A novel de novo FEM1C variant is linked to neurodevelopmental disorder with absent speech, pyramidal signs and limb ataxia.

The principal component of the protein homeostasis network is the ubiquitin-proteasome system. Ubiquitination is mediated by an enzymatic cascade involving, i.e. E3 ubiquitin ligases, many of which belong to the cullin-RING ligases family. Genetic defects in the ubiquitin-proteasome system components, including cullin-RING ligases, are known causes of neurodevelopmental disorders. Using exome sequencing to diagnose a pediatric patient with developmental delay, pyramidal signs and limb ataxia, we identified a de novo missense variant c.376G>C; p.(Asp126His) in the FEM1C gene encoding a cullin-RING ligase substrate receptor. This variant alters a conserved amino acid located within a highly constrained coding region and is predicted as pathogenic by most in silico tools. In addition, a de novo FEM1C mutation of the same residue p.(Asp126Val) was associated with an undiagnosed developmental disorder, and the relevant variant (FEM1CAsp126Ala) was found to be functionally compromised in vitro. Our computational analysis showed that FEM1CAsp126His hampers protein substrate binding. To further assess its pathogenicity, we used the nematode Caenorhabditis elegans. We found that the FEM-1Asp133His animals (expressing variant homologous to the FEM1C p.(Asp126Val)) had normal muscle architecture yet impaired mobility. Mutant worms were sensitive to the acetylcholinesterase inhibitor aldicarb but not levamisole (acetylcholine receptor agonist), showing that their disabled locomotion is caused by synaptic abnormalities and not muscle dysfunction. In conclusion, we provide the first evidence from an animal model suggesting that a mutation in the evolutionarily conserved FEM1C Asp126 position causes a neurodevelopmental disorder in humans.

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

BACKGROUND: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).

Study of nusinersen metabolites in the cerebrospinal fluid of children with spinal muscular atrophy using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

The study aimed to analyze nusinersen metabolites in the cerebrospinal fluid samples using ion-pair reversed-phase ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Three different sample preparation methods were tested for extraction and purification, but solid phase extraction appeared to be the most suitable, allowing a significant sample enrichment (40-fold). This step was necessary to detect and identify metabolites of nusinersen in the cerebrospinal fluid. The developed and applied analytical procedure enabled the identification of nusinersen metabolites: sequences shorter by several nucleotides from the 3' end; shorter by several nucleotides from both the 3' and 5' ends; and some depurination products. To the best of our knowledge, this is the first report on the analysis and identification of nusinersen metabolites in cerebrospinal fluid samples taken from children with spinal muscular atrophy treated with Spinraza.

Comparison of knowledge and awareness of epilepsy between medical students of two universities in Poland.

BACKGROUND: Epilepsy is one of the most common neurological disorders. As a chronic disease, associated with long-term treatment with antiseizure medication, it can have a negative impact on patients' quality of life. Moreover, patients are faced with a significant psychosocial burden associated with the stigma surrounding epilepsy. Medical professionals should be well educated and free of prejudices in order to provide adequate care for patients with epilepsy. The aim of the study was to evaluate the knowledge and awareness of epilepsy among medical students of years 1-6 in Poland and examine if certain personality traits influence students' view of epilepsy. METHODS: The study was conducted using snowball sampling of 166 Polish medical students from Medical University of Gdansk and Medical University of Warsaw. Participants completed a survey which consisted of their subjective assessment of knowledge of epileptology, actual knowledge of epileptology, and their view of stereotypes about epilepsy. In addition, students completed the IPIP-BFM-20 personality questionnaire. RESULTS: Polish medical students have sufficient basic knowledge about epilepsy (mean scores of students from both universities is 14 out of 25 points). There is still room for improvement, especially in the field of epidemiology, semiology, factors provoking seizures, antiseizure medications, and most importantly about first aid during seizure (e.g., 7% of respondents believed it is necessary to put something between teeth of a patient during seizure). Age and the year of study were well correlated with knowledge score (p = 0.008) and level of awareness of the stereotypes. We found that most personality traits do not have a strong impact on the level of knowledge about epilepsy. CONCLUSIONS: Most students have a satisfying level of knowledge about epilepsy. Academic teachers should put more emphasis on first aid during seizures and awareness of psychosocial challenges associated with the disease. It is crucial for future physicians to not only possess sufficient theoretical knowledge, but also establish an empathetic doctor-patient relationship in order to provide better care for patients with epilepsy and other chronic diseases.

Expanding the phenotype of DNAJC30-associated Leigh syndrome.

Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

Epilepsy awareness among school-aged students in Poland.

OBJECTIVE: Epilepsy can be a well-controlled condition with only a slight impact on patients' life. Lack of knowledge within society contributes to children with epilepsy experiencing discrimination and hostility. The aim of this study was to evaluate the awareness of epilepsy and general views on people struggling with this disease among school-aged children. METHODS: The study was conducted on a random sample of Polish school students, in total 472 participants. Participants' knowledge was assessed by a self-completed survey. RESULTS: Students are unaware of the wide range of symptoms occurring during seizures. More than half claimed that people experiencing epilepsy should not perform sports activities. Alarmingly, 30% of participants believe that those patients should not leave the house and they should be excluded from many jobs. Almost all participants would help a person experiencing seizures and remember proper head protection; shockingly, 20% of children would try to put something in the person's mouth. Older students seem to be better educated on epilepsy, but the percentage of incorrect personal beliefs and myths is similar for each age group. SIGNIFICANCE: School-aged students have insufficient knowledge of epilepsy. More emphasis should be put on first aid during seizures and on the spectrum of epilepsy symptoms. Educating society is important for life quality of people experiencing epilepsy.

COVID-19 pandemic influence on epilepsy course in pediatric patients.

INTRODUCTION: In 2020, Coronavirus Disease 2019 (COVID-19) was declared as a global pandemic. Self-reported stress, anxiety, and insomnia, which are believed to be common triggers for epilepsy, are more likely to occur. We aimed to establish the influence of COVID-19 pandemic itself on changes in the daily life routine related to pandemic on epilepsy course in pediatric patients. The unique form of clinical care which is telemedicine was also taken into consideration. We wanted to evaluate patients' satisfaction with telemedicine and if changing stationary visits into telemedicine influenced epilepsy course in our patients. METHODS: Patients, who attended developmental neurology outpatient clinic in the period March-December 2020 were collected. As patients were minors, legal guardians were asked to fill out the questionnaire. Patients were divided according to the outcome into three groups: those with a worsened, stable, or improved course of epilepsy during the pandemic. Appropriate statistical tests for two-group and multi-group comparisons have been implemented. Post hoc p values were also calculated. RESULTS: Four hundred and two questionnaires were collected. Most of the patients had a stable course of epilepsy during the pandemic; in 13% of participants an improvement has been observed, worsening of the disease was seen in 16% of patients. Age, sex, type of epilepsy, number of seizure incidents before pandemic, and duration of the disease had no statistically significant connection with changes in the course of the disease. Behavioral changes and altered sleep patterns were found to be more common in the worsened group. Fifty-eight percent of patients were satisfied with telemedicine. Poorer satisfaction was connected with less frequent visits, cancellation of scheduled appointments, and lack of help in case of need in an emergency situation. CONCLUSION: Epilepsy course in pediatric patients seems to be stable during COVID-19 pandemic. Sleep disturbances and changes in a child's behavior may be related to increase in seizure frequency. Telemedicine is an effective tool for supervising children with epilepsy. Patients should be informed about possible ways of getting help in urgent cases.

Development of the Method for Nusinersen and Its Metabolites Identification in the Serum Samples of Children Treated with Spinraza for Spinal Muscular Atrophy.

The application of oligonucleotides as drugs for different genetic diseases is increasing rapidly. Since 2016 they are used during spinal muscular atrophy treatment with the use of nusinersen oligonucleotide. The purpose of this study was to improve methods for the analysis of serum samples of patients treated with nusinersen. The results showed that liquid-liquid extraction (with phenol/chloroform) is insufficient and an additional purification step using solid-phase extraction is necessary. The best results were obtained for microextraction by packed sorbents. Important parameters in the optimization of the method were mainly the type of amine in the mobile phase and the stationary phase. Both influenced the selectivity of metabolite separation and thus their correct identification; while amine type impacted also the intensity of signals. Finally, the highest resolution of separation and the highest peak areas were obtained for N,N-dimethylbutylamine or N,N-diisopropylthylamine with an octadecyl column with a terminal aryl group. Over a dozen of metabolites were successfully identified with the use of methods developed during the study. The 3' exonucleases and 5' exonucleases were mainly responsible for nusinersen metabolism, consequently, 3'end shortmers, and 5'end shortmers were observed, as well as metabolites with simultaneous loss of bases at both ends of the sequence. However, some depurination and depyrimidination products were also identified. To the best of our knowledge, this is the first report on nusinersen and its metabolite identification in serum samples by liquid chromatography and mass spectrometry.

