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Item does not contain fulltext MEPs and CMAPs as prognostic tools for spina bifida. AIM: The aim of this prospective study was to determine the prognostic value of neurophysiological investigations compared to clinical neurological examination in infants with spina bifida. METHODS: Thirty-six neonates born with spina bifida between 2002 and 2007 were evaluated and followed for 2 years. Lumbar motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were obtained at the median age of 2 days old before surgical closure of the spinal anomaly. MEPs were recorded from the quadriceps femoris, tibialis anterior, and gastrocnemius muscles and CMAPs from the latter two muscles. Areas under the curve and latencies of the MEPs and CMAPs were measured. Clinical neurological outcome at the age of 2 years was described using Muscle Function Classes (MFCs) and ambulation status. RESULTS: The areas under the curve of MEPs and CMAPs in the legs were associated with lower neonatal levels of motor and sensory impairment. Better muscle function class of the lower limbs at 2 years of age was associated with larger MEP and CMAP areas of the gastrocnemius and tibialis anterior muscles at neonatal age. DISCUSSION: MEPs and CMAPs of the gastrocnemius and tibialis anterior muscles are of prognostic value for clinical neurological outcome in neonates born with spina bifida.

Item does not contain fulltext PURPOSE: Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of MR images of the malformation is not always straightforward. Morphometric analyses of the extent of Chiari II malformation may improve the assessment. In an attempt to select appropriate morphometric measures for this purpose, we investigated the interobserver reliability and diagnostic performance of several morphometric measures of Chiari II malformation on MR images. METHODS: Brain MR images of 79 children [26 with open spinal dysraphism, 17 with closed spinal dysraphism, and 36 without spinal dysraphism; mean age 10.6 (SD 3.2; range, 6-16) years] were evaluated. All children had been assessed for Chiari II malformation (defined as cerebellar herniation in combination with open spinal dysraphism; n = 23). Three observers blindly and independently reviewed the MR images for 21 measures of the cerebellum, brainstem, and posterior fossa in three planes. The interobserver reliability was assessed by an agreement index (AI = 1 - RRE) and the diagnostic performance by receiver operating characteristic analyses. RESULTS: Reliability was good for most measures, except for the degree of herniation of the vermis and tonsil. Most values differed statistically significantly between children with and without Chiari II malformation. The measures mamillopontine distance and cerebellar width showed excellent diagnostic performance. CONCLUSIONS: Morphometric measures may reliably quantify the morphological distortions of Chiari II malformation on MR images and provide additional tools to assess the severity of Chiari II malformation in clinical and research settings. 01 juli 2012

Contains fulltext : 89238.pdf (Publisher’s version ) (Closed access) BACKGROUND: Spina bifida is a complex neuroembryological disorder resulting from incomplete closure of the posterior neural tube. Morbidity in the different fields of motor and cognitive neurodevelopment is variable in nature and severity, and often hard to predict. AIMS: The current study investigates the relationship between cognitive functioning, fine motor performance and motor quality in children with spina bifida myelomeningocele (SBM) and SB-only, taking into consideration the cerebral malformations. MATERIAL AND METHODS: Forty-one children were included (22 girls and 19 boys aged between 6 and 14 years, mean age 10;0 years) in the study. A comprehensive assessment was conducted of cognitive functioning and motor profile, including fine motor and visual-motor functioning, and motor quality. The performance outcomes were analyzed for the total group of children and separately for the nonretarded children (FSIQ> or =70, N=30) to eliminate the influence of global intellectual impairment. RESULTS: Although the children with spina bifida showed increased incidence of cognitive and fine motor impairment, and impaired motor quality, after exclusion of the overall retarded children no associations were found between cognitive functioning and motor profile. In the comparison of SBM to SB-only specific differences were found for performance IQ, visual-motor functioning and motor quality, but not fine motor functioning. CONCLUSION: Our findings underscore the role of cerebral malformation in spina bifida and its consequences for neuropsychological functioning. The complicated developmental interactions found strengthen the need for an individualized management of children with SB. 01 januari 2010

Contains fulltext : 49874.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of the study was to determine the histological effect on the neural tissue of in utero covering of an experimental neural tube defect in fetal lambs, with the use of two different biomatrices. MATERIALS AND METHODS: In 23 fetal sheep, surgery was performed at 79 days' gestation. In 19 of these, a neural tube defect was created, while 4 fetuses served as sham-operated controls. In 7 of the 19 operated fetuses the defect was left uncovered. In the remaining 12 animals the defect was covered either with a collagen biomatrix (4 animals), skin (3 animals), or small intestinal submucosa biomatrix (5 animals). The lambs were sacrificed at 1 week of age and histological examination was performed. RESULTS: All lambs with an uncovered neural tube defect showed histological damage of the spinal cord. In lambs in which the neural tube defect was covered, one half showed a normal architecture of the spinal cord while minor histological damage was present in the other half. Between the three groups in which the defect was covered, the histological outcome was comparable. CONCLUSIONS: Acute covering of an experimental neural tube defect in fetal lambs prevents severe histological damage to the spinal cord independent of the two biomatrices used in this study.

