In March 1993 the gene IT 15 was identified on chromosome 4p and it was demonstrated that it cont... more In March 1993 the gene IT 15 was identified on chromosome 4p and it was demonstrated that it contained an unstable (CAG)n trinucleotide repeat that is elongated in patients with Huntington's chorea (HC). Persons with more than 37 (CAG)n repeats tend to have a higher risk of developing the disease. Testing the (CAG)n repeats in Austrian HC patients with PCR techniques shows correspondence between the clinical diagnosis of HC and genotypes [more than 42 (CAG)n repeats]. There was a weak correlation between the number of (CAG)n repeats and age of onset, however, this finding is without diagnostic value due to the scatter of the values.
Klinische Monatsblatter Fur Augenheilkunde, Oct 1, 2006
l " choroidale Neovaskularisation l " transpupillare Thermotherapie l " Low-grade-Hyperthermie l ... more l " choroidale Neovaskularisation l " transpupillare Thermotherapie l " Low-grade-Hyperthermie l " Hitzeschockproteine Key words l " choroidal neovascularisation l " transpupillary thermotherapy l " low-grade hyperthermia l " heat-shock proteins
ObjectiveIncreasing evidence supports the contribution of inflammatory mechanisms to the neurolog... more ObjectiveIncreasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well‐characterized patients with TSC and FCD2B.MethodsWe applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed.ResultsProtein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns.SignificanceOur results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.
Adaptive behaviour in Down syndrome is described to increase until middle childhood and to begin ... more Adaptive behaviour in Down syndrome is described to increase until middle childhood and to begin to decline in adolescence, whereas significant deterioration in middle adulthood has been attributed to early onset of dementia. Nevertheless, opinions diverge about when the slowing down of adaptive and cognitive abilities starts. Our aims were to describe the profile of adaptive behaviour in Down syndrome, the variability within different age-groups, age-related changes and the correlation to cognitive abilities. In a prospective cross-sectional study, individuals with Down syndrome all living in the family and without signs of dementia in 4 Italian sites were included and performed a detailed medical and neuropsychiatric work-up, as well as cognitive testing and adaptive behaviour, using the Vineland Adaptive Behaviour Scales. Seventy-five individuals with Down syndrome from 4 to 52 years were included. Adults from 20 to 30 years showed the highest performance of all groups. The area of communication, always an area of strength, did not change over time, in childhood and especially in adolescence daily living skills (p = 0.012) and socialisation (p = 0.021) scored on average, whereas in young and middle adulthood performance in daily living skills and socialisation and were areas of strength. Individuals with DS continue to increase competence in adaptive behaviour until 30 years, even when cognitive abilities reach a plateau. We found no major decline in middle adulthood. This may be due to exposure to daily life, but needs to be supported by further studies.
International Conference of the IEEE Engineering in Medicine and Biology Society, Oct 18, 2020
We apply information decomposition methods to elicit unique, redundant and synergistic causal con... more We apply information decomposition methods to elicit unique, redundant and synergistic causal contributions of ipsilateral and contralateral EEG activity to heart rate dynamics in epileptic children. We find that information flows from brain to heart according to opposite lateralization effects for the delta and alpha rhythms, suggesting that different neuroautonomic mechanisms take place in the pre- and post-ictal phases of temporal lobe seizures
Over 3 years we evaluated two patients, an adolescent and a child, with migraine-like headache an... more Over 3 years we evaluated two patients, an adolescent and a child, with migraine-like headache and ischemic stroke. Based on our clinical observations and on liter: review of migraine and stroke in the pediatric age group, we believe that the criteria of migrainous infarction outlined by the International Headache Society (IHS) could be occasionally too restrictive Therefore, we suggest subclassifying migrainous infarction into: (i) "definite", referring to the patient: ischemic stroke fulfills all the IHS criteria, (ii) "possible", referring to ischemic strokes which I 1 some, but not all, criteria. This subclassification of migrainous infarction may be relevant in cal practice and in human research studies. • Adolescence, childhood, migraine, stroke
A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (... more A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.
The strength of this association is confusing; it exceeds what would be predicted from our coffee... more The strength of this association is confusing; it exceeds what would be predicted from our coffee data were caffeine the responsible agent. Recent epidemiological analyses of fertility and caffeine have been inconsistent.3-S Laboratory animal studies have been largely negative, although instant coffee has been reported to cause infertility in mice.6 Those who study infertility or very early pregnancy loss should add soft drinks (caffeinated and uncaffeinated) to the list of variables that require further investigation.