Use of cannabidiol in the treatment of epilepsy.

INTRODUCTION: Cannabis sativa has been cultivated for human use for about 5,000 years, and has likewise been used in the treatment of epilepsy for thousands of years. STATE OF THE ART: Cannabidiol (CBD), which was isolated from cannabis sativa in 1940, has an anti-seizure effect and no psychoactive activity. Its effectiveness in reducing various types of seizures has been proven in animal seizure and epilepsy models. Recent randomised, placebo-controlled trials have confirmed its effectiveness in patients with drug-resistant epilepsy. CLINICAL IMPLICATIONS: The aim of this position paper was to present the specific mechanism of CBD's anti-seizure action and current indications for CBD's use in epilepsy. The only cannabis-derived drug that has successfully passed clinical trials and has obtained United States Food and Drug Administration and European Medicines Agency approval for epilepsy is Epidiolex®. This paper presents the outcomes of the completed clinical trials with the use of this drug. FUTURE DIRECTIONS: CBD may be an effective drug in drug-resistant epilepsy, particularly in Dravet Syndrome, Lennox- Gastaut Syndrome and seizures associated with tuberous sclerosis complex. Additional randomised, placebo-controlled studies with CBD are needed.

Milestones in genetics of cerebellar ataxias.

Cerebellar ataxias (CAs) comprise a group of rare, neurological disorders characterized by extensive phenotypic and genetic heterogeneity. The core clinical feature is the cerebellar syndrome, which is often accompanied by other neurological or non-neurological signs. In the last 30 years, our understanding of the CA etiology has increased significantly, and numerous ataxia-associated genes have been discovered. Conventional variants or tandem repeat expansions, localized in the coding or non-coding DNA sequences, lead to hereditary ataxia, which can display different patterns of inheritance. Advances in molecular techniques have enabled a rapid and cost-effective detection of causative variants in a significant number of CA patients. However, despite performing extensive investigations, a definite diagnosis is still unknown in the majority of affected individuals. In this review, we discuss the major advances in the genetics of CAs over the last 30 years, focusing on the impact of next-generation sequencing on the genetic landscape of childhood- and adult-onset CAs. Additionally, we outline possible directions for further genetic research in hereditary and sporadic CAs in the era of increasing application of whole-genome sequencing and genome-wide association studies in various neurological disorders.

Time to onset of cannabidiol (CBD) treatment effect in Lennox-Gastaut syndrome: Analysis from two randomized controlled trials.

OBJECTIVE: To estimate time to onset of cannabidiol (CBD) treatment effect (seizure reduction and adverse events [AEs]), we conducted post hoc analyses of data from two randomized, placebo-controlled, Phase 3 trials, GWPCARE3 (NCT02224560) and GWPCARE4 (NCT02224690), of patients with Lennox-Gastaut syndrome. METHODS: Patients received plant-derived pharmaceutical formulation of highly purified CBD (Epidiolex, 100 mg/ml oral solution) at 10 mg/kg/day (CBD10; GWPCARE3) or 20 mg/kg/day (CBD20; both trials) or placebo for 14 weeks. Treatment started at 2.5 mg/kg/day for all groups and reached 10 mg/kg/day on Day 7 and 20 mg/kg/day (CBD20 and matching placebo only) on Day 11. Percentage change from baseline in drop seizure frequency was calculated by cumulative day (i.e., including all previous days). Time to onset and resolution of AEs were evaluated. RESULTS: Overall, 235 patients received CBD (CBD10 [GWPCARE3 only], n = 67; CBD20 [pooled GWPCARE3&4], n = 168) and 161 received placebo. Mean (range) age was 15.3 years (2.6-48.0). Patients had previously discontinued a median (range) of six (0-28) antiepileptic drugs (AEDs) and were currently taking a median of three (0-5) AEDs. Differences in drop seizure reduction between placebo and CBD emerged during the titration period and became nominally significant by Day 6 (p = .008) for pooled CBD treatment groups. Separation between placebo and CBD in ≥50% responder rate emerged by Day 6. Onset of the first reported AE occurred during the titration period in 45% of patients (CBD10, 46%; CBD20, 52%; placebo, 38%). In patients with AEs, resolution occurred within 4 weeks of onset in 53% of placebo and 39% of CBD patients and by end of study in 63% of placebo and 61% of CBD patients. SIGNIFICANCE: Treatment effect (efficacy and AEs) of CBD may occur within 1 week of starting treatment. Although AEs lasted longer for CBD than placebo, most resolved within the 14-week period.

