Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 1, experiences and recommendations for service design.

Prospective parents whose fetus is diagnosed with a neurological anomaly go through a complex range of emotions. They describe their discussions of antenatal counselling from health care professionals as focusing too much on the nature of the anomaly involving unintelligible medical terminology, when what they really want is a picture of the best- and worst-case scenarios. Whilst information on the level of risk for their fetus is important, it is not the parents' primary concern. When statistics for risk are given, they may not be as well understood as the health care professionals think. This review discusses the published evidence on antenatal counselling and recommendations for explaining risk to parents of fetuses with neurological anomalies. From this data we make recommendations for the organization of antenatal counselling services.

Antenatal counselling for prospective parents whose fetus has a neurological anomaly: part 2, risks of adverse outcome in common anomalies.

After diagnosis of a fetal neurological anomaly, prospective parents want to know the best and worst-case scenarios and an estimation of the risk to their infant of having an atypical developmental outcome. The literature on developmental outcomes for fetal neurological anomalies is poor: studies are characterized by retrospective design, small sample size, often no standardized assessment of development, and differing definitions of anomalies. This review provides an aide-memoir on the risks of adverse neurodevelopmental outcome for ventriculomegaly, cortical anomalies, microcephaly, macrocephaly, agenesis of the corpus callosum, posterior fossa anomalies, and myelomeningocele, to assist healthcare professionals in counselling. The data in this review should be used alongside recommendations on counselling and service design described in part 1 to provide antenatal counselling.

How paediatricians investigate early developmental impairment in the UK: a qualitative descriptive study.

BACKGROUND: Early developmental impairment (EDI) is common and has many aetiologies and, therefore, potential investigations. There are several published guidelines recommending aetiological investigations, and paediatricians' views of them varies. Little is known on the thought processes underlying clinical decisions in investigating EDI. This study aimed to describe the thought processes affecting clinical decisions on the investigation of EDI within a nationalised health care system. METHODS: A qualitative descriptive study using semi-structured qualitative interviews performed in person or via video link with paediatricians who see children with EDI in England. As part of the interview, a case study of a fictional disease, Cavorite deficiency, modelled on biotinidase deficiency, was given to participants with the cost of testing, incidence and likelihood it would respond to treatment. This allowed exploration of cost without encumbrance from predisposing views and training on the condition. Thematic analysis was performed by iterative approach. Where participants stated they wanted to redirect money from investigations to treatment, were that even possible, we asked which services they would like to be better funded in their area. RESULTS: Interviews were conducted with 14 consultant paediatricians: 9 Community / Neurodisability, 2 General paediatricians, and 3 Paediatric Neurologists. Two themes were identified: the value of an aetiological diagnosis to families and managing risk and probability when investigating EDI. The latter contained 4 subthemes: 'circumspection' involved blanket investigations chosen irrespective of phenotype and high regard for guidelines; 'accepting appropriate risk' involved participants choosing investigations based on clinical phenotype, recognising some aetiologies would be missed; consultants found they 'transitioned between practices' during their career; and 'improved practice' was thought possible with better evidence on how to stratify investigations based on phenotype. Services that were most frequently reported to need additional funding were therapy services, early community developmental services, management of behaviour, sleep and mental health, and educational support. CONCLUSIONS: There are many factors that influence paediatricians' choice of aetiological investigation in EDI, but clinical factors are the most important. Paediatricians want better evidence to allow them to select the right investigations for each child without a significant risk of missing an important diagnosis.

Knowledge and attitudes of critical care providers towards neurophysiological monitoring, seizure diagnosis, and treatment.

AIM: To explore the attitudes of paediatric intensive care unit (PICU) health care professionals towards diagnosis and neurophysiological monitoring of seizures. METHOD: This study used an explanatory sequential mixed-methods approach, interconnecting quantitative and qualitative features, comprising questionnaires and interviews, with equal weighting between stages, of health care professionals working in UK PICUs. Interview data were analysed using thematic analysis and triangulated with questionnaire data. RESULTS: Seventy-two questionnaires were returned: 49 out of 60 (71.0%) of respondents reported that seizures were extremely hard or somewhat hard to diagnose in a critically ill child, and 81.2% had seen misdiagnosis occur. Thematic analysis revealed two main themes: (1) feeling out of control when faced with 'grey areas'; and (2) regaining control, which compromised three subthemes: aggressive intervention, accurate diagnosis, and eschewing diagnosis. INTERPRETATION: Health care professionals find accurate diagnosis of seizures difficult, particularly in sedated/paralysed children and those with chronic neurological disorders. They report they would like better educational opportunities on discriminating between epileptic and non-epileptic events to improve their confidence. Professionals want routine neurophysiological monitoring that can be applied and interpreted at the bedside throughout the day to regain a sense of control over their patient, direct treatment appropriately, and, potentially, improve outcomes, but report appropriate training and peer review are essential if it is to be introduced into routine care. What this study adds Paediatric intensive care unit (PICU) staff feel out of control when faced with diagnosing seizures. Neurophysiological monitoring is wanted to help diagnosis and treatment. Amplitude-integrated electroencephalography is the preferred, pragmatic tool by PICU staff.