Objective: Persistent exposure of the unprotected spinal cord to amniotic fluid and the uterine wall can lead to progressive damage of neural tissue in case of a myelomeningocele (two-hit hypothesis). The aim of this study was to evaluate whether in utero repair of an experimental neural tube defect in a fetal lamb could protect neural tissue from secondary injury and save neurologic functions after birth. Methods:In 19 fetal lambs, a neural tube defect was created at 79 days’ gestation. In 12 lambs the defect was covered either with a novel, molecular defined collagen-based biocompatible and biodegradable matrix (UMC) or with a small intestinal submucosa (SIS) biomatrix (Cook®) or by closing the skin over the defect. Results: All lambs with the defect covered showed no or minor neurologic morbidity in contrast to the lambs with the defect uncovered in which major neurologic morbidity was seen. Conclusions:These results demonstrate that long-term exposure of the open spinal cord to the intrauterine environment can lead to damage of neural tissue and, consequently loss of neurologic functions and that coverage of the defect can lead to a better neurologic outcome. Furthermore, we could show that a UMC biomatrix and an SIS biomatrix are useful for in utero coverage of a surgically created neural tube defect in our model.

Children with spina bifida (SB) often require special education. To date, little information is available about the educational career of these children. This study focuses on educational career and predictors of attending special education of young adults with SB, using a cross-sectional study including 178 young Dutch adults with SB aged from 16-25. The main outcome was attending regular versus special education. For searching predictive power we selected age, gender, type of SB, level of lesion, hydrocephalus (HC), number of surgical interventions, ambulation, continence and cognitive functioning. Chi-square tests and binary logistic regression were used in the data analysis. Participants with HC attended special primary education more often (59%) than participants without HC (17%). For those participants with HC, the necessity of special primary education was associated with below average intelligence (75% versus 35%), wheelchair dependence (82% versus 39%) and surgical interventions (74% versus 44%). Only half of the participants with HC followed regular secondary education, whereas for participants with SB without HC, the outcome in secondary education was similar to that of the general population (92%). Intelligence was the main predictor of attending special secondary education (odds 5.1:1), but HC (odds 4.3:1) and wheelchair dependence (odds 2.6:1) were also a significant. Other variables were not significant predictors of special secondary education.

Contains fulltext : 57742.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To investigate the association of viral infections and febrile seizures (FS). STUDY DESIGN: From April 1998 to April 2002, a prospective, population-based study was carried out among general practitioners to assess the incidence of FS in their practices. Data thus obtained were compared with the incidence of common viral infections recorded in a national registry. Poisson regression analysis was performed to investigate whether the season or the type of infection was associated with the variation observed in FS incidence. RESULTS: Throughout the 4-year period, 267 of 303 (88%) of general practitioners in the Dutch province of Friesland participated in the study. The estimated observation period was approximately 160,000 patient-years. We registered 654 cases of FS in 429 children. The estimated incidence of FS was 2.4 in 1000 patient-years. Poisson regression analysis revealed a positive correlation between recurrent FS and influenza A ( P = .01). CONCLUSIONS: Our study suggests a relation between recurrent FS and influenza A. Influenza vaccination should be considered in all children with a history of FS.

Item does not contain fulltext Although fever is regarded as the main trigger in the pathogenesis of febrile seizures (FS), it is not supposed to be the unique causative factor. In FS, there is a strong familial predisposition. This does not exclude infections as a causative factor because subtle genetic polymorphisms have been demonstrated to affect the course of infections. We review the literature on: (1) the role of fever, especially the height of temperature, its cause, and metabolic effects induced by temperature; (2) the role of heredity; (3) the role of cytokines which play a role in the induction of fever; and (4) the role of type of infection, with emphasis on newly identified agents and improved diagnostic techniques. With modern molecular techniques such as PCR, viruses have been detected in the CSF far more often than previously thought, even in the absence of pleocytosis of the CSF. This makes it difficult to distinguish FS from acute encephalitis. FS may be caused by neuroinvasion or intracerebral activation of viruses. Further studies should focus on these options because therapeutic intervention is possible and may prevent late sequelae such as recurrent FS and subsequent epilepsy.

The goal of this study was to develop a calibrated on-line technique to extract as much diagnostically-relevant information as possible from conventional video-format echograms. The final aim is to improve the diagnostic potentials of medical ultrasound. Video-output images were acquired by a frame grabber board incorporated in a multiprocessor workstation. Calibration images were obtained from a stable tissue-mimicking phantom with known acoustic characteristics. Using these images as reference, depth dependence of the gray level could fairly be corrected for the transducer performance characteristics, for the observer-dependent equipment settings and for attenuation in the examined tissues. Second-order statistical parameters still displayed some nonconsistent depth dependencies. The results obtained with two echoscanners for the same phantom were different; hence, an a posteriori normalization of clinical data with the phantom data is indicated. Prior to processing of clinical echograms, the anatomical reflections and echoless voids were removed automatically. The final step in the preprocessing concerned the compensation of the overall attenuation in the tissue. A ‘sliding window’ processing was then applied to a region of interest (ROI) in the ‘back-scan converted’ images. A number of first and second order statistical texture parameters and acoustical parameters were estimated in each window and assigned to the central pixel. This procedure results in a set of new ‘parametric’ images of the ROI, which can be inserted in the original echogram (gray value, color) or presented as a color overlay. A clinical example is presented for illustrating the potentials of the developed technique. Depending on the choice of the parameters, four full resolution calibrated parametric images can be calculated and simultaneously displayed within 5 to 20 seconds. In conclusion, an on-line technique has been developed to estimate acoustic and texture parameters with a reduced equipment dependence and to display acoustical and textural information that is present in conventional echograms.

