Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Time to onset of cannabidiol treatment effect and resolution of adverse events in tuberous sclerosis complex: Post hoc analysis of randomized controlled phase 3 trial GWPCARE6.

OBJECTIVE: To estimate the timing of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]) onset, we conducted a post hoc analysis of GWPCARE6 (NCT02544763), a randomized, placebo-controlled, phase 3 trial in patients with drug-resistant epilepsy associated with tuberous sclerosis complex (TSC). METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex; 100 mg/ml oral solution) at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or placebo for 16 weeks (4-week titration, 12-week maintenance). Treatment started at 5 mg/kg/day for all groups and reached 25 mg/kg/day on Day 9 and 50 mg/kg/day on Day 29. Percentage change from baseline in TSC-associated seizure (countable focal or generalized) count was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Of 224 patients, 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo. Median (range) age was 11.3 (1.1-56.8) years. Patients had discontinued a median (range) of 4 (0-15) antiseizure medications and were currently taking 3 (0-5). Difference in seizure reduction between CBD and placebo emerged on Day 6 (titrated dose, 15 mg/kg/day) and became nominally significant (p < .049) by Day 10. Separation between placebo and CBD in ≥50% responder rate also emerged by Day 10. Onset of AEs occurred during the first 2 weeks of the titration period in 61% of patients (CBD25, 61%; CBD50, 67%; placebo, 54%). In patients with an AE, resolution occurred within 4 weeks of onset in 42% of placebo and 27% of CBD patients and by end of trial in 78% of placebo and 51% of CBD patients. SIGNIFICANCE: Onset of treatment effect occurred within 6-10 days. AEs lasted longer for CBD than placebo, but the most common (diarrhea, decreased appetite, and somnolence) resolved during the 16-week trial in most patients.

Biogeochemical and climate drivers of wetland phosphorus and nitrogen release: Implications for nutrient legacies and eutrophication risk.

The dynamics and processes of nutrient cycling and release were examined for a lowland wetland-pond system, draining woodland in southern England. Hydrochemical and meteorological data were analyzed from 1997 to 2017, along with high-resolution in situ sensor measurements from 2016 to 2017. The results showed that even a relatively pristine wetland can become a source of highly bioavailable phosphorus (P), nitrogen (N), and silicon (Si) during low-flow periods of high ecological sensitivity. The drivers of nutrient release were primary production and accumulation of biomass, which provided a carbon (C) source for microbial respiration and, via mineralization, a source of bioavailable nutrients for P and N co-limited microorganisms. During high-intensity nutrient release events, the dominant N-cycling process switched from denitrification to nitrate ammonification, and a positive feedback cycle of P and N release was sustained over several months during summer and fall. Temperature controls on microbial activity were the primary drivers of short-term (day-to-day) variability in P release, with subdaily (diurnal) fluctuations in P concentrations driven by water body metabolism. Interannual relationships between nutrient release and climate variables indicated "memory" effects of antecedent climate drivers through accumulated legacy organic matter from the previous year's biomass production. Natural flood management initiatives promote the use of wetlands as "nature-based solutions" in climate change adaptation, flood management, and soil and water conservation. This study highlights potential water quality trade-offs and shows how the convergence of climate and biogeochemical drivers of wetland nutrient release can amplify background nutrient signals by mobilizing legacy nutrients, causing water quality impairment and accelerating eutrophication risk.

Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase-associated neurodegeneration. METHODS: A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase-associated neurodegeneration. RESULTS: We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1). CONCLUSION: Cannabis use was commonly reported among children with pantothenate kinase-associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02324673).

Impacts of acidification on brown trout Salmo trutta populations and the contribution of stocking to population recovery and genetic diversity.