Investigating and managing neonatal seizures in the UK: an explanatory sequential mixed methods approach.

BACKGROUND: Neonatal seizures are difficult to diagnose and, when they are, tradition dictates first line treatment is phenobarbital. There is little data on how consultants diagnose neonatal seizures, choose when to treat or how they choose aetiological investigations or drug treatments. The purpose of this study was to assess the variation across the UK in the management of neonatal seizures and explore paediatricians' views on their diagnosis and treatment. METHODS: An explanatory sequential mixed methods approach was used (QUAN→QUAL) with equal waiting between stages. We collected quantitative data from neonatology staff and paediatric neurologists using a questionnaire sent to neonatal units and via emails from the British Paediatric Neurology Association. We asked for copies of neonatal unit guidelines on the management of seizures. The data from questionnaires was used to identify16 consultants using semi-structured interviews. Thematic analysis was used to interpret qualitative data, which was triangulated with quantitative questionnaire data. RESULTS: One hundred questionnaires were returned: 47.7% thought levetiracetam was as, or equally, effective as phenobarbital; 9.2% thought it was less effective. 79.6% of clinicians had seen no side effects in neonates with levetiracetam. 97.8% of unit guidelines recommended phenobarbital first line, with wide variation in subsequent drug choice, aetiological investigations, and advice on when to start treatment. Thematic analysis revealed three themes: 'Managing uncertainty with neonatal seizures', 'Moving practice forward' and 'Multidisciplinary team working'. Consultants noted collecting evidence on anti-convulsant drugs in neonates is problematic, and recommended a number of solutions, including collaboration to reach consensus guidelines, to reduce diagnostic and management uncertainty. CONCLUSIONS: There is wide variation in the management of neonatal seizures and clinicians face many uncertainties. Our data has helped reveal some of the reasons for current practice and decision making. Suggestions to improve certainty include: educational initiatives to improve the ability of neonatal staff to describe suspicious events, greater use of video, closer working between neonatologists and neurologists, further research, and a national discussion to reach a consensus on a standardised approach to managing neonatal epileptic seizures.

What are the information needs of parents caring for a child with Glutaric aciduria type 1?

BACKGROUND: Newborn screening has enabled the early diagnosis of Glutaric aciduria type 1, with the possibility of improving neurological outcomes in affected children. Achieving those outcomes requires parents to effectively manage their child's condition by adherence to a strict dietary regime and responding to situations that may trigger decompensation. The specific information and support needs of this group of parents are unknown. METHODS: A focus group with five parents was conducted to gain insights into the information that parents needed and the ways in which they accessed and used information to manage their child's condition. A topic guide was used to direct the discussion which was recorded and fully transcribed. All participants gave informed consent. Data were analysed using thematic analysis, a structured approach that contributes to transparency and validity of results while allowing the integration of predetermined and emerging themes. To ensure rigour, two researchers were involved in initial coding of data and key analytic decisions. RESULTS: Two main themes were identified. 'Understanding the condition' explored parent's needs to understand the scientific complexity of the condition and to be aware of the worst case scenario associated with loss of metabolic control. 'Managing the condition' explained how parents co-ordinated and controlled the involvement of other carers and parents' need to be active partners in medical management to feel in control of the situation. CONCLUSIONS: The study highlights the importance of addressing parents' initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic harm.

Initial experience of an investigational 3T MR scanner designed for use on neonatal wards.

