Ketogenic diet modifies ribosomal protein dysregulation in KMT2D Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).

Ketogenic Diets in Children With Intractable Epilepsy and its Effects on Gastrointestinal Function, Gut Microbiome, Inflammation, and Quality of Life.

OBJECTIVES: The ketogenic diet (KD) is a treatment for children with intractable epilepsy (IE), can cause gastrointestinal symptoms, and have an adverse effect on growth, nutrition and quality of life (QOL). This study investigated the extent of these side effects by comparing children with IE on KDs to their counterparts on normal diets. METHODS: Patients with IE were categorized into patients with KD or control groups. Gastrointestinal side effects and QOL were assessed using the PedsQL Gastrointestinal Symptoms Module. Cross sectional growth, gut microbiome compositions, and inflammation levels were also analyzed. RESULTS: Fourteen patients on the KD and 13 control patients were enrolled. Patients had been on KD for a median duration of 15 months (interquartile range: 9.8-60 months). The patients on the KD reported a trend to lower total gastrointestinal symptoms scores (more symptoms) compared to control patients, at 71.1 and 84.9, respectively ( P = 0.06, not significant). Patients on the KD had significantly lower QOL scores compared to control patients ( P = 0.01). Patients on the KD were found to have consistently lower median height/length, weight, and body mass index z scores compared to the controls although these were not statistically significant. Patients on the KD had a lower microbial diversity, Both groups had a normal level of S100A12, a marker of gut inflammation. CONCLUSIONS: Patients on the KD reported a trend to more gastrointestinal symptoms and more QOL concerns compared to controls. Although microbial differences were noted in patients on the KD, this did not result in detectable gut inflammation.

Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant.

Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.

Intraoperative Fluorescein Angiography Can Efficiently Identify Biomarkers and Guide Surgical Decision-Making.

PURPOSE: We sought to develop an efficient method for fluorescein angiography (FA) during digitally assisted vitreoretinal surgery (DAVS). METHODS: A 485-nm bandpass filter was placed into the filter holder of the accessory light sources of the Constellation Vision System with steel modified washers to produce an exciter source. A barrier filter was placed into the blank slot of a switchable laser filter with a 535-nm bandpass filter and another washer or created digitally with a specific color channel using NGENUITY software version 1.4. Fluorescein, 250 to 500 mg, was then injected intravenously during retinal surgery. RESULTS: These fluorescence patterns accurately detect many fluorescein angiography biomarkers, such as determination of vascular filling times, ischemia, neovascularization, shunt vessels, microaneurysms, and leakage into the vitreous. This enhanced surgical visualization permitted intervention in real time such as laser or diathermy to residual microvascular abnormalities after delamination of retinal neovascularization as well as heavier panretinal laser placement in areas of retinal capillary dropout to relatively preserve areas of more intact retinal microcirculation. CONCLUSION: The authors of this study are the first to report an efficient method that permits high-resolution detection of many classic FA biomarkers such as during DAVS to enhance surgical visualization and intervention in real time.

Treatment of severe acute necrotizing encephalopathy of childhood with interleukin-6 receptor blockade in the first 24 h as add-on immunotherapy shows favorable long-term outcome at 2 years.

BACKGROUND: Acute necrotizing encephalopathy (ANE) of childhood is a rare and devastating infection-associated acute encephalopathy. While there are no consensus treatments for ANE, recent case reports suggest a beneficial role for the use of tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 (IL-6) receptor. The correlation of the timing of add-on tocilizumab in relation to long-term outcome has not been reported. METHODS: We report on the timing of administration of tocilizumab in two patients classified as high-risk using the ANE severity score (ANE-SS) with respect to the long-term outcome at 2 years. RESULTS: Case 1 was a 19-month-old previously well boy who presented to a tertiary children's hospital with seizures, evolving status dystonicus and shock. Case 2 was a three-year-old boy who presented to a peripheral hospital with fever, sepsis and encephalopathy. The patients were transferred to the tertiary intensive care unit and MRI confirmed ANE with extensive brainstem involvement. Case 1 received intravenous immunoglobulin (IVIg), methylprednisolone and tocilizumab at 21, 39 and 53 h respectively. His modified Rankin scale (mRS) at discharge and two years was unchanged at 5. The functional independence measure - for children (WeeFIM) at two years was very low (19/126). Case 2 received dexamethasone at 1 h, methylprednisolone at 21 h and IVIg and tocilizumab at 22 h. The mRS at discharge and two years was 4 and 3 respectively. The WeeFIM score at two years showed substantial improvement (96/126). CONCLUSION: The very early use of interleukin-6 blockade as 'add-on' immunotherapy in the first 24 h demonstrates potential for improving the long-term outcome in patients classified as high-risk using the ANE-SS.

