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Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect ≈90% of individuals with TSC and significantly reduce their quality of life (QoL). However, there are limited studies assessing pharmacotherapy for TAND. A plant-derived highly purified pharmaceutical formulation of cannabidiol (CBD; Epidiolex ® /Epidyolex ® oral solution) is approved for seizures associated with TSC. Anecdotal evidence also suggests psychiatric, neuropsychological, and behavioral benefits of CBD. EpiCom ( Epi lepsy Com orbidities; NCT05864846; EU-CT, 2023-507426-17), a multicenter, open-label, phase 3b/4 study, with hybrid decentralized approach, was designed in collaboration with patient advisory groups and healthcare professionals to evaluate behavioral and other outcomes following adjunctive CBD treatment in individuals with TSC-associated seizures. EpiCom will enroll participants, aged 1–65 years (United States [US]) or 2–65 years (United Kingdom [UK], Canada, and Poland), who are starting CBD for seizures and have moderate/severe behavioral challenges according to the Caregiver Global Impression of Severity scale at screening. Participants will receive CBD (up to 25 mg/kg/d based on individual response and tolerability) in addition to their standard of care (SoC) for 26 weeks, after which participants may choose to continue CBD with SoC or SoC alone for an additional 26 weeks. Key efficacy endpoints include change from baseline on the Aberrant Behavior Checklist (e.g., irritability subscale) and the most problematic behavior on the TAND-Self-Report, Quantified Checklist. Changes in executive function, sleep, QoL, family functioning, seizure outcomes (severity, responder rates, seizure-free days), retention rate, and safety will be evaluated. The trial will enroll ≈75 participants at ≈20 sites across the US, the UK, Canada, and Poland. EpiCom will assess the changes in behavioral and other outcomes associated with TAND and seizure outcomes, including overall symptom severity and treatment retention, following adjunctive CBD treatment in individuals with TSC-associated seizures. The results will inform future studies evaluating pharmacotherapy for behavioral outcomes in similar populations.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an ultrarare genetic condition causing developmental epileptic encephalopathy characterized by seizures and motor and intellectual disabilities. No disease-modifying therapies are available, and treatments focus mainly on symptom management to improve quality of life. The aim of this study was to better understand the burden of CDD based on family caregivers' perceptions. The study was a cross-sectional, web-based survey comprising 40 questions for caregivers of patients with CDD and focusing on sociodemographic and medical characteristics, disease burden, unmet needs, treatments, and support. An adapted version of the EQ-5D-5L instrument was included to measure patients' health-related quality of life as perceived by their caregivers. A total of 132 caregivers, mostly from western parts of Europe, responded. The median patient age was 7.6 (IQR 2.9-12.2) years. Seizure onset occurred early, with the median onset at 2.0 (IQR 1.0-3.0) months of age. The median age at diagnosis was 1.2 (IQR 0.6-4.0) years. Epilepsy (123/132, 93.2%) and limited communication skills (111/132, 84.1%) were the most commonly reported symptoms. The highest number of different types of symptoms was reported for patients aged 5-9 years, with a median of 9.0 (IQR 7.5-10.0) symptoms. Most patients with epilepsy experienced daily seizures (81/123, 65.9%), and nearly all (119/123, 96.7%) were on antiseizure medications. A minority was on a ketogenic diet (21/123, 17.1%) or underwent vagus nerve stimulation (14/123, 11.4%). The care received was multidisciplinary. Compared to younger patients, adults had fewer medical appointments and a smaller variety of health care professionals in their care team. The EQ-5D-5L, adapted for caregivers, indicated low health-related quality of life for patients, with a median global index value of 0.18 (IQR 0.11-0.32). The most severe consequences of CDD on patients' daily lives were reported for mobility (88/132, 66.7%), self-care (120/132, 90.9%), and everyday activities (103/132, 78.0%). Caregiver burden was also substantial, with all life aspects reportedly impacted by CDD, including professional life and financial resources (median impact ratings of 9.0/10 and 7.0/10, respectively). Access to support and care varied depending on location. Caregivers outside Europe reported a longer time between the first seizure and diagnosis (26.5, IQR 3.2-47.0 months) compared to European caregivers (11.0, IQR 5.0-45.0 months). They also reported a higher impact of CDD on their financial resources (rating of 10/10) compared to European caregivers (rating of 6/10) and greater challenges in covering costs. The study findings provide valuable insights on symptoms and disease burden related to CDD. This burden was quantitatively characterized with the EQ-5D-5L for the first time and was perceived as substantial by family caregivers. Discrepancies between geographic regions and age groups were highlighted, especially regarding available support and access to resources and care.

Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The disorder is characterized by intractable early‐onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment and microcephaly. With no disease‐modifying therapies available for CDD, treatment is symptomatic with an initial focus on seizure control. Another unmet need in the management of people with CDD is the lack of evidence to aid standardized care and guideline development. To address this gap, experts in CDD and representatives from patient advocacy groups from Denmark, Finland, France, Germany, Italy, Poland, Spain, and the United Kingdom convened to form an Expert Working Group. The aim was to provide an expert opinion consensus on how to ensure quality care in routine clinical practice within the European setting, including in settings with limited experience or resources for multidisciplinary care of CDD and other developmental and epileptic encephalopathies. By means of one‐to‐one interviews around the current treatment landscape in CDD, insights from the Expert Working Group were collated and developed into a Europe‐specific patient journey for individuals with CDD, which was later validated by the group. Further discussions followed to gain consensus of opinions on challenges and potential solutions for achieving quality care in this setting. The panel recognized the benefit of early genetic testing, a holistic personalized approach to seizure control (taking into consideration various factors such as concomitant medications and comorbidities), and age‐ and comorbidity‐dependent multidisciplinary care for optimizing patient outcomes and quality of life. However, their insights and experiences also highlighted much disparity in management approaches and resources across different European countries. Development of standardized European recommendations is required to align realistic diagnostic criteria, treatment goals, and management approaches that can be adapted for different settings. Plain language summary Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is a rare condition caused by a genetic mutation with a broad range of symptoms apparent from early childhood, including epileptic seizures that do not respond to medication and severe delays in development. Due to the lack of guidance on managing CDD, international experts and patient advocates discussed best practices in the care of people with CDD in Europe. The panel agreed that early testing, a personalized approach to managing seizures, and access to care from different disciplines are beneficial. Development of guidelines to ensure that care is standardized would also be valuable.

ObjectiveAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. Diagnosis of AADCd is often delayed because of variable clinical presentation. Patients are frequently misdiagnosed with more common conditions, such as cerebral palsy (CP) owing to a lack of AADCd awareness. REVEAL-CP is a prospective, multicentre, multinational, interventional, non-registrational study designed to investigate the prevalence of AADCd in patients presenting with symptoms of CP and to characterise genotypes associated with high 3-O-methyldopa (3-OMD) levels in dried blood spot samples. Following the study, UK paediatric neurologist investigators completed a survey on learning opportunities to improve the early identification of patients with AADCd who may be eligible for treatment.MethodsThe REVEAL-CP study screened patient records. After exclusion of patients with genetic and/or CSF neurotransmitter analysis, 49 UK patients were identified as being suitable for 3-OMD testing. Following the study, UK investigators completed a survey developed in collaboration with PharmaGenesis London, a third-party agency, including questions requiring yes/no, Likert scale (strongly agree; somewhat agree; neither agree nor disagree; somewhat disagree; strongly disagree; don’t know) and/or qualitative responses. Consensus was reached if the majority of investigator respondents somewhat or strongly agreed to individual questions.ResultsSix investigators completed the survey and reached consensus on the following recommendations to improve AADCd patient identification in the UK: adoption of a more centralised record system between NHS trusts, particularly between community and secondary paediatric practices; implementing genetic testing as the primary diagnostic tool for patients with CP-like symptoms of unknown aetiology; increasing awareness among clinicians of the differential diagnosis of neurotransmitter disorders in patients with CP-like symptoms; and earlier use of 3-OMD testing in the diagnostic workup of patients presenting with unexplained movement disorders or CP-like symptoms, alongside testing for serum prolactin and urinary organic acids including vanillactate, through the establishment of a nationally accredited 3-OMD service.ConclusionsA greater number of patients with CP-like symptoms of unknown aetiology could be screened for AADCd, taking into consideration the investigators’ suggestions. For rare diseases like AADCd, the provision of additional resources will be key for targeted patient screening. Given the recent EMA and MHRA marketing authorisation approvals for the first licensed gene therapy for AADCd, these improved efforts for early diagnosis could prove critical to the timely and effective management of patients with AADCd.ReferencesRizzi S, et al. Behav Neurol 2022;2022:2210555.Opladen T, et al. Mol Genet Metab Rep 2016;9:61–6.Burlina A, et al. Mol Genet Metab 2021;133:56–62.Chien YH, et al. Mol Genet Metab 2016;118:259–63.