OBJECTIVES: MR imaging of neonates is difficult for many reasons and a major factor is safe transport to the MR facilities. In this article we describe the use of a small, investigational 3-T MR customised for brain imaging and sited on a neonatal unit of a tertiary centre in the UK, which is in contrast to a 300-m journey to the whole-body MR scanner used at present for clinical cases. METHODS: We describe our methods for preparing babies for safe transport and scanning on an investigational 3-T MR scanner on a neonatal unit and the development of appropriate MR sequences. The MR scanner does not have CE marking at present so this early development work was undertaken on normal neonates whose parents consented to a research examination. RESULTS: Fifty-two babies were scanned and there were no serious adverse events. The MR examinations were considered to be diagnostically evaluable in all 52 cases and in 90% the imaging was considered to be at least as good as the quality obtained on the 1.5-T scanner currently used for clinical cases. CONCLUSION: We have shown that this investigational 3-T MR scanner can be used safely on a neonatal unit and we have refined the MR sequences to a point that they are clinically usable. KEY POINTS: • Access to neonatal MR imaging is limited. • We describe an investigational 3-T MR scanner site on a neonatal unit. • The scanner produces images suitable for clinical practice.

Anticoagulation in the management of neonatal cerebral sinovenous thrombosis: a systematic review and meta-analysis.

AIM: To determine whether anticoagulation therapy (ACT) in the treatment of neonatal cerebral sinovenous thrombosis (CSVT) improves outcomes, in the presence or absence of pre-existing intracerebral haemorrhage (ICH). METHOD: We searched CENTRAL, MEDLINE, Embase, CINAHL, the Web of Science, and clinical trial databases. We considered data from retrospective and prospective cohort studies, case series, and randomized controlled studies evaluating outcomes of CSVT treated with anticoagulation or no anticoagulation. Studies were included if they involved infants either younger than 28 days of age or younger than 44 weeks postmenstrual age at the time of diagnosis of CSVT in which ACT was considered. RESULTS: Seven non-randomized studies were included in meta-analysis. ACT had no significant effect on mortality before discharge either in the presence or absence of pre-existing ICH, nor on the incidence of extension of pre-existing ICH. ACT was associated with a reduced risk of propagation of thrombus (risk ratio 0.14, 95% confidence interval 0.03-0.72). INTERPRETATION: There are no randomized trials assessing the safety and efficacy of ACT in the treatment of neonatal CSVT. The results of this meta-analysis would justify a position of equipoise and support the need for well-designed randomized controlled trials of ACT in this population. WHAT THIS PAPER ADDS: No randomized studies have evaluated anticoagulation therapy (ACT) in neonatal cerebral sinovenous thrombosis. ACT may reduce thrombus propagation. No evidence of increased morbidity or mortality with ACT was demonstrated. A position of equipoise is justified, supporting the need for placebo-controlled randomized trials.

Cyclical vomiting syndrome secondary to a Chiari I malformation-a case report.

BACKGROUND: Cyclical vomiting syndrome is a disorder characterised by recurrent episodes of profuse vomiting. There are no cases in the literature on the management of children with presenting with cyclical vomiting syndrome and a Chiari malformation type I. DISCUSSION: We report the case of a 12-year-old child diagnosed with cyclical vomiting syndrome and a Chiari malformation type I. The patient received symptomatic relief following a craniocervical decompression.

Neonatal hypertonia - a diagnostic challenge.

In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested.

Neonatal seizures-part 2: Aetiology of acute symptomatic seizures, treatments and the neonatal epilepsy syndromes.

Most neonatal epileptic seizures are provoked by an underlying condition or problem-'acute symptomatic seizures'. However, a few neonatal epilepsy syndromes exist, and these are defined by the constellation of seizure types, EEG findings and family history seen. Making an accurate diagnosis of an epilepsy syndrome can help direct investigations, treatment options and provide prognostic information. This article discusses the investigative approach and treatments for neonatal epileptic seizures, including the neonatal epilepsy syndromes.

Neonatal seizures-part 1: Not everything that jerks, stiffens and shakes is a fit.

The neonatal period is the most frequent time of life to have epileptic seizures. However, neonates can also exhibit unusual movements that are not epileptic seizures. Differentiating between epileptic and non-epileptic movements can be difficult. Many neonatal seizures exhibit few or no clinical features at all. This article is for the benefit of paediatric trainees and reviews the published evidence on which neonatal movements are likely to be epileptic seizures and which are not. We also discuss epileptic seizure classification.

Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Neonatal cochlear function: measurement after exposure to acoustic noise during in utero MR imaging.