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

OBJECTIVE: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. METHODS: We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. RESULTS: All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day-10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n = 5), myoclonic (n = 2), epileptic spasms (n = 2), focal (n = 1), and migrating focal (n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value = .0085, log-rank test). SIGNIFICANCE: Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

Urgent computed tomography angiography in paediatric stroke.

AIM: To improve delivery of acute therapies for acute ischaemic stroke (AIS). METHOD: We identified factors influencing the speed of diagnosis and delivery of acute therapies in a prospective cohort of 21 children with suspected AIS (eight with AIS, 13 stroke mimics) and explored them in a retrospective cohort with confirmed AIS. RESULTS: Approximately half of the prospective and total AIS cohorts presented with acute, sustained hemiparesis, and were diagnosed relatively quickly. AIS was suspected and diagnosed more slowly in the half presenting with symptoms other than sustained hemiparesis. Thirty-one out of 51 patients with AIS (19 females, 32 males, mean age 8 years 6 months, SD 5 years 4 months) had arterial abnormalities identified by computed tomography angiography (CTA) or magnetic resonance angiography (MRA): 11 with large vessel occlusion, six with dissection, five with moyamoya disease, nine with other arteriopathies. Among these patients, those initially imaged with CTA were diagnosed more quickly than those with initial magnetic resonance imaging/angiography, which facilitated thrombectomy and thrombolytic therapy. Twenty out of 51 had AIS without arterial abnormalities on CTA or MRA: eight with lenticulostriate vasculopathy and 12 with other small-vessel AIS. Among these patients, 80% were ineligible for thrombolysis for reasons beyond delay to diagnosis, and all showed good outcomes with supportive treatments alone. INTERPRETATION: Clinical features at presentation influence rapidity with which childhood AIS is suspected and diagnosed. Readily available CTA can direct thrombectomy in patients with large vessel occlusion and thrombolysis in most, but not all, eligible patients. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) commonly present with symptoms other than sustained hemiparesis. Stroke is more slowly recognized in these patients, which limits potential therapies. Computed tomography angiography (CTA) accurately identifies AIS with large vessel occlusion, enabling timely endovascular thrombectomy. CTA is sufficient to direct thrombolytic therapy in most eligible children. Most childhood AIS without arterial abnormalities identified by CTA had good outcomes.

The need for improved management of status epilepticus in children in Australia: Time from seizure onset to treatment is consistently delayed.

AIM: To determine if the management of paediatric status epilepticus (SE) follows accepted clinical practice guidelines. METHODS: Retrospective, consecutive series of patients with SE who attended the emergency departments from two NSW sites over a 12-month period. SE was defined as a convulsive seizure, 5 min or more in duration. Time to presentation to the ED, time to first- and second-line treatment, number of benzodiazepine (BZD) doses given prior to intubation and adherence to guidelines were evaluated. The outcomes included seizure duration, need for respiratory support, admission to intensive care, morbidity and mortality. RESULTS: The time from onset of seizure to ED presentation was a median (p25-p75) time of 22 (15-40) min. Forty-eight of 59 presentations received pre-hospital midazolam. The median (p25-p75) time to first-line treatment was 15 (8-25) min and to second-line treatment was 43.5 (35-59) min. There was no significant difference in the results in the two hospitals. The total number of BZD doses ranged from 1 to 7 (median 3). There was non-adherence to the clinical practice guidelines in 55 (93.2%) of 59 presentations. CONCLUSIONS: We found excessive benzodiazepine use and delay in both definitive treatment of status epilepticus and in escalation from first- to second-line anticonvulsant treatment. This raises the need for rapid escalation of treatment. We propose a 'status epilepticus code' for emergency departments.

Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies.

OBJECTIVE: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). METHODS: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15). RESULTS: Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked. CONCLUSION: WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

Endovascular clot retrieval for acute ischaemic stroke due to basilar artery occlusion in childhood.

