Publications by authors named "Femke K Aarsen"

34 Publications

Neuropsychological and Psychosocial Functioning of Children with Perinatal HIV-Infection in The Netherlands.

Viruses 2021 Sep 28;13(10). Epub 2021 Sep 28.

Department of Child and Adolescent Psychiatry, Erasmus MC University Medical Center, 3015 CN Rotterdam, The Netherlands.

Advances in antiretroviral treatment improved the life expectancy of perinatally HIV-infected children. However, growing up with HIV provides challenges in daily functioning. This cross-sectional cohort study investigated the neuropsychological and psychosocial functioning of a group of perinatally HIV-infected children in the Netherlands and compared their outcomes with Dutch normative data and outcomes of a control group of uninfected siblings. The children's functioning was assessed with internationally well-known and standardized questionnaires, using a multi-informant approach, including the perspectives of caregivers, teachers, and school-aged children. In addition, we explored the associations of socio-demographic and medical characteristics of the HIV-infected children with their neuropsychological and psychosocial functioning. Caregivers reported compromised functioning when compared to Dutch normative data for HIV-infected children in the areas of attention, sensory processing, social-emotional functioning, and health-related quality of life. Teachers reported in addition compromised executive functioning for HIV-infected children. A comparison with siblings revealed differences in executive functioning, problems with peers, and general health. The concurrent resemblance between HIV-infected children and siblings regarding problems in other domains implies that social and contextual factors may be of influence. A family-focused approach with special attention to the child's socio-environmental context and additional attention for siblings is recommended.
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September 2021

School functioning of children with perinatal HIV-infection in high-income countries: A systematic review.

PLoS One 2021 4;16(6):e0252746. Epub 2021 Jun 4.

Centre of Expertise Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, The Netherlands.

Introduction: Since the introduction of combination antiretroviral therapy, human immunodeficiency virus (HIV) infection is a manageable chronic disease. However, school-age children (4-18 years) living with HIV could still experience problems with functioning at school, due to the impact of the virus itself, medication, comorbidities and social stigma. School functioning covers academic achievement, school attendance, and social relationships and is of utmost importance to optimize normal participation.

Methods: To gain insight in school functioning problems of perinatally HIV-infected children, we performed a systematic review of the literature in multiple databases from January 1997 up to February 2019. Studies were included if they described outcomes of school functioning of school-age children perinatally infected with HIV, in high-income countries. Meta-analyses were performed for sufficiently comparable studies.

Results And Discussion: Results from 32 studies show that HIV-infected children experience more problems in various areas of school functioning in comparison with national norms, matched healthy controls, siblings and HIV-exposed uninfected (HEU) children. The most pronounced differences concerned the usage of special educational services, general learning problems, and mathematics and reading performance scores. Comparisons with both national norms and siblings/HEU children show that the differences between HIV-infected children and siblings/HEU children were less pronounced. Moreover, siblings/HEU children also reported significantly worse outcomes compared to national norms. This suggests that problems in school functioning cannot be solely attributed to the HIV-infection, but that multiple socio-economic and cultural factors may play a role herein.

Conclusion: Perinatally HIV-infected children seem vulnerable to problems in various areas of school functioning. Therefore, monitoring of school functioning should be an important aspect in the care for these children. A family-focused approach with special attention to a child's socio-environmental context and additional attention for siblings and HEU children, is therefore recommended.
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November 2021

Can serial cerebral MRIs predict the neuronopathic phenotype of MPS II?

J Inherit Metab Dis 2021 05 25;44(3):751-762. Epub 2021 Jan 25.

Center for Lysosomal and Metabolic Diseases (Department of Pediatrics), Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Objective: To advance the prediction of the neurocognitive development in MPS II patients by jointly analyzing MRI and neurocognitive data in mucopolysaccharidosis (MPS) II patients.

Methods: Cognitive ability scores (CAS) were obtained by neuropsychological testing. Cerebral MRIs were quantified using a disease-specific protocol. MRI sumscores were calculated for atrophy, white-matter abnormalities (WMA) and Virchow-Robin spaces (VRS). To distinguish between atrophy and hydrocephalus the Evans' index and the callosal angle (CA) were measured. A random effects repeated measurement model was used to correlate CAS with the three MRI sumscores.

Results: MRI (n = 47) and CAS scores (n = 78) of 19 male patients were analyzed. Ten patients were classified as neuronopathic and nine as non-neuronopathic. Neuronopathic patients had normal cognitive development until age 3 years. Mental age plateaued between ages 3 and 6, and subsequently declined with loss of skills at a maximum developmental age of 4 years. MRIs of neuronopathic patients showed abnormal atrophy sumscores before CAS dropped below the threshold for intellectual disability (<70). White-matter abnormalities (WMA) and brain atrophy progressed. The calculated sumscores were inversely correlated with CAS (r = -.90 for atrophy and -.69 for WMA). This was not biased by the influence of hydrocephalus as shown by measurement of the Evans' and callosal angle. Changes over time in the Virchow-Robin spaces (VRS) on MRI were minimal.

Conclusion: In our cohort, brain atrophy showed a stronger correlation to a decline in CAS when compared to WMA. Atrophy-scores were higher in young neuronopathic patients than in non-neuronopathic patients and atrophy was an important early sign for the development of the neuronopathic phenotype, especially when observed jointly with white-matter abnormalities.
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May 2021

Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.

