Eyes on CVI: Eye movements unveil distinct visual search patterns in Cerebral Visual Impairment compared to ADHD, dyslexia, and neurotypical children.

Visual search problems are often reported in children with Cerebral Visual Impairment (CVI). To tackle the clinical challenge of objectively differentiating CVI from other neurodevelopmental disorders, we developed a novel test battery. Visual search tasks were coupled with verbal and gaze-based measurements. Two search tasks were performed by children with CVI (n: 22; mean age (SD): 9.63 (.46) years) ADHD (n: 32; mean age (SD): 10.51 (.25) years), dyslexia (n: 28; mean age (SD): 10.29 (.20) years) and neurotypical development (n: 44; mean age (SD): 9.30 (.30) years). Children with CVI had more impaired search performance compared to all other groups, especially in crowded and unstructured displays and even when they had normal visual acuity. In-depth gaze-based analyses revealed that this group searched in overall larger areas and needed more time to recognize a target, particularly after their initial fixation on the target. Our gaze-based approach to visual search offers new insights into the distinct search patterns and behaviours of children with CVI. Their tendency to overlook targets whilst fixating on it, point towards higher-order visual function (HOVF) deficits. The novel method is feasible, valid, and promising for clinical differential-diagnostic evaluation between CVI, ADHD and dyslexia, and for informing individualized training.

High-Dose Methylphenidate and Carboxylesterase 1 Genetic Variability in Patients With Attention-Deficit/Hyperactivity Disorder: A Case Series.

PURPOSE/BACKGROUND: Methylphenidate (MPH) is widely used to reduce symptoms of attention-deficit/hyperactivity disorder. Methylphenidate is metabolized by the carboxylesterase 1 (CES1) enzyme. Some patients need a very high dose of MPH to reach desired clinical effects, without having adverse effects. This may be due to differences in MPH pharmacokinetics (PK), potentially caused by DNA variants in CES1 , the gene encoding the enzyme that metabolizes MPH. Here we describe 3 patients requiring high-dose MPH and investigated the CES1 gene. METHODS/PROCEDURES: The 3 patients were using short-acting MPH in a dose of 180 to 640 mg instead of the maximum advised dose of around 100 mg MPH in the Netherlands. Plasma concentrations of MPH were determined at scheduled time points (day-curve). Methylphenidate plasma concentrations were used for PK analysis using an earlier published 2-compartment PK population model of MPH. Individual data of the 3 patients were compared with simulated population data, when equivalent doses were used. In addition, CES1 was genotyped (number of gene copies and single nucleotide polymorphisms) using real-time polymerase chain reaction. FINDINGS/RESULTS: Pharmacokinetic analysis in all 3 patients showed lower plasma concentrations of MPH in comparison with the population data. The mean absorption time and volume of distribution of the central compartment were equal, but the elimination clearance was higher. However, CES1 genotyping revealed no variations that could explain a higher metabolism of MPH. IMPLICATIONS/CONCLUSIONS: In these 3 cases, we could not demonstrate a correlation between MPH clearance and known genetic variants of the CES1 gene.

Primary carnitine deficiency is a life-long disease.

Primary carnitine deficiency is a rare autosomal recessive disease associated with acute hypoketotic hypoglycaemia, cardiomyopathy and sudden cardiac death. Effective treatment with carnitine supplementation is available. An 18 months old boy, who presented with cardiomyopathy was diagnosed with primary carnitine deficiency, and carnitine supplementation resulted in a full recovery. At age 13 years, he discontinued his medication and at 20 years, he discontinued clinical monitoring. Nine years later, age 29, he presented with heart failure and atrial fibrillation and was admitted to an intensive care unit, where he was treated with furosemide, enoximone and intravenous carnitine supplementation, this lead to improved cardiac function within 2 weeks, and with continued oral carnitine supplements, his left ventricular ejection fraction normalised. The last 8 years were uneventful and he continued to attend his regular follow-up visits at a specialised metabolic outpatient clinic. We report recurrent reversible severe heart failure in a patient with primary carnitine deficiency; it was directly related to non-compliance to carnitine supplementation (and monitoring). This case report emphasises first, the importance of continued monitoring of metabolic disease patients, second, the potential reversibility of cardiomyopathy in an adult patient, and third, the potential risks in the period of transition from the paediatric to adult care. This is an age where young adults desire to be healthy and ignore the need for ongoing medical treatment, even as simple as oral suppletion. Before they reach this age, adequate disease insight and self-management of the disease should be promoted.