European Journal of Paediatric Neurology, Jun 1, 2017
Objective: Eslicarbazepine acetate (ESL) has been approved as adjunctive therapy for focal seizur... more Objective: Eslicarbazepine acetate (ESL) has been approved as adjunctive therapy for focal seizures in adults and recently in children (!6years). Data is also available under 6years. This is an integrated analysis of the double-blind, placebo controlled studies performed with ESL in phase II & III. Methods: A metaanalysis was conducted for absolute and relative change in standardized-(/4weeks)-seizure-frequency (SSF) from doubleblind, placebo-controlled studies (harmonized population >6years). A POPPK model was developed (2e18years) as one-
Background and Objectives Multiple factors have been found to contribute to the high risk of epil... more Background and Objectives Multiple factors have been found to contribute to the high risk of epilepsy in infants with tuberous sclerosis complex (TSC), including evolution of EEG abnormalities, TSC gene variant, and MRI characteristics. The aim of this prospective multicenter study was to identify early MRI biomarkers of epilepsy in infants with TSC aged <6 months and before seizure onset, and associate these MRI biomarkers with neurodevelopmental outcomes at 2 years of age. The study was part of the EPISTOP project. Methods We evaluated brain MRIs performed in infants younger than 6 months with TSC. We used harmonized MRI protocols across centers and children were monitored closely with neuropsychological evaluation and serial video EEG. MRI characteristics, defined as tubers, radial migration lines, white matter abnormalities, cysts, calcifications, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA), were visually evaluated and lesions were detected semiautomatically. Lesion to brain volume ratios were calculated and associated with epilepsy and neurodevelopmental outcomes at 2 years. Results Lesions were assessed on MRIs from 77 infants with TSC; 62 MRIs were sufficient for volume analysis. The presence of tubers and higher tuber-brain ratios were associated with the development of clinical seizures, independently of TSC gene variation and preventive treatment. Furthermore, higher tuber-brain ratios were associated with lower cognitive and motor development quotients at 2 years, independently of TSC gene variation and presence of epilepsy. Discussion In infants with TSC, there is a significant association between characteristic TSC lesions detected on early brain MRI and development of clinical seizures, as well as neurodevelopmental outcomes in the first 2 years of life. According to our results, early brain MRI findings may guide clinical care for young children with TSC. Classification of Evidence This study provides Class I evidence that in infants with TSC, there is a significant association between characteristic TSC lesions on early brain MRI and the development of clinical seizures and neurodevelopmental outcomes in the first 2 years of life.
SummaryObjectiveTo study the association between timing and characteristics of the first electroe... more SummaryObjectiveTo study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED‐EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC).MethodsPatients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED‐EEG were studied in relation to clinical outcome. Epilepsy‐related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]).ResultsEighty‐three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14–54). Seventy‐nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23–111). Patients with a pathogenic TSC2 variant were significantly younger (P‐value .009) at first ED‐EEG and more frequently had multifocal IED (P‐value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED‐EEG was significantly associated with lower cognitive (P‐value .010), language (P‐value .001), and motor (P‐value .013) developmental quotients at 24 months.In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED‐EEG was predictive of earlier seizure onset (P‐value .030). Earlier recording of epileptiform discharges (P‐value .019), especially when multifocal (P‐value .026) was associated with higher risk of drug‐resistant epilepsy.In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED‐EEG, preventive treatment delayed the onset of seizures significantly (P‐value <.001).SignificanceEarly EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.
In neuroscience, data are typically generated from neural network activity. Complex interactions ... more In neuroscience, data are typically generated from neural network activity. Complex interactions between measured time series are involved, and nothing or only little is known about the underlying dynamic system. Convergent Cross Mapping (CCM) provides the possibility to investigate nonlinear causal interactions between time series by using nonlinear state space reconstruction. Aim of this study is to investigate the general applicability, and to show potentials and limitation of CCM. Influence of estimation parameters could be demonstrated by means of simulated data, whereas interval-based application of CCM on real data could be adapted for the investigation of interactions between heart rate and specific EEG components of children with temporal lobe epilepsy.
Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tube... more Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizurefree survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
Journal of Neurodevelopmental Disorders, Jan 15, 2022
Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by th... more Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes -cell-adhesion molecule contactin-3. Methods: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. Results: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = -0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of
The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple scle... more The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple sclerosis (MS) in adults. Its use, however, is limited by the risk of severe adverse events including cardiotoxicity, myelosuppression, liver toxicity and secondary leukemia. The aim of this retrospective study is to present data on the safety, tolerability and efficacy of mitoxantrone in a small cohort of children with MS. 4 pediatric MS patients with a high relapse rate or severe, disabling relapses were treated with mitoxantrone and followed for 3.8-18 years. The cumulative dose of mitoxantrone was 36, 68, 84 and 120 mg/m (2), respectively. The frequency and severity of relapses as well as disability scores, decreased in the year after treatment onset. Short-term adverse events were transient in all cases. Cardiac monitoring by transthoracic echocardiography (TTE) showed asymptomatic left ventricular dysfunction during treatment in 1 patient, which was again normal at the next assessment. Long-term adverse events, including late-onset mitoxantrone-induced cardiotoxicity or secondary leukemia did not occur during the follow-up period. In our cohort of pediatric MS patients, mitoxantrone showed short-term reduction of disease activity and no long-term adverse events on follow-up. However, the risk of mitoxantrone-induced cardiotoxicity or toxic leukemia remains a life-long threat.
In March 1993 the gene IT 15 was identified on chromosome 4p and it was demonstrated that it cont... more In March 1993 the gene IT 15 was identified on chromosome 4p and it was demonstrated that it contained an unstable (CAG)n trinucleotide repeat that is elongated in patients with Huntington's chorea (HC). Persons with more than 37 (CAG)n repeats tend to have a higher risk of developing the disease. Testing the (CAG)n repeats in Austrian HC patients with PCR techniques shows correspondence between the clinical diagnosis of HC and genotypes [more than 42 (CAG)n repeats]. There was a weak correlation between the number of (CAG)n repeats and age of onset, however, this finding is without diagnostic value due to the scatter of the values.
Klinische Monatsblatter Fur Augenheilkunde, Oct 1, 2006
l " choroidale Neovaskularisation l " transpupillare Thermotherapie l " Low-grade-Hyperthermie l ... more l " choroidale Neovaskularisation l " transpupillare Thermotherapie l " Low-grade-Hyperthermie l " Hitzeschockproteine Key words l " choroidal neovascularisation l " transpupillary thermotherapy l " low-grade hyperthermia l " heat-shock proteins
ObjectiveIncreasing evidence supports the contribution of inflammatory mechanisms to the neurolog... more ObjectiveIncreasing evidence supports the contribution of inflammatory mechanisms to the neurological manifestations of epileptogenic developmental pathologies linked to mammalian target of rapamycin (mTOR) pathway dysregulation (mTORopathies), such as tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD). In this study, we aimed to investigate the expression pattern and cellular distribution of the complement factors C1q and C3 in resected cortical tissue of clinically well‐characterized patients with TSC and FCD2B.MethodsWe applied immunohistochemistry in TSC (n = 29) and FCD2B (n = 32) samples and compared them to autopsy and biopsy controls (n = 27). Furthermore, protein expression was observed via Western blot, and for descriptive colocalization studies immunofluorescence double labeling was performed.ResultsProtein expression for C3 was significantly upregulated in TSC and FCD2B white and gray matter lesions compared to controls. Staining of the synaptic vesicle protein synaptophysin showed a remarkable increase in the white matter of both TSC and FCD2B. Furthermore, confocal imaging revealed colocalization of complement factors with astroglial, microglial, neuronal, and abnormal cells in various patterns.SignificanceOur results demonstrate that the prominent activation of the complement pathway represents a common pathological hallmark of TSC and FCD2B, suggesting that complement overactivation may play a role in these mTORopathies.
Adaptive behaviour in Down syndrome is described to increase until middle childhood and to begin ... more Adaptive behaviour in Down syndrome is described to increase until middle childhood and to begin to decline in adolescence, whereas significant deterioration in middle adulthood has been attributed to early onset of dementia. Nevertheless, opinions diverge about when the slowing down of adaptive and cognitive abilities starts. Our aims were to describe the profile of adaptive behaviour in Down syndrome, the variability within different age-groups, age-related changes and the correlation to cognitive abilities. In a prospective cross-sectional study, individuals with Down syndrome all living in the family and without signs of dementia in 4 Italian sites were included and performed a detailed medical and neuropsychiatric work-up, as well as cognitive testing and adaptive behaviour, using the Vineland Adaptive Behaviour Scales. Seventy-five individuals with Down syndrome from 4 to 52 years were included. Adults from 20 to 30 years showed the highest performance of all groups. The area of communication, always an area of strength, did not change over time, in childhood and especially in adolescence daily living skills (p = 0.012) and socialisation (p = 0.021) scored on average, whereas in young and middle adulthood performance in daily living skills and socialisation and were areas of strength. Individuals with DS continue to increase competence in adaptive behaviour until 30 years, even when cognitive abilities reach a plateau. We found no major decline in middle adulthood. This may be due to exposure to daily life, but needs to be supported by further studies.