Lancet Diabetes Endocrinol 2019 09 31;7(9):695-706. Epub 2019 Jul 31.

Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

Background: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T) concentrations (Allan-Herndon-Dudley syndrome). This chronic thyrotoxicosis leads to progressive deterioration in bodyweight, tachycardia, and muscle wasting, predisposing affected individuals to substantial morbidity and mortality. Treatment that safely alleviates peripheral thyrotoxicosis and reverses cerebral hypothyroidism is not yet available. We aimed to investigate the effects of treatment with the T analogue Triac (3,3',5-tri-iodothyroacetic acid, or tiratricol), in patients with MCT8 deficiency.

Methods: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T concentrations within the target range of 1·4-2·5 nmol/L. We assessed changes in several clinical and biochemical signs of hyperthyroidism between baseline and 12 months of treatment. The prespecified primary endpoint was the change in serum T concentrations from baseline to month 12. The co-primary endpoints were changes in concentrations of serum thyroid-stimulating hormone (TSH), free and total thyroxine (T), and total reverse T from baseline to month 12. These analyses were done in patients who received at least one dose of Triac and had at least one post-baseline evaluation of serum throid function. This trial is registered with, number NCT02060474.

Findings: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 μg/kg of bodyweight (range 6·4-84·3) to attain T concentrations within the target range. Serum T concentration decreased from 4·97 nmol/L (SD 1·55) at baseline to 1·82 nmol/L (0·69) at month 12 (mean decrease 3·15 nmol/L, 95% CI 2·68-3·62; p<0·0001), while serum TSH concentrations decreased from 2·91 mU/L (SD 1·68) to 1·02 mU/L (1·14; mean decrease 1·89 mU/L, 1·39-2·39; p<0·0001) and serum free T concentrations decreased from 9·5 pmol/L (SD 2·5) to 3·4 (1·6; mean decrease 6·1 pmol/L (5·4-6·8; p<0·0001). Additionally, serum total T concentrations decreased by 31·6 nmol/L (28·0-35·2; p<0·0001) and reverse T by 0·08 nmol/L (0·05-0·10; p<0·0001). Seven treatment-related adverse events (transiently increased perspiration or irritability) occurred in six (13%) patients. 26 serious adverse events that were considered unrelated to treatment occurred in 18 (39%) patients (mostly hospital admissions because of infections). One patient died from pulmonary sepsis leading to multi-organ failure, which was unrelated to Triac treatment.

Interpretation: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency.

Funding: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.
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September 2019

Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis.

Neurology 2018 05 27;90(22):e1997-e2005. Epub 2018 Apr 27.

From the Departments of Neurology (M.A.A.M.d.B., D.E.M.B., P.A.E.S.S., M.J.T.), Pediatric Neurology (F.K.A., M.P.v.O., M.M.v.d.K., C.E.C.-B., R.F.N.), and Immunology (M.W.J.S.), Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, the Netherlands.

Objective: To provide detailed long-term outcome data of children and adolescents following pediatric anti--methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL).

Methods: All Dutch children diagnosed with anti-NMDAR encephalitis were identified. Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment. The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue. Primary outcome measures were scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory.

Results: Twenty-eight patients were included. Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1-2, range 1-4), and 64% (18/28) of patients returned consistently to their previous school level. Twenty-two patients were included in the cross-sectional part of the long-term follow-up study. Median follow-up time was 31 months (interquartile range 15-49, range 5-91). There were problems with sustained attention ( = -2.10, 95% confidence interval = -2.71 to -1.46, < 0.0001) and fatigue ( = -0.96, 95% confidence interval = -1.64 to -0.28, = 0.008). Cognitive deficits were not correlated with QoL, while fatigue was strongly correlated with QoL ( = 0.82, < 0.0001).

Conclusions: Although follow-up is often reported as "good" following pediatric anti-NMDAR encephalitis, many patients have cognitive problems and fatigue, even up until adolescence, resulting in academic achievement problems and lower QoL. For physicians, it is essential to be aware of these problems, to provide valuable advice to patients and caregivers in the acute and follow-up phase, and to consider early neuropsychological counseling.
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May 2018

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain.

Dev Med Child Neurol 2018 06 24;60(6):579-586. Epub 2018 Mar 24.

Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands.

Aim: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy.

Method: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years.

Results: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities.

Interpretation: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease.

What This Paper Adds: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities.
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June 2018

Very Long-term Sequelae After Nonradical Surgery Combined With Brachytherapy in an Infant With a Chemotherapy-resistant Rhabdomyosarcoma of the Tongue.

J Pediatr Hematol Oncol 2017 10;39(7):566-569

*Princess Máxima Center for Pediatric Oncology §Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands †Department of Pediatrics, Erasmus MC-Sophia Children's Hospital ‡Department of Radiotherapy, Erasmus MC ∥Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital ¶Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.

In 2003, van Grotel and colleagues reported an infant suffering a chemotherapy-resistant eRMS of the tongue, that was treated with subtotal tumor resection and brachytherapy after major medical ethical discussions. As no long-term sequelae of such a procedure have been described, perspectives were uncertain at that time. Now, after 15 years, we describe hypoplasia of the mandibula, compromised dentation, osteopenia, neuropsychological deficits, and moderate speech impairment as the most prominent late effects. Also, mandibular cysts and basal cell carcinomas in the irradiated area, eventually led to the diagnosis Gorlin syndrome.
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October 2017

Development of emotional and behavioral problems in neurofibromatosis type 1 during young childhood.

