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ABSTRACT: Brain lesions to the white matter in peritrigonal regions, periventricular leukomalacia, in children who were born prematurely represent an important model for studying limitations on brain development. The lesional pattern is of early origin and bilateral, that constrains the compensatory potential of the brain. We suggest that (i) topography and severity of periventricular lesions may have a long-term predictive value for cognitive and social capabilities in preterm birth survivors; and (ii) periventricular lesions may impact cognitive and social functions by affecting brain connectivity, and thereby, the dissociable neural networks underpinning these functions. A further pathway to explore is the relationship between cerebral palsy and cognitive outcome. Restrictions caused by motor disability may affect active exploration of surrounding and social participation that may in turn differentially impinge on cognitive development and social cognition. As an outline for future research, we underscore sex differences, as the sex of a preterm newborn may shape the mechanisms by which the developing brain is affected.
Brain 04/2013; 136(Pt 4):998-1011. · 9.46 Impact Factor
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ABSTRACT: Metachromatic leukodystrophy (MLD) is a rare metabolic disorder leading to demyelination and rapid neurologic deterioration. As therapeutic options evolve, it seems essential to understand and quantify progression of the natural disease. The aim of this study was to assess cerebral volumetric changes in children with MLD in comparison to normal controls and in relation to disease course.
Eighteen patients with late-infantile MLD and 42 typically developing children in the same age range (20-59 months) were analyzed in a cross-sectional study. Patients underwent detailed genetic, biochemical, electrophysiologic, and clinical characterization. Cerebral gray matter (GM) and white matter (WM) volumes were assessed by multispectral segmentation of T1- and T2-weighted MRI. In addition, the demyelinated WM (demyelination load) was automatically quantified in T2-weighted images of the patients, and analyzed in relation to the clinical course.
WM volumes of patients did not differ from controls, although their growth curves were slightly different. GM volumes of patients, however, were on average 10.7% (confidence interval 6.0%-14.9%, p < 0.001) below those of normally developing children. The demyelination load (corrected for total WM volume) increased with disease duration (p < 0.003) and motor deterioration (p < 0.001).
GM volume in patients with MLD is reduced when compared with healthy controls, already at young age. This supports the notion that, beside demyelination, neuronal dysfunction caused by neuronal storage plays an additional role in the disease process. The demyelination load may be a useful noninvasive imaging marker for disease progression and may serve as reference for therapeutic intervention.
Neurology 09/2012; 79(16):1662-70. · 8.31 Impact Factor
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ABSTRACT: To evaluate the interrater reliability of the inclusion in registries and classification of children with cerebral palsy (CP).
Two studies were conducted. In study 1, 12 paediatricians from 11 countries viewed video sequences of 12 children with or without CP (nine males, three females; median age 6y; range 2-16). In study 2, 19 professionals from eight countries participated in an online exercise. They had to classify the same children but based on written vignettes. All participants had to evaluate whether the child had CP, the neurological subtype (Surveillance of Cerebral Palsy in Europe classification system), and gross motor function level (Gross Motor Function Classification System [GMFCS]). Kappa (κ) coefficients were calculated for categorical variables and intraclass correlation coefficients (ICCs) for ordinal data.
Reliability was excellent in assessing whether or not a child had CP in study 1 (κ=1.00) and substantial in study 2 (κ=0.73); 95% confidence interval [CI] 0.58-0.87). For the neurological subtype, overall κ between paediatricians was 0.85 (95% CI 0.68-0.98), with full agreement observed for eight children. In study 2, overall κ was 0.78 (95% CI 0.61-0.91) with full agreement seen for five children. For the GMFCS, the ICC was 0.88 (95% CI 0.78-0.95) in study 1 and 0.80 (95% CI 0.64-0.91) in study 2.
Reliability was excellent for all characteristics classified by paediatricians viewing the videos and substantial for professionals reading vignettes.
Developmental Medicine & Child Neurology 07/2012; 54(9):815-21. · 2.92 Impact Factor
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Acta Paediatrica 02/2012; 101(6):557-8. · 2.07 Impact Factor
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ABSTRACT: To investigate neurodevelopmental outcome and hearing in preterm children with breast milk transmitted human cytomegalovirus (HCMV) infection.
