Fully percutaneous fetoscopic repair of myelomeningocele: 30-month follow-up data.

OBJECTIVE: This observational study reports on the postnatal mortality and 30-month outcome of children who underwent fully percutaneous fetoscopic repair of myelomeningocele (MMC) at a single center in Giessen, Germany. METHODS: Between October 2010 and August 2014, a total of 72 patients underwent fully percutaneous fetoscopic MMC closure at 21 + 0 to 29 + 1 (mean, 23 + 5) weeks' gestation. Of these, 52 (72%) participated in this study; however, 30-month mortality data are available for all 72 children. Children were examined at four timepoints: shortly after birth and at 3 months, 12 months and 30 months of corrected age. The patients underwent age-specific standardized neurological examinations and assessment of leg movements and ambulation at all timepoints. Cognitive and motor development were assessed using the Bayley Scales of Infant Development, second edition (BSID-II), at 30 months. RESULTS: All 72 children survived the intrauterine procedure, however, four (5.6%) infants died postnatally (including two of the 52 comprising the study cohort). Of the 52 patients included in the study, 11.5% were delivered before the 30th week of gestation (mean, 33 + 1 weeks) and, of the survivors, 48.1% had ventriculoperitoneal shunt placement. Of the 50 infants that were alive at 30 months, independent ambulation, without orthosis, was feasible for 46%. At 30 months of follow-up, 46% of children presented with a functional level that was at least two segments better than the anatomical level of the lesion. At 30 months, 70% of the children presented with BSID-II psychomotor development index score of ≥ 70 and 80% with BSID-II mental development index score of ≥ 70. CONCLUSION: Intrauterine repair of MMC by percutaneous fetoscopy shows largely similar outcomes to those reported for open repair, with respect to mortality, prematurity, shunt-placement rates, motor and mental development and free ambulation. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

[Epilepsy-new diagnostic tools, old drugs? : Therapeutic consequences of epilepsy genetics]. / Epilepsie ­ neue Diagnostik, alte Medikamente? : Die Konsequenzen der Epilepsiegenetik.

BACKGROUND: Recent advances in the field of epilepsy genetics have led to an increased fraction of patients with epilepsies where the etiology of the disease could be identified. Nevertheless, there is some criticism regarding the use of epilepsy genetics because in many cases the identification of a pathogenetic mutation does not lead to an adaptation of therapy or to an improved prognosis. In addition, the interpretation of genetic results might be complicated due to the considerable numbers of variants of unclear significance. OBJECTIVE: This publication presents the arguments in favour of a broad use of genetic investigations for children with epilepsies. Several diseases where a genetic diagnosis does in fact have direct therapeutic consequences are mentioned. In addition, the indirect impact of an established etiology, encompassing the avoidance of unnecessary diagnostic measures, possibility of genetic counselling, and the easing of the psychologic burden for the caregivers, should not be underestimated. CONCLUSION: The arguments in favour of broad genetic diagnostics prevail notwithstanding the lack of relevant new developments regarding the therapy.

Percutaneous minimally invasive fetoscopic surgery for spina bifida aperta. Part III: neurosurgical intervention in the first postnatal year.

OBJECTIVE: To evaluate the need for postnatal neurosurgical intervention after fetoscopic patch coverage of spina bifida aperta (SBA). METHODS: This was a retrospective analysis of a cohort of 71 fetuses which underwent minimally invasive fetoscopic patch coverage of SBA between 21 + 0 and 29 + 1 weeks of gestation. Postnatal neurosurgical procedures were classified into two types: re-coverage of the SBA within the first 3 months following birth, and shunt placement as treatment of associated hydrocephalus within the first year. RESULTS: Location of the SBA was lumbosacral in 59 cases, lumbar in seven, thoracic in three and sacral in two. In total, 20/71 (28%) patients underwent early postnatal neurosurgical intervention by means of re-coverage of the SBA. This was performed because of cerebrospinal fluid leakage in seven (35%), adhesions with functional deterioration in three (15%), incomplete coverage in five (25%) and skin defect in five (25%) cases. Ventriculoperitoneal shunt placement within 1 year was required in 32 (45%) cases and was preceded by ventriculostomy in two. Three (4%) infants needed Chiari decompression surgery in the first 12 months following birth, because of syringomyelia or gait disturbance. CONCLUSIONS: Fetoscopic patch coverage of SBA may require postnatal re-coverage in some cases. In most cases, conservative wound treatment shows good results, without requiring neurosurgical intervention. The low 1-year-shunt rate is comparable to data of the Management of Myelomeningocele Study and lower compared with published data of patients with postnatal only coverage of SBA.

MERRF-like phenotype associated with a rare mitochondrial trnaile mutation (m.4284 G>A).

Nearly all patients affected by myoclonic epilepsy with ragged-red fibres (MERRF) harbour a mutation in the mitochondrial transfer RNALys gene. We report on an 8-year-old girl with clinical and diagnostic features of MERRF. After excluding one of the common mutations associated with MERRF, a complete sequence analysis of the mitochondrial genome revealed an m.4284 G>A mutation in the mitochondrial transfer RNAIle gene. This mutation has only once been described in a family with variable clinical symptoms, but has not yet been linked to MERRF. This case extends the mutational spectrum associated with the MERRF phenotype, and demonstrates the importance of performing a comprehensive mutational analysis in patients with suspected mitochondrial disease when common mutations have been ruled out.

