De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.

Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.

Long-term treatment with ganaxolone for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: Two-year open-label extension follow-up.

OBJECTIVE: In the placebo-controlled, double-blind phase of the Marigold study (NCT03572933), ganaxolone significantly reduced major motor seizure frequency (MMSF) in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD). We report 2-year safety and clinical outcomes data from the open-label extension (OLE) phase of Marigold. METHODS: Patients with CDD who completed the double-blind phase were eligible to continue in the OLE. Efficacy assessments included MMSF reduction from prerandomization baseline, responder rates, and Clinical Global Impression-Improvement scores, including assessment of seizure intensity and duration (CGI-CSID). Safety assessments included treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. RESULTS: Of 101 patients who enrolled in Marigold, 88 (87.1%) entered the OLE (median age = 5 years, 79.5% female). Median 28-day MMSF at baseline was 50.6. At 2 years in the OLE (months 22-24), MMSF was reduced by a median of 48.2% (n = 50); when missing data were imputed, median reduction in MMSF was 43.8% using a mixed effects model and 27.4% using a last observation carried forward model. During months 22-24, 23 of 50 (46.0%) patients experienced reductions in MMSF of ≥50%; 12 of 50 (24.0%) patients experienced MMSF reductions of ≥75%. During months 22-24, 40 of 49 (81.6%) patients were rated by caregivers as having improvement in seizure-related outcomes based on CGI-CSID scores. Thirty-seven patients discontinued ganaxolone due to lack of efficacy (n = 13), withdrawal by caregiver (n = 12), adverse event (n = 10), physician decision (n = 1), or death (n = 1; unrelated to study drug). The most common treatment-related TEAEs were somnolence (17.0%), seizure (11.4%), and decreased appetite (5.7%). Patients reported serious TEAEs (n = 28, 31.8%); those reported in ≥3% of patients were seizure (n = 6), pneumonia (n = 5), acute respiratory failure (n = 3), aspiration pneumonia (n = 3), and dehydration (n = 3). SIGNIFICANCE: Sustained reductions in MMSF at 2 years in the OLE support the efficacy of ganaxolone in seizures associated with CDD. Safety findings in the OLE were consistent with the double-blind phase.

Growth patterns in individuals with CDKL5 deficiency disorder.

AIM: To compare growth in individuals with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder with population norms and to investigate the effect of gastrostomy on growth. METHOD: The longitudinal study included 353 individuals from the International CDKL5 Disorder Database with any anthropometric measurement in baseline and/or follow-up questionnaires. The British 1990 growth reference was used to determine the age- and sex-standardized z-score. Repeated cross-sectional data were fitted using a Gaussian linear regression model with generalized estimating equations. RESULTS: All growth parameters were below the general population norm (mean z-scores: weight -0.97, height -0.65, body mass index [BMI] -0.81, head circumference -2.12). The disparity was particularly pronounced for all anthropometric measurements after 4 years of age except for BMI. Moreover, individuals with gastrostomy placement were shown to have a larger decrease than those without. INTERPRETATION: In addition to weight, height, and BMI, head circumference was also compromised in this disorder. Microcephaly could be considered a helpful diagnostic feature, especially in adults. Any benefit of gastrostomy on weight and BMI was mainly seen in the early years.

The journey of metformin from glycaemic control to mTOR inhibition and the suppression of tumour growth.

Our knowledge of the effect of metformin on human health is increasing. In addition to its ability to improve the control of hyperglycaemia, metformin has been shown to reduce the burden o,f ageing via effects on damaged DNA and the process of apoptosis. Studies have shown that metformin may reduce the risk of cardiovascular disease through influences on body weight, blood pressure, cholesterol levels and the progression of atherosclerosis. Studies also suggest that metformin may be beneficial for neuro-psychiatric disorders, cognitive impairment and in reducing the risk of dementia, erectile dysfunction and Duchenne muscular dystrophy. In vivo and in vitro studies have shown that metformin has anti-cancer properties, and population studies have suggested that metformin may reduce the risk of cancer or improve cancer prognosis. It is thought that it exerts its anti-cancer effect through the inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. Because of its effect on the mTOR pathway, there may be a role for metformin in slowing or reversing growth of life-threatening hamartomas in tuberous sclerosis complex.

Outcome and recurrence 1 year after pediatric arterial ischemic stroke in a population-based cohort.