Am J Med Genet A 2017 Sep 19;173(9):2373-2380. Epub 2017 Jun 19.

Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia Children's Hospital and ENCORE Expertise Centre for Neurodevelopmental Disorders, Rotterdam, The Netherlands.

This retrospective longitudinal study in young children with neurofibromatosis type 1 (NF1) aimed to identify if, and how early problems in behavior, intelligence, and language development are associated with later behavioral problems. At the first assessment at preschool age, we evaluated language skills, intelligence, and emotional and behavioral problems as reported by parents. The second assessment at school-age we evaluated intelligence, and emotional and behavioral problems as reported by parents and teachers. Association of baseline assessments with secondary assessment was evaluated using multivariable linear regression analysis. Of the 61 patients (25 males, 36 females; mean age 4;5 years [SD 1;1 years]) with NF1 who had a first assessment, 38 children (21 males, 17 females; mean age 7;11 years [SD 2;1 years]) had a second assessment after a mean period of 3;5 years. Longitudinal data on behavioral problems were collected for 23 of these children. Intelligence and language development were not associated with internalizing problems. Parent-rated internalizing behavioral problems significantly increased with age in this subgroup. Baseline internalizing problems predicted later internalizing problems (adjusted R  = 0.33, p = 0.003). The presence of these problems at pre-school age may be predictive of internalizing problems at a later age.
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September 2017

Eating behavior during dexamethasone treatment in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2017 Dec 9;64(12). Epub 2017 Jun 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background And Aim: Large prospective studies on dexamethasone-induced changes in eating behavior, energy, and nutrient intake are lacking in pediatric acute lymphoblastic leukemia (ALL). We prospectively studied eating behavior, energy, nutrient intake, and the effect on leptin and adiponectin levels during dexamethasone administration in children with ALL.

Patients: Parents of patients with ALL (3-16 years) completed a dietary diary for their child during 4 days of dexamethasone (6 mg/m ) administration. Energy intake and nutrient intake (energy percentage = E%) were assessed and compared with the recommended intake. The Dutch Eating Behavior Questionnaire for Children was completed before start and after 4 days of dexamethasone administration by patients of 7-12 years of age. Fasting leptin and adiponectin levels were also measured before start and after 4 days of dexamethasone administration.

Results: Energy intake per day(kcal) (N = 44) increased significantly during dexamethasone (median day 1: 1,103 (717-1,572) versus day 4: 1,482 (1,176-1,822), P < 0.01), including an increase in total protein, fat, saturated fat, carbohydrate, and sodium intake. Intake of saturated fat (median day 4: 12 E%) and salt (median day 4: 1.9 g/day) exceeded the healthy range for age and gender. With respect to eating behavior, dexamethasone significantly decreased restrained eating (P = 0.04). Leptin levels as well as adiponectin levels increased significantly during the dexamethasone course.

Conclusions: Four days of dexamethasone treatment significantly increased energy intake, including excessive saturated fat and salt intake, and changed eating behavior in children with ALL. Nutritional and behavioral interventions during dexamethasone treatment are recommended to stimulate a healthy lifestyle.
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December 2017

Risk factors for development of postoperative cerebellar mutism syndrome in children after medulloblastoma surgery.

J Neurosurg Pediatr 2017 Jul 12;20(1):35-41. Epub 2017 May 12.

Departments of 1 Pediatric Neurology.

OBJECTIVE Postoperative cerebellar mutism syndrome (pCMS) occurs in 7%-50% of children after cerebellar tumor surgery. Typical features include a latent onset of 1-2 days after surgery, transient mutism, emotional lability, and a wide variety of motor and neurobehavioral abnormalities. Sequelae of this syndrome usually persist long term. The principal causal factor is bilateral surgical damage (regardless of tumor location) to any component of the proximal efferent cerebellar pathway, which leads to temporary dysfunction of cerebral cortical regions as a result of diaschisis. Tumor type, cerebellar midline location, and brainstem involvement are risk factors for pCMS that have been identified repeatedly, but they do not explain its latent onset. Ambiguous or negative results for other factors, such as hydrocephalus, postoperative meningitis, length of vermian incision, and tumor size, have been reached. The aim of this study was to identify perioperative clinical, radiological, and laboratory factors that also increase risk for the development of pCMS. The focus was on factors that might explain the delayed onset of pCMS and thus might provide a time window for taking precautionary measures to prevent pCMS or reduce its severity. The study was focused specifically on children who had undergone surgery for medulloblastoma. METHODS In this single-center retrospective cohort study, the authors included 71 children with medulloblastoma, 28 of whom developed pCMS after primary resection. Clinical and laboratory data were collected prospectively and analyzed systematically. Variables were included for univariate and multivariate analysis. RESULTS Univariate regression analysis revealed 7 variables that had a significant influence on pCMS onset, namely, tumor size, maximum tumor diameter > 5 cm, tumor infiltration or compression of the brainstem, significantly larger decreases in hemoglobin (p = 0.010) and hematocrit (p = 0.003) in the pCMS group after surgery than in the no-pCMS group, significantly more reported incidents of severe bleeding in the tumor bed during surgery in the pCMS group, preoperative hydrocephalus, and a mean body temperature rise of 0.5°C in the first 4 days after surgery in the pCMS group. Multiple regression analysis revealed that tumor size, tumor infiltration into or compression of the brainstem, and higher mean body temperature in the first 4 postoperative days were independent and highly significant predictors for pCMS. CONCLUSIONS The authors confirmed earlier findings that tumor-associated preoperative conditions, such as a maximum tumor diameter ≥ 5 cm and infiltration into or compression of the brainstem, are associated with a higher risk for the development of pCMS. Most importantly, the authors found that a 0.5°C higher mean body temperature in the first 4 postoperative days increased the odds ratio for the development of pCMS almost 5-fold. These data suggest that an important focus for the prevention of pCMS in children who have undergone medulloblastoma surgery might be rigorous maintenance of normothermia as standard care after surgery.
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July 2017

Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.

Psychoneuroendocrinology 2016 10 11;72:190-5. Epub 2016 Jul 11.

Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands. Electronic address:

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity.
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October 2016

Health-related quality of life and emotional problems in children surviving brain tumor treatment: A descriptive study of 2 cohorts.

Pediatr Hematol Oncol 2016 Aug 23;33(5):282-294. Epub 2016 Jun 23.

a Department of Child and Adolescent Psychiatry and Psychology , Erasmus Medical Centre Rotterdam-Sophia Children's Hospital , Rotterdam , The Netherlands.

The survival of childhood brain tumors has improved in the past 30 years, but acquired brain injury due to damage caused by tumor invasion and side effects of different treatment modalities frequently occurs. This study focused on residual impairments, health-related quality of life (HRQoL), and emotional and behavioral problems in 2 cohorts of survivors diagnosed and treated for various types of brain tumors. Survivors in the 2004 cohort visited the Erasmus Medical Centre for standardized follow-up between 2003 and 2004, and in the 2014 cohort, between 2012 and 2014. Data of neurologically impairments of all children were extracted from medical records. Parents and survivors filled out questionnaires on quality of life and emotional and behavioral problems. In both cohorts, approximately 55% of the survivors displayed neurologic impairments. In comparison with the healthy reference group, a reduced parent-reported quality of life was found on the Motor, Cognition, and Autonomy (Cohort 2004) scales. Comparison between the cohorts showed that parents in the 2004 cohort reported a higher HRQoL on the Motor and Cognitive functioning scales. In the 2014 cohort, children reported less negative emotions than healthy children. No increase in emotional or behavioral problems were reported by children in both cohorts, whereas parents reported problems in social functioning and isolation related to a delay in emotional development. Children surviving brain tumor treatment have a reduced quality of life. The authors therefore recommend regular screening of HRQoL and emotional and behavioral problems and referral to specific aftercare.
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August 2016

Hydrocortisone as an Intervention for Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a Double-Blind, Randomized Controlled Trial.

J Clin Oncol 2016 07 9;34(19):2287-93. Epub 2016 May 9.

Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.

Purpose: Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL.

Patients And Methods: We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters.

Results: Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters.

Conclusion: Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.
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July 2016

Growing Up After Critical Illness: Verbal, Visual-Spatial, and Working Memory Problems in Neonatal Extracorporeal Membrane Oxygenation Survivors.

Crit Care Med 2016 06;44(6):1182-90

1Intensive Care Unit, Department of Pediatric Surgery Erasmus Medical Centre-Sophia Children's Hospital, Rotterdam, The Netherlands. 2Department of Neonatology Radboud University Medical Center, Nijmegen, The Netherlands.

Objectives: To assess neuropsychologic outcome in 17- and 18-year-old neonatal extracorporeal membrane oxygenation survivors.

Design: A prospective longitudinal follow-up study.

Setting: Follow-up program at the Erasmus MC-Sophia Children's Hospital in Rotterdam, The Netherlands.

Patients: Thirty adolescents 17 or 18 years old, treated between 1991 and 1997, underwent neuropsychologic assessment.

Interventions: None.

Measurements And Main Results: Attention, memory, executive functioning, visual-spatial functions, social-emotional functioning, and behavior were assessed with validated instruments, and data were compared with reference data. Included predictors for analysis of adverse outcome were diagnosis, age at start extracorporeal membrane oxygenation, convulsions, and use of antiepileptics. Adolescents' performance (expressed as mean [SD] z score) was significantly lower than the norm on short-term and long-term verbal memory (z score = -1.40 [1.58], p = 0.016; z score = -1.54 [1.67], p = 0.010, respectively), visual-spatial memory (z score = -1.65 [1.37], p = 0.008; z score = -1.70 [1.23], p = 0.008, respectively), and working memory (32% vs 9% in the norm population). Parents reported more problems for their children regarding organization of materials (z score = -0.60 [0.90]; p = 0.03) and behavior evaluation (z score = -0.53 [0.88]; p = 0.05) on a questionnaire. Patients reported more withdrawn/depressed behavior (z score = -0.47 [0.54]; p = 0.02), somatic complaints (z score = -0.43 [0.48]; p = 0.03), and social problems (z score = -0.41 [0.46]; p = 0.04). Patients reported more positive feelings of self-esteem and an average health status.

