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Background and purpose Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. Methods A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. Results A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ‐aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. Conclusions These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug‐related adverse events in individuals living with PMD‐related epilepsy.

Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.

Background Electroconvulsive therapy (ECT) is well-established and effective for treatment-resistant depression (TRD), but in Canada and the USA, less than 1% of patients with TRD receive ECT mainly due to its cognitive adverse effects (i.e. amnesia). Thus, new treatment alternatives for TRD are urgently needed. One such treatment is magnetic seizure therapy (MST). ECT involves applying a train of high-frequency electrical stimuli to induce a seizure, whereas MST involves applying a train of high-frequency magnetic stimuli to induce a seizure. Methods In this manuscript, we introduce our international, two-site, double-blinded, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. This trial will compare the efficacy of MST to right unilateral ultra-brief pulse width electroconvulsive therapy (RUL-UB-ECT) with a combined primary endpoint of remission of depression and superior cognitive adverse effects in 260 patients with TRD. Amelioration of suicidal ideation will be assessed as a secondary endpoint. Inpatients or outpatients, over 18 years of age with a MINI International Neuropsychiatric Interview (MINI) diagnosis of non-psychotic major depressive disorder (MDD) can be enrolled in the study provided that they meet illness severity and full eligibility criteria. Participants are randomized to receive MST or RUL-UB ECT, 2-3 days per week over seven weeks, or a maximum of 21 treatments. The study will involve before-, during-, and after-treatment assessments of depression severity, suicidal ideation, subjective side-effects, and cognitive performance consistent with an intent-to-treat study design approach. Discussion Positive results from this trial could have an immediate and tremendous impact for patients with TRD. If MST demonstrates comparable antidepressant treatment efficacy to ECT, but with greater cognitive safety, it could rapidly be adopted into clinical practice. Indeed, given that the administration of MST is nearly identical to ECT, the majority of ECT facilities in North America could readily adopt MST. Furthermore, the potential for cognitive safety could lead to improved treatment acceptability. Healthcare providers, patients and care partners, and policymakers would therefore demand this form of convulsive therapy. Trial status Enrollment for this study began on June 26, 2018, and is estimated to complete recruitment by July 2024. At the time of submission, we have enrolled and randomized 117 participants. Trial registration ClinicalTrials.gov NCT03191058 , Registered on June 19, 2017. Primary sponsor: Daniel Blumberger (DMB), Principal Investigator Daniel.Blumberger@camh.ca, 416-535-8501 x 33662 Contact for public queries: DMB, Daniel.Blumberger@camh.ca Contact for scientific queries: ZJD, Zdaskalakis@health.ucsd.edu

Background Electroconvulsive therapy (ECT) is an important treatment for several severe psychiatric conditions, yet its precise mechanism of action remains unknown. Increased inhibition in the brain after ECT seizures, mediated by γ-aminobutyric acid (GABA), has been linked to clinical effectiveness. Case series on epileptic patients report a postictal serum concentration increase of the GABA A receptor agonist allopregnanolone. Serum allopregnanolone remains unchanged after a full ECT series, but possible transient effects directly after a single ECT seizure remain unexplored. The primary aim was to measure serum concentrations of allopregnanolone and its substrate progesterone after one ECT seizure. Secondary aims were to examine whether concentrations at baseline, or postictal changes, either correlate with seizure generalization or predict clinical outcome ratings after ECT. Methods A total of 130 participants (18–85 years) were included. Generalization parameters comprised peak ictal heart rate, electroencephalographic (EEG) seizure duration, and prolactin increase. Outcome measures were ratings of clinical global improvement, perceived health status and subjective memory impairment. Non-parametric tests were used for group comparisons and correlations. The prediction analyses were conducted with binary logistic and simple linear regression analyses. Results Allopregnanolone and progesterone remained unchanged and correlated neither with seizure generalization nor with clinical outcome. In men ( n  = 50), progesterone increased and allopregnanolone change correlated negatively with EEG seizure duration. In a subgroup analysis ( n  = 62), higher baseline allopregnanolone and progesterone correlated with postictal EEG suppression. Conclusions ECT seizures have different physiologic effects than generalized seizures in epilepsy. Progesterone might have implications for psychiatric illness in men.