Objective : This study was meant to obtain insight in the inter- and intra-individual range of neonatal cerebral blood flow velocity and the factors which determine this range. Methods : The blood flow velocity in the internal carotid artery was followed during 5 days in fourteen healthy, appropriate for date preterm newborns, using Doppler ultrasound. Results : It was found that cerebral blood flow velocity varies more between than within the infants, and that this is partially attributable to an inverse relation between cerebral blood flow velocity and weight-for-gestational-age, and a positive relation between cerebral blood flow velocity and postnatal age. The relation with postnatal age could be explained in part by closure of the ductus arteriosus. The effects of weight-for-gestational-age and patent ductus arteriosus were greater for end-diastolic than for peak-systolic velocity. Postnatal age showed an opposite effect. Conclusion : Thus, weight-for-gestational-age, postnatal age and patent ductus arteriosus contribute to the inter-and intra-individual variation of cerebral blood flow velocity.

Contains fulltext : 48025.pdf (Publisher’s version ) (Closed access) During 2 consecutive influenza seasons we investigated the presence of influenza virus, human herpesvirus (HHV) type 6, and HHV-7 in cerebrospinal fluid samples from 9 white children suffering from influenza-associated encephalopathy. We conclude that it is unlikely that neuroinvasion by influenza virus or reactivation of either HHV-6 or HHV-7 is involved.

The aims of this thesis were: (1) to identify parental occupations with an increased risk of spina bifida in offspring; (2) to study whether parental occupational exposure to chemicals or radiation during or shortly before pregnancy is a risk factor for the occurrence of spina bifida. In order to answer these questions, an epidemiological case-referent study was designed. After an extensivere view of the literature on risk factors for neural tube defects, with emphasison occupational and environmental factors, methodological issues in the design of the survey are discussed. Subsequently the results of the case-referent study, in which questionnaires were used to assess the occupation of the parents at the time of conception, are discussed and compared with studies conducted in Sweden, Spain and Hungary. The most important finding of the core study was an increased risk of spina bifida for women who had an agricultural occupation around conception. Also, working as a cleaning women was found to be associated with spina bifida, although this association was less pronounced. The results with regard to paternal occupations suggest associations with welders and transport workers. However, occupational risk factors do not account for a large part of the prevalence of spina bifida in the total population.

The purpose of this study was to investigate whether the preference of periventricular hemorrhage (PVH) for the left hemisphere is due to asymmetry of cerebral blood flow (CBF) and, if so, whether this asymmetry is due to patent ductus arteriosus (PDA). Thirty-three preterm newborns at risk for PVH were followed during their first 5 days after birth. Internal carotid CBF velocity (CBFV) and the flow direction in the common pulmonary artery, both determined by ultrasound Doppler, served as measures of CBF and PDA, respectively. The difference between right and left CBFV was analyzed statistically, with outcome, PDA, capillary Pco 2 , behavior, heart rate, and the average of right and left CBFV as covariates. Infants who developed PVH (n = 7) exhibited CBFV asymmetry to the disadvantage of the left side. This finding was partially attributable to PDA. Without PVH there was no significant CBFV asymmetry. Because all hemorrhages were bilateral, a relationship with the side of the hemorrhage could not be explored. In conclusion, asymmetry of CBFV is not normal, but is associated with PVH and PDA.

The effect of interruption of positive end expiratory pressure (PEEP) on cerebral blood flow velocity (CBFV) and CBF fluctuation (CBFF) in the internal carotid arteries and on heart rate, restlessness and wakefulness has been studied in 17 mechanically ventilated neonates with RDS. A decrease in CBFV was found, but no significant change in CBFF. Multiple regression analysis showed that the decrease in CBFV is less pronounced if the PEEP interruption is accompanied by restlessness. It further appeared that the decrease in CBFV is more pronounced if CBFV is high, the ductus arteriosus is patent, or RDS follows a complicated course. These findings indicate that PEEP supports CBF, probably by a decrease in ductal stealing from the brain. Therewith PEEP protects against cerebral hypoperfusion which is one of the major risks in RDS and immaturity. Furthermore, our findings suggest that the decrease in CBF during PEEP interruption is moderated by restlessness and accentuated by brain damage.

Item does not contain fulltext PURPOSE: Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of morphological features of the malformation on MR images may not always be straightforward. In an attempt to select those features that unambiguously characterize the Chiari II malformation, we investigated the interobserver reliability of all its well-known MR features. METHODS: Brain MR images of 79 children [26 presumed to have Chiari II malformation, 36 presumed to have no cerebral abnormalities, and 17 children in whom some Chiari II malformation features might be present; mean age 10.6 (SD 3.2; range, 6-16) years] were blindly and independently reviewed by three observers. They rated 33 morphological features of the Chiari II malformation as present, absent, or indefinable in three planes (sagittal, axial, and coronal). The interobserver reliability was assessed using kappa statistics. RESULTS: Twenty-three of the features studied turned out to be unreliable, whereas the interobserver agreement was almost perfect (kappa value > 0.8) for nine features (eight in the sagittal plane and one in the axial plane, but none in the coronal plane). CONCLUSIONS: This study presents essential features of the Chiari II malformation on MR images by ruling out the unreliable features. Using these features may improve the assessment of Chiari II malformation in clinical and research settings. 01 juli 2012

Item does not contain fulltext Cognitive and motor problems are common in children with spina bifida (SB), particularly in those children with cerebral malformations (SBM). Little is known about how these conditions affect motor learning. This study examines motor sequence learning in children with SB, SBM, and healthy controls. Assessment consisted of neuropsychological tests, a simple drawing task, and a spatial motor sequence learning task. Implicit motor learning was unaffected in children with SB( M), and their sequence learning ability was also similar to that of controls. However, both groups (SB and SBM) showed impaired motor performance. The role of cerebellar malformation with SB(M) is discussed. 16 p.

