory focal epilepsy. It leads to a substantial decrease in the number and duration of urgent hospitalizations.
- MeSH
- antikonvulziva terapeutické užití MeSH
- dítě MeSH
- epilepsie parciální farmakoterapie terapie MeSH
- epilepsie tonicko-klonická farmakoterapie terapie MeSH
- hospitalizace statistika a číselné údaje MeSH
- incidence MeSH
- kašel etiologie MeSH
- lidé MeSH
- mladiství MeSH
- náhlé příhody epidemiologie MeSH
- následné studie MeSH
- poruchy polykání etiologie MeSH
- recidiva MeSH
- retrospektivní studie MeSH
- srdeční zástava etiologie MeSH
- vagová stimulace * škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antikonvulziva MeSH
Neuroactive steroids represent potential antiepileptic drugs. We tested a newly synthesized analogue of allopregnanolone 3alpha-hydroxy-21xi,22-oxido-21-homo-5alpha-pregnan-20-on (HOHP) against two types of pentylenetetrazol-induced seizures (100 mg/kg s.c.) in 12- and 25-day-old rats. Ganaxolone, a neuroactive steroid in clinical trials, served as a reference drug. Pretreatment with either steroid suppressed generalized tonic-clonic seizures in both age groups, their efficacy was comparable. HOHP as well as ganaxolone were more active in 12- than in 25-day-old rats (effective doses were 40 and 60 mg/kg, respectively). Minimal clonic seizures, which can be elicited only in 25-day-old rats, were not influenced by any drug. Very short duration of anticonvulsant action of HPOP demonstrated in 12-day-old animals indicates that this drug might be used only in acute treatment in epileptology.
- MeSH
- akutní nemoc MeSH
- antikonvulziva farmakologie MeSH
- epilepsie tonicko-klonická farmakoterapie MeSH
- krysa rodu Rattus MeSH
- pregnanolon analogy a deriváty farmakologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 3alpha-hydroxy-21epsilon,22-oxido-21-homo-5alpha-pregnan-20-one MeSH Prohlížeč
- antikonvulziva MeSH
- ganaxolone MeSH Prohlížeč
- pregnanolon MeSH
In immature rats, N-methyl-D-aspartate (NMDA) induces several seizure types: flexion seizures (FS; in rats younger than 3 weeks), clonic seizures (in animals older than 3 weeks), and clonic-tonic seizures (CTS; in rats of all ages). FS represent a model of human infantile spasms. Effects of vigabatrin and valproate against all types of NMDA-induced seizures were studied in rats at postnatal days 12 (P12) and 25 (P25). NMDA (60 or 300 mg/kg) was injected to animals pretreated with vigabatrin (300-1,200 mg/kg; 24 h before NMDA) or valproate (100-400 mg/kg; 15 min before NMDA). Vigabatrin suppressed FS in P12 rats, but was ineffective against CTS in both age groups. Valproate suppressed CTS in P12, but not in P25 rats. Clonic seizures were rare in NMDA-treated P25 rats, but valproate pretreatment increased their incidence significantly. Neither drug decreased NMDA-induced mortality, which occurred within approximately 15 min after NMDA administration and reached almost 100% in all groups.
- MeSH
- antikonvulziva farmakologie MeSH
- chování zvířat účinky léků fyziologie MeSH
- epilepsie tonicko-klonická chemicky indukované klasifikace patofyziologie MeSH
- kojenec MeSH
- křeče u dětí patofyziologie MeSH
- krysa rodu Rattus MeSH
- kyselina valproová farmakologie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- N-methylaspartát farmakologie MeSH
- novorozená zvířata MeSH
- potkani Wistar MeSH
- receptory N-methyl-D-aspartátu účinky léků MeSH
- věkové faktory MeSH
- vigabatrin farmakologie MeSH
- záchvaty chemicky indukované mortalita prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- kojenec MeSH
- krysa rodu Rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antikonvulziva MeSH
- kyselina valproová MeSH
- N-methylaspartát MeSH
- receptory N-methyl-D-aspartátu MeSH
- vigabatrin MeSH
Adenosine may represent an endogenous anticonvulsant in the brain. This study focused on the possible anticonvulsant action of an adenosine agonist, 2-chloroadenosine, against cortical epileptic afterdischarges (ADs) in immature rats. Three age groups of rat pups with implanted electrodes were studied: 12-, 18- and 25-days-old. The compound, 2-chloroadenosine, was injected after the first successful stimulation at doses of 1, 4 or 10 mg/kg intraperitoneally, and stimulation at the same intensity was repeated three more times. Movements directly elicited by stimulation, as well as clonic seizures accompanying electroencephalography (EEG) ADs, were markedly suppressed in only the 18-day-old animals. The effects in the 12- and especially the 25-day-old rats were moderate. The duration of the ADs decreased in all three age groups with 2-chloroadenosine treatment, and the shortest AD duration was seen in the treated, 12-day-old rats. The AD suppression also lasted longer in this age group than it did in the older animals. After a brief suppression of the second AD, the treated, 25-day-old group exhibited a significant AD rebound during the third and fourth stimulations. Taken together, our data show that 2-chloroadenosine exhibits an anticonvulsant effect that is dose- and age-dependent.