Conclusions: Adolescents treated with neonatal extracorporeal membrane oxygenation are at risk of verbal, visual-spatial, and working memory problems. Future research should focus on 1) the longitudinal outcome of specific neuropsychologic skills in adolescence and adulthood; 2) identifying risk factors of neuropsychologic dysfunction; 3) evaluating to what extent "severity of illness" is responsible for acquired brain injury; and 4) effects of timely cognitive rehabilitation.
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June 2016

Long-term cognitive follow-up in children treated for Maroteaux-Lamy syndrome.

J Inherit Metab Dis 2016 Mar 8;39(2):285-92. Epub 2015 Oct 8.

Center for Lysosomal and Metabolic Diseases, Department of Pediatrics, Erasmus MC University Medical Center - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.

Background: It remains unclear to what extent the brain is affected by Maroteaux-Lamy syndrome (MPS VI), a progressive lysosomal storage disorder. While enzyme replacement therapy (ERT) elicits positive effects, the drug cannot cross the blood-brain barrier. We therefore studied cognitive development and brain abnormalities in the Dutch MPS VI patient population treated with ERT.

Methods: In a series of 11 children with MPS VI (age 2 to 20 years), we assessed cognitive functioning and brain magnetic resonance imaging prospectively at the start of ERT and at regular times thereafter up to 4.8 years. We also assessed the children's clinical characteristics, their siblings' cognitive development, and their parents' educational levels.

Results: The patients' intelligence scores ranged from normal to mentally delayed (range test scores 52-131). In 90%, their scores remained fairly stable during follow-up, generally lying in the same range as their siblings' test scores (median for patients = 104, median for siblings = 88) and comparing well with the parental educational levels. Native-speaking patients had higher intelligence test scores than non-native-speaking patients. Two patients, both with high baseline glycosaminoglycan levels in their urine and severe mutations in the arylsulfatase B gene, scored clearly lower than expected. Patients with pY210C performed best. Brain abnormalities were aspecific, occurring more in patients with severe symptoms.

Conclusion: Our study shows that cognitive development in MPS VI patients is determined not only by familial and social-background factors, but, in patients with a severe form of the disease, also by the disease itself. Therefore in patients with severe disease presentation cognition should be monitored carefully.
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March 2016

Children with congenital colorectal malformations often require special education or remedial teaching, despite normal intelligence.

Acta Paediatr 2016 Feb 28;105(2):e77-84. Epub 2015 Oct 28.

Department of Paediatric Surgery, Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands.

Aim: This study prospectively evaluated neuropsychological functioning in 8-year-old patients with anorectal malformation (ARM) and Hirschsprung's disease (HD).

Methods: School functioning and behaviour were assessed in a standardised interview. Intelligence, attention, self-esteem and quality of life were evaluated with validated tests and questionnaires. The following predictors were assessed: socio-economic status, number of episodes of general anaesthesia, laxative treatment and premature birth. Severely intellectually disabled patients were excluded.

Results: In total, twelve of the 23 (52%) patients with ARM and 11 (55%) of the 20 patients with HD received special education or remedial teaching. The intelligence quotient was normal: mean (standard deviation or SD) was 98 (17) and 96 (17), respectively. However, sustained attention was below the norm: mean (SD) Z-score was -1.90 (1.94) and -1.43 (1.98) for ARM and HD patients; both p < 0.01. Self-esteem was normal: mean (SD) Z-score was 0.10 (1.29) and -0.20 (1.11) for ARM and HD patients. Quality of life was normal in ARM patients and slightly impaired in HD patients. No predictors for neuropsychological outcome were identified.

Conclusion: Despite normal intelligence, more than half of these patients received special education or remedial teaching. In addition, problems with sustained attention were found. These findings are important for long-term care.
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February 2016

Long-term outcome of Guillain-Barré syndrome in children.

J Peripher Nerv Syst 2014 Jun;19(2):121-6

Department of Pediatric Neurology, Erasmus MC and Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Neurology, Erasmus MC and Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC and Erasmus MC-Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

The objective of this study is to determine the long-term outcome and consequences of Guillain-Barré syndrome (GBS) in children. This is an observational cross-sectional cohort study of children diagnosed with GBS (0-18 years old) at the Sophia Children's Hospital in Rotterdam from 1987 to 2009. All patients were invited for a structured interview, questionnaires, and full neurologic exam to record their current clinical condition focused on complaints and symptoms, neurological deficits, disabilities, behavior, and quality of life. Thirty-seven patients participated, 23 were now adults, with a median age of 20 years (range 4-39 years) and a median follow-up time of 11 years (range 1-22 years). Residual complaints were reported by 24 (65%) patients, including paresthesias (38%), unsteadiness of gait in the dark (37%), painful hands or feet (24%), and severe fatigue (22%). Four patients had severe neurological deficits, including facial diplegia and limb weakness. Two patients had had a recurrence of GBS. In 10 patients (26%), GBS had a negative impact on their school career. Questionnaires identified a wide range of behavioral problems. Quality of life was below normal on the subscale vitality, and above normal on the subscales social functioning and positive emotions in the adult group. Most children show good recovery of neurological deficits after GBS, but many have persisting long-term residual complaints and symptoms that may lead to psychosocial problems interfering with participation in daily life.
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June 2014

Long-term outcome in children with low grade tectal tumours and obstructive hydrocephalus.

Eur J Paediatr Neurol 2014 Jul 12;18(4):469-74. Epub 2014 Mar 12.