Forty-one preterm children (born before 32 weeks of gestation or birth weight <1500 g; 20 HCMV positive, 21 HCMV negative) from an original cohort of 44 children were examined at school age. Assessments included neurological examination, assessment of motor [Movement Assessment Battery for Children (M-ABC)] and cognitive function [Kaufman Assessment Battery for Children (K-ABC)], audiological tests and anthropometric measures.
In both groups, irrespective of the presence or absence of a history of HCMV infection, performance in assessments of cognitive and motor function was within the normal range. However, significant differences between the HCMV-positive and the HCMV-negative group were found in both motor and cognitive function, with poorer performance in the HCMV-positive group. There were no significant differences in anthropometric parameters, and all 20 HCMV-positive children had normal hearing function.
In this study, cognitive and motor function in preterm children with early postnatally acquired HCMV infection transmitted via breast milk was within the normal range. However, the findings suggest that their outcome is poorer than outcome in preterm children without HCMV infection. These findings need to be replicated in larger scale studies.
Acta Paediatrica 11/2011; 101(4):e167-72. · 2.07 Impact Factor
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ABSTRACT: Language functions are generally represented in the left cerebral hemisphere. After early (prenatally acquired or perinatally acquired) left hemispheric brain damage language functions may be salvaged by reorganization into the right hemisphere. This is different from brain lesions acquired in adulthood which normally lead to aphasia. Right hemispheric reorganized language (RL) is not associated with obvious language deficits. In this pilot study we compared a group of German-speaking patients with left hemispheric brain damage and RL with a group of matched healthy controls. The novel combination of reliable language lateralization as assessed by neuroimaging (functional magnetic resonance imaging) and specific linguistic tasks revealed significant differences between patients with RL and healthy controls in both language comprehension and production. Our results provide evidence for the hypothesis that RL is significantly different from normal left hemispheric language. This knowledge can be used to improve counselling of parents and to develop specific therapeutic approaches.
Clinical Linguistics & Phonetics 07/2011; 26(2):135-47. · 0.64 Impact Factor
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ABSTRACT: Motor deterioration is a key feature in metachromatic leukodystrophy (MLD). The lack of data about its natural course impedes evaluation of therapeutic interventions. This study aimed to provide data about motor decline in MLD.
Fifty-nine patients (27 males, 32 females) with MLD (21 with late-infantile MLD and 38 with juvenile MLD) were recruited within a nationwide survey (the German LEUKONET). Median (range) age at onset was 17 months (9-27) for the group with late-infantile MLD and 6 years 2 months (2y 11mo-14y) for the group with juvenile MLD. Gross motor function was assessed using the Gross Motor Function Classification for MLD.
In late-infantile MLD, all patients showed loss of all gross motor function until 3 years 4 months of age. Patients with juvenile MLD showed a more variable and significantly longer motor decline (p<0.001). For a patient with the juvenile form showing first gait disturbances, the probability of remaining stable for more than 1 year was 84%, and 51% for more than 2 years. Having lost independent walking, subsequent motor decline was as steep as in the late-infantile form (median 5 mo, interquartile range 3-22).
The course of motor disease was more variable in juvenile MLD with respect to onset and dynamics. However, the motor decline after the loss of independent walking was similarly steep in both forms. These data can serve as a reference for clinical studies that are topics of current research and allow definition of inclusion/exclusion criteria.
Developmental Medicine & Child Neurology 06/2011; 53(9):850-5. · 2.92 Impact Factor
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ABSTRACT: Metachromatic Leukodystrophy (MLD) is a rare disorder leading to demyelination and neurological impairment. A natural history study within the German leukodystrophy network analyzed MRI changes with respect to the clinical course.
113 MR images of 68 patients (33 late-infantile, 35 juvenile) were studied cross-sectionally and longitudinally. MRI and motor deterioration were assessed using standardized scoring systems.
