Disrupted de novo pyrimidine biosynthesis impairs adult hippocampal neurogenesis and cognition in pyridoxine-dependent epilepsy.

Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with ALDH7A1 mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

Comparison of Different Adjuvant Therapies for Hypothermia in Neonates with Hypoxic-Ischemic Encephalopathy: A Systematic Review and Network Meta-Analysis.

OBJECTIVES: Neonatal hypoxic-ischemic encephalopathy is a major cause of perinatal death and neurodevelopmental impairment (NDI). Hypothermia (HT) is the standard of care; however, additional neuroprotective agents are required to improve prognosis. The authors searched for all drugs in combination with HT and compared their effects using a network meta-analysis. METHODS: The authors searched PubMed, Embase, and Cochrane Library until September 24, 2022 for articles assessing mortality, NDI, seizures, and abnormal brain imaging findings in neonates with hypoxic-ischemic encephalopathy. Direct pairwise comparisons and a network meta-analysis was performed under random effects. RESULTS: Thirteen randomized clinical trials enroled 902 newborns treated with six combination therapies: erythropoietin magnesium sulfate, melatonin (MT), topiramate, xenon, and darbepoetin alfa. The results of all comparisons were not statistically significant, except for NDI, HT vs. MT+HT: odds ratio = 6.67, 95% confidence interval = 1.14-38.83; however, the overall evidence quality was low for the small sample size. CONCLUSIONS: Currently, no combination therapy can reduce mortality, seizures, or abnormal brain imaging findings in neonatal hypoxic-ischemic encephalopathy. According to low quality evidence, HT combined with MT may reduce NDI.

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report.

OBJECTIVE: Transcutaneous auricular vagus nerve stimulation (taVNS) was performed in two patients suffering structural focal epilepsy with preserved intellectual ability to show the feasibility of taVNS for specific patient groups. CASE PRESENTATIONS: Patient 1 was a 24-year-old woman with frontal lobe epilepsy who had weekly hyperkinetic seizures despite multiple anti-seizure medications. Patient 2 was a 27-year-old woman with parietal lobe epilepsy and focal cortical dysplasia in the vicinity of the lipoma in the corpus callosum. She experienced weekly focal-impaired awareness seizures even with anti-seizure medication. taVNS was applied to the left earlobe of both patients at 1.5 mA, 25 Hz, 250 µs pulse width, and 30 s stimulation with 30 s rest for 4 h per day. Over an 8-week baseline and 20 weeks of stimulation, the rate of reduction in seizure frequency was evaluated, along with quality-of-life using the Short-Form 36-Item Health survey. RESULTS: At baseline, we measured up to 11 and 12 focal seizures per week in Patient 1 and 2, respectively, with both patients achieving seizure freedom after 4 and 20 weeks taVNS, respectively. Patient 1 and 2 were observed for 18 and 14 months, respectively, including the clinical trial and follow-up observation period. Quality-of-life ratings increased in both patients, and no significant adverse events occurred during the study period. During the maintenance period after 20 weeks, seizures remained absent in Patient 1, and seizures remained reduced in Patient 2. CONCLUSION: Our results demonstrate that taVNS may be a promising tool for structural focal epilepsy with preserved cognitive function. A multicenter double-blind clinical trial is needed to confirm the role of taVNS as an anti-seizure tool.

A randomized controlled trial of loading dose alone versus pritchard regimen of magnesium sulphate, for seizure prophylaxis in severe preeclampsia.

Background: Preeclampsia poses a significant risk of maternal and neonatal morbidity and mortality. Magnesium sulfate superiority for seizure prophylaxis in severe preeclampsia has been proven globally. However, the search for the lowest effective dose is an area of continuing research. Aim: The aim of this study was to compare the effectiveness of loading dose with the Pritchard regimen of magnesium sulfate for seizure prophylaxis in severe preeclampsia. Materials and Methods: A total of 138 eligible women after 28-week gestation with severe preeclampsia were randomized to either receiving a single loading dose of MgSO4 (study arm: n = 69) or Pritchard regimen of MgSO4 (control: n = 69). The effectiveness was assessed by the development of seizure. The results obtained were analyzed using SPSS version 21. Categorical variables were analyzed using the Chi-square test and normally distributed continuous variables were analyzed with t-test and Fisher's exact test. P < 0.05 was considered statistical significance. Results: There were no significant differences between those who received only the loading dose when compared with those who had Pritchard regimen other than a single recorded convulsion among the control group (P = 0.316). Similarly, except for the duration of hospital stay which was significantly longer in the Pritchard group (P = 0.019), both the arms of the study shared similar maternal and fetal outcomes. Conclusion: This study suggests the effectiveness of just the loading dose of magnesium sulfate when compared with the standardized Pritchard regimen in the prevention of seizure among women with severe preeclampsia. The study also demonstrated safety and similarity in fetal-maternal outcome. The loading dose only had an added advantage of shorter duration of hospital stay.