International Conference of the IEEE Engineering in Medicine and Biology Society, Oct 18, 2020
We apply information decomposition methods to elicit unique, redundant and synergistic causal con... more We apply information decomposition methods to elicit unique, redundant and synergistic causal contributions of ipsilateral and contralateral EEG activity to heart rate dynamics in epileptic children. We find that information flows from brain to heart according to opposite lateralization effects for the delta and alpha rhythms, suggesting that different neuroautonomic mechanisms take place in the pre- and post-ictal phases of temporal lobe seizures
Over 3 years we evaluated two patients, an adolescent and a child, with migraine-like headache an... more Over 3 years we evaluated two patients, an adolescent and a child, with migraine-like headache and ischemic stroke. Based on our clinical observations and on liter: review of migraine and stroke in the pediatric age group, we believe that the criteria of migrainous infarction outlined by the International Headache Society (IHS) could be occasionally too restrictive Therefore, we suggest subclassifying migrainous infarction into: (i) "definite", referring to the patient: ischemic stroke fulfills all the IHS criteria, (ii) "possible", referring to ischemic strokes which I 1 some, but not all, criteria. This subclassification of migrainous infarction may be relevant in cal practice and in human research studies. • Adolescence, childhood, migraine, stroke
A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (... more A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.
The strength of this association is confusing; it exceeds what would be predicted from our coffee... more The strength of this association is confusing; it exceeds what would be predicted from our coffee data were caffeine the responsible agent. Recent epidemiological analyses of fertility and caffeine have been inconsistent.3-S Laboratory animal studies have been largely negative, although instant coffee has been reported to cause infertility in mice.6 Those who study infertility or very early pregnancy loss should add soft drinks (caffeinated and uncaffeinated) to the list of variables that require further investigation.
European Journal of Paediatric Neurology, Jun 1, 2017
Objective: Eslicarbazepine acetate (ESL) has been approved as adjunctive therapy for focal seizur... more Objective: Eslicarbazepine acetate (ESL) has been approved as adjunctive therapy for focal seizures in adults and recently in children (!6years). Data is also available under 6years. This is an integrated analysis of the double-blind, placebo controlled studies performed with ESL in phase II & III. Methods: A metaanalysis was conducted for absolute and relative change in standardized-(/4weeks)-seizure-frequency (SSF) from doubleblind, placebo-controlled studies (harmonized population >6years). A POPPK model was developed (2e18years) as one-
Background and Objectives Multiple factors have been found to contribute to the high risk of epil... more Background and Objectives Multiple factors have been found to contribute to the high risk of epilepsy in infants with tuberous sclerosis complex (TSC), including evolution of EEG abnormalities, TSC gene variant, and MRI characteristics. The aim of this prospective multicenter study was to identify early MRI biomarkers of epilepsy in infants with TSC aged &lt;6 months and before seizure onset, and associate these MRI biomarkers with neurodevelopmental outcomes at 2 years of age. The study was part of the EPISTOP project. Methods We evaluated brain MRIs performed in infants younger than 6 months with TSC. We used harmonized MRI protocols across centers and children were monitored closely with neuropsychological evaluation and serial video EEG. MRI characteristics, defined as tubers, radial migration lines, white matter abnormalities, cysts, calcifications, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA), were visually evaluated and lesions were detected semiautomatically. Lesion to brain volume ratios were calculated and associated with epilepsy and neurodevelopmental outcomes at 2 years. Results Lesions were assessed on MRIs from 77 infants with TSC; 62 MRIs were sufficient for volume analysis. The presence of tubers and higher tuber-brain ratios were associated with the development of clinical seizures, independently of TSC gene variation and preventive treatment. Furthermore, higher tuber-brain ratios were associated with lower cognitive and motor development quotients at 2 years, independently of TSC gene variation and presence of epilepsy. Discussion In infants with TSC, there is a significant association between characteristic TSC lesions detected on early brain MRI and development of clinical seizures, as well as neurodevelopmental outcomes in the first 2 years of life. According to our results, early brain MRI findings may guide clinical care for young children with TSC. Classification of Evidence This study provides Class I evidence that in infants with TSC, there is a significant association between characteristic TSC lesions on early brain MRI and the development of clinical seizures and neurodevelopmental outcomes in the first 2 years of life.