Endovascular clot retrieval (ECR) is an emerging therapy for treatment of acute ischaemic stroke (AIS) in adults, including basilar artery occlusion (BAO). Its role in children is not well established. We report four consecutive children with AIS due to BAO treated with ECR in Sydney, Australia. We reviewed the literature to characterize the 'natural course' of AIS due to BAO in children not treated with thrombolysis or ECR, and compared their outcome with our patients and reported children with BAO treated with ECR. Despite delays in diagnosis, ECR achieved recanalization in our four children. Three children had a good outcome (Paediatric Modified Rankin Score [PedmRS] 0-2). One child with acute leukaemia suffered recurrent basilar occlusion and died of brainstem dysfunction. Literature review identified 111 children exhibiting the natural course of AIS due to BAO, among whom 42% had good outcomes (PedmRS 0-2), 48% had significant residual disability (PedmRS 3-5), and 10% died. Of 34 children treated with ECR, 28 (82%) had good outcomes (PedmRS 0-2), five (15%) had significant residual disability (PedmRS 3-5), and one (3%) died. Complications of ECR were uncommon. These observations suggest ECR may be beneficial for children with AIS due to BAO. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) due to basilar artery occlusion (BAO) experience significant morbidity and mortality. Endovascular clot retrieval may be beneficial in children with AIS due to BAO.

Management of status epilepticus in children prior to medical retrieval: Deviations from the guidelines.

AIM: To evaluate the influence of adherence to treatment guidelines on outcomes in children presenting with status epilepticus (SE) using the Newborn and Paediatric Emergency Transport Service, New South Wales prospective registry. METHODS: We reviewed the treatment of children with SE, transported by the Newborn And Paediatric Emergency Transport Service to a tertiary paediatric hospital, over 1 year. We evaluated variation in management from the New South Wales clinical practice guideline. RESULTS: There was excessive administration of benzodiazepines (BZD) and a delay in administration of appropriate second-line treatment of status (median 45 min). There was excessive use of BZD, with five or more doses of BZD associated with significantly higher odds for intubation. CONCLUSION: There is considerable scope to improve clinician compliance with the SE clinical practice guidelines.

Myotonic dystrophy type 1: clinical manifestations in children and adolescents.

OBJECTIVE: Myotonic dystrophy type 1 (DM1) is an autosomal-dominant neuromuscular disease with variable severity affecting all ages; however, current care guidelines are adult-focused. The objective of the present study was to profile DM1 in childhood and propose a framework to guide paediatric-focused management. DESIGN, SETTING AND PATIENTS: 40 children with DM1 (mean age 12.8 years; range 2-19) were studied retrospectively for a total of 513 follow-up years at Sydney Children's Hospital. 143 clinical parameters were recorded. RESULTS: The clinical spectrum of disease in childhood differs from adults, with congenital myotonic dystrophy (CDM1) having more severe health issues than childhood-onset/juvenile patients (JDM1). Substantial difficulties with intellectual (CDM1 25/26 96.2%; JDM1 9/10, 90.0%), fine motor (CDM1 23/30, 76.6%; JDM1 6/10, 60.0%), gastrointestinal (CDM1 17/30, 70.0%; JDM1 3/10, 30.0%) and neuromuscular function (CDM1 30/30, 100.0%; JDM1 25/30, 83.3%) were evident. CONCLUSION: The health consequences of DM1 in childhood are diverse, highlighting the need for paediatric multidisciplinary management approaches that encompass key areas of cognition, musculoskeletal, gastrointestinal, respiratory, cardiac and sleep issues.

Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

OBJECTIVE: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment. STUDY DESIGN: Prospective, open label cohort study. SETTING: Three tertiary NSW referral centres with paediatric neurology services. PARTICIPANTS: First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures. INTERVENTION: Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks. OUTCOME MEASURES: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity. RESULTS: Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved. CONCLUSION: Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.

Cost implications of PSA screening differ by age.

BACKGROUND: Multiple guidelines seek to alter rates of prostate-specific antigen (PSA)-based prostate cancer screening. The costs borne by payers associated with PSA-based screening for men of different age groups-including the costs of screening and subsequent diagnosis, treatment, and adverse events-remain uncertain. We sought to develop a model of PSA costs that could be used by payers and health care systems to inform cost considerations under a range of different scenarios. METHODS: We determined the prevalence of PSA screening among men aged 50 and higher using 2013-2014 data from a large, multispecialty group, obtained reimbursed costs associated with screening, diagnosis, and treatment from a commercial health plan, and identified transition probabilities for biopsy, diagnosis, treatment, and complications from the literature to generate a cost model. We estimated annual total costs for groups of men ages 50-54, 55-69, and 70+ years, and varied annual prostate cancer screening prevalence in each group from 5 to 50% and tested hypothetical examples of different test characteristics (e.g., true/false positive rate). RESULTS: Under the baseline screening patterns, costs of the PSA screening represented 10.1% of the total costs; costs of biopsies and associated complications were 23.3% of total costs; and, although only 0.3% of all screen eligible patients were treated, they accounted for 66.7% of total costs. For each 5-percentage point decrease in PSA screening among men aged 70 and older for a single calendar year, total costs associated with prostate cancer screening decreased by 13.8%. For each 5-percentage point decrease in PSA screening among men 50-54 and 55-69 years old, costs were 2.3% and 7.3% lower respectively. CONCLUSIONS: With constrained financial resources and with national pressure to decrease use of clinically unnecessary PSA-based prostate cancer screening, there is an opportunity for cost savings, especially by focusing on the downstream costs disproportionately associated with screening men 70 and older.