Résumé Contexte: La prééclampsie pose un risque important de morbidité et de mortalité maternelle et néonatale. La supériorité du sulfate de magnésium pour 15 prophylaxies épileptiques dans la prééclampsie sévère a été prouvée à l'échelle mondiale. Cependant, la recherche de la dose efficace la plus faible est un domaine de recherche continue. Objectif: L'objectif de cette étude était de comparer l'efficacité de la dose de charge avec le schéma de Pritchard de sulfate de magnésium pour la prophylaxie de 17 épilepsies dans la prééclampsie sévère. Matériels et méthodes: Un total de 138 femmes éligibles après 28 semaines de gestation atteintes de 18 prééclampsie ont été randomisés pour recevoir soit une dose de charge unique de MgSO4 (groupe d'étude : n = 69) soit un régime de Pritchard de MgSO4 (contrôle : n = 69). L'efficacité a été évaluée par le développement de saisie. Les résultats obtenus ont été analysés à l'aide de SPSS version 21. Les 19 variables catégorielles ont été analysées à l'aide du test du chi carré et les variables continues normalement distribuées ont été analysées à l'aide du test t et du test exact de Fisher. 20 P < 0,05 était considéré comme une signification statistique. Résultats: Il n'y avait pas de différences significatives entre ceux qui n'avaient reçu que la dose de charge 21 par rapport à ceux qui avaient reçu le régime de Pritchard autre qu'une seule convulsion enregistrée parmi le groupe témoin (P = 0,316). 22 De même, à l'exception de la durée du séjour à l'hôpital qui était significativement plus longue dans le groupe Pritchard (P = 0,019), les deux bras de l'étude 23 partageaient des résultats maternels et fœtaux similaires. Conclusion: Cette étude suggère l'efficacité de la seule dose de charge de sulfate de magnésium par rapport au régime de Pritchard standardisé dans la prévention des convulsions chez les femmes atteintes de prééclampsie sévère. L'étude a également démontré 24 l'innocuité et la similarité des résultats fœto-maternels. La dose de charge n'avait qu'un avantage supplémentaire de durée d'hospitalisation plus courte. 25. Mots-clés: Éclampsie, dose de charge, sulfate de magnésium, régime de Pritchard, prophylaxie des crises, prééclampsie sévère.

Characteristics of electroencephalogram changes and correlation with seizures in hospitalised patients.

INTRODUCTION: Electroencephalogram (EEG) is an important investigational tool that is widely used in the hospital settings for numerous indications. The aim was to determine factors associated with abnormal EEG and its clinical correlations in hospitalised patients. MATERIALS AND METHODS: Patients with at least one EEG recording were recruited. The EEG and clinical data were collated. RESULTS: Two hundred and fifty patients underwent EEG and 154 (61.6%) were found to have abnormal EEG. The abnormal changes consist of theta activity (79,31.6%), delta activity (20, 8%), focal discharges (41,16.4%) and generalised discharges (14, 5.6%). Older patients had 3.481 higher risk for EEG abnormalities, p=0.001. Patients who had focal seizures had 2.240 higher risk of having EEG abnormalities, p<0.001. Low protein level was a risk for EEG abnormalities, p=0.003. CONCLUSION: This study emphasised that an abnormal EEG remains a useful tool in determining the likelihood for seizures in a hospital setting. The risk factors for EEG abnormality in hospitalised patients were age, focal seizures and low protein level. The EEG may have an important role as part of the workup in hospitalised patients to aid the clinician to tailor their management in a holistic manner.

Deep Brain Stimulation of the Anterior Nucleus of the Thalamus in Drug-Resistant Epilepsy in the MORE Multicenter Patient Registry.