SummaryObjectiveTo study the association between timing and characteristics of the first electroe... more SummaryObjectiveTo study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED‐EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC).MethodsPatients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous sclerosis complex (EPISTOP) trial, had serial EEG monitoring until the age of 24 months. The timing and characteristics of the first ED‐EEG were studied in relation to clinical outcome. Epilepsy‐related outcomes were analyzed separately in a conventionally followed group (initiation of vigabatrin after seizure onset) and a preventive group (initiation of vigabatrin before seizures, but after appearance of interictal epileptiform discharges [IEDs]).ResultsEighty‐three infants with TSC were enrolled at a median age of 28 days (interquartile range [IQR] 14–54). Seventy‐nine of 83 patients (95%) developed epileptiform discharges at a median age of 77 days (IQR 23–111). Patients with a pathogenic TSC2 variant were significantly younger (P‐value .009) at first ED‐EEG and more frequently had multifocal IED (P‐value .042) than patients with a pathogenic TSC1 variant. A younger age at first ED‐EEG was significantly associated with lower cognitive (P‐value .010), language (P‐value .001), and motor (P‐value .013) developmental quotients at 24 months.In the conventional group, 48 of 60 developed seizures. In this group, the presence of focal slowing on the first ED‐EEG was predictive of earlier seizure onset (P‐value .030). Earlier recording of epileptiform discharges (P‐value .019), especially when multifocal (P‐value .026) was associated with higher risk of drug‐resistant epilepsy.In the preventive group, timing, distribution of IED, or focal slowing, was not associated with the epilepsy outcomes. However, when multifocal IEDs were present on the first ED‐EEG, preventive treatment delayed the onset of seizures significantly (P‐value &lt;.001).SignificanceEarly EEG findings help to identify TSC infants at risk of severe epilepsy and neurodevelopmental delay and those who may benefit from preventive treatment with vigabatrin.
In neuroscience, data are typically generated from neural network activity. Complex interactions ... more In neuroscience, data are typically generated from neural network activity. Complex interactions between measured time series are involved, and nothing or only little is known about the underlying dynamic system. Convergent Cross Mapping (CCM) provides the possibility to investigate nonlinear causal interactions between time series by using nonlinear state space reconstruction. Aim of this study is to investigate the general applicability, and to show potentials and limitation of CCM. Influence of estimation parameters could be demonstrated by means of simulated data, whereas interval-based application of CCM on real data could be adapted for the investigation of interactions between heart rate and specific EEG components of children with temporal lobe epilepsy.
Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tube... more Purpose: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. Results: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizurefree survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.
Journal of Neurodevelopmental Disorders, Jan 15, 2022
Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by th... more Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes -cell-adhesion molecule contactin-3. Methods: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. Results: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = -0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of
The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple scle... more The chemotherapeutic agent mitoxantrone is approved for the treatment of aggressive multiple sclerosis (MS) in adults. Its use, however, is limited by the risk of severe adverse events including cardiotoxicity, myelosuppression, liver toxicity and secondary leukemia. The aim of this retrospective study is to present data on the safety, tolerability and efficacy of mitoxantrone in a small cohort of children with MS. 4 pediatric MS patients with a high relapse rate or severe, disabling relapses were treated with mitoxantrone and followed for 3.8-18 years. The cumulative dose of mitoxantrone was 36, 68, 84 and 120 mg/m (2), respectively. The frequency and severity of relapses as well as disability scores, decreased in the year after treatment onset. Short-term adverse events were transient in all cases. Cardiac monitoring by transthoracic echocardiography (TTE) showed asymptomatic left ventricular dysfunction during treatment in 1 patient, which was again normal at the next assessment. Long-term adverse events, including late-onset mitoxantrone-induced cardiotoxicity or secondary leukemia did not occur during the follow-up period. In our cohort of pediatric MS patients, mitoxantrone showed short-term reduction of disease activity and no long-term adverse events on follow-up. However, the risk of mitoxantrone-induced cardiotoxicity or toxic leukemia remains a life-long threat.
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Papers by Martha Feucht