A qualitative and quantitative study of self-reported positive characteristics of individuals with ADHD.

Research in Attention-deficit/hyperactivity disorder (ADHD) has had a clear focus on treatment and the dysfunction in specific situation associated with the condition. However, self-report, observational and anecdotal evidence indicates that there are also positive aspects associated with ADHD. Research on the potential positive features in individuals with an ADHD diagnosis is still limited, especially studies with larger representative samples. Here we performed qualitative research to identify positive aspects and strengths associated with ADHD in a large convenience sample from the Dutch organization for people with ADHD, dyslexia and dyscalculia. We sent out open-ended questionnaires to the members of the organization, asking what they consider to be positive aspects of their ADHD. From the responses of individuals with ADHD (n = 206), we extracted 116 codes, which were assigned to thirteen subthemes, which in turn led to five themes. These themes were: Creativity, Being dynamic, Flexibility, Socio-affective skills, and Higher-order cognitive skills. Core symptoms of ADHD such as impulsivity and hyperactivity were also considered positive aspects of ADHD by a minority of participants. After showing our results to a group of additional individuals with ADHD (focus group) they confirmed the identified positive aspects of ADHD. They also helped us with the interpretation of our findings and mentioned certain positive aspects to be a consequence of living with ADHD (being open minded and being honest). In conclusion, experiencing positive aspects seems to be common in ADHD as almost all participants reported positive aspect of ADHD, these aspects cover many different domains. Awareness about ADHD's strengths might help individuals with ADHD and their environment to better cope with, accept or embrace their diagnosis and for example make educational or occupational choices that fit them well. To incorporate these positive aspects in the understanding of ADHD, future research should focus on quantifying strengths in ADHD, and on investigating the link between these aspects and clinical characteristics and how this new knowledge can be implemented in psychoeducation and find its way to education and occupational settings.

Stability of Methylphenidate under Various pH Conditions in the Presence or Absence of Gut Microbiota.

Methylphenidate is one of the most widely used oral treatments for attention-deficit/hyperactivity disorder (ADHD). The drug is mainly absorbed in the small intestine and has low bioavailability. Accordingly, a high interindividual variability in terms of response to the treatment is known among ADHD patients treated with methylphenidate. Nonetheless, very little is known about the factors that influence the drug's absorption and bioavailability. Gut microbiota has been shown to reduce the bioavailability of a wide variety of orally administered drugs. Here, we tested the ability of small intestinal bacteria to metabolize methylphenidate. In silico analysis identified several small intestinal bacteria to harbor homologues of the human carboxylesterase 1 enzyme responsible for the hydrolysis of methylphenidate in the liver into the inactive form, ritalinic acid. Despite our initial results hinting towards possible bacterial hydrolysis of the drug, up to 60% of methylphenidate is spontaneously hydrolyzed in the absence of bacteria and this hydrolysis is pH-dependent. Overall, our results indicate that the stability of methylphenidate is compromised under certain pH conditions in the presence or absence of gut microbiota.

Time-shifting effects of methylphenidate on daily rhythms in the diurnal rodent Arvicanthis ansorgei.