BACKGROUND AND OBJECTIVES: The efficacy of deep brain stimulation of the anterior nucleus of the thalamus (ANT DBS) in patients with drug-resistant epilepsy (DRE) was demonstrated in the double-blind Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy randomized controlled trial. The Medtronic Registry for Epilepsy (MORE) aims to understand the safety and longer-term effectiveness of ANT DBS therapy in routine clinical practice. METHODS: MORE is an observational registry collecting prospective and retrospective clinical data. Participants were at least 18 years old, with focal DRE recruited across 25 centers from 13 countries. They were followed for at least 2 years in terms of seizure frequency (SF), responder rate (RR), health-related quality of life (Quality of Life in Epilepsy Inventory 31), depression, and safety outcomes. RESULTS: Of the 191 patients recruited, 170 (mean [SD] age of 35.6 [10.7] years, 43% female) were implanted with DBS therapy and met all eligibility criteria. At baseline, 38% of patients reported cognitive impairment. The median monthly SF decreased by 33.1% from 15.8 at baseline to 8.8 at 2 years (p < 0.0001) with 32.3% RR. In the subgroup of 47 patients who completed 5 years of follow-up, the median monthly SF decreased by 55.1% from 16 at baseline to 7.9 at 5 years (p < 0.0001) with 53.2% RR. High-volume centers (>10 implantations) had 42.8% reduction in median monthly SF by 2 years in comparison with 25.8% in low-volume center. In patients with cognitive impairment, the reduction in median monthly SF was 26.0% by 2 years compared with 36.1% in patients without cognitive impairment. The most frequently reported adverse events were changes (e.g., increased frequency/severity) in seizure (16%), memory impairment (patient-reported complaint, 15%), depressive mood (patient-reported complaint, 13%), and epilepsy (12%). One definite sudden unexpected death in epilepsy case was reported. DISCUSSION: The MORE registry supports the effectiveness and safety of ANT DBS therapy in a real-world setting in the 2 years following implantation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that ANT DBS reduces the frequency of seizures in patients with drug-resistant focal epilepsy. TRIAL REGISTRATION INFORMATION: MORE ClinicalTrials.gov Identifier: NCT01521754, first posted on January 31, 2012.

Clinical Characteristics, Imaging Findings, and Outcomes of Cerebral Air Embolism.

BACKGROUND: Arterial cerebral air embolism (CAE) is an uncommon but potentially catastrophic event. Patients can present with focal neurologic deficits, seizures, or coma. They may be treated with hyperbaric oxygen therapy. We review the causes, radiographic and clinical characteristics, and outcomes of patients with CAE. METHODS: We performed a retrospective chart review via an existing institutional database at Mayo Clinic to identify patients with arterial CAE. Demographic data, clinical characteristics, and diagnostic studies were extracted and classified on predefined criteria of diagnostic confidence, and descriptive and univariate analysis was completed. RESULTS: Fifteen patients met criteria for inclusion in our study. Most presented with focal deficits (80%) and/or coma (53%). Seven patients (47%) had seizures, including status epilepticus in one (7%). Five presented with increased muscle tone at the time of the event (33%). Computed tomography (CT) imaging was insensitive for the detection of CAE, only identifying free air in 4 of 13 who underwent this study. When obtained, magnetic resonance imaging typically showed multifocal areas of restricted diffusion. Six patients (40%) were treated with hyperbaric oxygen therapy. Age, Glasgow Coma Scale score at nadir, and use of hyperbaric oxygen therapy were not associated with functional outcome at 1 year in our cohort. Twenty-six percent of patients had a modified Rankin scale score of 0 one year after the event, and functional improvement over time was common after discharge. CONCLUSIONS: A high index of clinical suspicion is needed to identify patients with CAE because of low sensitivity of free air on CT imaging and nonspecific clinical presentation. Acute alteration of consciousness, seizures, and focal signs occur frequently. Because improvement over time is possible even among patients with severe presentation, early prognostication should be approached with caution.

A case of GFAP-IgG positivity followed by anti-NMDAR encephalitis.

