Evaluation of a standardised protocol to measure the disease burden of respiratory syncytial virus infection in young children in primary care.

BACKGROUND: A better understanding of the burden of respiratory syncytial virus (RSV) infections in primary care is needed for policymakers to make informed decisions regarding new preventive measures and treatments. The aim of this study was to develop and evaluate a protocol for the standardised measurement of the disease burden of RSV infection in primary care in children aged < 5 years. METHODS: The standardised protocol was evaluated in Italy and the Netherlands during the 2019/20 winter. Children aged < 5 years who consulted their primary care physician, met the WHO acute respiratory infections (ARI) case definition, and had a laboratory confirmed positive test for RSV (RT-PCR) were included. RSV symptoms were collected at the time of swabbing. Health care use, duration of symptoms and socio-economic impact was measured 14 days after swabbing. Health related Quality of life (HRQoL) was measured using the parent-proxy report of the PedsQL™4.0 generic core scales (2-4 years) and PedsQL™4.0 infant scales (0-2 years) 30 days after swabbing. The standardised protocol was evaluated in terms of the feasibility of patient recruitment, data collection procedures and whether parents understood the questions. RESULTS: Children were recruited via a network of paediatricians in Italy and a sentinel influenza surveillance network of general practitioners in the Netherlands. In Italy and the Netherlands, 293 and 152 children were swabbed respectively, 119 and 32 tested RSV positive; for 119 and 12 children the Day-14 questionnaire was completed and for 116 and 11 the Day-30 questionnaire. In Italy, 33% of the children had persistent symptoms after 14 days and in the Netherlands this figure was 67%. Parents had no problems completing questions concerning health care use, duration of symptoms and socio-economic impact, however, they had some difficulties scoring the HRQoL of their young children. CONCLUSION: RSV symptoms are common after 14 days, and therefore, measuring disease burden outcomes like health care use, duration of symptoms, and socio-economic impact is also recommended at Day-30. The standardised protocol is suitable to measure the clinical and socio-economic disease burden of RSV in young children in primary care.

Classification of intellectual disability according to domains of adaptive functioning and between-domains discrepancy in adults with epilepsy.

BACKGROUND: In the Diagnostic and Statistical Manual of Mental Disorders-Fifth edition (DSM-5), the diagnostic criteria of intellectual disability (ID) include three domains of adaptive deficits: the conceptual, social and practical. Substantial intra-individual differences between domains can be considered an ID domain discrepancy. METHOD: We explored the associations between ID domains, discrepancies and epilepsy in 189 adults (mean age = 47.9; SD = 15.6). Each DSM-5 ID domain was assessed separately, using subscales of the Vineland II for the social and practical domains, and psychological instruments, including intelligence tests, for the conceptual domain. A set of standardised criteria is proposed to identify an ID domain discrepancy. RESULTS: An ID domain discrepancy seemed to be present in about one-third of subjects and was particularly present in subjects with moderate ID (53.4%). Impairment in the social domain was most often the reason for the discrepancy. The presence of a discrepancy was significantly related to a focal (localised) epilepsy type (OR = 2.3, P = .028) and a mixed seizure type (OR = 1.4, P = .009). Epilepsy characteristics that are indicative of a more severe and refractory epilepsy, including various seizure types, a high seizure frequency, a combined epilepsy type (both focal and generalised epilepsy) and an early age at onset, were significantly related to more severe impairments in conceptual, social and practical adaptive behaviour (all P values <.01). CONCLUSIONS: With a substantial proportion of the subjects who had both ID and epilepsy with an ID discrepancy, professionals should be aware of this and take all domains of ID into account when studying or working with this vulnerable population.

The Dutch Dystrophinopathy Database: A National Registry with Standardized Patient and Clinician Reported Real-World Data1.

