Lower Seizure Threshold Research Articles

Astaxanthin Attenuates Neuroinflammation in Status Epilepticus Rats by Regulating the ATP-P2X7R Signal.

BackgroundAs a life-threatening neurological emergency, status epilepticus (SE) is often refractory to available treatment. Current studies have shown a causal role of neuroinflammation in patients with lower seizure thresholds and driving seizures. The ATP-gated purinergic P2X7 receptor (P2X7R) is mainly expressed on the microglia, which function as gatekeepers of inflammation. Although emerging evidence has demonstrated significant anti-inflammatory effects of astaxanthin (AST) in SE, the associated mechanism remains unclear. Therefore, this study aimed to clarify the effects of AST on P2X7R-related inflammation in SE.MethodsSE was induced in rats using lithium–pilocarpine, and AST was administered 1 h after SE induction. Rat microglia were treated with lipopolysaccharide (LPS), AST, ATP, 2,3-O-4-benzoyl-4-benzoyl-ATP (BzATP) and oxidized ATP (oxATP). The Morris water maze, immunohistochemistry, and Nissl staining were performed in rats. Expressions of P2X7R and inflammatory cytokines (such as cycloxygenase-2 (Cox-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)) were detected using real-time polymerase chain reaction (RT-PCR) and Western blot (WB) both in rats and microglia. ATP concentration in the microglia was evaluated using ELISA.ResultsThe AST alleviated hippocampal injury and improved cognitive dysfunction induced by SE. AST also effectively inhibited inflammation and downregulated P2X7R expression in both rat brain and microglia. The results also showed that AST reduced the extracellular ATP levels and that P2X7R expression could be increased by extracellular ATP. In addition, BzATP upregulates the expression of P2X7R and inflammatory factors in microglia. Conversely, it downregulates the expression of P2X7R and inflammatory factors.ConclusionOur study suggests that AST attenuated ATP-P2X7R mediated inflammation in SE.

Myoclonus-dystonia (DYT11, DYT-SGCE) - a channelopathy?

Kaczyńska et al. reported a family with myoclonus-dystonia (M-D) caused by a truncating SGCE mutation, in which two members had epilepsy. Further, patients had mild psychiatric and developmental deficits. Characteristic motor features of M-D include myoclonus, dystonia and tremor. A wide range of additional disease manifestations are known. A few patients with M-D have seizures. Altered neuronal excitability has been found in the pathogenesis of M-D. This may explain the partial effectiveness of antiepileptics and a lower seizure threshold, and could encourage trials of other membrane stabilisers. Careful clinical observations of seemingly well-known diseases remain important.

Nontraumatic Pediatric Intracerebral Hemorrhage.

Nontraumatic Pediatric Intracerebral Hemorrhage.

Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy

Mutations in the GAP activity toward RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2 and NPRL3) have been associated with focal epilepsy and focal cortical dysplasia (FCD). GATOR1 functions as an inhibitor of the mTORC1 signalling pathway, indicating that the downstream effects of mTORC1 deregulation underpin the disease. However, the vast majority of putative disease-causing variants have not been functionally assessed for mTORC1 repression activity. Here, we develop a novel in vitro functional assay that enables rapid assessment of GATOR1-gene variants. Surprisingly, of the 17 variants tested, we show that only six showed significantly impaired mTORC1 inhibition. To further investigate variant function in vivo, we generated a conditional Depdc5 mouse which modelled a ‘second-hit’ mechanism of disease. Generation of Depdc5 null ‘clones’ in the embryonic brain resulted in mTORC1 hyperactivity and modelled epilepsy and FCD symptoms including large dysmorphic neurons, defective migration and lower seizure thresholds. Using this model, we validated DEPDC5 variant F164del to be loss-of-function. We also show that Q542P is not functionally compromised in vivo, consistent with our in vitro findings. Overall, our data show that mTORC1 deregulation is the central pathological mechanism for GATOR1 variants and also indicates that a significant proportion of putative disease variants are pathologically inert, highlighting the importance of GATOR1 variant functional assessment.

Oligodendrocyte Kir4.1 Channels Clear Out Congested K.