From four Dutch families six patients, who have congenital muscular dystrophy, involvement of the central nervous system and of the eyes, or the so-called "muscle, eye and brain disease" (MEB-D), are reported. Two patients are still alive, in four autopsy could be performed. The clinical and morphological data of our patients are compared to those described in recent literature. The progression of the disease was rapid in five of our six patients. Our study supports the idea that within the MEB-D syndrome there are at least two different types of clinical expression, one with a rapid progression as described by Dobyns et al 1989 (9) and one with a slower progression as described in most patients of Santavuori et al 1989 (23). The study also confirms the autosomal recessive mode of inheritance of MEB-D.

Background Children with the severe form of spina bifida (SBM: spina bifida with myelomeningocele with accompanying hydrocephalus) may manifest attention deficits, and have a similar psychological profile to children with hydrocephalus due to other etiologies. It is unclear to what extent tests to assess attention in SBM are confounded by the accompanying cognitive or visual-motor impairments. The aim of this study was to analyse attention functions by administering two different types of attention tests, one with high and the other with low cognitive and motor requirements. This enabled the possible interaction between attention and cognitive and motor impairment to be assessed. Methods The study group comprised 31 children with SBM with shunted hydrocephalus. Twenty children with SB-only formed a closely matched comparison group. Of these, 19 children with SBM and 18 with SB had a full-scale IQ (FSIQ) higher than 70. All had undergone spinal surgery and all children with SBM had been shunted within the first months of life. Between 6 and 15 years of age, the children were assessed on focused and sustained attention, encoding, and distractibility/impulsivity, using both traditional tests and computerized attention tests. Results Compared to the SB group, attention scores of children with SBM were lower on the traditional tests, but when interfering cognitive and visual-motor requirements were eliminated using the computerised tasks, most differences disappeared. Furthermore, in contrast to traditional attention tasks, computerized tests showed no significant correlations with IQ-scores and visual-motor skills. Conclusion Assessment of attention functions in children with SBM by traditional tests may be misleading, because this paediatric population with complex cerebral malformations has difficulty with the cognitive and visual-motor requirements. To control for these interactions, the use of both traditional and computerized attention tests is recommended.

Item does not contain fulltext BACKGROUND: Spina bifida (SB) can place parents at risk for increased levels of parenting stress. Little is known, however, about the role of parents' intrapersonal resources. Therefore, based on ideas of the Disability-Stress-Coping Model, relations between the severity of SB, parents' personality traits and parenting stress were examined. METHODS: Forty-six mothers and 37 fathers of children with SB (6-14 years) participated. Severity of SB (physical dysfunctions and cognitive functions), parental personality (Big Five) and parenting stress (Parenting Stress Index) were measured. Multiple regression analyses were performed. RESULTS: The severity of the child's physical dysfunctions was positively associated with parenting stress. Extraversion (mothers only), emotional stability and agreeableness (fathers only) were negatively related to parenting stress. In the final model, 64% of the variance in mothers' and 67% of the variance in fathers' levels of parenting stress was explained. Parents' personality traits explained the largest proportions of variance in parenting stress. CONCLUSION: Mobility, bladder and bowel dysfunctions in school-aged children with SB represent ongoing stressors for parents. Parents' intrapersonal resources of positive affectivity, however, are more important determinants of parental adjustment to SB than the child's physical dysfunctions.

Contains fulltext : 69210.pdf (Publisher’s version ) (Closed access) We discuss four cases of acid alpha-glucosidase deficiency (EC, 3.2.1.3/20) without evident symptoms of Pompe disease (OMIM No 232300) in individuals of Asian descent. In three cases, the deficiency was associated with homozygosity for the sequence variant c.[1726G>A; 2065G>A] in the acid alpha-glucosidase gene (GAA) translating into p.[G576S; E689K]. One of these cases was a patient with profound muscular atrophy, another had cardio-myopathy and the third had no symptoms. The fourth case, the mother of a child with Pompe disease, was compound heterozygote for the GAA sequence variants c.[1726G>A; 2065G>A]/c.2338G>A (p.W746X) and had no symptoms either. Further investigations revealed that c.[1726A; 2065A] is a common GAA allele in the Japanese and Chinese populations. Our limited study predicts that approximately 4% of individuals in these populations are homozygote c.[1726A; 2065A]. The height of this figure in contrast to the rarity of Pompe disease in Asian populations and the clinical history of the cases described in this paper virtually exclude that homozygosity for c.[1726A; 2065A] causes Pompe disease. As c.[1726A; 2065A] homozygotes have been observed with similarly low acid alpha-glucosidase activity as some patients with Pompe disease, we caution they may present as false positives in newborn screening programs especially in Asian populations.