Background: Duchenne and Becker muscular dystrophy lack curative treatments. Registers can facilitate therapy development, serving as a platform to study epidemiology, assess clinical trial feasibility, identify eligible candidates, collect real-world data, perform post-market surveillance, and collaborate in (inter)national data-driven initiatives. Objective: In addressing these facets, it's crucial to gather high-quality, interchangeable, and reusable data from a representative population. We introduce the Dutch Dystrophinopathy Database (DDD), a national registry for patients with DMD or BMD, and females with pathogenic DMD variants, outlining its design, governance, and use. Methods: The design of DDD is based on a system-independent information model that ensures interoperable and reusable data adhering to international standards. To maximize enrollment, patients can provide consent online and participation is allowed on different levels with contact details and clinical diagnosis as minimal requirement. Participants can opt-in for yearly online questionnaires on disease milestones and medication and to have clinical data stored from visits to one of the national reference centers. Governance involves a general board, advisory board and database management. Results: On November 1, 2023, 742 participants were enrolled. Self-reported data were provided by 291 Duchenne, 122 Becker and 38 female participants. 96% of the participants visiting reference centers consented to store clinical data. Eligible patients were informed about clinical studies through DDD, and multiple data requests have been approved to use coded clinical data for quality control, epidemiology and natural history studies. Conclusion: The Dutch Dystrophinopathy Database captures long-term patient and high-quality standardized clinician reported healthcare data, supporting trial readiness, post-marketing surveillance, and effective data use using a multicenter design that is scalable to other neuromuscular disorders.

Ketogenic diet effects on cognition, mood, and psychosocial adjustment in children.

INTRODUCTION: The ketogenic diet (KD) is increasingly used for the treatment of refractory epilepsy. The aim of this study was to evaluate possible adverse effects of the diet on cognition, behavior, psychosocial adjustment, and quality of life in school-aged children and adolescents. METHOD: Fifteen subjects were assessed before diet initiation. After approximately 6 months, on diet treatment 11 patients (73%) were reassessed. We used a combination of individually administered psychological tests for the children and parent report questionnaires. RESULTS: Five of 15 patients had a seizure reduction of more than 50%. Cognition showed a small trend toward improvement in most patients. Psychosocial adjustment, on the other hand, showed small trends toward worsening. For mood, two areas showed a larger change, revealing more mood problems although this was not on a statistically significant level. CONCLUSION: In this small group of children, there is no indication that the KD has a negative impact on cognition or social adaptation at short term. There is a tendency toward an increase in mood problems.

Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature.

This review addresses the effect on language function of nocturnal epileptiform EEG discharges and nocturnal epileptic seizures in children. In clinical practice, language impairment is frequently reported in association with nocturnal epileptiform activity. Vice versa, nocturnal epileptiform EEG abnormalities are a common finding in children with specific language impairment. We suggest a spectrum that is characterized by nocturnal epileptiform activity and language impairment ranging from specific language impairment to rolandic epilepsy, nocturnal frontal lobe epilepsy, electrical status epilepticus of sleep, and Landau-Kleffner syndrome. In this spectrum, children with specific language impairment have the best outcome, and children with electrical status epilepticus of sleep or Landau-Kleffner syndrome, the worst. The exact nature of this relationship and the factors causing this spectrum are unknown. We suggest that nocturnal epileptiform EEG discharges and nocturnal epileptic seizures during development will cause or contribute to diseased neuronal networks involving language. The diseased neuronal networks are less efficient compared with normal neuronal networks. This disorganization may cause language impairments.

Levetiracetam therapy for treatment of choreoathetosis in dyskinetic cerebral palsy.