OBJECTIVE: Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population-based cohort. METHODS: Children aged 29 days to < 16 years with radiologically confirmed AIS occurring over a 1-year period residing in southern England (population = 5.99 million children) were eligible for inclusion. Outcome was assessed during a home visit using the Pediatric Stroke Outcome Measure (PSOM). Parental impressions of recovery were assessed using the Pediatric Stroke Recurrence and Recovery Questionnaire. PSOM score was estimated via telephone interview or clinician interview whenever home visit was not possible. RESULTS: Ninety-six children with AIS were identified. Two children were lost to follow-up. Nine of 94 (10%) children died before the 12-month follow-up. One child had an AIS recurrence. PSOM scores were available for 78 of 85 living children at follow-up. Thirty-nine of 78 (50%) had a good outcome (total PSOM score < 1), and 39 of 78 (50%) had a poor outcome. Seizures at onset of AIS were associated with a poor outcome (odds ratio = 3.5, 95% confidence interval = 1.16-10.6). Twenty-eight of 73 (38%) children were judged by their carers to have fully recovered. Ten of 84 (12%) children had recurrent seizures, and 17 of 84 (20%) reported recurrent headaches. INTERPRETATION: AIS carries a significant risk of mortality and long-term neurological deficit. However, the rates of mortality, recurrence, and neurological impairment were markedly lower in this study than previously published figures in the United Kingdom. Ann Neurol 2016;79:784-793.

Causes of mortality in individuals with tuberous sclerosis complex.

AIM: The causes of death in patients with tuberous sclerosis complex (TSC) have rarely been studied, with only one published account, which was reported from the Mayo Clinic in 1991. We aimed to investigate mortality in a large cohort of patients with TSC from one of two national referral clinics in the UK. METHOD: We identified 284 patients who attended Bath TSC clinic between 1981 and 2015, and ascertained causes of death by reviewing medical records, death certificates, and postmortem reports. RESULTS: Sixteen patients died from complications of TSC: eight from TSC kidney diseases; four from sudden unexpected death in epilepsy (SUDEP); two from lymphangioleiomyomatosis; one from a subependymal giant cell astrocytoma; and one from a pancreatic malignancy. The median age of death was 33 years (interquartile range [IQR] 26-46). Mortality was significantly more common in patients with learning disabilities than in those without (13/135 [9%] vs 3/131 [2%]; two-tailed Fisher exact test p=0.020). INTERPRETATION: Renal disease is a major cause of mortality in TSC. Lifelong surveillance and early intervention is warranted. SUDEP is also an important cause of mortality. Patients with learning disabilities are at significantly greater risk of early mortality and this implies the need for greater vigilance for TSC-related complications in this group. Female patients are vulnerable to pulmonary and renal disease. Pancreatic lesions are a rare but potentially treatable cause of mortality.

Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people.

BACKGROUND: Idiopathic 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: This 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.

Providing quality care for people with CDKL5 deficiency disorder: A European expert panel opinion on the patient journey.

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.

Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments.

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.

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Marinus Pharmaceuticals.

International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.

Treatment Guidelines for Rare, Early-Onset, Treatment-Resistant Epileptic Conditions: A Literature Review on Dravet Syndrome, Lennox-Gastaut Syndrome and CDKL5 Deficiency Disorder.

Background: Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) and CDKL5 deficiency disorder (CDD) are rare epileptic conditions, characterised by drug-resistant seizures. Seizure management in these patients requires careful therapy selection. This targeted literature review (TLR) aimed to collate and synthesise information from country-specific and international treatment guidelines for DS, LGS and CDD. Methods: A TLR was performed between 25th January and 11th March 2021. Online rare diseases and guideline databases were manually searched in addition to websites of national health technology assessment bodies for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK and US, as defined by pre-specified eligibility criteria. Search terms, developed for each condition, were translated into local languages where appropriate. Descriptive analyses were performed to examine the geographical distribution of included guidelines; methodologies used to develop guidelines; cross-referencing of treatment recommendations made within other guidelines; patterns of treatment recommendations. An author map was created using R version 3.5.1, to visualise the extent of collaboration between authors. Results: Forty total guidelines were included, of which 29, 34 and 0 contained recommendations for DS, LGS and CDD, respectively (some provided recommendations for ≥1 condition). Most were country-specific, with guideline authors predominantly publishing in regional groups. Five guidelines were classified as "International" and displayed connections between author groups in the US, UK, France and Italy. Reported guideline development processes were lacking [43% (17 guidelines) had unclear/absent literature review methodologies] and those reported were variable, including both systematic and targeted literature reviews. Use of expert consultation was also variable. A high degree of heterogeneity was observed in the availability of treatment recommendations across disorders, with 271 and 190 recommendations for LGS and DS, respectively, and contradictory positive and negative treatment recommendations for several drugs in each indication [35% (11/31) and 22% (6/27) in LGS and DS, respectively]. Conclusions: This review highlights the need for further high-quality international consensus-based treatment guidelines for LGS, DS, and particularly for CDD (for which no treatment guidelines were identified). Supra-national consensus guidance based on findings from a wider geographical range may improve resource allocation and establish an improved world-wide standard of care.