Contains fulltext : 69026.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To test the presence and progress of Pediatric Medical Traumatic Stress (PMTS) symptoms in parents of children with spina bifida (SB). METHODS: Parents of 23 newborns with SB were interviewed prospectively and parents of 58 school-aged children with SB were interviewed retrospectively. PMTS symptoms were assessed with 17 DSM-IV criteria for the clusters Intrusion, Avoidance, and Increased Arousal. RESULTS: Within 3 months after the SB diagnosis, 75% of the parents met diagnostic criteria for symptoms of Intrusion and Increased Arousal, but not of Avoidance. In parents of school-aged children with SB, PMTS symptoms had declined in the first 4 years of the child's life and stabilized during the school years. Approximately 30% of the mothers and 20% of the fathers still met diagnostic criteria for Intrusion, Avoidance and Increased Arousal. In mothers of children with open SB, symptoms of Intrusion and Increased Arousal had decreased more slowly than in mothers of children with closed SB. CONCLUSIONS: An SB diagnosis initially provokes traumatic stress symptoms in three-quarters of the parents; however, in most of them, these symptoms diminish during the first 4 years of the child's life. In a minority of the parents, severe stress symptoms persist beyond middle childhood. Professional psychological help may need to be offered to this selective group of parents whose levels of stress do not decline after the child's preschool years. Longitudinal research is needed to further investigate and confirm the trends that were found in parents' psychological adjustment to SB.

Contains fulltext : 71503.pdf (Publisher’s version ) (Closed access) The aim of this study was to investigate the relationship between compound muscle action potentials (CMAPs) and neurological impairment in newborn infants with spina bifida. Thirty-one newborn infants (17 males, 14 females, mean gestational age 39 wks [SD 2]; mean birthweight 3336 g [SD 496]) with spina bifida were investigated at a median age of 2 days (range 1-18 d). Motor and sensory impairment and muscle stretch reflexes were assessed and neuroimaging was performed. CMAPs were recorded from the tibialis anterior muscle and the gastrocnemius muscle after percutaneous electrical nerve stimulation. CMAPs were obtained in almost all infants. The area under the curve of the CMAP (CMAP-area) was associated with motor and sensory impairment and with the presence of muscle stretch reflexes, but not with the morphological level of the spinal anomaly. These associations were stronger for the gastrocnemius muscle than for the tibialis anterior muscle. In conclusion, the CMAP-area correlates with neurological impairment in neonatal spina bifida and provides an estimate of residual motor neuron function in affected spinal segments. The assessment of CMAPs after percutaneous electrical nerve stimulation is recommended as an additional instrument to the clinical neurological examination and imaging studies.

Contains fulltext : 71385reimer.pdf (Publisher’s version ) (Closed access) Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder with multi-organ involvement. The diagnosis is suspected at fetal ultrasound on the discovery of multiple cardiac rhabdomyomas (CRs). They typically develop in utero and undergo spontaneous regression during the first years of live. With developing neuroradiological methods more light is shed on antenatal cerebral lesions like cortical tubers or giant cell astrocytomas. Unfortunately these do not regress, but instead are in principle progressive in size and number, correlated with epilepsy, mental retardation and behavioral problems. It is unknown whether fetal cerebral lesions, are always correlated with a poor neurological outcome or a progressive course of disease. This makes prenatal counseling extremely difficult. We report one case of de novo TSC with first detection of cortical tubers on fetal ultrasound, later developing multiple CRs. The pregnancy was continued and the child is developing well during 16 months of follow-up. Minor motor seizures from the 10th month onwards are successfully treated with Valproate. The published cases with antenatal diagnosis of TSC are revised, trying to get more insight into the postnatal course of prenatally diagnosed TSC. This is crucial, either when termination of pregnancy (TOP) is considered, but even more for proper postnatal care and follow-up.

Contains fulltext : 51744.pdf (Publisher’s version ) (Closed access) Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.

Item does not contain fulltext Spina bifida is a multifaceted neurological condition with complex neuropsychological sequelae. The cognitive outcome in spina bifida has frequently been attributed to the severity of the hydrocephalus. However, because of complex neuropathology, the influence of hydrocephalus alone does not sufficiently explain the deficits in the cognitive profile in spina bifida. To date, little is known of the role of Arnold-Chiari-II malformation (ACM) in the cognitive profile of these patients. Aim of the current study is to delineate the specific contribution of the ACM in spina bifida by comparing children with ACM and those without ACM. 46 children between 6 and 15 years of age underwent a neuropsychological assessment covering intelligence and a wide range of cognitive functions, such as visuo-motor processing, attention, memory, word fluency and speed of information processing. Comparisons were made between patients with ACM (ACM+) and those without ACM (ACM-); all children with ACM+ also had hydrocephalus. Confounding effects of global cognitive impairment were excluded, such that groups were matched on verbal IQ. Because of complex neuropathology, which is inherent to spina bifida, the method applied was based on a comparison of cognitive profiles of the study group with profiles of patients with cerebellar damage and hydrocephalus found in the literature. Impaired visual analysis and synthesis, verbal memory, and verbal fluency, even after correction for global cognitive impairment, were observed in children with ACM. The hypothesis that in addition to impairment in visual analysis and synthesis, which are related to both hydrocephalus and ACM, specific deficiencies in verbal memory and fluency may be attributed to ACM is supported.

Material and methods Study subjects were fetal lambs with an, at 79 days gestation, surgically created opening of the spinal canal. Biomatrix covering, applied immediately after creation of the spinal defect, was taken as a tool for surgery improvement. The clinical and pathological findings at full-term age were taken as outcome measures. For comparison, two procedures were used, i.e., spinal canal opening without closure; and closure using skin.