The temporal and spatial patterns of MR severity scores differed between the late-infantile and juvenile form. Although early (involving central white matter, corpus callosum) and late signs (involving pons, cerebellum, cerebral atrophy) were similar, high MRI scores (mean 18, SD 1.2, p < 0.001) were evident in the juvenile form already at the onset of first symptoms and even in presymptomatic patients. The progression rate of the MRI score was clearly higher and more uniform in the late-infantile (on average 8 per year, p < 0.0001) than in the juvenile patients (on average 0.4 per year, p < 0.08). In late-infantile patients, MRI changes correlated highly with motor deterioration (rho = 0.73, p < 0.001), this was less remarkable in the juvenile form (rho = 0.50, p < 0.01). Severe motor dysfunction was associated with U-fiber involvement and cerebellar changes (p < 0.05).
MRI showed a typical spatial pattern, which evolved gradually and uniformly during disease progression in late-infantile MLD. In juvenile MLD MRI changes were already observed at disease onset and temporal patterns were more variable. As therapeutic options for MLD are evolving, these findings are not only important for patient counseling but also for the evaluation of therapeutic interventions.
Journal of Inherited Metabolic Disease 06/2011; 34(5):1095-102. · 3.58 Impact Factor
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ABSTRACT: Resting-state functional magnetic resonance imaging (fMRI) can be used to study the functional connectivity in the somatosensory system. However, the relationship between sensory network connectivity, sensory deficits, and structural abnormality remains poorly understood. Previously, we investigated the motor network in children with congenital hemiparesis due to middle cerebral artery strokes (MCA, n = 6) or periventricular lesions (PL, n = 8). In the present study, we validate the use of interleaved resting-state data from blocked fMRI designs to investigate the somatosensory network in these patients. The approach was validated by assessing the predicted "crossed-over" connectivity between the cerebral cortex and the cerebellum. Furthermore, the impact on the volume of gray-matter (GM) in primary (S1) and secondary (S2) somatosensory cortex on functional connectivity measures was investigated. We were able to replicate the well-known "crossed-over" pattern of functional connectivity between cerebral and cerebellar cortex. The MCA group displayed more sensory deficit and significantly reduced functional connectivity in the lesioned S2 (but not in lesioned S1) when compared with the PL group. However, when accounting for GM volume loss, this difference disappeared. This study demonstrates the applicability of analyzing resting-state connectivity in patients with brain lesions. Reductions of functional connectivity within the somatosensory network were associated with sensory deficits, but were fully explained by the underlying GM damage.
Human Brain Mapping 03/2011; 33(3):628-38. · 5.88 Impact Factor
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ABSTRACT: The developing brain possesses a high potential for neuroplasticity. Yet, this remarkable potential of (re-)organization is not a general principle. It seems to vary among different functional systems. Here, we show that distinct brain structures involved in somatosensory processing are already prenatally determined so that a pre- or perinatally acquired (congenital) brain damage of such structures results in a persistent somatosensory deficit. Eleven patients with hemiparesis due to congenital cortico-subcortical unilateral stroke who showed versus not showed a somatosensory deficit were contrasted with magnetic resonance imaging lesion-behavior mapping. The brain areas which were typically damaged in patients with a somatosensory deficit but typically spared in patients without a somatosensory deficit were located in the primary and secondary somatosensory cortex (S1, S2) as well as the inferior parietal cortex directly neighboring S1 and S2. The results argue for an early functional determination of primary and secondary somatosensory cortex, without substantial capacities for (re-)organization. They demonstrate that cortical damage of these areas cannot be compensated by shifting the functional representation to undamaged parts of the cortex.
Cerebral Cortex 01/2011; 21(8):1827-31. · 6.54 Impact Factor
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ABSTRACT: Body motion is a rich source of information for social cognition. However, gender effects in body language reading are largely unknown. Here we investigated whether, and, if so, how recognition of emotional expressions revealed by body motion is gender dependent. To this end, females and males were presented with point-light displays portraying knocking at a door performed with different emotional expressions. The findings show that gender affects accuracy rather than speed of body language reading. This effect, however, is modulated by emotional content of actions: males surpass in recognition accuracy of happy actions, whereas females tend to excel in recognition of hostile angry knocking. Advantage of women in recognition accuracy of neutral actions suggests that females are better tuned to the lack of emotional content in body actions. The study provides novel insights into understanding of gender effects in body language reading, and helps to shed light on gender vulnerability to neuropsychiatric and neurodevelopmental impairments in visual social cognition.
Frontiers in psychology. 01/2011; 2:16.