BACKGROUND: In recent years, there have been an increasing number of reports on overlapping antibodies in autoimmune encephalitis (AE). There are various types of overlapping antibodies, but the clinical significance of each type is not yet clear. Glial antibodies, such as MOG, AQP4, and especially NMDAR, can be detected in patients with AE. However, little is known about the overlapping antibodies of anti-glial fibrillary acidic protein (GFAP), and only a few case reports have described this overlap. Case presentation The patient was a 7-year-old girl with recurrent intermittent fever and seizures, and viral encephalitis was diagnosed at the beginning of the disease. She was discharged after treatment with acyclovir, high-dose immunoglobulins, and valproic acid as an antiseizure medication. Subsequently, the patient still had occasional seizures and abnormal behavior, and the anti-NMDAR antibody test was positive (1:3.2). She was treated with high-dose methylprednisolone and antiseizure therapy. Approximately half a year later, the patient experienced fever and seizures again, serum GFAP IgG was 1:100, and a head MRI indicated new lesions. Improvement was achieved after repeated high-dose methylprednisolone and continuous prednisone anti-inflammatory therapy. CONCLUSIONS: Anti-NMDAR encephalitis combined with GFAP-IgG is uncommon, and repeated tests for AE-associated antibodies may be required in patients with recurrent encephalitis. Compared with cerebrospinal fluid antibody-positive children, serum GFAP IgG-positive children should be comprehensively diagnosed according to their clinical manifestations. It is worth considering whether overlapping antibody syndrome can still be an issue for patients with AE who recover and have negative antibodies after a few months if disease recurrence and new antibodies are detected.

Confusion and Hallucination in a Geriatric Patient. Pitfalls of a Rare Differential: Case Report of an Anti-LGI1-Encephalitis.

Background: Confusion and hallucinations in geriatric patients are frequent symptoms and typically associated with delirium, late-life psychosis or dementia syndromes. A far rarer but well-established differential in patients with rapid cognitive deterioration, acute psychosis, abnormal movements and seizures is autoimmune encephalitis. Exemplified by our case we highlight clinical and economic problems arising in management of geriatric patients with cognitive decline and psychotic symptoms. Case Presentation: A 77-year-old female caucasian patient with an unremarkable medical history was hospitalized after a fall in association with diarrhea and hyponatremia. Upon adequate therapy, disorientation and troubled short-term memory persisted. Within a week the patient developed visual hallucinations. Basic blood and urine samples and imaging (cranial computed tomography and magnetic resonance imaging) were unremarkable. With progressive cognitive decline, amnestic impairment, word finding difficulty and general apathy, psychiatric and neurologic expertise was introduced. Advanced diagnostics did not resolve a final diagnosis; an electroencephalogram showed unspecific generalized slowing. Extended clinical observation revealed visual hallucinations and faciobrachial dystonic seizures. A treatment with anticonvulsants was initiated. Cerebrospinal fluid ultimately tested positive for voltage-gated potassium channel LGl1 (leucine-rich-inactivated-1) antibodies confirming diagnosis of autoimmune anti-LGI1 encephalitis. Immediate immunotherapy (high-dose glucocorticoids and administration of intravenous immunoglobulin G) led to a rapid improvement of the patient's condition. After immunotherapy was tapered, the patient had one relapse and completely recovered with reintroduction of glucocorticoids and initiation of therapy with rituximab. Conclusion: Rapidly progressive dementia in geriatric patients demands a structured and multidisciplinary diagnostic approach. Accurate management and financially supportable care is a major issue in rare diseases such as anti-LGI1-encephalitis. Education and awareness about autoimmune encephalitis of all physicians treating a geriatric population is important in order to involve expertise and establish treatment within reasonable time.

Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.

Association between serum vitamin D levels and age in patients with epilepsy: a retrospective study from an epilepsy center in Saudi Arabia.

BACKGROUND: Vitamin D deficiency has been linked to various medical conditions such as bone loss, decreased mineralization, endocrine disorders, and central nervous system disorders, including epilepsy. Vitamin D deficiency is prevalent among patients with epilepsy (PWE). However, the specific association between vitamin D levels and age in PWE is unclear. OBJECTIVES: Identify the relation between vitamin D level and age in PWE and evaluate factors that may play a role in seizure control. DESIGN: Retrospective analytical medical record review SETTING: Outpatient epilepsy research clinic in Saudi Arabia PATIENTS AND METHODS: Between November 2016 and April 2020, we selected eligible PWE aged older than 14 years whose vita-min D levels were recorded at least once after reviewing 1550 patient electronic files. We analyzed data on serum vitamin D level by age and other factors, vitamin D supplement use, seizure classification, and conducted a multivariate logistic regression to assess associations with seizure control. MAIN OUTCOME MEASURES: Relationships between vitamin D levels and age and factors that might affect seizure control. SAMPLE SIZE: 524 patients RESULTS: The prevalence of low serum vitamin D levels was high (86.8%). The median vitamin D level in all patients was low (38 nmol/L), and was lower in young PWE than in adult PWE (P<.01). Only 146 patients received vitamin D supplements. High vitamin D levels were associated with a 40% seizure reduction. CONCLUSION: Vitamin D deficiency is underestimated in PWE in Saudi Arabia, and is more prevalent among young adults and patients on polytherapy than in other PWE. Patients with high vitamin D levels had good seizure control compared with those with low levels. The effect of vitamin D supplements on seizure control should be further investigated in randomized control trials. LIMITATIONS: Retrospective study and no categorization by presence of supplementation. CONFLICT OF INTEREST: None.