Department of Paediatric Neurology, Erasmus MC/ Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: Neuropsychological deficits after treatment of paediatric brain tumour are well known, but not the role of hydrocephalus in these deficits.

Aims: To study long-term neurological, cognitive, and behavioural deficits in children with a low grade tectal tumour and acquired obstructive hydrocephalus.

Methods: In a consecutive series of 12 children with low-grade tectal tumour diagnosed in our hospital between 1994 and 2008, neurologic, neuropsychological, and radiologic data were prospectively collected. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Median follow-up was 2 years and 9 months.

Results: At follow-up, most frequent neurologic disability was fatigue in children with a low-grade tectal tumour. They scored lower on sustained attention, long-term memory and had more behavioural problems. Factor influencing cognition was persisting severe hydrocephalus at time of assessment. The cognitive problems resulted in 60% of children needing assistances of special services at school.

Conclusions: At long-term, children with a low-grade tectal tumour display invalidating neuropsychological impairments resulting in educational problems. Adequate treatment of hydrocephalus may result in better cognitive functioning. Our findings suggest that part of the symptoms of the cerebellar cognitive affective syndrome may not have resulted from a cerebellar lesion itself but rather from a cerebral dysfunction or compression of supratentorial structures in the cerebello-cortical circuitry due to the obstructive hydrocephalus.
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July 2014

Emotional distress in 652 Dutch very long-term survivors of childhood cancer, using the hospital anxiety and depression scale (HADS).

J Pediatr Hematol Oncol 2013 Oct;35(7):525-9

*Department of Paediatric Oncology/Haematology, Erasmus MC-Sophia Children's Hospital †Department of Obstetrics and Gynaecology, Division of Reproductive Medicine ‡Department of Biostatistics §Department of Internal Medicine/Endocrinology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Background: After a more successful treatment of pediatric cancer, the number of childhood cancer survivors is progressively increasing. Consequently, awareness of psychological late sequelae is important.

Procedure: The Hospital Anxiety and Depression Scale (HADS) was used as a screening tool for emotional distress in a single center cohort of 652 childhood cancer survivors (median age 23 y [range, 15 to 46 y], median follow-up time 15 y [range, 5 to 42 y]). Results were compared with a control group of 440 Dutch subjects. A higher HADS score linearly reflect a higher level of emotional distress, and a score ≥15 is indicative of clinically significant emotional distress.

Results: Mean HADS score of the childhood cancer survivors was not different from the control group (P=0.38). Survivors exposed to global central nervous system (CNS) irradiation had a significantly higher HADS score than the control group (8.3±6.6; P=0.05) as well as other survivors (P=0.01). Forty-three survivors (7%) had a HADS score ≥15. Survivors with a HADS score ≥15 were variously spread over the diagnostic-related and treatment-related subgroups. Linear regression analysis showed that high educational achievement (β=-1.28; P<0.01) and age at the time of the study (β=0.08; P=0.03) were both significantly associated with the HADS score.

Conclusions: Emotional distress does not occur more often in childhood cancer survivors than in the normal population. No disease-related or treatment-related variable was independently associated with emotional distress.
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October 2013

Long-term follow-up and treatment in nine boys with X-linked creatine transporter defect.

J Inherit Metab Dis 2012 Jan 10;35(1):141-9. Epub 2011 May 10.

Department of Clinical Genetics, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

The creatine transporter (CRTR) defect is a recently discovered cause of X-linked intellectual disability for which treatment options have been explored. Creatine monotherapy has not proved effective, and the effect of treatment with L-arginine is still controversial. Nine boys between 8 months and 10 years old with molecularly confirmed CRTR defect were followed with repeated (1)H-MRS and neuropsychological assessments during 4-6 years of combination treatment with creatine monohydrate, L-arginine, and glycine. Treatment did not lead to a significant increase in cerebral creatine content as observed with H(1)-MRS. After an initial improvement in locomotor and personal-social IQ subscales, no lasting clinical improvement was recorded. Additionally, we noticed an age-related decline in IQ subscales in boys affected with the CRTR defect.
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January 2012

Motor learning in children with neurofibromatosis type I.

Cerebellum 2011 Mar;10(1):14-21

Department of General Pediatrics, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.

The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1.
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March 2011

The spectrum of neurobehavioural deficits in the Posterior Fossa Syndrome in children after cerebellar tumour surgery.

Cortex 2010 Jul-Aug;46(7):933-46. Epub 2009 Oct 29.

Department of Paediatric Neurology, Erasmus University/Sophia Children's Hospital, Dr. Molewaterplein 60, Rotterdam, The Netherlands.

Introduction: The Posterior Fossa Syndrome (PFS) may occur in children after resection of cerebellar tumours. The most common feature is mutism, but also oropharyngeal dyspraxia, emotional lability and neuropsychiatric symptoms occur. We analysed the spectrum of behavioural abnormalities, speech and language characteristics during PFS.

Methods: In order to identify PFS, all children with a cerebellar tumour admitted to our centre in the study period were prospectively assessed before and after tumour surgery. In the case of PFS, children were systematically followed by means of a standard protocol that included a daily neurological examination and assessment of speech behaviour. Speech was recorded on videotape before and immediately after surgery, and in cases of PFS at as short possible intervals for 4 weeks and subsequently every second week until the recurrence of speech and normalisation of behaviour. Data regarding clinical and behavioural features, duration of symptoms and mode of recovery were collected. Pre- and postoperative MRI data were studied. In 13 children with and two children without PFS a (99m)Tc-hexamethylpropyleneamine oxime-Single Photon Emission Tomography (SPECT) scan could be performed.