Oligodendrocytes Control Potassium Accumulation in White Matter and Seizure Susceptibility.Larson VA, Mironova Y, Vanderpool KG, Waisman A, Rash JE, Agarwal A, Bergles DE. Elife. 2018 Mar 29;7. pii: e34829. doi:10.7554/eLife.34829.The inwardly rectifying K+ channel Kir4.1 is broadly expressed by central nervous system glia and deficits in Kir4.1 lead to seizures and myelin vacuolization. However, the role of oligodendrocyte Kir4.1 channels in controlling myelination and K+ clearance in white matter has not been defined. Here, we show that selective deletion of Kir4.1 from oligodendrocyte progenitors or mature oligodendrocytes did not impair their development or disrupt the structure of myelin. However, mice lacking oligodendrocyte Kir4.1 channels exhibited profound functional impairments, including slower clearance of extracellular K+ and delayed recovery of axons from repetitive stimulation in white matter, as well as spontaneous seizures, a lower seizure threshold, and activity-dependent motor deficits. These results indicate that Kir4.1 channels in oligodendrocytes play an important role in extracellular K+ homeostasis in white matter and that selective loss of this channel from oligodendrocytes is sufficient to impair K+ clearance and promote seizures.

Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies

BackgroundThe seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that lowers seizure threshold and may also enhance epileptogenesis. In this study, three patients diagnosed with SZT2‐related developmental and epileptic encephalopathies (DEEs) were reviewed aiming to expand knowledge of the genotype and phenotype of SZT2 mutations.MethodsTargeted next‐generation sequencing was performed to identify pathogenic mutations in 205 cases with DEEs of unknown etiology. Detailed clinical and genetic data were collected from SZT2‐associated patients.ResultsFour novel mutations were found (c.1626 + 1G>A, c.5772dupA, c.4209C > A, c.7307_7308insG) in three patients. All the variants were inherited from their parents. Two patients were siblings and harbored the same mutations and presented developmental delay prior to the onset of seizures. All the individuals were diagnosed as DEEs, drug refractory epilepsy, and experienced status epilepticus (SE); one patient died of SE. One subject showed subependymal nodules as similar as those of tuberous sclerosis complex (TSC) in cranial magnetic resonance imaging (MRI).ConclusionOur results expand the genotype and phenotypes of SZT2‐related DEEs, suggesting that SZT2 mutations play a role in developmental delay and epileptic encephalopathy, with high susceptibility to SE and relatively specific MRI findings.

Dexmedetomidine infusions and phenobarbital in the treatment of an unusual presentation of benzodiazepine-resistant alcohol withdrawal

Background: Alcohol withdrawal is a life-threatening condition characterized by a myriad of physiologic changes including tachycardia, hypertension, lowered seizure threshold, hallucinations, and potential for delirium tremens. Benzodiazepines remain the gold standard for treatment of alcohol withdrawal, although few studies have compared barbiturates to benzodiazepines as first-line treatment. Methods: This study is a single patient chart review. Results: Over the course of his hospital stay, in addition to receiving a continuous infusion of dexmedetomidine, the patient received a total of 389 mg lorazepam, 650 mg phenobarbital, 40 mg haloperidol, 25 mg quetiapine, 5 mg midazolam, and 75 mg diphenhydramine. Conclusion: Phenobarbital is an effective first line agent for management of alcohol withdrawal and may be a safer and more effective treatment with lower rates of intubation and shorter hospital stays than benzodiazepines. It is particularly successful in patients who require high doses of benzodiazepines or ICU admission. Furthermore, the role of dexmedetomidine infusions in alcohol withdrawal remains unclear but may play a critical role in mitigating tachycardia and hypertension though it poses a risk of bradycardia and hypotension. Keywords: Alcohol withdrawal, Dexmedetomidine, Precedex, Phenobarbital, Ativan, Lorazepam, CIWA, GABA channel.

Protective effect of minocycline on LPS-induced mitochondrial dysfunction and decreased seizure threshold through nitric oxide pathway