PURPOSE: To establish whether fetal exposure to the operating noise of 1.5-T magnetic resonance (MR) imaging is associated with cochlear injury and subsequent hearing loss in neonates. MATERIALS AND METHODS: The study was performed with local research ethics committee approval and written informed parental consent. Neonatal hearing test results, including otoacoustic emission (OAE) data, were sought for all neonates delivered in Sheffield who had previously undergone in utero MR imaging between August 1999 and September 2007. The prevalence of hearing impairment in these neonates was determined, with corresponding 95% confidence intervals calculated by using the binomial exact method, and mean OAE measurements were compared with anonymized local audiometric reference data by using the t test. RESULTS: One hundred three neonates who had undergone in utero MR imaging were identified; 96 of them had completed hearing screening assessment. Thirty-four of these babies were admitted to the neonatal intensive care unit (NICU), and one of them had bilateral hearing impairment. The prevalence of hearing impairment was 1% (one of 96; 95% confidence interval: 0.03%, 5.67%), which is in accordance with the prevalence expected, given the high proportion of babies in this study who had been in the NICU (ie, NICU graduates). In addition, for the well babies, there was no significant difference in mean OAE cochlear response compared with that for a reference data set of more than 16,000 OAE results. When NICU graduates were included in the comparison, a significant difference (P = .002) was found in one of four frequency bands used to analyze the cochlear response; however, this difference was small compared with the normal variation in OAE measurements. CONCLUSION: The findings in this study provide some evidence that exposure of the fetus to 1.5-T MR imaging during the second and third trimesters of pregnancy is not associated with an increased risk of substantial neonatal hearing impairment.

Diffusion-weighted imaging of cerebral white matter and the cerebellum following preterm birth.

AIM: The aim of this study was to determine if apparent diffusion coefficients (ADCs) generated with diffusion-weighted imaging of cerebral white matter and the cerebellum are affected by white matter damage. METHOD: Seventy-two preterm infants (32 males, 40 females; mean gestational age at birth 30.3 wks, SD 3.0 wks; mean birthweight 1458g, SD 534g) underwent magnetic resonance imaging of the brain around term-equivalent age and were categorized into three groups: normal, overt abnormality, and diffuse excessive high signal intensity (DEHSI). ADC values were calculated from cerebral white matter, cerebellar hemispheres, and cerebellar midline, and were compared between groups. Regression analysis identified clinical parameters correlated with ADC values. RESULTS: Imaging was normal in 27 infants, and revealed overt abnormalities in 14 and DEHSI in 31. ADC values did not differ between groups. ADC values from cerebral white matter were negatively correlated with the number of episodes of postnatal sepsis (p=0.002). ADC values from cerebellar hemispheres (p=0.007) and cerebellar midline (p=0.036) correlated with gestational age at birth. INTERPRETATION: ADC values from white matter are not altered in preterm infants with DEHSI but are negatively correlated with the number of episodes of postnatal sepsis. ADC values in the cerebellum are not altered by white matter damage, but are affected by preterm birth itself.

Appearances of diffuse excessive high signal intensity (DEHSI) on MR imaging following preterm birth.

BACKGROUND: Diffuse damage to the periventricular white matter has recently been suggested to be a cause of the cognitive deficits seen following preterm birth. It is unclear whether this form of injury can be visualised on MR imaging, but one group has described diffuse excessive high signal intensity (DEHSI) as a possible form of diffuse white matter injury. This finding is dependent on window imaging and the subjective assessment of the reviewer, but little data have been published on the degree of subjectivity on its appearance among raters. OBJECTIVE: To assess the subjectivity of DEHSI on conventional and ultrafast T2-weighted MR imaging following preterm birth. MATERIALS AND METHODS: An observational study of 40 preterm infants who had MR imaging of the brain around term-equivalent age, including conventional fast spin-echo (FSE) and ultrafast single-shot fast spin-echo (SSFSE) T2-weighted sequences in the axial plane. Images were anonymised and scored twice by four observers for the presence of DEHSI. Inter- and intra-observer agreement were calculated. RESULTS: Sixty-five percent of conventional and 100% of the ultrafast images were of diagnostic quality. DEHSI was noted in between 0% and 69.2% of conventional images and 27.5-90% of the ultrafast images. Inter- and intra-observer agreement ranged from none to moderate. CONCLUSION: The visual appearances of DEHSI on conventional FSE and ultrafast SSFSE T2-W images are highly subjective, limiting its clinical application.