People suffering of attention-deficit/hyperactivity disorder (ADHD) and treated with the psychostimulant methylphenidate (MPH) show sleep-wake cycle and daily rhythm alterations despite the beneficial effects of MPH on behavioral symptoms (i.e., hyperactivity, attention). In nocturnal rodents (i.e., mice), chronic exposure to MPH alters the neural activity of the circadian clock in the suprachiasmatic nucleus (SCN), behavioral rhythms, and the sleep-wake cycle. Here, we studied the effects of MPH on daily rhythms of behavior and body temperature of the diurnal rodent Arvicanthis ansorgei. Under a light-dark cycle, chronic exposure to MPH in drinking water delayed the onset of both activity and body temperature rhythms. Interestingly, delays were larger when MPH access was restricted to the first 6 h of the light phase (i.e., activity phase) of the 24-h cycle. Since MPH effects are dependent on animal's fluid intake, in a last experiment, we controlled the time and dose of MPH delivery in Arvicanthis using an intraperitoneal perfusion method. Similarly to the experiment with MPH in drinking water, Arvicanthis showed a delay in the onset of general activity and body temperature when MPH infusions, but not vehicle, were during the first 6 h of the light phase. This study indicates that MPH alters daily rhythms in a time-dependent manner and proposes the use of a diurnal rodent for the study of the effects of MPH on the circadian clock. Knowing the circadian modulation on the effects of MPH in behavior could give new insights in the treatment of ADHD.

Five years of Kawasaki disease in the Netherlands: a national surveillance study.

BACKGROUND: The aim of this study was to evaluate the incidence, disease presentation, treatment and cardiac outcome of Kawasaki disease (KD) in The Netherlands. METHODS: The national Dutch Pediatric Surveillance Unit was used to prospectively register new KD cases from 2008 through 2012. Questionnaires were sent to pediatricians to obtain clinical information. RESULTS: Nationwide 341 cases were reported during the 5-year study period, of which 319 questionnaires (93.0%) were returned. The mean incidence of KD was estimated to be 5.8/100,000 children <5 years of age. The median age at disease onset was 2.4 years (range 0.1-14.6 years) and 79.2% of cases were <5 years of age. The male-to-female ratio was 1.5 to 1. Incomplete KD was diagnosed in 22.3% of cases and these cases were significantly younger than complete cases [median: 1.1 (0.1-13.7) vs. 2.8 (0.2-14.6) years, P < 0.001]. In total, 308 patients (96.6%) received intravenous immunoglobulins (IVIG). Retreatment with IVIG was given in 71 (23.1%) and additional steroid treatment in 17 patients (5.5%). During the acute phase, coronary artery aneurysms developed in 43 cases (13.5%). Multivariate logistic regression analysis showed that male gender, delay of treatment (>10 days) and IVIG retreatment were independent risk factors for coronary artery aneurysms development. CONCLUSIONS: This prospective study of KD in The Netherlands revealed a mean annual incidence of 5.8/100,000 children <5 years of age. Clinicians should consider the diagnosis of KD in young (male) children with persistent inexplicable fever to start IVIG treatment within 10 days to prevent development of coronary artery aneurysms.

Methylphenidate modifies the motion of the circadian clock.

People with attention-deficit/hyperactivity disorder (ADHD) often experience sleep problems, and these are frequently exacerbated by the methylphenidate they take to manage their ADHD symptoms. Many of the changes to sleep are consistent with a change in the underlying circadian clock. The present study was designed to determine if methylphenidate alone could alter properties of the circadian clock. Young male mice were examined in light-dark cycles and in constant darkness and recordings were performed on behavioral activity, sleep, and electrical activity in the suprachiasmatic nucleus (SCN) of freely moving mice. Methylphenidate in the drinking water (0.08%) significantly increased activity in the mid-to-late night, and led to a delay in the onset of activity and sleep relative to the light-dark cycle. While locomotor levels returned to baseline after treatment ended, the phase angle of entrainment required at least a week to return to baseline levels. In constant darkness, the free-running period of both wheel-running and general locomotor rhythms was lengthened by methylphenidate. When the treatment ended, the free-running period either remained stable or only partially reverted to baseline levels. Methylphenidate also altered the electrical firing rate rhythms in the SCN. It induced a delay in the trough of the rhythm, an increment in rhythm amplitude, and a reduction in rhythm variability. These observations suggest that methylphenidate alters the underlying circadian clock. The observed changes are consistent with clock alterations that would promote sleep-onset insomnia.