Background This study is part of the multidisciplinary research program "Prognosis of Spina Bifida" of the Radboud University Nijmegen (The Netherlands). Recent studies indicate that children with hydrocephalus have difficulty on attention and memory tests. However, it remains unclear whether these problems stem from deficits in the attentional system or from the perceptual and motor requirements of the task. The purpose of the current study is to investigate attention functions in children with spina bifida and hydrocephalus (SBH) as compared to those without hydrocephalus (SB) by administering a neuropsychological test procedure that takes into account the different task demands.

Background This study is part of the multidisciplinary research program "Prognosis of Spina Bifida" performed at the Radboud University Nijmegen (The Netherlands). From a macroscopic point of view, spina bifida is a congenital malformation of the central nervous system in which both spinal cord and the brain are involved. However, from a microscopic point of view, little is known about how spina bifida affects the cortical and spinal interneuronal network. Assessment of the silent period (SP) following Transcranial Magnetic Stimulation (TMS) allows the opportunity to investigate inhibitory deficits in this network. Our aim was to investigate if inhibitory deficits are involved in the pathophysiology of spina bifida. Therefore, we studied the SP in children with spina bifida.

We present a child with the rare association of congenital muscular dystrophy, hypoplasia of the lateral abdominal wall musculature and hypoplasia of the external genitalia.

Contains fulltext : 50334.pdf (Publisher’s version ) (Closed access) Searching for a tool to quantify motor impairment in spina bifida, transcranial and lumbar magnetic stimulation were applied in affected newborn infants. Lumbar magnetic stimulation resulted in motor evoked potentials in both the quadriceps muscle and the tibialis anterior muscle in most (11/13) subjects. However, transcranial magnetic stimulation did not lead to any response at all. A strong left-to-right correlation existed for amplitude and for latency. Lumbar magnetic stimulation proved to be applicable in newborn infants with spina bifida. Although current concepts regarding spina bifida suppose lower motor neuron dysfunction, the results of this study suggest that lower motor neuron integrity is at least partly preserved after birth. Transcranial magnetic stimulation does not lead to responses in healthy newborn infants because of insufficient synaptogenesis, myelinogenesis, and axon thickness. Therefore, conclusions on upper motor neuron function in spina bifida cannot be drawn. To what extent the method used here can achieve the aim of quantifying motor impairment is a matter of further study.

Contains fulltext : 57409.pdf (Publisher’s version ) (Closed access) Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. The disease is caused by mutations in the methyl-CpG-binding protein 2 gene (MECP2), and various mutations have been reported. The phenotypic spectrum in both female and male patients is diverse, ranging from very mild to congenital encephalopathy and prenatal lethality. In this study, the question was addressed as to whether implementation of systematic screening of MECP2 in patients with an unexplained mental retardation in DNA diagnostics would be reasonable, and the spectrum of phenotypes resulting from mutations in this gene was further explored. Mutational analysis of MECP2 was performed in mentally retarded female patients who were negative for FMR1 CGG repeat expansion, in male and female patients with clinical features suggestive of either Angelman or Prader-Willi syndrome without methylation defects on chromosome 15q11-q13. In the cohort of females negative for the molecular Fragile-X studies (N=92), one nonsense mutation (p.Q406X) was found. In the cohort of Angelman-negative patients (N=63), two missense mutations (p.R133C in a female patient and a mosaic p.T158M in a male patient) were found, which have been reported many times in patients with classical RTT syndrome. In the Prader-Willi-negative group (N=98), no pathogenic mutations were found. The results support testing of patients with features suggestive of Angelman syndrome, but without methylation defects on chromosome 15q11-q13 for mutations in MECP2. In the remaining patients with unexplained mental retardation, additional clinical features should determine whether analysis of MECP2 is indicated.

Item does not contain fulltext We describe the clinical and neuropathological presentation of a male with an MECP2 mutation whose sister has Rett syndrome (RS). He presented with severe neonatal encephalopathy and died at the age of 13 months. Mutation analysis of the MECP2 gene demonstrated a 488 - 489 del mutation in his and his sister's copies of the gene. Post mortem examination revealed bilateral polymicrogyria in the perisylvian region. This malformation was visibly more severe than previously described in females with RS and another male with an MECP2 mutation. As bilateral polymicrogyria was described in congenital perisylvian syndrome, the presented patient could be regarded as having suffered from a severe form of this syndrome. We conclude that MECP2 screening should be considered in males with severe neonatal encephalopathy and in males and females with a bilateral polymicrogyria syndrome.

Cat scratch disease (CSD) was first described in 1950 as a benign regional lymphadenitis. This infection is caused by Bartonella henselae . The clinical range of CSD has expanded beyond the classic presentation. In 5%–20% of the infected patients the disease may spread to other organs. However, neurological complications associated with CSD are rare, with encephalopathy being by far the most common form (90%) of nervous system involvement. Encephalopathy occurs in 2%–3% of patients and is more common in adults than in children with the onset varying from a few days to months after diagnosis of CSD.1 Other known neurological manifestations, often in combination with encephalopathy, are neuroretinitis, oculoglandular disease of Parinaud, myelopathy, radiculopathy or abducens nerve, and facial nerve paresis. We report on a 3 year old boy who developed chronic inflammatory demyelinating polyneuropathy (CIDP) 6 weeks after identification of CSD. (A) Sural nerve. Low power electron micrograph. Demyelinated fibres (arrows) and thinly remyelinated fibres. Bar=2.0 μm. (B) Sural nerve; detail of myelinated fibre. Macrophage has invaded the myelinated fibre; process of macrophage is extending between axon and myelin sheath (arrow head). The damaged inner major dense line is terminating as a small dark swelling …