Accuracy of in-utero MRI to detect fetal brain abnormalities and prognosticate developmental outcome: postnatal follow-up of the MERIDIAN cohort.

BACKGROUND: In utero MRI (iuMRI) detects fetal brain abnormalities more accurately than ultrasonography and provides additional clinical information in around half of pregnancies. We aimed to study whether postnatal neuroimaging after age 6 months changes the diagnostic accuracy of iuMRI and its ability to predict developmental outcome. METHODS: Families enrolled in the MERIDIAN study whose child survived to age 3 years were invited to have a case note review and assessment of developmental outcome with the Bayley Scales of Infant and Toddler Development, the Ages and Stages Questionnaire, or both. A paediatric neuroradiologist, masked to the iuMRI results, reviewed the postnatal neuroimaging if the clinical report differed from iuMRI findings. Diagnostic accuracy was recalculated. A paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iuMRI and ultrasonography to predict developmental outcome were assessed. FINDINGS: 210 participants had case note review, of whom 81 (39%) had additional investigations after age 6 months. The diagnostic accuracy of iuMRI remained higher than ultrasonography (proportion of correct cases was 529 [92%] of 574 vs 387 [67%] of 574; absolute difference 25%, 95% CI 21 to 29; p<0·0001). Developmental outcome data were analysed in 156 participants, and 111 (71%) were categorised as normal or at risk. Of these 111 participants, prognosis was normal or favourable for 56 (51%) using ultrasonography and for 76 (69%) using iuMRI (difference in specificity 18%, 95% CI 7 to 29; p=0·0008). No statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity 4%, 95% CI -10 to 19; p=0·73). INTERPRETATION: iuMRI remains the optimal tool to identify fetal brain abnormalities. It is less accurate when used to predict developmental outcome, although better than ultrasonography for identifying children with normal outcome. Further work is needed to determine how the prognostic abilities of iuMRI can be improved. FUNDING: National Institute for Health Research Health Technology Assessment programme.

Profound encephalopathy with complete recovery in three children with familial hemiplegic migraine.

We describe three cousins who presented with agitation, dysphasia and/or coma, and developed hemiplegia following initial onset of symptoms. Two cases followed minor head injuries, two were pyrexial and two were associated with neutrophilia. Two cases required ventilatory support on the intensive care unit. Magnetic resonance imaging in all three cases showed cortical swelling, and one had evidence of restricted water diffusion on diffusion-weighted imaging, suggestive of ischaemia/infarction. A complete family history at the time of presentation would have led to an earlier diagnosis of profound encephalopathy in familial hemiplegic migraine, which would have enabled better prognostication of their clinical course and caused less distress for the families.

N-carbamoylglutamate-responsive carbamoyl phosphate synthetase 1 (CPS1) deficiency: A patient with a novel CPS1 mutation and an experimental study on the mutation's effects.

N-carbamoyl-l-glutamate (NCG), the N-acetyl-l-glutamate analogue used to treat N-acetylglutamate synthase deficiency, has been proposed as potential therapy of carbamoyl phosphate synthetase 1 deficiency (CPS1D). Previous findings in five CPS1D patients suggest that NCG-responsiveness could be mutation-specific. We report on a patient with CPS1D, homozygous for the novel p.(Pro1211Arg) CPS1 mutation, who presented at 9 days of life with hyperammonemic coma which was successfully treated with emergency measures. He remained metabolically stable on merely oral NCG, arginine, and modest protein restriction. Ammonia scavengers were only added after poor dietary compliance following solid food intake at age 1 year. The patient received a liver transplantation at 3.9 years of age, having normal cognitive, motor, and quality of life scores despite repeated but successfully treated episodes of hyperammonemia. Studies using recombinantly produced mutant CPS1 confirmed the partial nature of the CPS1D triggered by the p.(Pro1211Arg) mutation. This mutation decreased the solubility and yield of CPS1 as expected for increased tendency to misfold, and reduced the thermal stability, maximum specific activity (V max; ~2-fold reduction), and apparent affinity (~5-fold reduction) for ATP of the purified enzyme. By increasing the saturation of the NAG site in vivo, NCG could stabilize CPS1 and minimize the decrease in the effective affinity of the enzyme for ATP. These observations, together with prior experience, support the ascertainment of clinical responsiveness to NCG in CPS1 deficient patients, particularly when decreased stability or lowered affinity for NAG of the mutant enzyme are suspected or proven.