Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study.

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre.

How to use lumbar puncture manometry in children.

Measurement of cerebrospinal fluid pressure through lumbar puncture (LP) manometry is an essential practical skill all paediatricians should possess competency in. The ability to perform manometry is crucial in the diagnosis of idiopathic intracranial hypertension and can provide critical information on raised (or lowered) intracranial pressure in other clinical scenarios. Practitioners should be familiar with the procedure and in particular with equipment available to them locally. In this article, we will describe an approach to LP manometry. The online supplemental material includes an instructional video as well as supporting practical information.

Bulging Anterior Fontanelle Caused by Severe Acute Respiratory Syndrome Coronavirus-2.

Neurologic manifestations of the 2019 novel coronavirus disease in children are varied. We present the case of a 9-month-old child with bulging anterior fontanelle caused by severe acute respiratory syndrome coronavirus-2.

Neonatal venlafaxine discontinuation syndrome: A mini-review.

During pregnancy, the developing fetal brain may be exposed to a range of psychotropic medications. The serotonin-noradrenergic reuptake inhibitor venlafaxine is one such drug, when used as a maternal antidepressant. Here we review the discontinuation phenomenon that may follow in exposed neonates following birth. Adults who abruptly stop taking venlafaxine can experience withdrawal symptoms. Venlafaxine and its metabolites cross the placenta and so the newborn can be exposed to this risk, as well as potential toxicity. Several case reports document features of encephalopathy following birth in exposed neonates. It is suggested that a possible combination of partial toxicity together with withdrawal may lead to these symptoms - a discontinuation syndrome. The underlying neurobiology is not yet established. Common symptoms and signs seen in affected neonates include poor feeding, jitteriness, respiratory distress and myoclonic seizure-like activity. Onset is typically between birth and day 4 of life with resolution by 2-21 days of life. Electroencephalography does not necessarily correlate with clinical seizures, or response to anticonvulsants. In limited follow-up data, no long-term consequences of this discontinuation syndrome are reported. We suggest where it is not possible for mothers to be switched from venlafaxine to other antidepressant drugs, that their infants are observed closely for 2-4 days following delivery. In symptomatic neonates, following exclusion of other causes, supportive care including breastfeeding may be sufficient for management. Clinicians should be vigilant to venlafaxine discontinuation as a cause for encephalopathy or paroxysmal episodes in exposed neonates.

Recognition and management of sepsis by junior doctors.

There is growing evidence that outcomes in sepsis are improved by early recognition and treatment. In this study, we assessed junior doctors' ability to recognise and manage sepsis. We also explored junior doctors' perceptions regarding barriers to delivering timely sepsis care. From 46 respondents, only 4% were able to list the systemic inflammatory response syndrome (SIRS) criteria, 50% could define sepsis and 46% could list the Sepsis Six. Following further teaching on sepsis, 35% could list the SIRS criteria, 87% correctly defined sepsis, and 91% could state the Sepsis Six. Junior doctors perceived time pressure when on call to be the greatest barrier in treating sepsis, and their own knowledge to be the least important barrier. Our data suggest that knowledge of sepsis among junior doctors is poor and that there is a lack of insight into this competency gap.

The burden of sepsis in the Emergency Department: an observational snapshot.

The primary aim of our study was to establish what proportion of patients in the Emergency Department (ED) fulfill the criteria for sepsis. All adult patients presenting to ED in two 1-week periods, 6 months apart, were included. Notes were reviewed retrospectively to identify which patients fulfilled the criteria for sepsis and severe sepsis. The proportion of patients with sepsis was 4.3% (95% confidence interval 3.3-5.2%) and the proportion with severe sepsis was 2.2% (95% confidence interval 1.5-2.8%). In conclusion our results suggest that sepsis is more common than previously reported and this represents a significant burden on ED.

Sertraline and mirtazapine as geriatric antidepressants.

BACKGROUND: Depression within the geriatric patient population is an important issue as it is associated with increased mortality. Such depression may have a different aetiology to that in younger patients and be associated with comorbid chronic physical health problems or cognitive impairment. However, there is no specific UK guideline for the treatment of depression within elderly patients. The first-line pharmacological treatment recommended by the National Institute for Health and Care Excellence (NICE) is to use a serotonin-selective reuptake inhibitor (SSRI). Unfortunately these can have significant side-effects in the elderly such as hyponatraemia. Sertraline is one such SSRI commonly used in the geriatric population. Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSa) is seeing increasing usage as an alternative agent. Here we evaluate the role of using the NaSSA in place of the SSRI and how such drugs may be cross-titrated. METHODS: PubMed and an internet search engine were used to identify relevant studies and information sources. CONCLUSIONS: Limited evidence suggests that for certain elderly patients, mirtazapine may be preferable to sertraline for treatment of depression. It may also be more cost-effective in patients who have dementia. The choice is highly dependent upon individual co-morbidities and subsequent polypharmacy. If required, sertaline can be cross-titrated to mirtazapine.