Results: PFS occurred in 41 of 148 children. During recovery all children were dysarthric, but only in a few speech features specific for cerebellar dysarthria occurred. A significant correlation was found between duration of mutism and severity of neurological symptoms. Significant correlations were also found between duration of mutism and abnormalities on SPECT scans of the left temporal lobe, the left and right basal nuclei, and the right frontal lobe.

Conclusions: In this study, impairments of higher cognitive functions were observed in the context of PFS. They varied in severity and composition between children with symptoms fitting into the spectrum of the Cerebellar Cognitive Affective Syndrome. SPECT scan findings suggest that these impairments are secondary to supratentorial metabolic hypofunction following cerebellar surgery.
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August 2010

Paediatric arterial ischaemic stroke: functional outcome and risk factors.

Dev Med Child Neurol 2010 Apr 18;52(4):394-9. Epub 2010 Jan 18.

Department of Paediatric Oncology and Haematology, Erasmus Medical Centre/Sophia Children's Hospital, Rotterdam, the Netherlands.

Aim: To study functional outcome in children aged 1 month to 18 years after paediatric arterial ischaemic stroke (PAIS) and to identify risk factors influencing their quality of life.

Method: In a consecutive series of 76 children (35 males 41 females, median age at diagnosis 2y 6mo, range 1mo-17y 2mo; median length of follow-up 2y 4mo, range [7mo-10y 6mo]) with PAIS diagnosed at the Erasmus Medical Centre Sophia Children's Hospital between 1997 and 2006, we collected clinical, biochemical, and radiological data prospectively. In 66 children surviving at least 1 year after PAIS, functional outcome could be evaluated with the World Health Organization's International Classification of Impairments, Disabilities and Handicaps.

Results: Significant risk factors at presentation for a poor neurological outcome were young age, infarction in the right middle cerebral artery territory, and fever at presentation. Fifty-four % of children had severe neurological impairments at 12 months after PAIS, and at last follow-up more than half needed remedial teaching, special education, or institutionalization. Health-related quality of life (HRQOL) questionnaires showed a significantly lower HRQOL in all age groups. Children with a longer follow-up had a lower HRQOL in the cognitive functioning domain.

Interpretation: Our study shows significant morbidity and mortality and a reduced HRQOL after PAIS depending on age, fever at presentation, and infarction in the right middle cerebral artery territory.
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April 2010

Fatigue and depression in children with multiple sclerosis and monophasic variants.

Eur J Paediatr Neurol 2010 Jul 12;14(4):320-5. Epub 2009 Oct 12.

Department of Neurology, Erasmus MC, Rotterdam, the Netherlands.

Background: Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue.

Methods: We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n=22) or definite MS (n=10). This was measured with the Checklist Individual Strength. A score of >or=40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children.

Results: The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers.

Conclusion: The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.
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July 2010

Landau-Kleffner syndrome and CSWS syndrome: treatment with intravenous immunoglobulins.

Epilepsia 2009 Aug;50 Suppl 7:55-8

Department of Paediatric Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

This study reports results of therapy with immunoglobulin in children with Landau-Kleffner syndrome (LKS) or the syndrome of continuous spikes and waves during sleep (CSWS syndrome). In a prospective study, children diagnosed between 2002 and 2006 with either LKS or CSWS syndrome were treated soon after diagnosis with intravenous courses of immunoglobulin (IVIg). We compared the results with those reported in the literature and with data from a retrospective survey of our earlier patients. Six children (two girls), aged 4-9 years, were included. Three had LKS, and three had CSWS syndrome. One child-with typical LKS-had been treated with prednisone before (without response). No patient had seizures during IVIg treatment and follow-up. Their electroencephalography (EEG) findings did not improve. Neuropsychological improvement occurred in one child with CSWS syndrome. Three children did not show any beneficial effect; they were subsequently treated with steroids, one with a clearly positive result. We conclude that successful treatment of LKS and CSWS syndrome with IVIg occurs occasionally. However, the improvement cannot always be clearly attributed to this. It might also reflect the natural course of the disease. Although the temporal relation between IVIg treatment and clinical improvement cannot be denied in individual patients, its real value remains to be determined.
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August 2009

Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up.

Pediatr Blood Cancer 2009 Dec;53(6):1048-53

Department of Pediatric Neurology, Erasmus MC/Sophia Children's Hospital, Rotterdam, the Netherlands.

Background: Kinsbourne syndrome or opsoclonus myoclonus syndrome (OMS) is characterized by rapid, involuntary, irregular conjugate eye movements (opsoclonus), myoclonic jerking of the limbs and trunk, ataxia, and behavioral disturbances. In general, the outcome of neurologic and behavioral symptoms is poor. Studies on quality of life (Qol) and recovery after very long-term follow-up of children with OMS are lacking.

Methods: We studied long-term cancer survival, neurologic recovery, and Qol of a consecutive series of eight patients with OMS that were treated in our center. Two cross-sectional follow-up evaluations were conducted at a 3-year interval (T1 and T2).