Anthropogenic acidification in SW-Scotland, from the early 19th Century onwards, led to the extinction of several loch (lake) brown trout (Salmo trutta) populations and substantial reductions in numbers in many others. Higher altitude populations with no stocking influence, which are isolated above natural and artificial barriers and subjected to the greatest effect of acidification, exhibited the least intrapopulation genetic diversity (34% of the allelic richness of the populations accessible to anadromous S. trutta). These, however, were characterised by the greatest interpopulation divergence (highest pairwise DEST 0.61 and FST 0.53 in contemporary samples) based on 16 microsatellite loci and are among the most differentiated S. trutta populations in NW-Europe. Five lochs above impassable waterfalls, where S. trutta were thought to be extinct, are documented as having been stocked in the late 1980s or 1990s. All five lochs now support self-sustaining S. trutta populations; three as a direct result of restoration stocking and two adjoining lochs largely arising from a small remnant wild population in one, but with some stocking input. The genetically unique Loch Grannoch S. trutta, which has been shown to have a heritable increased tolerance to acid conditions, was successfully used as a donor stock to restore populations in two acidic lochs. Loch Fleet S. trutta, which were re-established from four separate donor sources in the late 1980s, showed differential contribution from these ancestors and a higher genetic diversity than all 17 natural loch populations examined in the area. Genetically distinct inlet and outlet spawning S. trutta populations were found in this loch. Three genetically distinct sympatric populations of S. trutta were identified in Loch Grannoch, most likely representing recruitment from the three main spawning rivers. A distinct genetic signature of Loch Leven S. trutta, the progenitor of many Scottish farm strains, facilitated detection of stocking with these strains. One artificially created loch was shown to have a population genetically very similar to Loch Leven S. trutta. In spite of recorded historical supplemental stocking with Loch Leven derived farm strains, much of the indigenous S. trutta genetic diversity in the area remains intact, aside from the effects of acidification induced bottlenecks. Overall genetic diversity and extant populations have been increased by allochthonous stocking.

Examining the Sociocultural Context of HIV-related Risk Behaviors Among Kathoey (Male-to-female Transgender Women) Sex Workers in Bangkok, Thailand.

Kathoey (male-to-female transgender) sex workers (KSW) in Thailand are at high risk for sexually transmitted infections; however, few qualitative studies have been conducted to understand the sociocultural context of engaging in HIV risk behaviors. A total of 24 participants were purposively sampled in Bangkok based on KSW work venues and substance use. Results revealed the importance of participants' understanding of the self in relation to establishing economic independence through sex work, which could then be used to re-establish support from family, who often have not accepted a son's gender transition. Participants linked being kathoey to a belief in fate but did not view engagement in sex work in the same way. Different sex work venues exposed KSW to different risky situations. HIV prevention programs for kathoey must address the importance of economic security and its relation to social support and gender transition within a cultural- and work-environment-specific framework.

Diagnosis, treatment and prevention of gonorrhoea.

Neisseria gonorrhoeae is a Gram-negative bacteria responsible for the sexually transmitted infection gonorrhoea, which is increasingly common in the UK. Drug-resistant strains of the bacteria have emerged, which is making gonorrhoea difficult to treat. Therefore, preventing infection is important. This article identifies people at increased risk of contracting the infection, and explores how nurses can offer testing and treatment as well as helping to prevent infection through education and health promotion.

Focal cortical dysplasia is more common in boys than in girls.

Genetics and environment likely contribute to the development of medically intractable epilepsy; however, in most patients the specific combination of etiologies remains unknown. Here, we undertook a multicenter retrospective cohort study of sex distribution in pediatric patients undergoing epilepsy surgery and carried out a secondary analysis of the same population subdivided by histopathologic diagnosis. In the multicenter cohort of patients with intractable epilepsy undergoing surgery regardless of etiology (n=206), 63% were boys, which is significantly more boys than expected for the general population (Fisher exact two-tailed p=0.017). Subgroup analysis found that of the 90 patients with a histopathologic diagnosis of focal cortical dysplasia, 72% were boys, giving an odds ratio (OR) of 2.5 (95% CI, 1.34 to 4.62) for male sex. None of the other etiologies had a male sex predominance. Future studies could examine the biological relevance and potential genetic and pathophysiological mechanisms of this observation.