- MeSH
- 2-chloradenosin aplikace a dávkování farmakologie MeSH
- antikonvulziva * MeSH
- elektroencefalografie účinky léků MeSH
- epilepsie tonicko-klonická farmakoterapie patofyziologie MeSH
- epilepsie farmakoterapie patofyziologie MeSH
- implantované elektrody MeSH
- injekce intraperitoneální MeSH
- krysa rodu Rattus MeSH
- mozková kůra účinky léků patofyziologie MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- stárnutí fyziologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 2-chloradenosin MeSH
- antikonvulziva * MeSH
In the present study, we investigated the effects of vagus nerve stimulation (VNS), a proposed treatment for patients with intractable epilepsy, on cardiac rhythm following seizures induced by pentylenetetrazole (PTZ) in Wistar rats. After a baseline recording of electroencephalogram (EEG), electrocardiogram (ECG) and blood pressure (BP), rats in the first group received a single convulsive dose of PTZ (70 mg/kg) (Group 1). In the other two groups, the Wistar rats were implanted with a cuff electrode on the left cervical vagus nerve. One day after surgery, rats in the second group were treated with VNS (Group 2), whereas rats in the third group were connected to the stimulator but did not receive VNS (Group 3). Ten minutes after VNS onset, 70 mg/kg dose of PTZ was injected. EEG, ECG and BP were continuously recorded during post-injection period. Seizure severity was scored behaviorally. Then, baseline, ictal and postictal periods were analyzed for cardiac rhythms, seizure severity and blood pressure variability. PTZ treatment induced tonic-clonic seizure activity in all animals of Group 1 and Group 3. In these groups a marked increase of mean arterial blood pressure (MABP) but a significant decrease in heart rate and PP interval fluctuations was observed at postictal period. However, in the VNS-treated group the seizure scores and cardiac parameter returned to the baseline level. Present results emphasize that VNS effectively reduces seizure severity and suppress the seizure-induced cardiac rhythm changes.
- MeSH
- elektroencefalografie MeSH
- elektrokardiografie MeSH
- epilepsie tonicko-klonická chemicky indukované patofyziologie terapie MeSH
- krevní tlak * MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- pentylentetrazol MeSH
- potkani Wistar MeSH
- srdeční arytmie etiologie patofyziologie prevence a kontrola MeSH
- srdeční frekvence * MeSH
- vagová stimulace * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- pentylentetrazol MeSH
GABA exhibits depolarizing action in the immature neurons due to high intracellular activity of chloride ions. It is maintained by cation-chloride cotransporter NKCC1 which is present in immature brain. Bumetanide is a specific inhibitor of this cotransporter. We studied possible anticonvulsant activity of bumetanide in pentylenetetrazol-induced seizures in three age groups of rat pups (7, 12, and 18 days old). Pretreatment with bumetanide (0.2-1 mg/kg i.p.) resulted in dose-dependent decrease of incidence of the tonic phase of generalized tonic-clonic seizures in 12-day-old rats only. No effect was observed in younger and older animals. Higher dose of bumetanide (2.5 mg/kg) did not affect tonic convulsions but, on the contrary, decreased latencies of generalized seizures in 12-day-old animals. Lack of marked anticonvulsant effect is probably due to relative maturity of neurons in the brainstem where the generator of generalized seizures is localized. Age- and dose-specific suppression of the tonic phase needs further analysis.
- MeSH
- antikonvulziva farmakologie MeSH
- bumetanid farmakologie MeSH
- epilepsie tonicko-klonická chemicky indukované metabolismus prevence a kontrola MeSH
- GABA metabolismus MeSH
- inhibitory Na-K-Cl symportérů farmakologie MeSH
- krysa rodu Rattus MeSH
- modely nemocí na zvířatech MeSH
- pentylentetrazol MeSH
- potkani Wistar MeSH
- reakční čas MeSH
- rodina nosičů rozpuštěných látek 12, člen 2 MeSH
- sodík-draslík-chloridové symportéry účinky léků metabolismus MeSH
- stárnutí MeSH
- věkové faktory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antikonvulziva MeSH
- bumetanid MeSH
- GABA MeSH
- inhibitory Na-K-Cl symportérů MeSH
- pentylentetrazol MeSH
- rodina nosičů rozpuštěných látek 12, člen 2 MeSH
- Slc12a2 protein, rat MeSH Prohlížeč
- sodík-draslík-chloridové symportéry MeSH
Status epilepticus (SE) in developing rats leads to neuronal degeneration in many brain structures including neocortex but the functional consequences of cortical damage were studied only exceptionally. Lithium-pilocarpine SE was elicited in 12- (P12) and 25-day-old (P25) rats, convulsions were interrupted after 2h by paraldehyde. Cortical electrodes were implanted 3, 6, 9, 13 and/or 26 days after SE. Low-frequency stimulation of sensorimotor cortex was repeated with at least 10-min intervals with a stepwise increasing intensity (0.2-14 mA). Thresholds for movements elicited by stimulation, spike-and-wave afterdischarges (ADs), clonic seizures, mixed ADs (transition into a limbic type of ADs) and recurrent ADs as well as duration of ADs were evaluated. The first three phenomena were not influenced by SE with the exception of lower thresholds for movements during stimulation. Transition into limbic seizures and recurrent seizures were delayed in both age groups and threshold intensities for limbic ADs were at some intervals higher in SE than in control animals. Duration of ADs was changed only at short intervals after SE; it was shortened at 3 and 6 days in P25 and 3 days in P12 rats, respectively. P12 group then exhibited a transient increase in duration of ADs 6 days after SE. Our results did not prove a higher cortical excitability after SE in either age group. On the contrary, there were some signs of a decreased excitability.