Dyskinetic cerebral palsy (CP) is a movement disorder that is difficult to treat and which causes major disability. We report on two female patients (aged 5y and 8y) who experienced severe perinatal asphyxia and developed dyskinetic CP, clinically characterized by choreoathetosis. Neuropsychological testing of these children showed a low average developmental quotient and no attentional deficit. Monotherapy with levetiracetam was initiated to improve balance control and fine motor skills. Treatment was evaluated by use of video and the Visual Analog Scale. In both children an impressive improvement of balance control and fine motor skills was observed. No side effect occurred. Furthermore, both patients showed more interest and pleasure during activities according to their parents. In a recent multidisciplinary evaluation of the initiated therapy, the parents, the therapist, and the rehabilitation doctor all confirmed that the effect initially observed was still present at 14 and 26 months later. To our knowledge, this report on two patients with dyskinetic CP is the first suggesting that levetiracetam may offer an alternative to the standard therapy of involuntary, uncontrolled movements in this group of patients.

Cognitive functioning of adolescents and young adults with meningomyelocele and level of everyday physical activity.

PURPOSE: To explore whether cognitive functioning in patients with meningomyelocele (MMC) is related to level of everyday physical activity. METHOD: In a cross-sectional study in 14 patients with MMC (aged 14 - 26 years) a neuropsychological test battery was administered to each patient. Everyday physical activity of the patients was measured with an accelerometry-based Activity Monitor (AM), and compared to 14 healthy comparison subjects. RESULTS: Intellectual ability of 10 patients was in the normal range. For memory and verbal learning, executive functioning, divided attention and reaction speed subnormal scores were present in six or more patients. Time spent on dynamic activities was low in patients with MMC as compared to healthy subjects. After controlling for intellectual ability, we found that in patients with MMC (i) executive functioning was positively related, and (ii) word production was negatively related to everyday physical activity. CONCLUSION: We found some indication that specific impairments in executive functioning might be related to everyday physical activity of adolescents and young adults with MMC.

Controlled visuomotor preparation deficits in attention-deficit/hyperactivity disorder.

To the best of the authors' knowledge, there are no published reports on visuomotor preparation in attention-deficit/hyperactivity disorder (ADHD). This is unfortunate, because research suggests that ADHD is an output-related deficit, and suboptimal execution of tasks may be the result of incomplete visuomotor preparation. The authors compared 19 children with ADHD with 124 healthy and 120 pathological controls in terms of their performance (speed, speed variability, and accuracy) on the finger precuing test, a test measuring (automatic and controlled) visuomotor preparation. The data implied that children with ADHD have an impaired ability to engage in effortful, controlled visuomotor preparation activities. Fast, automatic response preparation was not affected by ADHD. In addition, children with ADHD showed more variability in overall test performance than other children. No group differences were found in response accuracy.

Diagnostic overshadowing in a population of children with neurological disabilities: A cross sectional descriptive study on acquired ADHD.

AIM: Diagnostic overshadowing refers to the underdiagnosis of comorbid conditions in children with known neurological diagnoses. To demonstrate diagnostic overshadowing we determined the prevalence of attention deficit-hyperactivity disorders (ADHD) in a cohort of children with a wide range of neurological disabilities. METHOD: The study cohort consisted of 685 children (mean age 10.3 years, SD: 3.1; 425 boys and 260 girls) who visited a tertiary outpatient multidisciplinary clinic for neurological learning disabilities. Patients with ADHD were identified by retrospective chart review using DSM-IV criteria. RESULTS: The prevalence of ADHD in this cohort was 38.8% (266 children); of these children only 28.2% (75 children) were diagnosed with ADHD before referral. INTERPRETATION: ADHD is a common problem in children with neurological disabilities and may be underdiagnosed due to overshadowing of somatic, physical or syndromal features of the disability. In our heterogeneous population ADHD was overshadowed in 71.8% of the cases. This finding may have important implications for diagnosis and treatment of mental health needs in children with neurological disabilities.

Sequence variability of the meningococcal lactoferrin-binding protein LbpB.