Association between MTHFR polymorphism and seizure control in epileptic patients with hyperhomocysteinaemia

Objective: The aim of this study was to investigate possible associations between MTHFR polymorphism and seizure control of epileptic patients with hyperhomocysteinaemia. Methods: A total of 81 epileptic patients with hyperhomocysteinaemia treated with oxcarbazepine monotherapy were enrolled in this study. All patients were offered vitamin B supplementation (2.5 mg/d folate and 1.5 mg/d mecobalamine) for six months. MTHFR C677T and A1298C polymorphisms, serum homocysteine, folate and vitamin B12 levels as well as seizure frequency and score based on the Hamilton depression scale (HAMD) were evaluated at baseline and after six months of follow-up. Results: Spearman correlation analysis showed that the extent of decline of seizure frequency positively correlated with a dynamic change in serum homocysteine concentration between baseline and after six months of follow-up (t=0.241, p=0.015 [Spearman's coefficient]). For the MTHFR C677T polymorphism, compared to the CC genotype, the TT genotype was associated with a significant downtrend of homocysteine (19.69 vs 10.28 mmol/L, p=0.006) and uptrend of folate (6.21 vs 2.49 ng/mL; p=0.004). The decrease in homocysteine (17.94 vs 12.52 mmol/L, p=0.001) and increase of folate (5.08 vs 2.86 ng/mL; p=0.003) were significantly greater in patients with the T allele compared to those with the C allele. Also, the TT genotype (2.33 vs 1.4, p=0.056) and T allele (1.95 vs 1.38, p=0.037) were associated with a greater decrease in seizure frequency compared to the CC genotype or C allele. The A1298C polymorphism alone was not associated with elevated homocysteine or decreased folate levels at baseline, and showed little association with response to vitamin B supplementation in epileptic patients with hyperhomocysteinaemia. However, in patients with combined 677TT/1298AA or 677TT/1298AC polymorphisms, the changes in homocysteine and folate levels and seizure frequency were more obvious. Significance: MTHFR C677T polymorphism was associated with seizure control in epileptic patients with hyperhomocysteinaemia; individuals with the 677TT genotype or T allele demonstrated better seizure control.

A scoping review on cannabidiol therapy in tuberous sclerosis: Current evidence and perspectives for future development.

Cannabidiol (CBD) has recently been approved as an add-on therapy by various regulatory agencies for tuberous sclerosis complex (TSC)-associated seizures based on its short-term efficacy and safety in a pivotal randomized controlled trial. However, critical information about which patients with TSC and seizure types respond best to CBD (clinical, electrophysiological, and genetic predictors of responsiveness), when to use CBD in the treatment algorithm, and how CBD can be combined with other antiseizure medications (ASMs) in the form of a rational polypharmacy therapy is still lacking. In general, there is a limited in-depth critical review of CBD for the treatment of TSC to facilitate its optimal use in a clinical context. Here, we utilized a scoping review approach to report the current evidence of efficacy and safety of pharmaceutical-grade CBD in patients with TSC, including relevant mechanism of action and drug-drug interactions with other ASMs. We also discussed emerging information about CBD's long-term efficacy and safety data in patients with TSC. Finally, we discussed some critical unanswered questions in several domains related to effective clinical management of TSC using CBD, including barriers to early and aggressive treatment in infants, difficulty with universal access to CBD, a lack of studies to understand CBD's impact on seizure severity and specific seizure types, insufficient exploration of CBD in TSC-related cognitive and behavioral issues, and the need for more research into CBD's effects on various biomarkers.