Effects of a restricted elimination diet on the behaviour of children with attention-deficit hyperactivity disorder (INCA study): a randomised controlled trial.

BACKGROUND: The effects of a restricted elimination diet in children with attention-deficit hyperactivity disorder (ADHD) have mainly been investigated in selected subgroups of patients. We aimed to investigate whether there is a connection between diet and behaviour in an unselected group of children. METHODS: The Impact of Nutrition on Children with ADHD (INCA) study was a randomised controlled trial that consisted of an open-label phase with masked measurements followed by a double-blind crossover phase. Patients in the Netherlands and Belgium were enrolled via announcements in medical health centres and through media announcements. Randomisation in both phases was individually done by random sampling. In the open-label phase (first phase), children aged 4-8 years who were diagnosed with ADHD were randomly assigned to 5 weeks of a restricted elimination diet (diet group) or to instructions for a healthy diet (control group). Thereafter, the clinical responders (those with an improvement of at least 40% on the ADHD rating scale [ARS]) from the diet group proceeded with a 4-week double-blind crossover food challenge phase (second phase), in which high-IgG or low-IgG foods (classified on the basis of every child's individual IgG blood test results) were added to the diet. During the first phase, only the assessing paediatrician was masked to group allocation. During the second phase (challenge phase), all persons involved were masked to challenge allocation. Primary endpoints were the change in ARS score between baseline and the end of the first phase (masked paediatrician) and between the end of the first phase and the second phase (double-blind), and the abbreviated Conners' scale (ACS) score (unmasked) between the same timepoints. Secondary endpoints included food-specific IgG levels at baseline related to the behaviour of the diet group responders after IgG-based food challenges. The primary analyses were intention to treat for the first phase and per protocol for the second phase. INCA is registered as an International Standard Randomised Controlled Trial, number ISRCTN 76063113. FINDINGS: Between Nov 4, 2008, and Sept 29, 2009, 100 children were enrolled and randomly assigned to the control group (n=50) or the diet group (n=50). Between baseline and the end of the first phase, the difference between the diet group and the control group in the mean ARS total score was 23·7 (95% CI 18·6-28·8; p<0·0001) according to the masked ratings. The difference between groups in the mean ACS score between the same timepoints was 11·8 (95% CI 9·2-14·5; p<0·0001). The ARS total score increased in clinical responders after the challenge by 20·8 (95% CI 14·3-27·3; p<0·0001) and the ACS score increased by 11·6 (7·7-15·4; p<0·0001). In the challenge phase, after challenges with either high-IgG or low-IgG foods, relapse of ADHD symptoms occurred in 19 of 30 (63%) children, independent of the IgG blood levels. There were no harms or adverse events reported in both phases. INTERPRETATION: A strictly supervised restricted elimination diet is a valuable instrument to assess whether ADHD is induced by food. The prescription of diets on the basis of IgG blood tests should be discouraged. FUNDING: Foundation of Child and Behaviour, Foundation Nuts Ohra, Foundation for Children's Welfare Stamps Netherlands, and the KF Hein Foundation.

[Diagnosis of fetal alcohol spectrum disorders]. / Diagnostiek van foetale alcoholspectrumstoornissen.

Prenatal alcohol exposure may cause decreased growth of the child, congenital abnormalities, specific facial characteristics, and, most importantly, mental retardation and behavioural disorders, all known as fetal alcohol spectrum disorders (FASD). A significant number of pregnant women in the Netherlands drink alcohol, but the prevalence of FASD in our country is unknown. Repeated and high peak blood alcohol concentrations, for example in the case of binge drinking by the mother, result in more severe abnormalities; a safe limit for alcohol consumption in pregnancy cannot be defined. In 2007 and 2008, Dutch paediatricians reported a total of 56 diagnosed cases of FASD, mostly adopted and foster children. Possibly the condition has not always been diagnosed. Use of international guidelines for diagnosis by the medical profession may improve detection. The guidelines of the Canadian Public Health Agency provide a useful and generally accepted classification, with strict cut-off points to avoid overdiagnosis; attention should always be paid to the broad differential diagnosis.