ObjectiveIn a recent review of life expectancy for those with severe impairment with cerebral palsy (CP), Rosenthal’s conclusions stated, ‘tracheostomies deserve further debate and data acquisition’.1 We sourced clinical information using healthcare coding data (used for funding within the National Health Service) from one regional hospital.MethodsThe authors collaborated with business intelligence data analysts to identify two deceased CP datasets with and without a history of tracheostomy. ICD10 codes were used for CP and tracheostomy in addition to OPCS4 (procedural codes). Medical records of deceased patients with CP were reviewed. The data collected included: demographic data, age at death, cause of death, aetiology, age of tracheostomy and comorbidity data of tube feeding, non-invasive ventilation, epilepsy, movement disorder, severe learning difficulties and unassisted ambulation. Patients born after a single point in time were used to ensure comparable medical care. Patients with tracheostomy were cross-checked with an in-department record; no records had been omitted, and missing data were presented in the analysis.ResultsIn those with CP and tracheostomy (CPTrache) (n=6), the median age of death was 14.6 (range: 6.1 – 37.3) and a median age of tracheostomy insertion of 7.9 (range: 0.0 – 29.0). Those with CP who had not undergone tracheostomy insertion (CPNoTrache) had a median age of death of 12.5 (range 0.5 – 36.6). Compared to the CPNoTrache group, the CPTrache group had a higher prevalence of grade 5 GMFCS (CPTrache vs CPNoTrache; 100% vs 52%), tube-feeding (100% vs 76%), Non-invasive ventilation (67% vs 12%), and severe learning difficulties (100% vs 82%) compared to the CPNoTrache group.ConclusionsWe prove that coding data can support clinical research on rare and complex conditions. We have demonstrated that this method does not omit patients with a history of tracheostomy. We provide the first observational data on the outcomes of individuals with CP with tracheostomy and the differing prevalence of comorbidities compared to the CP population without tracheostomy. Although there is no significant difference in survival age, the patients with CP who have undergone tracheostomy insertion appear to have higher rates of comorbidities. This study would benefit from a greater cohort size via analysis of national Hospital Episode Statistics and data and the use of additional codes to assess for comorbidities, e.g., epilepsy, in place of an author review of medical notes.ReferenceRosenthal M. Life expectancy and its adjustment in cerebral palsy with severe impairment: Are we doing this right? Developmental Medicine and Child Neurology 2022;64(6):709–14.

CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2–21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of –30·7% (IQR –49·5 to –1·9) in the ganaxolone group and of –6·9% (–24·1 to 39·7) in the placebo group (p=0·0036). The Hodges–Lehmann estimate of median difference in responses to ganaxolone versus placebo was –27·1% (95% CI –47·9 to – 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. Marinus Pharmaceuticals.

BackgroundThe evidence base to guide the pharmacological management of tone and abnormal movements in cerebral palsy (CP) is limited, as is an understanding of routine clinical practice in the UK. We aimed to establish details of motor phenotype and current pharmacological management of a representative cohort across a network of UK tertiary centres.MethodsProspective multicentre review of specialist motor disorder clinics at nine UK centres, collecting data on clinical features and pharmacological management of children and young people (CYP) with CP over a single calendar month.ResultsData were collected from 275 CYP with CP reviewed over the calendar month of October 2017. Isolated dystonia or spasticity was infrequently seen, with a mixed picture of dystonia and spasticity ± choreoathetosis identified in 194/275 (70.5%) of CYP. A comorbid diagnosis of epilepsy was present in 103/275 (37.4%). The most commonly used medications for abnormal tone/movement were baclofen, trihexyphenidyl, gabapentin, diazepam and clonidine. Medication use appeared to be influenced separately by the presence of dystonia or spasticity. Botulinum toxin use was common (62.2%). A smaller proportion of children (12.4%) had undergone a previous neurosurgical procedure for tone/movement management.ConclusionsCYP with CP frequently present with a complex movement phenotype and comorbid epilepsy. They have multiple therapy, medical and surgical management regimens. Future trials of therapeutic, pharmacological or surgical interventions in this population must adequately encompass this complexity in order to be translatable to clinical practice.

BackgroundIdiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children’s Headache Network to propose a best-practice diagnostic and therapeutic pathway.MethodsThe Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part.ResultsThe Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3.ConclusionsThis UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children’s Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

AimsIdiopathic Intracranial Hypertension (IIH) is associated with headaches and a potential loss of vision. The prevalence may rise with childhood obesity. As there is no strong evidence to support the way IIH is diagnosed or treated, it is important to establish consensus to guide management and identify areas of uncertainty for further research. We conducted a national Delphi consensus process to inform a national guideline for the management of IIH in children and young people.MethodsThe Delphi focused on all aspects of IIH including initial assessments (referral, assessments, laboratory tests, LP, ophthalmology assessments), diagnosis (criteria and terminology) and treatment (including conservative, drug and neurosurgical interventions), follow-up, and surveillance.General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists, and neurosurgeons known to have a clinical interest or experience in IIH were invited to take part.The charity IIH-UK contributed to represent patients and their families. A priori consensus was defined as 70% agreement.ResultsRecommendations are proposed, based on areas of consensus and relate to aspects of IIH patient management, including: timing of assessment, baseline assessments and investigations, recommended diagnostic criteria, LP and CSF pressure interpretation, neuroimaging, MDT meetings, ophthalmological assessments, method for LP (including use of local and general anaesthetic), dietary recommendations, acetazolamide use and neurosurgical management. (For detail please refer to table 2)Abstract 397 Table 1Friedman’s criteriaAbstract 397 Table 2Recommendations based on area of consensusConclusionThis new UK consensus for the management and surveillance of IIH provides a realistic and pragmatic approach, based on expert opinion for best clinical care for children and young people with IIH. We hope these recommendations will minimise under and over diagnosis, improve the care offered, and outcomes obtained.