Long-term safety and efficacy of add-on cannabidiol in patients with Lennox-Gastaut syndrome: Results of a long-term open-label extension trial.

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add-on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long-term open-label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. METHODS: Patients received plant-derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. RESULTS: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3-1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE-related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty-five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%-71% for drop seizures and 48%-68% for total seizures through 156 weeks. Across all 12-week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: Long-term add-on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long-term benefits of CBD treatment for patients with LGS.

Peri-ictal headaches in the paediatric population - prospective study.

INTRODUCTION: The co-occurrence of headache and epilepsy is well-documented in the adult population. The aim of the prospective study was to analyse in the paediatric population the correlations between the types of peri-ictal headaches and types of seizures. Furthermore, an attempt was made to find trends in characteristic features of peri-ictal headaches.Material: A total of 57 children with peri-ictal headache were enrolled in the study. The participants' guardians were asked to keep a diary of the seizure and peri-ictal headache episodes during a 180-day period. During follow-up visits, systematic history regarding peri-ictal headaches was taken. RESULTS: A total of 913 seizure and 325 peri-ictal headache episodes were noted during the study. Post-ictal headaches were most common, occurring in < 1 h after the seizure, lasting minutes to hours and more likely to occur after generalised seizures, whereas pre-ictal headaches occurred 30-240 min before the seizure. In the analysed group, peri-ictal headaches were most often moderate in intensity. Only 30% of patients took analgesic medication, usually to treat post-ictal headaches. CONCLUSION: Peri-ictal headaches are a significant health problem for patients with epilepsy. The most common type are post-ictal headaches, and they are most likely to appear after a generalised seizure.

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.

OBJECTIVES: To assess the efficacy and safety profile of add-on cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) on clobazam and in the overall population of four randomized, controlled phase 3 trials. METHODS: Patients received plant-derived, highly purified CBD medicine (Epidiolex® in the USA; Epidyolex® in Europe; 100 mg/ml oral solution) at a dose of 10 or 20 mg/kg/day, or placebo for 14 weeks. A subgroup analysis of patients on clobazam and meta-analysis by syndrome were conducted. The primary endpoint was percentage reduction in primary seizure type during the treatment period. RESULTS: 396 patients with LGS (49% on clobazam) and 318 patients with DS (64% on clobazam) were included. CBD treatment resulted in a reduction in primary seizure frequency vs placebo in the overall population (treatment ratio [95% confidence interval]: LGS, 0.70 [0.62-0.80]; DS, 0.71 [0.60-0.83]) and in patients receiving clobazam (LGS, 0.56 [0.47-0.67]; DS, 0.63 [0.52-0.77]). The antiseizure efficacy of CBD was also demonstrated across other endpoints vs placebo (≥50% responder rate, total seizure frequency, number of seizure-free days, and Subject/Caregiver Global Impression of Change scores) in the overall populations and in patients receiving clobazam. There were higher incidences of somnolence and sedation in patients on CBD and clobazam. Most incidences of elevated transaminases occurred in patients on concomitant valproate and, to a lesser extent, clobazam. CONCLUSIONS: Add-on CBD was effective in reducing seizures in the overall populations and in conjunction with clobazam. Somnolence and sedation occurred more frequently in patients on CBD and clobazam.

Nusinersen treatment of Spinal Muscular Atrophy Type 1 - results of expanded access programme in Poland.

AIM OF THE STUDY: This study aimed to evaluate the effects of nusinersen therapy in Polish children with SMA type 1. CLINICAL RATIONALE OF STUDY: Spinal muscular atrophy (SMA) is a neuromuscular disorder that is characterised by the loss of motor neurons, progressive muscle weakness and atrophy, leading to increased disability and mortality. Nusinersen, an antisense oligonucleotide that promotes production of the functional survival motor neuron protein is approved for the treatment of SMA 5q in the European Union. In 2017, an early access programme (EAP) for nusinersen was launched in Poland. In this study, we present the results of nusinersen treatment in Polish patients participating in the EAP. MATERIALS AND METHODS: We collected prospectively clinical data including mutational analysis of SMN1 and SMN2 genes, motor function outcomes as measured on a standardized scales, ventilatory and nutritional status, on SMA type 1 patients receiving nusinersen in three EAP centres in Poland. Scores on the CHOP-INTEND scale after 18-26 months of treatment were compared to baseline. RESULTS: We analysed data from 26 patients with SMA type 1, mean age 4.79 (2-15) years. The mutational analysis revealed two SMN2 gene copies in the majority of patients (61.54%). Three and four copies were found in 34.62% and 3.84%, respectively. Median disease duration was 21 months. Half (n = 13) of the patients required mechanical ventilation at baseline and 57.69% (n = 15) were fed by nasogastric tube or percutaneous endoscopic gastrostomy. No patient worsened during the follow-up. Mean improvement in CHOP-INTEND from baseline to the last follow-up was 7.38 points (p < 0.001). CHOP-INTEND scores did not decline for any patient. Patients with three or more SMN2 gene copies had higher scores than did the patients with two copies (p = 0.013), and they tended to show greater improvement over time, but the difference was not significant (p = 0.324). Shorter disease duration and higher CHOP-INTEND baseline score were associated with a better response (p = 0.015). Patients with a CHOP-INTEND score above the median had higher scores overall than the rest (p < 0.0013), and they improved significantly more than the rest (p = 0.037). Nusinersen was well tolerated, no new safety findings were identified. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our data indicates that nusinersen treatment might be effective in SMA type 1 patients, regardless of their age and functional status.

Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. METHODS: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. FINDINGS: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. INTERPRETATION: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. FUNDING: GW Pharmaceuticals.

Cannabidiol in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE: In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Diffusion tensor tractography imaging in pediatric epilepsy - A systematic review.

PURPOSE: Recent years brought several experimental and clinical reports applying diffusion tensor tractography imaging (DTI) of the brain in epilepsy. This study was aimed to evaluate current evidence for adding the DTI sequence to the standard diagnostic magnetic resonance imaging (MRI) protocol in pediatric epilepsy. MATERIAL AND METHODS: Rapid and qualitative systematic review (RAE, Rapid Evidence Assessment), aggregating relevant studies from the recent 7 years. The PubMed database was hand searched for records containing terms "tractography AND epilepsy." Only studies referring to children were included; studies were rated using "final quality of evidence." RESULTS: Out of 144 screened records, relevant 101 were aggregated and reviewed. The synthesis was based on 73 studies. Case-control clinical studies were the majority of the material and comprised 43.8% of the material. Low 'confirmability' and low 'applicability' referred to 18 and 17 articles (29.5% and 27.9%), respectively. The sufficient quality of evidence supported performing DTI in temporal lobe epilepsy, malformations of cortical development and prior to a neurosurgery of epilepsy. CONCLUSIONS: The qualitative RAE provides an interim estimate of the clinical relevance of quickly developing diagnostic methods. Based on the critical appraisal of current knowledge, adding the DTI sequence to the standard MRI protocol may be clinically beneficial in selected patient groups with childhood temporal lobe epilepsy or as a part of planning for an epilepsy surgery.

Challenges of caring for a patient with a rare disease--as demonstrated by Cornelia de Lange Syndrome.

There are over 12,500 diseases defined by European researchers as rare disorders occurring in less than 1:2000 live births. The majority of these manifest in childhood. The clinical picture of a rare disorder is dominated by intellectual disability of various severity and organ defects. Targeted therapy is not available for the majority of rare disorders, therefore multidisciplinary patient care is the only means of improving the quality and duration of the patient's life. In this paper, the authors share their experience organizing a system of care for patients with Cornelia de Lange Syndrome. Over the last 13 years, multidisciplinary diagnostics and consultations were provided to 92 patients and their families, including rehabilitation and psychological support. The model suggested here demonstrates a shorter diagnostic process, continuous contact with the patient, his/her family and pediatrician. Guidelines and recommendations regarding the particular rare disease should be published.

EEG biomarkers for the prediction of post-traumatic epilepsy - a systematic review of an emerging field.

Traumatic brain injury (TBI) is often followed by post-traumatic epilepsy (PTE), a condition often difficult to treat and leading to a substantial decline in quality of life as well as increased long-term mortality. The latent period between TBI and the emergence of spontaneous recurrent seizures provides an opportunity for pharmacological intervention to prevent epileptogenesis. Biomarkers capable of predicting PTE development are urgently needed to facilitate clinical trials of putative anti-epileptogenic drugs. EEG is a widely available and flexible diagnostic modality that plays a fundamental role in epileptology. We systematically review the advances in the field of the discovery of EEG biomarkers for the prediction of PTE in humans. Despite recent progress, the field faces several challenges including short observation periods, a focus on early post-injury monitoring, difficulties in translating findings from animal models to scalp EEG, and emerging evidence indicating the importance of assessing altered background scalp EEG activity alongside epileptiform activity using quantitative EEG methods while also considering sleep abnormalities in future studies.