Pyridoxine or pyridoxal-5-phosphate treatment for seizures in glycosylphosphatidylinositol deficiency: A cohort study.

AIM: To investigate the short-term efficacy and safety of high-dose pyridoxine and pyridoxal 5-phosphate (P5P) in the treatment of inherited glycosylphosphatidylinositol (GPI) deficiency-associated epilepsy. METHOD: Participants with genetically confirmed GPI deficiency were treated with oral pyridoxine or P5P as compassionate use in an agreed-upon clinical regimen. Pyridoxine (20-30 mg/kg/day) was used for 3 months. Baseline evaluation included 4 weeks of prospective seizure data and one video electroencephalogram (EEG). Seizure frequency was captured daily. The EEG was repeated after reaching maximum dosage of pyridoxine. Pyridoxine was switched to P5P (20-30 mg/kg/day) if seizure burden was unchanged after 3 months' treatment. Another EEG was done after 3 months of P5P treatment. Primary outcome measures were reduction of seizure frequency and EEG improvements. RESULTS: Seven participants (one female, six males; age range 5-23 year; mean age 11 years 10 months, SD 5 year 2 months) were included. The genetic causes of inherited GPI deficiency were phosphatidylinositol N-acetylglucosaminyltransferase subunit A/T/V deficiency. All had drug-resistant epilepsy and neurodevelopmental impairment. We observed more than 50% seizure frequency reduction in 2 out of 7 and less than 50% reduction in another 3 out of 7 participants. No participants reached seizure freedom. No remarkable changes in electrophysiological findings were observed in 6 out of 7 participants treated with pyridoxine or P5P when comparing the baseline and follow-up EEGs. INTERPRETATION: We observed no long-lasting electrophysiological improvements during treatment but pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. WHAT THIS PAPER ADDS: Inherited glycosylphosphatidylinositol (GPI) deficiency often causes early-onset and drug-resistant epilepsy. Vitamin B6 is a potential disease-specific treatment; however, efficacy and safety are ill-defined. Pyridoxine may reduce seizure frequency or burden in inherited GPI deficiency. Pyridoxine and P5P could prove to be a useful treatment in some individuals with inherited GPI deficiency and epilepsy.

Sex differences in the developing brain impact stress-induced epileptogenicity following hyperthermia-induced seizures.

Febrile seizures (FS) are common, affecting 2-5% of children between the ages of 3 months and 6 years. Complex FS occur in 10% of patients with FS and are strongly associated with mesial temporal lobe epilepsy. Current research suggests that predisposing factors, such as genetic and anatomic abnormalities, may be necessary for complex FS to translate to mesial temporal lobe epilepsy. Sex hormones are known to influence seizure susceptibility and epileptogenesis, but whether sex-specific effects of early life stress play a role in epileptogenesis is unclear. Here, we investigate sex differences in the activity of the hypothalamic-pituitary-adrenal (HPA) axis following chronic stress and the underlying contributions of gonadal hormones to the susceptibility of hyperthermia-induced seizures (HS) in rat pups. Chronic stress consisted of daily injections of 40 mg/kg of corticosterone (CORT) subcutaneously from postnatal day (P) 1 to P9 in male and female rat pups followed by HS at P10. Body mass, plasma CORT levels, temperature threshold to HS, seizure characteristics, and electroencephalographic in vivo recordings were compared between CORT- and vehicle (VEH)-injected littermates during and after HS at P10. In juvenile rats (P18-P22), in vitro CA1 pyramidal cell recordings were recorded in males to investigate excitatory and inhibitory neuronal circuits. Results show that daily CORT injections increased basal plasma CORT levels before HS and significantly reduced weight gain and body temperature threshold of HS in both males and females. CORT also significantly lowered the generalized convulsions (GC) latency while increasing recovery time and the number of electrographic seizures (>10s), which had longer duration. Furthermore, sex-specific differences were found in response to chronic CORT injections. Compared to females, male pups had increased basal plasma CORT levels after HS, longer recovery time and a higher number of electrographic seizures (>10s), which also had longer duration. Sex-specific differences were also found at baseline conditions with lower latency to generalized convulsions and longer duration of electrographic seizures in males but not in females. In juvenile male rats, the amplitude of evoked excitatory postsynaptic potentials, as well as the amplitude of inhibitory postsynaptic currents, were significantly greater in CORT rats when compared to VEH littermates. These findings not only validate CORT injections as a stress model, but also show a sex difference in baseline conditions as well as a response to chronic CORT and an impact on seizure susceptibility, supporting a potential link between sustained early-life stress and complex FS. Overall, these effects also indicate a putatively less severe phenotype in female than male pups. Ultimately, studies investigating the biological underpinnings of sex differences as a determining factor in mental and neurologic problems are necessary to develop better diagnostic, preventative, and therapeutic approaches for all patients regardless of their sex.