The study aims to compare the clinical efficacy and cognitive side effect of magnetic seizure therapy (MST) and modified electroconvulsive therapy (MECT) on clozapine resistant schizophrenia (CRS). Sixteen patients with CRS were enrolled in this randomized, parallel-group, controlled clinical trial. Patients were randomly allocated to receive 10 sessions of add-on MST or MECT over 4 weeks (1:1 ratio) and continued clozapine therapy during the study. Efficacy and neurocognition were assessed at baseline, 4-week and 8-week follow-up. (1) Clinical efficacy: MST significantly improved symptoms of schizophrenia from baseline to 4 weeks, as shown in PANSS total (p = 0.009), PANSS positive (p = 0.026), PANSS negative (p = 0.031) and PANSS general psychopathology (p = 0.023); we also observed significant reductions in PANSS total (p = 0.049) and PANSS positive (p = 0.037) at 8-week follow-up. MECT group also witnessed clinical improvement from baseline to 4-week in PANSS total (p = 0.035) and PANSS positive (p = 0.001); significant reduction in PANSS positive was also observed at 8-week follow-up (p = 0.041). From baseline to 8 weeks, PANSS negative had greater reduction in MST group compared with MECT group (p = 0.042). (2) Neurocognition: Pre-and post-treatment data showed no significant cognitive adverse effects in both groups. Immediate memory is better in patients who received MST than MECT at 4-week follow-up (p = 0.030). In this pilot study, MST and MECT equally improved positive symptoms of CRS, while MST was more effective in relieving negative symptoms. Evidence showed negligible cognitive side effects in MST, with less adverse effect on immediate memory than MECT. As a promising alternative to MECT, MST requires further research in larger clinical population.

Neonatal seizures are one of the most common comorbidities of neonatal encephalopathy, with seizures aggravating acute injury and clinical outcomes. Current treatment can control early life seizures; however, a high level of pharmacoresistance remains among infants, with increasing evidence suggesting current anti-seizure medication potentiating brain damage. This emphasises the need to develop safer therapeutic strategies with a different mechanism of action. The purinergic system, characterised by the use of adenosine triphosphate and its metabolites as signalling molecules, consists of the membrane-bound P1 and P2 purinoreceptors and proteins to modulate extracellular purine nucleotides and nucleoside levels. Targeting this system is proving successful at treating many disorders and diseases of the central nervous system, including epilepsy. Mounting evidence demonstrates that drugs targeting the purinergic system provide both convulsive and anticonvulsive effects. With components of the purinergic signalling system being widely expressed during brain development, emerging evidence suggests that purinergic signalling contributes to neonatal seizures. In this review, we first provide an overview on neonatal seizure pathology and purinergic signalling during brain development. We then describe in detail recent evidence demonstrating a role for purinergic signalling during neonatal seizures and discuss possible purine-based avenues for seizure suppression in neonates.

Background Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood. Methods/design This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity. Discussion ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments. Trial registration ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017.

There is mounting evidence for the role of the gut microbiota and gut–brain interactions in neurological diseases. We present six patients with drug-resistant epilepsy who attained temporary seizure freedom during antibiotic treatment. The effect on seizure frequency waned within 2 weeks after cessation of antibiotic treatment. We hypothesized that antibiotic treatments may have a short-term effect, through gut microbiota disruption, on gut–brain interactions and ultimately seizure frequency. This observed impact of antibiotics on seizure frequency hints at a possible role of the gut microbiota in epilepsy and its manifestations. This begs the question: can epilepsy be treated by antibiotics? Or perhaps in a broader sense: can alterations in the gut microbiota be used as a treatment modality in drug-resistant epilepsy? This concept and the six intriguing cases provide interesting leads for epilepsy management.

A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A1Rs, were reduced if mice expressed reduced A1Rs, and were unaltered if mice lacked A1Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an A1R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine-metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A1R-mediated inhibition.

There is growing evidence that ketone bodies (KB)—derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets—can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.