Lipopolysaccharide (LPS) increases inflammatory cytokines of the brain and deregulates the mitochondrial function, thus could increase the seizure susceptibility. Studies have shown that minocycline has neuroprotective and antioxidant properties. In this study, we aimed to evaluate the anticonvulsant properties of minocycline in LPS-treated animals and the possible involvement of nitric oxide and mitochondrial pathways. In a PTZ model of seizure in mice, minocycline was administrated to LPS-treated mice. Then followed by co-injection of its sub-effective dose and NOS inhibitors including 7-Nitroindazole (7-NI), aminoguanidine (AG) and L-NG-Nitroarginine methyl ester (L-NAME) to evaluate the changes in seizure threshold and the possible involvement of nitrergic system. Molecular assessments were used to evaluate the effects of each treatment on inflammation and mitochondrial function in the brain. LPS-treated animals had lower seizure threshold compared to intact animals; injection of minocycline (80 mg/kg) to LPS-treated mice reversed this effect. Co-injection of sub-effective doses of minocycline (40 mg/kg) and L-NAME to LPS-treated animals significantly increased seizure threshold. We observed that co-treatment of minocycline and AG dissimilar to 7-NI could increase the seizure threshold of LPS-treated animals. L-arginine reversed the anticonvulsant effect of minocycline. Also, molecular evaluations showed that LPS could increase the ATP levels, GSH levels, and reactive oxygen species formation. However, minocycline at both doses significantly reversed the effect of LPS. Minocycline counteracts the proconvulsant effects of LPS through regulating of mitochondrial function and decreasing of neuro-inflammation. Also, co-administration of minocycline and i-NOS inhibitors could intensify anticonvulsant effects of minocycline.

Seizures in Premature Infants Born at Less than 28 Weeks’ Gestation

Background: The incidence of seizures in the neonatal period is thought to be high due to a lower seizure threshold of the immature brain. Data on seizures in extremely premature infants are scarce. Objectives: The aim of this study was to determine whether seizures are an independent risk factor for in-hospital death and to determine the incidence of seizures in extremely premature infants. Methods: This was a retrospective cohort study. Included were infants born under 28 weeks’ gestation and monitored with amplitude-integrated electroencephalography (aEEG) over the first 3 days of life. The number and duration of seizures was retrieved from aEEG recordings together with clinical data. The association of seizures and other parameters with mortality was assessed using univariable analyses methods. Relevant parameters were used for a multivariable Cox regression analysis. Results: Overall, 229 infants were included in the study. Forty-six infants had at least one seizure episode yielding an incidence of 20%. In univariable analyses, gestational age (p < 0.001), birthweight Z-score (p < 0.001), seizures (p = 0.025), suppressed background aEEG (p < 0.001), and severe intraventricular hemorrhage (IVH; p < 0.001) were associated with death before discharge. In multivariable analysis, gestational age (HR = 0.61, p < 0.001), background aEEG activity (HR = 0.30, p < 0.001), birth weight Z-score (HR = 0.51, p = 0.04), and severe IVH (HR = 2.60, p < 0.001) were found to be significant predictors of mortality while the presence of seizures in the first 3 days of life trended to significantly predict an increased risk of mortality (HR = 1.53, p = 0.09). Conclusions: Although seizure incidence was relatively high in this cohort of extremely preterm infants and infants with seizures were more likely to die, seizures alone are not a predictor for early death. However, they may be an important indicator of pathologies that are not immediately diagnosed yet could eventually lead to death among this vulnerable population.

Antipsychotics for the treatment of sympathomimetic toxicity: A systematic review

ObjectiveBenzodiazepines are often recommended first-line for management of cocaine and amphetamine toxicity while antipsychotic treatment is discouraged due to the potential for lowering seizure threshold, prolonging the QT interval, and decreasing heat dissipation. We performed a systematic review including animal and human studies to elucidate the efficacy and safety of antipsychotics in managing sympathomimetic toxicity specifically evaluating the effect of treatment on mortality, seizures, hyperthermia, and cardiovascular effects. MethodsWe searched MEDLINE, Embase, BIOSIS Previews, Web of Science, Scopus, CENTRAL and gray literature from inception to 31 May 2017 to answer: Can antipsychotics be used safely and effectively to treat cocaine or amphetamine toxicity? Citations were screened by title and abstract. Additional citations were identified with citation tracking. Data were extracted from full-texts. Results6539 citations were identified; 250 full-text articles were assessed. Citation tracking identified 2336 citations; 155 full texts were reviewed. Seventy-three papers were included in this review. In 96 subjects with cocaine toxicity treated with an antipsychotic, there were three deaths, two cardiac arrests, two seizures, and one episode of hyperthermia. In 330 subjects with amphetamine toxicity treated with an antipsychotic, there were two episodes of coma and QT prolongation and one episode of each: hypotension, NMS, cardiac arrest, and death. ConclusionThis systematic review represents an exhaustive compilation of the available evidence. There is neither a clear benefit of antipsychotics over benzodiazepines nor a definitive signal of harm noted. We encourage clinicians to adapt treatment based on specific circumstances and characteristics of their individual patients.