The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a genetic disorder characterised by the development of benign tumours secondary to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. Metformin inhibits the mTOR pathway. We investigated whether metformin would reduce growth of hamartomas associated with tuberous sclerosis complex. METHODS: In this multicentre randomized, double-blind, placebo-controlled trial, patients with a clinical diagnosis of tuberous sclerosis, aged over 10 years and with at least one renal angiomyolipoma of greater than 1 cm in diameter were enrolled. Participants were randomly allocated (1:1) by a secure website to receive metformin or placebo for 12 months. The primary outcome was percentage volume change of renal angiomyolipomas (AML) at 12 months compared to baseline. Secondary outcomes were percentage change at 12 months from baseline in volume of cerebral Subependymal Giant Cell Astrocytomas (SEGA); appearance of facial and ungual hamartomas; frequency of epileptic seizures; and adaptive behaviour. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 92545532, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2011-001319-30. FINDINGS: Between 1 November 2012 and 30 September 2015 72 patients were screened and 55 were randomly assigned to metformin (28) or placebo (27). Four participants withdrew between randomisation and starting treatment. All 51 patients who started therapy completed the trial and were assessed for outcome at 12 months. The median percentage change in angiomyolipoma (AML) volume was +7.6% (IQR -1.8% to +42.6%) for the placebo group and +8.9% (IQR 1.3% to 19.5%) for the metformin group (p = 0.28). Twenty-seven patients had SEGAs: 13 received placebo and 14 metformin. The median percentage change in SEGA volume was +3.0% (IQR -22.8% to +27.7%) for the placebo group and - 20.8% (IQR - 47.1% to - 5.0%) for the metformin group (p = 0.03). Twenty-one patients were assessed for seizure frequency: 9 received placebo and 12 received metformin. In the metformin group, a mean reduction of 43.7% from baseline in seizures was observed and in the placebo group a 3.1% mean reduction was observed, with a difference in response of 40.6% (95% CI -3.1% to +84.2%, p = 0.03). There were no significant differences between metformin and placebo groups for the other secondary outcomes. There were no deaths. Three serious adverse events (SAEs) occurred during the trial (all patients on metformin). INTERPRETATION: Metformin did not reduce AML volume. Metformin did reduce SEGA volume and seizure frequency compared with placebo. There may be a role for metformin in slowing or reversing growth of some life-threatening hamartomas in TSC and for reducing seizure frequency. Further study is justified. FUNDING: This study was funded by the National Institute for Health and Research (NIHR) through the The Research for Patient Benefit Programme (RfPB).

Intrathecal baclofen pumps in the management of hypertonia in childhood: a UK and Ireland wide survey.

BACKGROUND: Intrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland. METHODS: An electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset. RESULTS: 176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%). CONCLUSIONS: ITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.

Quality of life in patients with Tuberous Sclerosis Complex (TSC).

BACKGROUND: The quality of life (QoL) of patients with Tuberous Sclerosis Complex (TSC) has not been studied before. We aimed to investigate the impact of the disease on QoL. We studied the QoL of 91 TSC patients who have attended the Bath TSC clinic, UK over 6 months. QoL was evaluated using the PedsQL for children, and SF-36 for adults. RESULTS: Impaired QoL is found in all patients with TSC regardless of the presence of epilepsy and learning disabilities (LD). Total mean self-reported score for children was 71 out of 100, compared to a UK norm of 84, p < 0.000. The proxy mean score was 48, (UK norm 85, p < 0.000). Physical Functioning score for adults with TSC was 70, compared to a UK norm of 94, p < 0.000. The Social Functioning score for adults with TSC was 71, (UK norm 88, p < 0.000). CONCLUSIONS: Impaired QoL is found in all patients with TSC regardless of the presence of epilepsy and learning disabilities. The psychosocial domain is most affected. The quality of life of children with TSC is lower than children who suffer from asthma, diabetes, cancer and inflammatory bowel disease. To improve health related quality of life in TSC, a focus on patient's physical health, educational performances, and overall quality of life is crucial. In order to achieve this, coordinated medical care across disciplines, and psychosocial and social support is necessary.

Pharmacological management of abnormal tone and movement in cerebral palsy.

BACKGROUND: The 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. METHODS: Prospective 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. RESULTS: Data 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. CONCLUSIONS: CYP 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.

Severity Assessment in CDKL5 Deficiency Disorder.

BACKGROUND: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. METHODS: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. RESULTS: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. CONCLUSIONS: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.