Cannabidiol for Treatment of Childhood Epilepsy–A Cross-Sectional Survey

Background: The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner's attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available.Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy.Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018.Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1–35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient's quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option.Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment

Corticosteroids versus clobazam for treatment of children with epileptic encephalopathy with spike-wave activation in sleep (RESCUE ESES): a multicentre randomised controlled trial

BACKGROUND: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a rare syndrome associated with cognitive and behavioural regression. On the basis of mostly small observational and retrospective studies, corticosteroids and clobazam are often considered the most effective treatments for this syndrome. We aimed to compare cognitive outcomes of children with EE-SWAS 6 months after starting treatment with either corticosteroids or clobazam. METHODS: We did a multicentre, randomised controlled trial at eight tertiary referral centres for rare epilepsies in seven European countries. Children were eligible to participate if they were aged 2-12 years, were diagnosed with EE-SWAS within 6 months before inclusion, and had not been treated with corticosteroids or clobazam previously. Participants were randomly assigned (1:1) to treatment with corticosteroids (either continuous treatment with 1-2 mg/kg per day of prednisolone orally or pulse treatment with 20 mg/kg per day of methylprednisolone intravenously for 3 days every 4 weeks) or clobazam (0·5-1·2 mg/kg per day orally). The primary outcome was cognitive functioning after 6 months of treatment, which was assessed by either the intelligence quotient (IQ) responder rate (defined as improvement of ≥11·25 IQ points) or the cognitive sum score responder rate (defined as improvement of ≥0·75 points). Safety was assessed by number of adverse events and serious adverse events. Data were analysed in the intention-to-treat population, which included all children as randomised who had primary outcome data available at 6 months. The trial is registered with the Dutch Trial Register, Toetsingonline, NL43510.041.13, and the ISRCTN registry, ISRCTN42686094. The trial was terminated prematurely because enrolment of the predefined number of 130 participants was deemed not feasible. FINDINGS: Between July 22, 2014, and Sept 3, 2022, 45 children were randomly assigned to either corticosteroids (n=22) or clobazam (n=23); two children assigned clobazam dropped out before 6 months and were excluded from the intention-to-treat analysis. At the 6-month assessment, an improvement of 11·25 IQ points or greater was reported for five (25%) of 20 children assigned corticosteroids versus zero (0%) of 18 assigned clobazam (risk ratio [RR] 10·0, 95% CI 1·2-1310·4; p=0·025). An improvement of 0·75 points or more in the cognitive sum score was recorded for one (5%) of 22 children assigned corticosteroids versus one (5%) of 21 children assigned clobazam (RR 1·0, 95% CI 0·1-11·7, p=0·97). Adverse events occurred in ten (45%) of 22 children who received corticosteroids, most frequently weight gain, and in 11 (52%) of 21 children who received clobazam, most often fatigue and behavioural disturbances. Occurrence of adverse events did not differ between groups (RR 0·8, 95% CI 0·4-1·4; p=0·65). Serious adverse events occurred in one child in the corticosteroid group (hospitalisation due to laryngitis) and in two children in the clobazam group (hospitalisation due to seizure aggravation, and respiratory tract infection). No deaths were reported. INTERPRETATION: The trial was terminated prematurely, and the target sample size was not met, so our findings must be interpreted with caution. Our data indicated an improvement in IQ outcomes with corticosteroids compared with clobazam treatment, but no difference was seen in cognitive sum score. Our findings strengthen those from previous uncontrolled studies that support the early use of corticosteroids for children with EE-SWAS. FUNDING: EpilepsieNL, WKZ fund, European Clinical Research Infrastructure Network, and Ming fund

Stromelysin-3 over-expression enhances tumourigenesis in MCF-7 and MDA-MB-231 breast cancer cell lines: involvement of the IGF-1 signalling pathway