Synthesis and Anticonvulsant Activity of α-Amino Acid Amide Derivatives

Background: Epilepsy is a disease of the central nervous system that affects approximately 50 million individuals worldwide. Although several new drugs have been marketed in the last 25 years, almost one-third of patients are not protected. In many cases, currently available drugs produce undesirable side effects. As a result, a need exists for novel anticonvulsants with unique mechanisms of action and minimal side effects. Methods: A mixed anhydride coupling procedure and standard deprotection procedures were utilized to prepare 36 α-amino acid amides. All final products were evaluated in mice and rats utilizing a standard battery of anticonvulsant tests. Results: α-Amino acids containing a 2,6-dimethylanilide group exhibited anticonvulsant activity in the maximal electroshock seizure test and 6 Hz test in mice and rats. A small, branched-chain on the α- carbon generally maintained or enhanced anticonvulsant activity in the maximal electroshock seizure test. The (R)-α-amino acid amides were typically more potent and slightly more neurotoxic than the corresponding (S)-enantiomers. The valine dimethylanilide (R)-42 was highly active in the MES test in mice (ED50 = 3.6mg/kg) and rats (ED50 = 3.8 mg/kg). (R)-42 also demonstrated excellent anticonvulsant activity in the 6 Hz, picrotoxin, and corneal kindled mouse tests. Furthermore, (R)-42 did not lower seizure threshold when evaluated in the intravenous metrazol seizure test. Conclusion: α-Amino acid 2,6-dimethylanilides exhibited potent activity in a variety of anticonvulsant tests in mice and rats. The valine derivative (R)-42 represents a promising compound for potential use in complex partial seizures.

SZT2 mutation in a boy with intellectual disability, seizures and autistic features

The seizure threshold 2 (SZT2) gene has been shown to confer a low seizure threshold and may enhance epileptogenesis in mice. However, its biological function is still not known. Mutations in SZT2 have been reported in very few patients and features range from mild to moderate intellectual disability without seizures to severe intellectual disability with epileptic encephalopathies with severe developmental delay. Here, we report a six-year-old boy with a novel homozygous mutation in SZT2 gene with intellectual disability, seizures, absent speech and autistic features. We are reporting the first patient with autistic features including very little or no eye contact, arm flapping and repetitive behaviour.

Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy

Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures.

Monophosphoryl Lipid A and Pam3Cys Prevent the Increase in Seizure Susceptibility and Epileptogenesis in Rats Undergoing Traumatic Brain Injury.

Five percent of all epilepsy cases are attributed to traumatic brain injury (TBI), which are known as post-traumatic epilepsy (PTE). Finding preventive strategies for PTE is valuable. Remarkable feature of TBI is activation of microglia and subsequent neuroinflammation, which provokes epileptogenesis. The toll-like receptor agonists monophosphoryl lipid A (MPL) and tri-palmitoyl-S-glyceryl-cysteine (Pam3Cys) are safe, well-tolerated and effective adjuvants existing in prophylactic human vaccines. We examined the impact of early injection of MPL and Pam3Cys to rats, on the rate of kindled seizures acquisition following TBI. Rats received a single dose (1µg/rat) of MPL or Pam3Cys through intracerebroventricular injection. 5days later, trauma was exerted to temporo-parietal cortex of rats by controlled cortical impact device. After 24h, traumatic rats underwent amygdala kindling. Brain level of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) was also measured in traumatic rats by immunoblotting. Compared to non-traumatic (sham-operated) rats, traumatic rats showed three times lower seizure threshold (133 ± 5µA vs. 416.3 ± 16µA, p < 0.001); about three times less number of stimuli to become kindled (5 ± 1 vs. 14 ± 2, p < 0.01); longer duration of kindled seizure parameters including entire seizure behavior, generalized seizures, and afterdischarges (p < 0.001); and a two times increase in the TNF-α level. MPL and Pam3Cys did not change kindling rate and the seizure parameters in sham-operated rats. The MPL- and Pam3Cys-pretreated traumatic rats displayed seizure threshold, speed of kindling, and duration of kindled seizure parameters, similar to the non-traumatic rats. Pretreatment by MPL and Pam3Cys prevented the increase in TNF-α level by trauma. Given that MPL and Pam3Cys currently have clinical use as well-tolerated vaccines with reliable safety, they have the potential to be used in prevention of PTE.