Late adolescence mortality in mice with brain-specific deletion of the volume-regulated anion channel subunit LRRC8A.

The leucine-rich repeat-containing family 8 member A (LRRC8A) is an essential subunit of the volume-regulated anion channel (VRAC). VRAC is critical for cell volume control, but its broader physiological functions remain under investigation. Recent studies in the field indicate that Lrrc8a disruption in the brain astrocytes reduces neuronal excitability, impairs synaptic plasticity and memory, and protects against cerebral ischemia. In the present work, we generated brain-wide conditional LRRC8A knockout mice (LRRC8A bKO) using NestinCre -driven Lrrc8aflox/flox excision in neurons, astrocytes, and oligodendroglia. LRRC8A bKO animals were born close to the expected Mendelian ratio and developed without overt histological abnormalities, but, surprisingly, all died between 5 and 9 weeks of age with a seizure phenotype, which was confirmed by video and EEG recordings. Brain slice electrophysiology detected changes in the excitability of pyramidal cells and modified GABAergic inputs in the hippocampal CA1 region of LRRC8A bKO. LRRC8A-null hippocampi showed increased immunoreactivity of the astrocytic marker GFAP, indicating reactive astrogliosis. We also found decreased whole-brain protein levels of the GABA transporter GAT-1, the glutamate transporter GLT-1, and the astrocytic enzyme glutamine synthetase. Complementary HPLC assays identified reduction in the tissue levels of the glutamate and GABA precursor glutamine. Together, these findings suggest that VRAC provides vital control of brain excitability in mouse adolescence. VRAC deletion leads to a lethal phenotype involving progressive astrogliosis and dysregulation of astrocytic uptake and supply of amino acid neurotransmitters and their precursors.

Induction of Tertiary Phase Epileptiform Discharges after Postasphyxial Infusion of a Toll-Like Receptor 7 Agonist in Preterm Fetal Sheep.

BACKGROUND: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic-ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. METHODS: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. RESULTS: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r2 = 0.61, p < 0.05) and CA1/2 hippocampal region (r2 = 0.66, p < 0.05). CONCLUSION: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions.

Exogenous ketone ester delays CNS oxygen toxicity without impairing cognitive and motor performance in male Sprague-Dawley rats.

Hyperbaric oxygen (HBO2) is breathing >1 atmosphere absolute (ATA; 101.3 kPa) O2 and is used in HBO2 therapy and undersea medicine. What limits the use of HBO2 is the risk of developing central nervous system (CNS) oxygen toxicity (CNS-OT). A promising therapy for delaying CNS-OT is ketone metabolic therapy either through diet or exogenous ketone ester (KE) supplement. Previous studies indicate that KE induces ketosis and delays the onset of CNS-OT; however, the effects of exogeneous KE on cognition and performance are understudied. Accordingly, we tested the hypothesis that oral gavage with 7.5 g/kg induces ketosis and increases the latency time to seizure (LSz) without impairing cognition and performance. A single oral dose of 7.5 g/kg KE increases systemic ß-hydroxybutyrate (BHB) levels within 0.5 h and remains elevated for 4 h. Male rats were separated into three groups: control (no gavage), water-gavage, or KE-gavage, and were subjected to behavioral testing while breathing 1 ATA (101.3 kPa) of air. Testing included the following: DigiGait (DG), light/dark (LD), open field (OF), and novel object recognition (NOR). There were no adverse effects of KE on gait or motor performance (DG), cognition (NOR), and anxiety (LD, OF). In fact, KE had an anxiolytic effect (OF, LD). The LSz during exposure to 5 ATA (506.6 kPa) O2 (≤90 min) increased 307% in KE-treated rats compared with control rats. In addition, KE prevented seizures in some animals. We conclude that 7.5 g/kg is an optimal dose of KE in the male Sprague-Dawley rat model of CNS-OT.