Routine cerebral ultrasound examinations of the neonatal brain often show the choroid plexus to be enlarged, without revealing any other structural pathology. This enlargement might be due to congestion of the choroid plexus as a result of increased cerebral blood flow, due to increased partial pressure of carbon dioxide, amongst other factors. In this exploratory study, 76 cerebral ultrasound examinations, performed on 42 newborn infants within the first 10 days after birth, were analysed retrospectively. The ultrasonograms were classified into three diagnostic groups: normal, congestion of the choroid plexus and haemorrhage. The relationship between the diagnostic groups and the estimated mean arterial partial pressure of carbon dioxide (P(a)CO(2)) was investigated. In the first three postnatal days, the estimated mean P(a)CO(2) in the normal group was significantly lower than in the congestion group (P0.001). No significant differences were found between the P(a)CO(2) in the congestion and the haemorrhage groups. The findings might support a relation between a high P(a)CO(2) and congestion of the choroid plexus in the first three postnatal days and might be a sign of increased risk for a periventricular haemorrhage.

This study addresses the value of operator-independent computer processing of ultrasonograms of the developing brain. With this aim, routine cranial ultrasonograms obtained from 39 term and preterm infants without clinical or sonographic evidence of brain damage were analyzed by five observers. The procedure, respectively, included: 1. the definition of four regions of interest (ROI), one white matter and one grey matter area on each side of the brain; 2. digitization of the sonogram data within these ROIs; 3. correction for the equipment settings, using data from a tissue-mimicking phantom as a reference; and 4. calculation of four sonogram characteristics (i.e., mean echo level, MEAN, signal-to-noise ratio, SNR, and axial and lateral correlation, CORAX and CORLAT, of the echo level co-occurrence matrix). Significant differences between both sides of the brain or a significant influence of ROI size were not found. The interobserver spread was considerable, but less than the intersubject spread. Two sonogram characteristics seemed strongly correlated in white and grey matter (CORAX and CORLAT) and another only in white matter (SNR with CORAX and CORLAT). MEAN seemed not to be correlated with any other characteristic. Furthermore, it was found that maturation equally decreases white and grey matter MEAN and, thus, hardly affects the ratio between the two. An effect on the other sonogram characteristics was only found in the white matter (i.e., an increase of SNR and a decrease of CORAX and CORLAT). Except for MEAN, the grey matter sonogram characteristics seem hardly affected by maturation. In view of these findings, we conclude that quantitative ultrasonography reveals white and grey matter maturation and, furthermore, provides a conceptional-age-independent reference (MEAN white:grey matter ratio) that might be found to facilitate the detection of pathologic brain alterations.

The authors report a child with a spinal muscular atrophy (SMA)-like picture, cardiomyopathy, and cytochrome c oxidase (COX) deficiency. Electromyography and muscle biopsy showed findings typical of SMA. However, COX staining of the muscle was negative. DNA analysis did not detect deletions in the survival motor neuron (SMN) gene. The lactate and lactate-to-pyruvate ratios were increased in blood and CSF. COX activity was decreased in muscle and fibroblasts. Western blot analysis showed reduced contents for all COX subunits. Patients with clinical features resembling SMA but with an intact SMN gene should be screened for a mitochondrial disorder.

The present study addressed the hypotheses that cerebral ischemia and/or excessive cerebral blood pulsation contribute to periventricular hemorrhage in preterm newborns with respiratory distress and that the pulse width is a valuable tool to estimate the contribution of cerebral blood pulsation. These hypotheses were tested by following preterm newborns at risk for respiratory distress and periventricular hemorrhage. We monitored for cerebral blood flow velocity (CBFV), cerebral pulse width, and cerebral pulsatility index; for patent ductus arteriosus, capillary Pco2, heart rate (HR) and behavior; and for the occurrence of respiratory distress and periventricular hemorrhage (PVH). The data obtained were analyzed with linear regression with the mode of respiration (spontaneous or supported) and postnatal age as additional covariates. We observed that (a) respiratory distress, either uncomplicated or complicated by PVH, correlates with a low CBFV and a high cerebral pulsatility index; (b) PVH also correlates with a high cerebral pulse width; (c) the increased pulse width precedes the onset of the hemorrhage; and (d) these CBF alterations can be partly attributed to ductal shunting and are ameliorated by mechanical ventilation.

The relationship of cerebral blood flow fluctuation (CBFF) with periventricular haemorrhage (PVH) and respiratory distress syndrome (RDS) was studied in 35 preterm newborns. CBFF was defined as the interquartile range in the ensemble of pulses of a 20-s Doppler recording of CBF velocity (CBFV) in the internal carotid artery. We found a statistically significant increase in end diastolic CBFF in PVH and RDS. This increase was related to the mode of respiration (spontaneous or mechanically supported), the state of the ductus arteriosus, and the level of end diastolic CBFV. Differences before and after the onset of PVH were not found. In view of this, we conclude that RDS increases CBFF, that this increase is related to pleural pressure fluctuations, that these can be damped by mechanical ventilation, and that their propagation to the CBF is promoted by patency of the ductus arteriosus and foramen ovale. Whether the CBFF increase causes PVH, or is merely an expression of coincident RDS, remains a question that needs further investigation.