Review: Pharmacotherapy for smoking cessation

Smoking is associated with numerous cancers and atherosclerosis. Smoking cessationhas substantial potential in reducing morbidity and mortality worldwide. The initial steps “5 A’s”(Ask, Advise, Assess, Assist, Arrange) should be applied in all patients. Behavioral counselingand pharmacotherapy are both effective, but the combination of the two is more effective thaneither alone. The first-line pharmacotherapy includes nicotine replacement, bupropion, andvarenicline. Nicotine replacement therapy (NRT) consists of long-active formulations, such asin a patch, and short-acting formulations such as in gum, lozenge, inhaler, and nasal spray. Ascompared to placebo, NRT increases the chances of quitting smoking. Nicotine replacementtherapy does not increase cardiovascular risk and is safe in patients with cardiovasculardisease. Sustained-release bupropion is more effective than nicotine patches and can becombined with nicotine patches. Buprenorphine is generally well tolerated, except that it lowersseizure threshold and is contraindicated in patients with seizure disorders. Varenicline alsosignificantly improves the success rate of smoking cessation. The latest evidence suggeststhat varenicline is not associated with an increased risk of neuropsychiatric or cardiovascularevents. In conclusion, the use of NRT (nicotine patch + nicotine gum/lozenge/inhaler/spray),bupropion (with NRT), or varenicline is strongly recommended for smoking cessation, unlessthey are contraindicated.

To reveal or conceal? Adult patient perspectives on SUDEP disclosure

ObjectiveThe study aimed to evaluate adult patient or caregiver feelings and viewpoints about sudden unexpected death in epilepsy (SUDEP) awareness. BackgroundThe decision to discuss SUDEP with patients and families has created much debate. Many healthcare providers (HCPs) are hesitant to discuss SUDEP because of the perception of evoking unnecessary fear in patients while others argue that informing patients about SUDEP may enhance patient compliance, improve seizure control, and aid in saving lives. This study quantifies patient viewpoints regarding their right to information, requirements of disclosure, and initial responses of fear and patient motivation toward behavioral change. Design/methodsThis was a prospective random sample survey of adult patients with epilepsy or their caregivers. Every third eligible adult patient with epilepsy or caregiver was given a one-page SUDEP information sheet promoted by the Epilepsy Foundation of America. Participants were then asked if they were interested in completing an eight-item questionnaire assessing their perception of the information. ResultsNinety-four of ninety-six subjects completed the survey (98%). One hundred percent (n = 94) of responders felt they had a right to be informed about SUDEP, and 95% felt that their HCP should be required to inform them. Respondents also indicated that SUDEP awareness motivated them for better medication adherence (89%) and management of lifestyle factors that lower seizure threshold (88%). Thirty percent endorsed increased fear. However, 100% of those patients or caregivers who endorsed fear still felt it was their right to be informed. Patients who endorsed fear were also more likely to be interested in nonpharmacologic treatment options as a result of SUDEP disclosure. ConclusionsPatients and caregivers feel it is their right to be informed about SUDEP, irrespective of evoked fear. The vast majority of participants endorsed a requirement for HCPs to disclose related information. While some participants endorsed fear, most agreed that SUDEP awareness motivated them to better manage factors that trigger seizures. Patient education regarding SUDEP may play a key role in encouraging modifying lifestyle factors that lower seizure threshold and facilitate more aggressive interventions in patients with pharmacoresistant epilepsy.

Genetic Modulation of HSPA1A Accelerates Kindling Progression and Exerts Pro-convulsant Effects

Strong evidence exists that Toll-like receptor (TLR)-mediated effects on microglia functional states can promote ictogenesis and epileptogenesis. So far, research has focused on the role of high-mobility group box protein 1 as an activator of TLRs. However, the development of targeting strategies might need to consider a role of additional receptor ligands.Considering the fact that heat shock protein A1 (hsp70) has been confirmed as a TLR 2 and 4 ligand, we have explored the consequences of its overexpression in a mouse kindling paradigm. The genetic modulation enhanced seizure susceptibility with lowered seizure thresholds prior to kindling. In contrast to wildtype (WT) mice, HSPA1A transgenic (TG) mice exhibited generalized seizures very early during the kindling paradigm. Along with an increased seizure severity, seizure duration proved to be prolonged in TG mice during this phase. Toward the end of the stimulation phase seizure parameters of WT mice reached comparable levels. However, a difference between genotypes was still evident when comparing seizure parameters during the post-kindling threshold determination.Surprisingly, HSPA1A overexpression did not affect microglia activation in the hippocampus.In conclusion, the findings demonstrate that hsp70 can exert pro-convulsant effects promoting ictogenesis in naïve animals. The pronounced impact on the response to subsequent stimulations gives first evidence that genetic HSPA1A upregulation may also contribute to epileptogenesis. Thus, strategies inhibiting hsp70 or its expression might be of interest for prevention of seizures and epilepsy. However, conclusions about a putative pro-epileptogenic effect of hsp70 require further investigations in models with development of spontaneous recurrent seizures.