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ABSTRACT: Functional MRI (fMRI) for the assessment of language functions is increasingly used in the diagnostic workup of patients with epilepsy. Termed "clinical fMRI," such an approach is also feasible in children who may display specific patterns of language reorganization. This study was aimed at assessing language reorganization in pediatric epilepsy patients, using fMRI. We studied 26 pediatric epilepsy patients (median age, 13.05 years; range, 5.6-18.7 years) and 23 healthy control children (median age, 9.37 years; range, 6.2-15.4 years), using two child-friendly fMRI tasks and adapted data-processing streams. Overall, 81 functional series could be analyzed. Reorganization seemed to occur primarily in homotopic regions in the contralateral hemisphere, but lateralization in the frontal as well as in the temporal lobes was significantly different between patients and controls. The likelihood to find atypical language organization was significantly higher in patients. Additionally, we found significantly stronger activation in the healthy controls in a primarily passive task, suggesting a systematic confounding influence of antiepileptic medication. The presence of a focal cortical dysplasia was significantly associated with atypical language lateralization. We conclude that important confounds need to be considered and that the pattern of language reorganization may be distinct from the patterns seen in later-onset epilepsy.
Human Brain Mapping 12/2010; 32(11):1882-93. · 5.88 Impact Factor
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ABSTRACT: Functional MRI is increasingly used to determine the hemispheric dominance for language. This is especially relevant in children who may not be able to comply with the high demands of a Wada test. We here report on two children in which the full extent of language reorganization was only determined when two fMRI tasks were analyzed; in the first case, the results from the second task corroborated the shifted hemispheric dominance seen in the first task. In the second case, the second task showed an opposite hemispheric dominance, suggesting a hemispheric dissociation of language functions. These cases underline the necessity to use more than one fMRI task for the determination of hemispheric dominance, whenever possible. This is particularly relevant in children as unusual patterns of reorganization may be more likely.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 11/2010; 14(6):474-8. · 2.01 Impact Factor
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ABSTRACT: Motor deterioration is a key feature of late infantile and juvenile metachromatic leucodystrophy (MLD). Assessment of the disease course implies the need for a standardized description of motor decline. The aim of this study was to establish a classification system for gross motor function in MLD and to assess its interrater reliability.
The Gross Motor Function Classification in MLD (GMFC-MLD) was modelled analogous to the Gross Motor Function Classification System in cerebral palsy. Motor data from 59 individuals (27 male; 32 female) with MLD (21 late infantile; 38 juvenile) born between 1970 and 2007 were gathered from a nationwide survey and classified by six independent raters. Median age at onset was 17 months (range 9-27 mo) for the late infantile group and 74 months (35-168 mo) for the juvenile group.
The GMFC-MLD consists of seven levels and is applicable from the age of 18 months. It represents all clinically relevant stages from normal (level 0) to loss of all gross motor function (level 6). The kappa coefficient was 0.90 for overall rater agreement. There were no significant differences between level-specific kappa coefficients.
The GMFC-MLD is a highly reliable, feasible tool for standardized assessment of gross motor function in MLD which can be used for the description of the natural course of the disease and for evaluation of therapeutic options such as stem cell transplantation and enzyme replacement, both of which are topics of current research.
Developmental Medicine & Child Neurology 11/2010; 53(2):156-60. · 2.92 Impact Factor
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ABSTRACT: Perception of dispositions of others revealed by movement is an essential ingredient of adaptive daily-life social behavior. Brain imaging points to several brain regions involved in visual processing of social interaction represented by motion of geometric shapes. However, temporal interrelations among these regions remain unknown. Keeping in mind that successful visual social perception depends on intact communication throughout the brain, we focus here on analysis of the induced gamma neuromagnetic response to social interaction revealed by motion. A peak of induced gamma activity of 62 Hz was found at 1 s from the stimulus onset over the right parieto-temporal junction. Two further enhancements in gamma response of lower frequency of 44 Hz occurred at 1.4 s over the medial prefrontal and posterior temporal cortices in the right hemisphere. Subsequent boosts of 44 Hz were found at 1.6 s over the left temporal and right posterior temporal cortices. For the first time, the findings identify the cortical network engaged in visual processing of social interaction revealed by motion and help to better understand proper functioning of the social brain circuitry.