The lactoferrin receptor of Neisseria meningitidis consists of two proteins, LbpA and LbpB. LbpB is considered a promising vaccine candidate, and therefore its sequence variability was studied. LbpB from five different strains exhibited 70-80% mutual identity at the amino acid level. Most sequence variability was found in two stretches with a high content of negatively charged amino acids. These stretches were sequenced from six additional strains. One of the stretches is of variable length and is missing in some of the strains. The other stretch is present in all strains, but varies considerably in its exact amino acid sequence. The high degree of variability is disadvantageous for vaccine development, but may be useful for epidemiological studies.

Thyrotropin-releasing hormone action in the preoptic/anterior hypothalamus decreases thermoregulatory set point in ground squirrels.

Earlier work has shown that thyrotropin releasing hormone (TRH) produces dose-dependent decreases in body temperature (Tb) and metabolic rate when microinjected into the dorsal hippocampus (HPC) or preoptic/anterior hypothalamus (PO/AH) of awake ground squirrels. This study employed a behavioral paradigm to investigate the possibility that TRH-induced hypothermia is associated with a decrease in thermoregulatory set point. Six animals were successfully trained to press a bar for radiant heat escape and cool air reinforcement in order to obtain a cooler ambient temperature (Ta). During experimental testing, the animals were microinjected remotely with TRH (10-1000 ng/microliters) or a control solution (sterile saline or TRH-OH) into the PO/AH. The micro-injections were delivered via bilateral injection cannulae inserted through chronic bilateral cannula guides that had been stereotaxically implanted under pentobarbital anesthesia. Cumulative and time-integrated bar presses were obtained on a computer generated display. Tb, measured in the brain via a bead-type thermistor, and chamber Ta were recorded continuously. Following TRH administration, a significant increase in mean bar-press rate was observed during the period in which Tb was falling, when compared to a comparable time period just prior to the microinjection. These findings complement results obtained from four animals that were trained to press a bar for heat reinforcement in a cold (- 10 degrees C) environment. In this alternative behavioral paradigm, microinjection of TRH into the PO/AH or HPC induced a decrease in mean bar-press rate as Tb was falling. The results support the hypothesis that TRH-induced hypothermia in golden-mantled ground squirrels is achieved by lowering thermoregulatory set point.

Child psychiatric diagnoses in a population of Dutch schoolchildren aged 6 to 8 years.

OBJECTIVE: To determine the prevalence rates of child psychiatric diagnoses in a school-based population of children aged 6 to 8 years in the south of the province of Limburg (The Netherlands). METHOD: In a two-stage design 1,317 children were screened with the Child Behavior Checklist. From 403 of these children, child psychiatric information was obtained with the Amsterdam Diagnostic Interview for Children and Adolescents (ADIKA, DSM-III-R/IV). Data were generalized to the responder group (n = 1,317) and to the entire cohort (N = 2,290). For the latter procedure, a prediction model was used to generalize ADIKA results to the nonresponders (n = 973). RESULTS: Estimates of the prevalence of different ADIKA diagnoses in the responder group were quite comparable with those for the entire cohort. Twenty-four percent of the entire cohort met criteria for a single disorder, and 21.0% met criteria for two or more disorders. However, in only 5.7% of the cases parents did report a need for help. CONCLUSIONS: Where other studies generalize psychiatric diagnoses to the responder group only, this report adds new information by generalizing the prevalence to a school-based cohort of children aged 6 to 8 years. These prevalence estimates are of importance with regard to the demand for care for child psychopathology.

Neighbourhood level and individual level SES effects on child problem behaviour: a multilevel analysis.