Adolescent alcohol intoxication in the Dutch hospital Departments of Pediatrics.

OBJECTIVE: This study was conducted to investigate the number and characteristics of adolescent alcohol intoxication cases in hospital Departments of Pediatrics. The study also analyzes drinking patterns and intoxication characteristics. METHOD: Data were collected using the Dutch Pediatric Surveillance System, in which about 92% of general pediatricians and 83% of academic pediatricians participate. In 2007, questionnaires were collected every month within 56 hospitals. A total of 297 adolescent alcohol intoxications were reported, of which 231 cases were analyzed. RESULTS: Hospital-admitted adolescents in this study are 12-18 years old, with an average age of 15.3 years. Intoxicated adolescents appear to be a representative sample of the Dutch population on all background variables (gender, educational level, family structure). CONCLUSIONS: This study shows the serious nature of adolescent intoxication and may indicate that more strict governmental alcohol control policies are required.

A nationwide study on hospital admissions due to dehydration in exclusively breastfed infants in the Netherlands: its incidence, clinical characteristics, treatment and outcome.

AIMS: To estimate the incidence and clinical characteristics in hospital admissions due to dehydration or undernutrition and their laboratory evaluation and treatment outcome in exclusively breastfed infants. METHODS: All hospital admissions during the first 3 months of life assessed by the Dutch Paediatric Surveillance Unit (DPSU) between mid 2003 and mid 2005. RESULTS: Nationwide 158 cases reported, correspond to an incidence of 58/y/100,000 breastfed infants; it is lower for severe dehydration at risk for hypernatraemia; 20/y/100,000. Sixty-five per cent of cases were <2 weeks old, their median weight loss was 9.3% and median age at admission 5 days; Serum sodium value was measured in only 12% of all cases. Insufficient volume intake and inadequate growth were most frequently reported (61% and 41%). Lethargy, jaundice or clinical dehydration was scored in 11-25%, seizures or shock in 3%. A breast pump at home was used in only 31%. In the hospital breast pumps were available (82%) as lactation consultants (73%). For treatment 65% was offered formula, in 30% by nasogastric drip. Most admissions lasted up to 3 days, all recovered fully and 33% were breastfed exclusively at discharge. CONCLUSION: The incidence of severe dehydration in the Netherlands is relatively low. With extended use of breast pumps at home it could be lower. To prevent complications, we recommend applying a reference weight chart, a full clinical examination and more extensive screening of serum sodium and glucose.

A randomised controlled trial into the effects of food on ADHD.

The aim of this study is to assess the efficacy of a restricted elimination diet in reducing symptoms in an unselected group of children with Attention deficit/hyperactivity disorder (ADHD). Dietary studies have already shown evidence of efficacy in selected subgroups. Twenty-seven children (mean age 6.2) who all met the DSM-IV criteria for ADHD, were assigned randomly to either an intervention group (15/27) or a waiting-list control group (12/27). Primary endpoint was the clinical response, i.e. a decrease in the symptom scores by 50% or more, at week 9 based on parent and teacher ratings on the abbreviated ten-item Conners Scale and the ADHD-DSM-IV Rating Scale. The intention-to-treat analysis showed that the number of clinical responders in the intervention group was significantly larger than that in the control group [parent ratings 11/15 (73%) versus 0/12 (0%); teacher ratings, 7/10 (70%) versus 0/7 (0%)]. The Number of ADHD criteria on the ADHD Rating Scale showed an effect size of 2.1 (cohen's d) and a scale reduction of 69.4%. Comorbid symptoms of oppositional defiant disorder also showed a significantly greater decrease in the intervention group than it did in the control group (cohens's d 1.1, scale reduction 45.3%). A strictly supervised elimination diet may be a valuable instrument in testing young children with ADHD on whether dietary factors may contribute to the manifestation of the disorder and may have a beneficial effect on the children's behaviour.

Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline.

Vitamin K prophylaxis is recommended to prevent the hazard of haemorrhage caused by vitamin K deficiency in newborns. The present Dutch guideline recommends 1 mg of vitamin K(1) orally at birth, followed by a daily dose of 25 microg of vitamin K(1) from 1 to 13 weeks of age for breastfed infants. Since the introduction of this prophylaxis, the incidence of vitamin K deficiency bleeding (VKDB) has decreased; however, late VKDB is still reported. From 1 January to 31 December 2005, a nationwide active surveillance was performed by the Netherlands Paediatric Surveillance Unit (NSCK) to study the current incidence and aetiology of late VKDB in infants. Six cases could be validated as late VKDB: all were breastfed, one fatal idiopathic intracranial haemorrhage at the age of 5 weeks and five bleedings secondary to an underlying cholestatic liver disease between the age of 3 and 7 weeks. The total incidence of late VKDB and idiopathic late VKDB was calculated to be 3.2 (95% CI: 1.2-6.9) and 0.5 (95% CI: 0-2.9) per 100,000 live births, respectively. With the current Dutch guideline, idiopathic late VKDB is rare but late VKDB secondary to cholestasis still occurs in breastfed infants. Doubling the daily dose of vitamin K(1) to 50 microg, as is comparable to formula-feeding, may possibly prevent VKDB in this group. Further research, however, is needed to prove this hypothesis.

Henoch Schonlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria.

BACKGROUND: The aim of the present study on the occurrence of Henoch-Schönlein Purpura (HSP) in Dutch children is to give some insight into the epidemiology of HSP in the Netherlands, to record the diagnostic criteria used by Dutch paediatricians and to evaluate the accuracy of the latter using the presence of IgA in the skin when biopsies are available. METHODS: Each month in 2004, all Dutch paediatricians received an electronic card asking them to mention new diagnosed HSP. Paediatricians reporting one or more new patients with HSP were sent a list of questions concerning various parameters. RESULTS: 232 patients from 0 to 18 years of age (6.1/10(5)) were reported as having contracted HSP in 2004. 29% presented renal symptoms. In accordance with the classification criteria of the American College of Rheumatology, 80% of paediatricians consider that isolated purpura (without haematological abnormalities) is sufficient to allow the diagnosis of HSP in children. From the 17 skin biopsies performed, only 9 (53%) presented IgA deposits. The follow-up duration, considered as necessary, was longer in case of renal symptoms at presentation. However, 45% of patients without renal symptoms would be followed for more than 1 year. CONCLUSION: Considering the recent (2006) EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides, HSP should have been diagnosed in only 160 of the 179 patients of our study. The use of isolated non-thrombocytopenic purpura as the only criterion to diagnose HSP in children might therefore lead to over diagnosis and unnecessary follow-up.

Identification of the first AHI1 gene mutations in nephronophthisis-associated Joubert syndrome.

Joubert syndrome (JBTS) is an autosomal recessive multisystem disease characterized by cerebellar vermis aplasia, mental retardation, muscular hypotonia, an irregular breathing pattern in the neonatal period and abnormal eye movements. Some individuals have progressive renal failure characterized by nephronophthisis (NPHP) and/or retinal dystrophy. Homozygous deletions of NPHP1 on chromosome 2q13 have been identified in individuals with NPHP-associated JBTS. Recently, mutations in AHI1 on chromosome 6q23.3 were found in JBTS patients without NPHP. Here, by direct sequencing, we identify novel truncating mutations within AHI1 in affected patients from two families. One patient had the association of JBTS and NPHP with chronic renal failure. This is the first report of AHI1 mutations causing JBTS associated with NPHP, confirming the clinical and genetic heterogeneity of NPHP.