Cerebral Cortex 10/2010; 20(10):2361-7. · 6.54 Impact Factor
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Yasmin Namavar,
Peter G Barth,
Paul R Kasher,
Fred van Ruissen,
Knut Brockmann,
Günther Bernert,
Karin Writzl,
Karen Ventura,
Edith Y Cheng,
Donna M Ferriero, [......],
Linda De Meirleir,
Mary King,
John M Graham,
Arpad von Moers,
Nine Knoers,
Laszlo Sztriha,
Rudolf Korinthenberg,
William B Dobyns,
Frank Baas,
Bwee Tien Poll-The
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ABSTRACT: Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
Brain 10/2010; 134(Pt 1):143-56. · 9.46 Impact Factor
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ABSTRACT: Time trends for cerebral palsy (CP) prevalence in children born > or =2,500 g vary across studies and scarce data exist on trends by subtype of CP. The objective of this study was to describe changes in prevalence of CP in infants born > or =2,500 g between 1980 and 1998 in Europe. Data were collated from the SCPE (Surveillance of Cerebral Palsy in Europe collaboration) common database. Poisson regression was used to test for change in prevalence over time. Birth year and register effects were explored and trends in prevalence were estimated by CP subtype and severity. Four thousand and two children with CP and birthweight > or =2,500 g were recorded in 15 population based-registers. The overall prevalence of CP was 1.16 per 1,000 live births (99% CI, 0.88-1.48) in 1980 and 0.99 (CI, 0.80-1.20) in 1998. The trend was not significant (P = .14), except in two registers. However, there were significant changes in the prevalence of spastic CP subtypes, with a decrease in the bilateral spastic form (P < .001), and an increase in the unilateral spastic form (P = .004). There was a concurrent reduction in neonatal mortality of children with birthweight > or =2,500 g: from 1.7 (CI, 1.4-2.1) to 0.9 (CI, 0.7-1.1) per 1,000 live births. In conclusion, for children born with birthweight > or =2,500 g, the prevalence of CP in Europe was stable in spite of changes by subtype and a significant decrease in neonatal mortality.
European Journal of Epidemiology 09/2010; 25(9):635-42. · 4.71 Impact Factor
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Ingeborg Krägeloh-Mann
Developmental Medicine & Child Neurology 08/2010; 52(8):694. · 2.92 Impact Factor
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ABSTRACT: The ability of humans to predict and explain other people's actions is of immense value for adaptive behavior and nonverbal communication. Gender differences are often evident in the comprehension of social signals, but the underlying neurobiological basis for these differences is unclear. Combining visual psychophysics with an analysis of neuromagnetic activity, we assessed gender effects on the induced oscillatory response to visual social interaction revealed by motion. A robust difference in the induced gamma response was found between females and males over the left prefrontal cortex, a region implicated in perceptual decision making. The induced gamma neuromagnetic response peaked earlier in females than in males. Moreover, it appears that females anticipate social interaction predicting others' actions ahead of their realization, whereas males require accumulation of more sensory evidence for proper social decisions. The findings reflect gender-dependent modes in cortical processing of visually acquired social information. Contrary to popular wisdom, the outcome of this study indicates that gender effects are not evident in the neural circuitry underpinning visual social perception, but in the regions engaged in perceptual decision making.
NeuroImage 04/2010; 50(3):1327-32. · 5.89 Impact Factor
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ABSTRACT: To develop subjective (visual) and objective (morphometric) rating scales for the classification of MRI in infants who had microcephaly with a simplified gyral pattern (MSGP) and to validate the first by the latter.
We compared the MRI of 12 patients with MSGP and of 5 term-born control infants. Visual rating and morphometric analysis was performed for gyration and associated brain abnormalities of basal ganglia, lateral ventricles, pons, cerebellum, and corpus callosum.
Gyral pattern was rated reliably as normal in the control infants, simplified in 6 patients, and severely simplified in the other 6 patients. Associated brain abnormalities were reported in 10 of 12 patients. Visual rating correlated well with the morphometric measures.
Our visual rating scale for a simplified gyral pattern proved to be sensitive and reliable. Associated brain abnormalities are frequent, which underlines the need for a consistent scoring in these patients.
Neurology 02/2010; 74(5):386-91. · 8.31 Impact Factor