Vagus nerve stimulation for partial and generalized epilepsy from infancy to adolescence.

OBJECT: Vagus nerve stimulation (VNS) is approved by the FDA for the treatment of partial epilepsy in patients older than 12 years. Authors of the current study performed a large retrospective analysis and comparison of VNS outcomes in children with an age ≥ and < 12 years, including those with partial and generalized epilepsy. METHODS: A retrospective review of the records of pediatric patients (age < 18 years) who had undergone primary VNS system implantation between 2001 and 2010 by a single pediatric neurosurgeon was undertaken. Considered data included demographics, epilepsy type (partial vs generalized), seizure frequency, seizure duration, postictal period duration, and antiepileptic medication use. RESULTS: One hundred forty-six patients (49% female) were followed up for a mean of 41 months after VNS implantation. Thirty-two percent of patients had partial epilepsy and 68% had generalized epilepsy. After VNS system implantation, seizure frequency was reduced in 91% of patients, seizure duration in 50%, postictal period in 49%, and antiepileptic medication use in 75%. There was no significant difference in age, sex, or duration of follow-up according to epilepsy type. Neither was there any significant difference in seizure frequency reduction, seizure duration, postictal period, medication use, overall clinical improvement, or improvement in quality of life based on an age ≥ or < 12 years or epilepsy type. CONCLUSIONS: Vagus nerve stimulation reduced both seizure frequency and antiepileptic medication use in the majority of pediatric patients regardless of sex, age cohort, or epilepsy type. Vagus nerve stimulation also reduced seizure duration and postictal period in approximately half of the pediatric patients. Contrary to expectation, children with partial epilepsy do not benefit from VNS at higher rates than those with generalized epilepsy.

Transendoscopic intraoperative recording of gelastic seizures from a hypothalamic hamartoma.

OBJECT: The differential diagnosis of hypothalamic masses in children includes hamartomas, which are associated with gelastic seizures and endocrine dysfunction. The purpose of this study was to utilize transendoscopic electroencephalography (EEG) recording at the time of tissue biopsy to further assist in diagnosis, determination of prognosis, and treatment planning. METHODS: We present the case of an infant with gelastic seizures and a large hypothalamic mass lesion. Despite a clinical and radiographic presentation typical of hypothalamic hamartoma (HH), slight growth on serial imaging raised concern for a diagnosis of intrinsic neoplasm. Biopsy of the lesion was recommended. RESULTS: Transventricular, endoscopic biopsy, was undertaken, with concurrent intraoperative, transendoscopic EEG recording using a standard epilepsy depth recording macroelectrode. Numerous electrographic seizures were recorded. Histopathology revealed a HH. CONCLUSION: This is the first report of intraoperative macroelectrode recording of electrographic seizures transendoscopically from a HH. This technique may prove useful for diagnosis, prognosis and treatment planning, as well as to guide transendoscopic therapeutic interventions for HH.

Skull-fixated fiducial markers improve accuracy in staged frameless stereotactic epilepsy surgery in children.