OBJECTIVE: This study examined whether neighbourhood level socioeconomic variables have an independent effect on reported child behaviour problems over and above the effect of individual level measures of socioeconomic status. DESIGN AND SETTING: Multilevel analysis of cross sectional survey data relating individual level child behavioural problems and parental measures of socioeconomic status with neighbourhood level measures of socioeconomic deprivation in the city of Maastricht, the Netherlands. PARTICIPANTS: Children born in the years 1990-1991 attending the second grade of normal kindergarten schools in the city of Maastricht, the Netherlands. Out of 1417 eligible 5-7 year olds, the parents of 734 children (51.8%) agreed to participate. MAIN RESULTS: Child behaviour problems were more frequent in families of low parental occupation and education (F=14.51, df 3, 721, p<0.001; F=12.20, df 3, 721, p<0.001, respectively) and in families living in deprived neighbourhoods (F=13.26, df 2, 722, p<0.001). Multilevel random effects regression analysis showed that the effect of neighbourhood level deprivation remained after adjustment for individual level socioeconomic status (B over three levels of deprivation: 1.36; 95%CI=0.28, 2.45). CONCLUSIONS: Living in a more deprived neighbourhood is associated with higher levels of child problem behaviour, irrespective of individual level socioeconomic status. The additional effect of the neighbourhood may be attributable to contextual variables such as the level of social cohesion among residents.

Temporalis muscle hypertrophy and reduced skull eccentricity in Duchenne muscular dystrophy.

Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship.

Normal variability of children's scaled scores on subtests of the Dutch Wechsler Preschool and Primary scale of Intelligence - third edition.

Intelligence tests are included in millions of assessments of children and adults each year (Watkins, Glutting, & Lei, 2007a , Applied Neuropsychology, 14, 13). Clinicians often interpret large amounts of subtest scatter, or large differences between the highest and lowest scaled subtest scores, on an intelligence test battery as an index for abnormality or cognitive impairment. The purpose of the present study is to characterize "normal" patterns of variability among subtests of the Dutch Wechsler Preschool and Primary Scale of Intelligence - Third Edition (WPPSI-III-NL; Wechsler, 2010 ). Therefore, the frequencies of WPPSI-III-NL scaled subtest scatter were reported for 1039 healthy children aged 4:0-7:11 years. Results indicated that large differences between highest and lowest scaled subtest scores (or subtest scatter) were common in this sample. Furthermore, degree of subtest scatter was related to: (a) the magnitude of the highest scaled subtest score, i.e., more scatter was seen in children with the highest WPPSI-III-NL scaled subtest scores, (b) Full Scale IQ (FSIQ) scores, i.e., higher FSIQ scores were associated with an increase in subtest scatter, and (c) sex differences, with boys showing a tendency to display more scatter than girls. In conclusion, viewing subtest scatter as an index for abnormality in WPPSI-III-NL scores is an oversimplification as this fails to recognize disparate subtest heterogeneity that occurs within a population of healthy children aged 4:0-7:11 years.

Diagnostic and prognostic prediction models.

Risk prediction models can be used to estimate the probability of either having (diagnostic model) or developing a particular disease or outcome (prognostic model). In clinical practice, these models are used to inform patients and guide therapeutic management. Examples from the field of venous thrombo-embolism (VTE) include the Wells rule for patients suspected of deep venous thrombosis and pulmonary embolism, and more recently prediction rules to estimate the risk of recurrence after a first episode of unprovoked VTE. In this paper, the three phases that are recommended before a prediction model may be used in daily practice are described: development, validation, and impact assessment. In the development phase, the focus is on model development commonly using a multivariable logistic (diagnostic) or survival (prognostic) regression analysis. The performance of the developed model is expressed by discrimination, calibration and (re-) classification. In the validation phase, the developed model is tested in a new set of patients using these same performance measures. This is important, as model performance is commonly poorer in a new set of patients, e.g. due to case-mix or domain differences. Finally, in the impact phase the ability of a prediction model to actually guide patient management is evaluated. Whereas in the development and validation phase single cohort designs are preferred, this last phase asks for comparative designs, ideally randomized designs; therapeutic management and outcomes after using the prediction model is compared to a control group not using the model (e.g. usual care).

Cognitive effects of interictal epileptiform discharges in children.