Outcomes of deviation from treatment guidelines in status epilepticus: A systematic review.

OBJECTIVE: Due to a gap between published clinical guidelines on status epilepticus SE and clinician management of SE, a systematic review was performed to investigate treatment adherence to SE guidelines and its impact on patient outcomes. METHODS: Medline and Embase searches were conducted for studies appraising adherence to SE guidelines (from 1970 and 1st April 2018). The quality of eligible studies was assessed by QUADAS- 2 criteria. Comparison was made between patients where guidelines were followed and not followed. Various patient outcomes including intubation, ICU admission, morbidity and mortality were compared. A Forest plot was used to investigate the effect of adherence on outcome. RESULTS: A total of 3424 titles and abstracts were screened from the initial search after removal of duplicates. A total of 441 full text articles were reviewed in detail, and 22 articles were included in this study. The proportion of deviations ranged from 10.7% to 66.1%. Four studies were descriptive. Eighteen studies looked at the adverse effects of non-adherence. Eight studies showed respiratory depression and intubation were associated with excessive benzodiazepine use. A subset analysis showed 5.79 times higher odds of respiratory depression and intubation], if excessive benzodiazepines were given. The next most common variations were delayed management and insufficient treatment. These variations from the guidelines were associated with prolonged seizures. CONCLUSIONS: This review provides preliminary evidence that non-adherence to SE guidelines negatively impacts on patient outcomes. Appropriate and timely treatment is imperative for rapid seizure termination and improving outcomes.

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

Cannabis for paediatric epilepsy: challenges and conundrums.

Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term.

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness.

BACKGROUND: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. METHODS: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. RESULTS: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported. CONCLUSION: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.

Risk Factors for Peri-Procedural Arterial Ischaemic Stroke in Children with Cardiac Disease.

Improved survival of children with congenital heart disease has led to increasing focus on neurodevelopmental outcome, as close to half of the infants undergoing cardiac surgery are affected by neurodevelopmental disability. Stroke is particularly important as it frequently results in permanent neurologic sequelae. The aim of this study was to investigate risk factors for peri-procedural arterial ischaemic stroke (AIS) in children with cardiac disease. A retrospective case-control analysis of children aged <18 years with radiologically confirmed AIS following a cardiac procedure admitted to the Royal Children's Hospital Melbourne between 1993 and 2010. Each case was matched with two controls with similar cardiac diagnosis, procedure type, age and date of procedure. Demographics and peri-procedural data were collected from medical records and departmental database. Fifty-two cases were identified. Multivariable analysis identified post-procedural infection (OR 6.1, CI 1.3-27, p = 0.017) and length of ICU stay (OR 4.0, CI 1.4-11, p = 0.009) as risk factors for AIS. Although the study is limited to a single-centre cohort, length of ICU stay and post-procedural infection were identified as risk factors for AIS. These findings demonstrate these factors to be important areas to focus attention for stroke prevention in children with cardiac disease.

Quality of life and excessive daytime sleepiness in children and adolescents with myotonic dystrophy type 1.

OBJECTIVES: Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disease with variable severity that affects all ages. Sleepiness is an important co-morbidity affecting a large proportion of paediatric DM1 patients. The current study examined the relationship between sleepiness and quality of life in a paediatric DM1 cohort. METHODS: A cross-sectional study was conducted in children and adolescents with DM1 attending a multi-disciplinary neuromuscular clinic in a tertiary paediatric centre. The modified Epworth sleepiness scale (ESS), the PedsQL™ quality of life (version 4.0) and neuromuscular modules (version 3.0) were used to measure sleepiness, generic quality of life and neuromuscular-specific quality of life, respectively. RESULTS: Seventeen current patients with DM1 completed all questionnaires and assessments. Of them, 35.5% had abnormal scores on the modified ESS, which is indicative of excessive daytime sleepiness (EDS). Higher ESS scores were highly significantly related to reduced quality of life in neuromuscular-specific (r = 0.77, p < 0.001) and generic measures (r = 0.78, p < 0.001). EDS was not significantly related to intellectual function or sleep disorders as detected on polysomnography. CONCLUSIONS: EDS is common in children and adolescents with DM1. It is associated with reduced quality of life and should be routinely assessed. Further studies to develop treatments of EDS in this population are required and may improve overall outcomes.