T18. High dose phenobarbital is safe and effective treatment for SCN2A related epilepsy

Introduction Voltage-gated sodium channels play major role in neuronal excitability. Nav1.1, Nav1.2, Nav1.3 and Nav1.6 sodium channels found in the brain differ in α -subunits, encoded by SCN1A, SCN2A, SCN3A, and SCN8A genes respectively. NaV1.2 Channels is the only sodium channel expressed during early development at nodes of Ranvier and in the axon initial segment (AIS) in developing and mature neurons, particularly cortical glutamatergic pyramidal cells. NaV1.2 channel has relatively high exictation threshold. NaV1.2 is regulated developmentally by alternative splicing to produce ‘neonatal’ and ‘adult’ isoforms. ‘Neonatal’ form is less excitable than ‘adult’ conferring reduced neuronal excitability and seizure susceptibility. Most dominantly inherited missense genetic variants of NaV1.2 manifests as familial epilepsy while de novo mutations as severe epileptic encephalopathy, both have gain of function with increased excitability and lowered seizure threshold. Cortical pyramidal neurons AIS receives exclusively inhibitory GABA-ergic input from specific set of interneurons called chandelier cells. Methods A FT, WF child born via planned caesarian to a healthy 27 yr G2P2A0L2 with APGAR 8, 9 at 1, 5 min at OSH. On DOL 2, developed seizure manifested as chocking, left arm forced flexion with leftward head deviation, right arm extension evolve into whole body jerking with apnea. Ictal EEG documented left frontal-temporal onset focal seizure. She received two loading doses of Phenobarbital followed by maintenance of 5 mg/kg/day. At therapeutic level of 44 mcg/ml, seizures remained under controlled. On DOL 22, presented to OSH with right arm twitching. Random PHB level was 27.5 mcg/ml. She received load of PHB and Levetiracetam 20 mg/kg each. Seizures continued overnight leading to transfer to our institute. Patient physcial and neurologic exam was normal. Ictal EEG re-demonstrated left central onset rhythmic spike-wave seizure evolution pattern clinically manifesting wide-eyed gaze with right face and upper extremity clonic jerking. Patient received total dose of 40 mg/kg of levetiracetam without improvement. Later, two 10 mg/kg doses of PHB given at couple of hours interval stopped seizures. Maintenance dosing of PHB was increased to 6 mg/kg/day. PHB level obtained was 54.2mcg/ml. It was tolerated well without sedation, hypotonia or adverse effects. She has been weaned off PHB at 7 months of age and has been seizure free with normal development at 14 months of age. Gene DX Comprehensive Epilepsy Panel revealed pathogenic variant of the SCN2A gene (p. Val261Met). Results We described infant with de novo SCN2A mutation presenting as benign familial neonatal infantile epilepsy well controlled with high therapeutic phenobarbital level without experiencing adverse side effects. Conclusion Phenobarbital at very high therapeutic level exerted seizure control probably via inhibitory effects of Chanderlier cell counterbalancing increased excitability of genetic missense variant of NaV1.2 at the AIS.

A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice

Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study’s in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1–11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice.

Oligodendrocytes control potassium accumulation in white matter and seizure susceptibility.

The inwardly rectifying K+ channel Kir4.1 is broadly expressed by CNS glia and deficits in Kir4.1 lead to seizures and myelin vacuolization. However, the role of oligodendrocyte Kir4.1 channels in controlling myelination and K+ clearance in white matter has not been defined. Here, we show that selective deletion of Kir4.1 from oligodendrocyte progenitors (OPCs) or mature oligodendrocytes did not impair their development or disrupt the structure of myelin. However, mice lacking oligodendrocyte Kir4.1 channels exhibited profound functional impairments, including slower clearance of extracellular K+ and delayed recovery of axons from repetitive stimulation in white matter, as well as spontaneous seizures, a lower seizure threshold, and activity-dependent motor deficits. These results indicate that Kir4.1 channels in oligodendrocytes play an important role in extracellular K+ homeostasis in white matter, and that selective loss of this channel from oligodendrocytes is sufficient to impair K+ clearance and promote seizures.