Frequent interictal epileptiform discharges (IEDs) may have effects on cognition. We analysed a group of 182 children with different epilepsy syndromes as well as children with IEDs without observed seizures [corrected], with 24-h ambulatory EEG and cognitive tests. The IED index was estimated, in wakefulness and in sleep, as percentage of time in five categories (0%, <1%, 1-10%, ≥10-50% and ≥50%). IEDs were defined as spikes or spike-wave complexes, isolated or occurring serially (in runs) without evident clinical signs of a seizure. The IED categories were correlated to cognitive test results and epilepsy characteristics. The group of patients with diurnal IEDs in ≥10% of the EEG record showed impaired central information processing speed, short-term verbal memory and visual-motor integration. This effect was seen independently from other EEG-related and epilepsy-related characteristics, and independently from epilepsy syndrome diagnosis. The impact of the nocturnal IEDs was of less importance; only contributing partially to the slowing of central information processing speed. We conclude that frequent IEDs (in more than 10% of the record) in the awake EEG can impair cognitive performance in children. Whether children with a high diurnal spike frequency and low seizure frequency can benefit from antiepileptic treatment should be examined in controlled trials.

Psychosocial adjustment in a Dutch sample of children with cerebral palsy.

BACKGROUND: Over the last couple of years, there has been increasing interest for QoL in children with CP. Psychosocial adjustment in these children remains underrepresented in current literature. AIMS: To describe psychosocial adjustment in children with CP by means of the Psychosocial Adjustment and Role Skills Scale III (PARS-III), to describe the psychometric properties of this questionnaire, to identify a cut-off score for psychosocial maladjustment and to investigate the relationship between patient characteristics (i.e. predictive factors) and psychosocial adjustment. METHODS: The parents of 93 children with CP (59 boys, 34 girls; mean age 12.3 years, SD 3.8; 4-18; GMFCS 1: 28, GMFCS 2: 5, GMFCS 3: 19, GMFCS 4: 18, GMFCS 5: 23) completed the PARS-III and the Child Behavior Checklist (CBCL) concerning the psychosocial and behavioral functioning of their child. RESULTS: Cronbach's alpha-coefficient for the PARS-III was 0.89 indicating good internal consistency. High correlation with the CBCL was found. Confirmatory factor analysis confirmed the 6 domain structure of the PARS-III. Overall, children with CP achieved lower psychosocial adjustment scores compared to healthy children. A cut-off score (1 SD below the mean) of 78 was found. When predicting psychosocial maladjustment in children with CP, less gross motor function, hand function, communication skills and bilateral involvement of CP are the most important factors, but these can only explain 36% of variation in psychosocial adjustment. CONCLUSION: Using the by-proxy version of the PARS-III it was found that children with CP are reported to achieve lower psychosocial adjustment scores than healthy children.

Impaired language performance as a precursor or consequence of Rolandic epilepsy?

OBJECTIVES: A correlation between language impairment and Rolandic epilepsy is frequently reported. It is unknown whether this language impairment develops gradually as a consequence of Rolandic epilepsy or precedes the onset of seizures. In the latter case both language impairment and Rolandic epilepsy may be symptoms of an underlying syndrome or both develop during the process of epileptogenesis. METHODS: Non-comparative clinical cohort study of 48 children with Rolandic epilepsy (children's mean age is 9 years, and 7 months; SD is 1 year, and 8 months). They were screened for previous and current language impairment and their reading skills were examined. RESULTS: 23% of children with Rolandic epilepsy had speech therapy in the past and 35% repeated a year on primary school, which is more often compared to the Dutch population of children. Their results on a reading task revealed lower scores. CONCLUSIONS: Language is impaired in children with Rolandic epilepsy. In some children this impairment of language may even be a precursor, for the Rolandic epilepsy. It is undecided however, whether the language impairment develops gradually after the onset of epilepsy, whether Rolandic epilepsy and language impairment are both symptoms of an underlying syndrome or both develop during the process of epileptogenesis as we observed in some children the onset of language impairment before the onset of epilepsy.