- MeSH
- elektrická stimulace MeSH
- elektroencefalografie MeSH
- epilepsie tonicko-klonická patofyziologie MeSH
- konvulzíva MeSH
- krysa rodu Rattus MeSH
- lithiumkarbonát MeSH
- longitudinální studie MeSH
- mozková kůra patofyziologie MeSH
- pilokarpin MeSH
- pohyb fyziologie MeSH
- pohybová aktivita fyziologie MeSH
- potkani Wistar MeSH
- stárnutí fyziologie MeSH
- status epilepticus chemicky indukované patofyziologie psychologie MeSH
- záchvaty patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- konvulzíva MeSH
- lithiumkarbonát MeSH
- pilokarpin MeSH
Patients suffering form epilepsy have an increased risk for fractures. Beside fractures caused by fall or accident muscles forces alone generated during tonic-clonic seizure can result in severe musculoskeletal injury. Contractions of strong paraspinal muscles can lead to compression fracture of the mid-thoracic spine. We report a patient who had suffered from a tonic-clonic seizure during early morning hours. After a cracking sound the patient woke up in a state of post-ictal disorientation, loss of urine and tongue bite. He was admitted to our facilities with the suspected vertebral fracture albeit he just reported of mild lower back pain. Native X-rays and computer-tomography scans showed instable burst fractures of L2 and L4. The fractures were stabilised with a dorsally instrumented internal fixator from L1 to L5 followed by hemi-laminectomy and ventral spondylodesis. Muscle force alone can result in severe skeletal trauma including vertebral fractures. This example emphasizes the importance of critical examination of patients after grand mal seizures. Seizures-induced injuries can appear clinically asymptomatic and can easily be overseen due to absence of trauma and post-ictal impairment of consciousness.
The anticonvulsant action of two neuroactive steroids, 3alpha-hydroxy-5beta-pregnan-20-one (pregnanolone) and triethylammonium 3 alpha-hydroxy-20-oxo-5 alpha-pregnan-21-yl hydrogensuccinate (THDOC-conjugate), was tested against motor seizures induced by pentetrazol in immature rats. Five age groups (7, 12, 18 and 25 days old and adult rats) were pretreated with the steroids in doses from 2.5 to 40 mg/kg i.p. Twenty minutes later pentetrazol (100 mg/kg s.c.) was administered. Minimal seizures (clonic seizures of head and forelimb muscles with preserved righting ability) could be induced in the three older age groups. They were suppressed by pregnanolone in all these tested groups (this effect was best expressed in 18-day-old rats and decreased with age), whereas significant changes in THDOC-conjugate-pretreated animals appeared only in 18-day-old rats. Generalized tonic-clonic seizures were suppressed by both neuroactive steroids in all age groups, this effect being more marked with pregnanolone and again decreased with age. The 7- and 12-day-old rats exhibited higher sensitivity of the tonic phase so that generalized clonic seizures were observed. Duration of the effect was studied in 12- and 25-day-old animals; it was substantially shorter in the older rats than in 12-day-old animals. Both drugs exhibited an anticonvulsant action in developing rats but, unfortunately, their effect was only shortlasting.
- MeSH
- anestetika farmakologie MeSH
- deoxykortikosteron analogy a deriváty farmakologie MeSH
- epilepsie generalizovaná chemicky indukované farmakoterapie MeSH
- epilepsie tonicko-klonická chemicky indukované farmakoterapie MeSH
- konvulzíva MeSH
- krysa rodu Rattus MeSH
- novorozená zvířata MeSH
- pentylentetrazol MeSH
- potkani Wistar MeSH
- pregnanolon farmakologie MeSH
- věkové faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anestetika MeSH
- deoxykortikosteron MeSH
- konvulzíva MeSH
- pentylentetrazol MeSH
- pregnanolon MeSH
- tetrahydrodeoxycorticosterone MeSH Prohlížeč