BACKGROUND: Stromelysin-3 (ST-3) is over-expressed in the majority of human carcinomas including breast carcinoma. Due to its known effect in promoting tumour formation, but its impeding effect on metastasis, a dual role of ST-3 in tumour progression, depending on the cellular grade of dedifferentiation, was hypothesized. METHODS: The present study was designed to investigate the influence of ST-3 in vivo and in vitro on the oestrogen-dependent, non-invasive MCF-7 breast carcinoma cell line as well as on the oestrogen-independent, invasive MDA-MB-231 breast carcinoma cell line. Therefore an orthotopic human xenograft tumour model in nude mice, as well as a 3D matrigel cell culture system, were employed. RESULTS: Using both in vitro and in vivo techniques, we have demonstrated that over-expression of ST-3 in MCF-7 and MDA-MB-231 cells leads to both increased cell numbers and tumour volumes. This observation was dependent upon the presence of growth factors. In particular, the enhanced proliferative capacity was in MCF-7/ST-3 completely and in MDA-MB-231/ST-3 cells partially dependent on the IGF-1 signalling pathway. Microarray analysis of ST-3 over-expressing cells revealed that in addition to cell proliferation, further biological processes seemed to be affected, such as cell motility and stress response. The MAPK-pathway as well as the Wnt and PI3-kinase pathways, appear to also play a potential role. Furthermore, we have demonstrated that breast cancer cell lines of different differentiation status, as well as the non-tumourigenic cell line MCF-10A, have a comparable capability to induce endogenous ST-3 expression in fibroblasts. CONCLUSION: These data reveal that ST-3 is capable of enhancing tumourigenesis in highly differentiated "early stage" breast cancer cell lines as well as in further progressed breast cancer cell lines that have already undergone epithelial-mesenchymal transition. We propose that ST-3 induction in tumour fibroblasts leads to the stimulation of the IGF-1R pathway in carcinoma cells, thus enhancing their proliferative capacity. In addition, further different cellular processes seem to be activated by ST-3, possibly accounting for the dual role of ST-3 in tumour progression and metastasis

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients’ Perspectives

Background The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis

Effect of Cannabidiol on Interictal Epileptiform Activity and Sleep Architecture in Children with Intractable Epilepsy: A Prospective Open-Label Study

Background!#!Cannabidiol has been shown to be effective in seizure reduction in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis. However, very little is known about its potential to reduce interictal epileptiform activity and improve sleep architecture.!##!Objective!#!The objective of this prospective study was to evaluate the influence of cannabidiol therapy on the frequency of interictal epileptiform discharges (IEDs) and sleep microstructure in a cohort of children with drug-resistant epilepsy.!##!Methods!#!Children with drug-resistant epilepsy were prospectively followed from November 2019 to January 2021 during an open-label trial of cannabidiol at a dose of 20 mg/kg/day (to a maximum of 50 mg/kg/day) and stable concomitant medication. Electroencephalograms were recorded at baseline (T0) and after 3 months (T1). Two independent raters, blinded to clinical outcome, evaluated 5-min segments of sleep stage 2 or low-noise awake state. IEDs were visually identified and rates per minute calculated. Sleep microstructure was considered improved if sleep structures were seen at T1 that were not present at T0. IED rates at T0 and T1 were compared and correlated with seizure outcome, cannabidiol dose, initial IED rate, and disease duration.!##!Results!#!In total, 35 children (mean ± standard deviation age 10.1 ± 0.86) were included. The IED rate at T1 was significantly lower than at T0 (19.6 ± 19.5 vs. 36.8 ± 27.2, respectively; p < 0.0001). We found a moderate correlation between IED reduction and percentage of seizure reduction compared with baseline (Pearson's r = 0.39; p = 0.02), a moderate negative correlation between IED reduction and IED rate at T0 (r = - 0.34; p = 0.04), and a trend towards a moderate negative correlation between IED reduction and disease duration (r = - 0.32; p = 0.06). Sleep was recorded in 23 patients. Sleep microstructure was initially abnormal in 56.5% of sleep recordings and improved in 84.6% of those cases.!##!Conclusion!#!Our results strongly suggest the utility of cannabidiol in reducing IEDs and improving sleep microstructure in children with drug-resistant epilepsy. Larger controlled studies are needed to evaluate the clinical relevance of this effect in different epilepsy types.!##!Trial registration!#!DRKS00013177; 25 June 2019

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of- function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of- function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of- function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants

Sleep quality, anxiety, symptoms of depression, and caregiver burden among those caring for patients with Dravet syndrome: a prospective multicenter study in Germany

Abstract Background This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. Methods This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers’ work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. Results Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients’ sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. Conclusions Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients’ sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. Trial registration: German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS0001696