Cerebral blood flow (CBF) fluctuation was studied by analyzing Doppler internal carotid blood velocity recordings of 13 healthy preterm newborns obtained in the course of their first 5 days of life. As measures of fluctuation we used the interquartile range (IQR) and the coefficient of variation (CV) of the ensemble of heart beats of a 20-s recording. In this way we determined fluctuation of the following velocity curve parameters (VCPs): end diastolic velocity; mean velocity; peak systolic velocity and pulsatility index (PI). The pooled data 5–95% intervals for fluctuation thus measured, were: 93–281% for CV; 0.6–3.7 cm/s for the IQR of the velocities; and 4–19% for the PI-IQR. Multiple regression analysis of IQR revealed significant relationships with: the VCP level; with restlessness; and with patency of the ductus arteriosus. Our findings imply that: (1) CBF has various qualities with different stability, mean velocity being the most stable; (2) for all the VCPs investigated, fluctuation is physiological in the early days after preterm birth; (3) most likely, there exists no age trend; (4) restlessness rather than wakefulness, enhances fluctuation; (5) patent ductus arteriosus destabilizes CBF; and (6) for a proper insight into fluctuation, the level of the VCP in question must be taken into account. We suggest that, the enhancing effect that patent ductus arteriosus has on fluctuation pays a contribution to the pathogenesis of brain damage. Finally, we conclude that the IQR represents fluctuation better than does the more commonly used CV.

Congenital muscular dystrophy (CMD) associated with cerebro-ocular dysplasia named muscle-eye-brain disease (MEB-D) is described in two sisters. Progressive hypotonia, mental retardation and severe visual failure appeared immediately after birth. Pathological examination demonstrated muscular dystrophy, hydrocephalus, type II lissencephaly and defective eye development of foetal origin. The great similarity of the clinical and neuropathological picture of both sisters is in agreement with an autosomal recessive inheritance. Neuropathological distinction between Fukuyama-CMD and MEB-D is a more severe and earlier cerebral developmental defect and the association with ocular dysplasia in MEB-D.

Background It is widely agreed that the typical cognitive profile of children with spina bifida is influenced by medical variables such as hydrocephalus, the height of the lesion and other physical complications [1]. However, very little is known about the specific contribution of the Arnold-Chiari malformation (ACM) in the information processing of these children. The aim of this study is to delineate in the cognitive profile the specific contribution of the ACM by comparing within a group of children with spina bifida among those with and without ACM.

Clinical background This study is part of the multidisciplinary research program "Prognosis of Spina Bifida" of the Radboud University Nijmegen (The Netherlands). Outcome prediction of spina bifida is difficult and an ongoing discussion about quality of life and selective treatment exists. Since new diagnostic instruments have become available, revision of the Lorber criteria, which were set in 1970, is warranted. Hence, we investigated the applicability of magnetic motor evoked potentials (MEP) in a prognostic model for spina bifida and we aim to determine motor conduction in neonatal spina bifida.

Accuracy of transfontanellar Doppler ultrasound measurement of blood flow velocity and its variability in the supraclinoid segment of the internal carotid artery was studied in preterm newborns. Measurements were performed in duplicate, on a well defined site, under negligible angle of insonation, and during stable physical condition. The measurements included the base value and variability over 20 seconds, for: diastolic velocity; mean velocity; systolic velocity; resistance index; diastolic time interval; systolic time interval; heart beat duration. As a measure of accuracy the coefficient of repeatability was calculated for each parameter. Coefficients several times smaller than the range of measured values, were found for most parameters. These parameters and their coefficients include: diastolic velocity (base value 3.1 cm s-1, variability 1.6 cm s-1); mean velocity base value 3.1 cm s-1; systolic velocity base value 4.5 cm s-1; resistance index (base value 0.13, variability 0.08); diastolic time interval base value 25 ms; systolic time interval base value 27 ms; heart beat duration base value 27 ms. Thus, Doppler ultrasound enables differentiation within the biological variation of certain properties of cerebral blood flow.

Using combined echoencephalography and Doppler flow determination the diagnosis Arteriovenous aneurysm of the great cerebral vein of Galen could be made in two infants. Without vascular surgery one patient died, the other recovered completely. CT scanning confirmed the diagnosis. Invasive methods such as cerebral angiography were avoided. Case histories, neuropathological findings, ultrasound method and results are presented. Pathogenesis, clinical signs, treatment and prognosis are discussed. With the ultrasound method presented, the nature and location of the vascular anomaly were demonstrable, thus additional higher risk diagnostic methods could be avoided or planned more purposefully.

We report the cases of 18 patients with congenital muscular dystrophy, six of whom also have involvement of the central nervous system, corresponding to the Fukuyama type of congenital muscular dystrophy. In four patients, both the central nervous system and the eyes are involved, and the diagnosis of "muscle, eye and brain disease" was made. A comparative study of these patients with those whose cases were recently reported indicates that there is a wide variability of clinical and laboratory expression of the dystrophy, but a constant feature in all patients is a progression of motor disability. The association of congenital muscular dystrophy with brain abnormalities indicates a poor clinical prognosis. At present it remains an open question whether the three variants of the disease are separate diseases or only different expressions of the same syndrome, but our study tends to support the latter hypothesis.

We studied three unrelated infants and three adolescent siblings with Cockayne syndrome. The infants showed severe psychomotor retardation. Neurologic manifestations in the siblings were less severe and only slowly progressive. All patients had slowed peripheral nerve conduction. Nerve biopsies demonstrated segmental demyelination and remyelination in each case. In the infantile cases this process was severe and rapidly progressive; in the juvenile cases it was mild and chronic. Distinctive membrane-bound polymorphous inclusions were found in occasional Schwann cells.