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The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62·0% vs 136·9%, 75% decrease, 95% CI 42.4–107.4%; p<0·0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0·0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0·0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger. The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.

A previous report showed that the use of caffeine to treat apnea of prematurity reduces the risk of bronchopulmonary dysplasia, but whether it has long-term effects on neurodevelopment and growth is unknown. In this placebo-controlled, randomized trial, treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Treatment with caffeine significantly improved the rate of survival without neurodevelopmental disability at 18 to 21 months. Apnea of prematurity is one of the most common reasons for the initiation of drug therapy in neonatal medicine. 1 The methylxanthines — aminophylline, theophylline, and caffeine — have been administered to preterm infants as respiratory stimulants for more than 30 years. 2 Caffeine is presently one of the 10 most frequently prescribed medications in neonatal intensive care. 1 Despite their widespread use, caffeine and the other methylxanthines have been evaluated in only a few small, short-term studies. 3 – 5 It has been uncertain whether these drugs might adversely affect the development of the preterm brain and of other organs. Methylxanthines are inhibitors of . . .

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model ( Scn1a   Stop/+ ) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Na v 1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells. Dravet syndrome is a devastating epileptic encephalopathy caused by Scn1a gene haploinsufficiency. Exploiting a novel knock-in mouse model, here the authors show that restoring Scn1a expression after symptom onset is sufficient to rescue main phenotypic manifestations of the syndrome.

Introduction Intracerebral hemorrhage (ICH) is associated with a risk of early seizure and guidelines recommend consideration of prophylactic antiepileptic drugs (AEDs) for some patients, although the utility is uncertain. Methods We analyzed data from the placebo arm of the Cerebral Hemorrhage and NXY-059 Trial (CHANT), an international multicenter randomized trial of a potential neuroprotectant that enrolled patients within 6 h of the onset of acute ICH. Logistic regression analyses were performed to determine whether early AED use was associated with poor outcome at day 90, defined as a modified Rankin Scale of 5 or 6 (severely disabled or dead). Results Excluding patients who were previously on AEDs, the primary analysis included 295 patients. The median ICH volume at admission was 14.9 (interquartile range, IQR 7.9–32.7) ml and the mean was 23.3 (±SD 22.8) ml. Seizures occurred in 5 patients (1.7%) after enrollment and 82 patients (28%) had a poor outcome at day 90. AEDs were initiated on 23 patients (8%) without documented seizure during the first 10 days of the trial. In logistic regression, initiation of AEDs was robustly associated with poor outcome (OR 6.8; 95% CI: 2.2–21.2, P  = 0.001) after adjustment for other known predictors of outcome after ICH (age, initial hematoma volume, presence of intraventricular blood, initial Glasgow coma score, and prior warfarin use). Conclusions In this clinical trial cohort, seizures were rare after the first few hours following ICH. In addition, prophylactic AED use was associated with poor outcome independent of other established predictors. Given the potential for residual confounding in this cohort, a randomized trial needs to be performed.

Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Objective This study evaluates the potential protective effects of statins against epilepsy, focusing on their differential impacts on focal and generalized epilepsy. It investigates the role of statins through the HMGCR gene and associated low‐density lipoprotein (LDL) cholesterol levels. Methods A two‐sample Mendelian randomization (MR) and summary‐data‐based MR (SMR) approach were employed using genetic instruments from genome‐wide association studies (GWASs) and expression quantitative trait loci (eQTLs). Subgroup analyses examined focal and generalized epilepsy, with sensitivity tests, including MR‐Egger regression and MR‐PRESSO, to assess horizontal pleiotropy and robustness. Results SMR analysis found no significant association between HMGCR expression and epilepsy risk across subtypes (p > 0.05). However, inverse‐variance‐weighted MR (IVW‐MR) showed that elevated LDL cholesterol mediated by HMGCR was linked to an increased risk of focal epilepsy (OR = 1.251, 95% CI = 1.135–1.378). No such association was observed for generalized epilepsy. Statins showed promise in reducing post‐stroke epilepsy risk, likely through anti‐inflammatory and neuroprotective effects. Significance The findings suggest that statins' protective effects may be subtype‐specific, particularly in post‐stroke focal epilepsy. Further research is needed to elucidate underlying mechanisms and optimize their therapeutic potential in epilepsy management. Plain Language Summary Statins, drugs typically used to manage cholesterol, may also lower the risk of developing certain types of epilepsy, especially post‐stroke focal epilepsy, by reducing inflammation and protecting brain cells. The research found no clear effect of statins on generalized epilepsy or epilepsy caused by other factors. These results could aid in creating better treatments for epilepsy in the future.