Results: In four out of eight children with OMS a neuroblastoma (NBL) was diagnosed and surgically removed completely. All children received immuno-modulatory therapy, consisting of prednisone (three children), prednisone and ACTH (four children), or prednisone, ACTH, and gammaglobulin (one child). At T1, median follow-up time was 9.5 years (range 3-14 years) after OMS onset and at T2, 11.6 years (range 6-17 years). Neurologic functioning improved in all children, reflected by a significant improvement of the mean Z-score in the motor domain of the Qol questionnaire at T2 as compared to T1. In contrast, seven children continued to have a severe developmental delay at T2. No significant difference in any of the variables was found between NBL survivors and OMS patients without NBL.

Conclusion: Cognitive and behavioral impairments and not a motor impairment, such as ataxia, appear to be predominant at long-term in children with OMS.
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December 2009

Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood.

J Clin Oncol 2009 Jul 11;27(21):3526-32. Epub 2009 May 11.

MSc, Department of Pediatric Neurology, Erasmus Medical Center-Sophia Children's Hospital, PO Box 2060, 3000 CB Rotterdam, the Netherlands.

PURPOSE To prospectively study cognitive deficits and predictors 3 years after diagnosis in a large series of pediatric patients treated for pilocytic astrocytoma (PA). PATIENTS AND METHODS Sixty-one of 67 children were grouped according to infratentorial, supratentorial midline, and supratentorial hemispheric site. Intelligence, memory, attention, language, visual-spatial, and executive functions were assessed. Included predictors were sex, age, relapse, diagnosis-assessment interval, hydrocephalus, kind of treatment, and tumor variables. Results All children with PA had problems with sustained attention and speed. In the infratentorial group, there also were deficits in verbal intelligence, visual-spatial memory, executive functioning, and naming. Verbal intelligence and verbal memory problems occurred in the brainstem tumor group. The supratentorial hemispheric tumor group had additional problems with selective attention and executive functioning, and the supratentorial midline tumor group displayed no extra impairments. More specifically, the dorsal supratentorial midline tumor group displayed problems with language and verbal memory. Predictors for lower cognitive functioning were hydrocephalus, radiotherapy, residual tumor size, and age; predictors for better functioning were chemotherapy or treatment of hydrocephalus. Almost 60% of children had problems with academic achievement, for which risk factors were relapse and younger age at diagnosis. CONCLUSION Despite normal intelligence at long-term follow-up, children treated for PA display invalidating cognitive impairments. Adequate treatment of hydrocephalus is important for a more favorable long-term cognitive outcome. Even children without initial severe deficits may develop cognitive impairments years after diagnosis, partly because of the phenomenon of growing into deficit, which has devastating implications for academic achievement and quality of life (QOL).
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July 2009

Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior.

J Pediatr 2009 Mar 31;154(3):420-5, 425.e1. Epub 2008 Oct 31.

NF1 CoRe Team (Cognitive Research Team), Department of General Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Objective: To investigate health-related quality of life (HR-QOL) in children with neurofibromatosis type 1 (NF1) with parental reports and children's self-reports, and to investigate the potential contribution of demographic factors, disease-specific factors, and problems in school performance or behavior.

Study Design: In a prospective observational study, parents of 58 children with NF1 (32 boys, 26 girls, age 12.2 +/- 2.5 years) visiting a university clinic, and their 43 children 10 years or older were assessed with the Child Health Questionnaire (CHQ). Potential determinants of domain scores were assessed in 3 explorative regression models.

Results: Parents reported a significant impact of NF1 on 9/13 CHQ scales, with moderate effect sizes on 8 (general health perceptions, physical functioning, general behavior, mental health, self esteem, family activities, role functioning emotional/behavioral, and parent emotional impact). Children report an impact on bodily pain, and an above average general behavior. Multiple CHQ scales were sensitive to demographic factors and behavioral problems, and 1 to NF1 severity. NF1 visibility and school problems did not influence HR-QOL.

Conclusions: Parents, but not the children with NF1, report a profound impact of NF1 on physical, social, behavioral, and emotional aspects of HR-QOL. Multiple HR-QOL domains were most sensitive to behavioral problems, which points to an exciting potential opportunity to improve HR-QOL in children with NF1 by addressing these behavioral problems.
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March 2009

Impact of neurofibromatosis type 1 on school performance.

J Child Neurol 2008 Sep;23(9):1002-10

Department of General Pediatrics, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

School functioning of 86 Dutch neurofibromatosis type 1 children (7-17 years) using teacher questionnaires was analyzed to determine the impact of neurofibromatosis type 1 on school performance. In all, 75% of the neurofibromatosis type 1 children performed more than 1 standard deviation below grade peers in at least one of the domains of spelling, mathematics, technical reading or comprehensive reading. Furthermore, neurofibromatosis type 1 children had a 4-fold increased risk for attending special education and a 6-fold increased risk for receiving remedial teaching for learning, behavior, speech, or motor problems. Children without apparent learning disabilities still frequently displayed neuropsychological deficits. Only 10% of the children did not show any school-functioning problems. Finally, it was found that the clinical severity of neurofibromatosis type 1 correlated with the cognitive deficits. Taken together, it was shown that neurofibromatosis type 1 has profound impact on school performance. Awareness of these problems may facilitate timely recognition and appropriate support.
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September 2008