OBJECT: Surgery to monitor and resect epileptogenic foci may be undertaken in 2 stages, providing an opportunity to use skull-fixated fiducials implanted during the first stage to improve the accuracy of cortical resection during the second stage. This study compared the intrinsic accuracy of skin-based and skull-fixated fiducial markers in registering frameless stereotaxy during pediatric epilepsy surgery. To the authors' knowledge, these modalities of registration have not previously been directly compared in this population. METHODS: The authors undertook a retrospective review of pediatric patients who underwent resection of epileptogenic foci in 2 stages with frameless stereotactic assistance, performed by a single surgeon at Oregon Health & Science University. For the first stage (subdural grid implantation), 9 skin fiducial markers were used to register anatomical data in a frameless stereotactic station. Intraoperatively, four 3-mm screws were placed circumferentially around the craniotomy. Postoperatively, thin-slice brain MR and CT images were obtained and fused. For the second stage, the 4 screws were used as fiducial markers to register the stereotactic anatomical data. For both stages, accuracy (difference in millimeters from zero of the manual fiducial registration compared with the computer model) was determined using navigation software. The intrinsic accuracy of these 2 methods of fiducial registration was compared using a paired Student t-test. RESULTS: Between 2004 and 2009, 40 pediatric patients with epilepsy underwent frameless stereotactic surgical procedures. Fourteen patients who had 2-stage procedures using skin-based and skull-fixated registration with complete accuracy data were included in this retrospective review. Mean registration error was significantly lower using skull-fixated fiducials (1.35 mm, 95% CI 1.09-1.60 mm) than using skin-based fiducials (1.85 mm, 95% CI 1.56-2.13 mm; p = 0.0016). CONCLUSIONS: A significantly higher degree of accuracy was achieved using 4 skull-fixated fiducials compared with using 9 skin-based fiducials. This simple and accurate method for registering frameless stereotactic anatomical data does not involve the potential time, expense, discomfort, and morbidity of extraoperative skull-fixated fiducial placement. The method described in this paper could also be extrapolated to other planned 2-stage cranial surgical procedures such as combined skull base approaches.

Focal seizure propagation in the intracranial EEG.

INTRODUCTION: intracranial EEG offers a unique opportunity to study epileptic seizures in humans. Seizure propagation has not been extensively studied. We aimed to compare the propagation of focal seizures with onset in different brain regions. METHODS: seven zones were defined as medial frontal (MF), dorsolateral frontal (DLF), orbitofrontal (OF), medial temporal (MF), lateral temporal (LT), parietal (P) and occipital (O). Routes and times of ipsilateral (IPT) and contralateral (CPT) propagation as well as ictal frequency in onset zone and propagation zone were compared. RESULTS: forty patients had 112 seizures. (Mean and median number of seizures per zone was 16 and 15). Preferred routes of propagation, based on ictal onset, were: MF to contralateral MF; DLF to ispilateral temporal lobe; OF to contralateral OF and ispilateral temporal lobe; MT to contralateral MT; LT to ispilateral MT and OF and contralateral LT and MT; P to ispilateral temporal lobe, DLF and O; O to ipsilateral MT. IPT and CPT varied markedly between zones. Ictal onset frequency was faster than propagated frequency. CONCLUSION: seizure propagation varies according to onset zone possibly following major pathways. This needs confirmation. The findings could aid in the interpretation of symptoms and EEG and may result useful for future treatment using brain stimulation or disconnective surgery. The limitations are clearly stated.

Gender differences in structured risk assessment: comparing the accuracy of five instruments.

Structured risk assessment should guide clinical risk management, but it is uncertain which instrument has the highest predictive accuracy among men and women. In the present study, the authors compared the Psychopathy Checklist-Revised (PCL-R; R. D. Hare, 1991, 2003); the Historical, Clinical, Risk Management-20 (HCR-20; C. D. Webster, K. S. Douglas, D. Eaves, & S. D. Hart, 1997); the Risk Matrix 2000-Violence (RM2000[V]; D. Thornton et al., 2003); the Violence Risk Appraisal Guide (VRAG; V. L. Quinsey, G. T. Harris, M. E. Rice, & C. A. Cormier, 1998); the Offenders Group Reconviction Scale (OGRS; J. B. Copas & P. Marshall, 1998; R. Taylor, 1999); and the total previous convictions among prisoners, prospectively assessed prerelease. The authors compared predischarge measures with subsequent offending and instruments ranked using multivariate regression. Most instruments demonstrated significant but moderate predictive ability. The OGRS ranked highest for violence among men, and the PCL-R and HCR-20 H subscale ranked highest for violence among women. The OGRS and total previous acquisitive convictions demonstrated greatest accuracy in predicting acquisitive offending among men and women. Actuarial instruments requiring no training to administer performed as well as personality assessment and structured risk assessment and were superior among men for violence.