Physiological functioning and homeostasis of the brain rely on finely tuned synaptic transmission, which involves nanoscale alignment between presynaptic neurotransmitter-release machinery and postsynaptic receptors. However, the molecular identity and physiological significance of transsynaptic nanoalignment remain incompletely understood. Here, we report that epilepsy gene products, a secreted protein LGI1 and its receptor ADAM22, govern transsynaptic nanoalignment to prevent epilepsy. We found that LGI1–ADAM22 instructs PSD-95 family membrane-associated guanylate kinases (MAGUKs) to organize transsynaptic protein networks, including NMDA/AMPA receptors, Kv₁ channels, and LRRTM4–Neurexin adhesion molecules. Adam22ΔC5/ΔC5 knock-in mice devoid of the ADAM22–MAGUK interaction display lethal epilepsy of hippocampal origin, representing the mouse model for ADAM22-related epileptic encephalopathy. This model shows less-condensed PSD-95 nanodomains, disordered transsynaptic nanoalignment, and decreased excitatory synaptic transmission in the hippocampus. Strikingly, without ADAM22 binding, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Furthermore, forced coexpression of ADAM22 and PSD-95 reconstitutes nano-condensates in nonneuronal cells. Collectively, this study reveals LGI1–ADAM22–MAGUK as an essential component of transsynaptic nanoarchitecture for precise synaptic transmission and epilepsy prevention.

Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.

Epigenetic modifications, including changes in DNA methylation, lead to altered gene expression and thus may underlie epileptogenesis via induction of permanent changes in neuronal excitability. Therapies that could inhibit or reverse these changes may be highly effective in halting disease progression. Here we identify an epigenetic function of the brain's endogenous anticonvulsant adenosine, showing that this compound induces hypomethylation of DNA via biochemical interference with the transmethylation pathway. We show that inhibition of DNA methylation inhibited epileptogenesis in multiple seizure models. Using a rat model of temporal lobe epilepsy, we identified an increase in hippocampal DNA methylation, which correlates with increased DNA methyltransferase activity, disruption of adenosine homeostasis, and spontaneous recurrent seizures. Finally, we used bioengineered silk implants to deliver a defined dose of adenosine over 10 days to the brains of epileptic rats. This transient therapeutic intervention reversed the DNA hypermethylation seen in the epileptic brain, inhibited sprouting of mossy fibers in the hippocampus, and prevented the progression of epilepsy for at least 3 months. These data demonstrate that pathological changes in DNA methylation homeostasis may underlie epileptogenesis and reversal of these epigenetic changes with adenosine augmentation therapy may halt disease progression.

Background:Single small enhancing CT lesions (SSECTL) of the brain with or without perifocal oedema are common in patients with symptomatic epilepsy in India. Solitary cysticercus granuloma, a benign form of parenchymal neurocysticercosis, is considered to be the most common aetiology for SSECTL. Definite information is lacking regarding the effectiveness of antiparasitic treatment on resolution of these lesions and on long term seizure recurrence.Objective:To evaluate the response to albendazole treatment in patients who had SSECTL and new onset seizures treated with antiepileptic drugs (AED) in a prospective clinical trial.Methods:43 patients who presented with new onset seizures and were documented to have SSECTL were alternatively allocated to receive albendazole 15 mg/kg/day for 2 weeks or no cysticidal therapy. All patients were treated with AED and followed for at least 6 months for seizure recurrence, and serial CT scans were obtained at 4 weeks, 3 months and at study completion.Results:28 (65%) patients were aged 5–25 years and 31 (72%) presented clinically with partial motor seizures with or without generalisation. Most of the SSECTL were ring lesions (75%) and located in and around the sensory–motor cortex at the gray–white junction (65%). In the albendazole group, 56% of patients compared with 35% in the control group showed resolution of SSECTL (p = 0.154) at 1 month. 22 of 23 patients (95.6%), who received albendazole, compared with 14 of 20 patients (70%) in the control group, demonstrated radiological resolution on study completion (p = 0.03). Punctate residual calcification and seizure recurrence were observed in four patients (9.3%) in the control group and in three (7%) patients in the albendazole group (p = 0.47).Conclusions:In patients presenting with seizures due to single viable parenchymal neurocysticercosis, albendazole hastens the resolution of SSECTL if treatment is given in the early phase of the illness.