Progressive biological behavior of a dysembryoplastic neuroepithelial tumor.

We present the case of a 13-month-old girl with a right occipital cortical alteration on MRI that proved to be a growing lesion. Tumor growth had been observed over a period of 15 months before total resection was performed, revealing a dysembryoplastic neuroepithelial tumor WHO grade I. This case shows that dysembryoplastic neuroepithelial tumors can present as growing neoplasias. It underlines the importance of obtaining histologic diagnosis and close follow-up examinations using MRI, even in so-called stable lesions that are only unveiling through epileptic seizures.

Neurological, cognitive, and behavioural outcome of higher order multiple births.

The purpose of this study was to assess the neurodevelopmental outcome in a larger cohort of higher order multiple births (HOM). To accomplish this, we analysed the perinatal records of 90 HOM from 28 pregnancies (69 triplets, 16 quadruplets and 5 quintuplets) born at the University Hospital Kiel during the period from 1980 to 1994. Sixty-eight out of 79 surviving children (87.2%) were re-examined at a median age of 7.8 years (range: 3 to 14.5 years). Re-examination included assessment of the neurological, psychomotor (Denver developmental scale, Columbia mental maturity scale), and behavioural (childhood behaviour checklist) status. Perinatal mortality was 12%. In 62% of subjects, neurological and cognitive status at follow-up were completely normal; 32% revealed minor and 6% major neurodevelopmental deficits. Comparison between VLBW and LBW HOM disclosed significantly more neurological deficits, lower IQs and more behaviour problems in children with VLBW. Especially social problems, attention deficit, anxiety and depression symptoms were more frequent in the VLBW HOM than in the LBW HOM group. VLBW HOM parents felt significantly more stressed and VLBW HOM mothers reported reduced coping skills. These findings suggest that the overall cognitive and neurological outcome of HOM surviving the neonatal period is good, but that minor neurocognitive deficits are frequent. LBW HOM have less neurological and behaviour problems than VLBW HOM.

Treatment of gastroesophageal reflux with nissen fundoplication and gastrostomy tube insertion in infantile pompe's disease.

In infantile Pompe's disease, enzyme replacement therapy (ERT) has been shown to reverse cardiomyopathy, improve skeletal muscle strength, and prolong survival. We report on five patients in whom complications related to gastroesophageal reflux (GER) resulted in deterioration of their clinical status despite initial improvement under ERT. Surgical antireflux therapy, performed in four, yielded positive results in two. Three patients experienced severe aspirations related to GER and underwent fundoplication and gastrostomy subsequently. Two did not regain former motor functions and deceased shortly thereafter, while one slowly recuperated and is in a stable state at age 53 months. In a further patient, severe GER prompted fundoplication at age 17 months. No aspirations occurred until the girl deceased probably due to cardiac arrest 20 months later. These cases suggest that infants with Pompe's disease under ERT may benefit from timely performed fundoplication and gastric tube placement.

Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia.

Mutations in SCN2A cause epilepsy syndromes of variable severity including neonatal-infantile seizures. In one case, we previously described additional childhood-onset episodic ataxia. Here, we corroborate and detail the latter phenotype in three further cases. We describe the clinical characteristics, identify the causative SCN2A mutations and determine their functional consequences using whole-cell patch-clamping in mammalian cells. In total, four probands presented with neonatal-onset seizures remitting after five to 13 months. In early childhood, they started to experience repeated episodes of ataxia, accompanied in part by headache or back pain lasting minutes to several hours. In two of the new cases, we detected the novel mutation p.Arg1882Gly. While this mutation occurred de novo in both patients, one of them carries an additional known variant on the same SCN2A allele, inherited from the unaffected father (p.Gly1522Ala). Whereas p.Arg1882Gly alone shifted the activation curve by -4 mV, the combination of both variants did not affect activation, but caused a depolarizing shift of voltage-dependent inactivation, and a significant increase in Na(+) current density and protein production. p.Gly1522Ala alone did not change channel gating. The third new proband carries the same de novo SCN2A gain-of-function mutation as our first published case (p.Ala263Val). Our findings broaden the clinical spectrum observed with SCN2A gain-of-function mutations, showing that fairly different biophysical mechanisms can cause a convergent clinical phenotype of neonatal seizures and later onset episodic ataxia.

Centrotemporal spikes in families with rolandic epilepsy: linkage to chromosome 15q14.

OBJECTIVE: To localize a gene predisposing to benign epilepsy of childhood with centrotemporal spikes (BECTS). BACKGROUND: BECTS, or rolandic epilepsy, is the most prevalent idiopathic epilepsy syndrome in childhood. Functional relevant defects in the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor (AChR) have been demonstrated in autosomal dominant nocturnal frontal lobe epilepsy, which, like BECTS, is an idiopathic partial epilepsy. METHODS: A DNA linkage study was conducted screening all chromosomal regions known to harbor neuronal nicotinic AChR subunit genes. Twenty-two nuclear families with BECTS were analyzed. RESULTS: In an "affected-only" study, best p values and lod scores were reached between D15S165 and D15S1010 on chromosome 15q14. In multipoint nonparametric linkage analysis a nominal p value of 0.000494 was calculated by GENEHUNTER. Best parametric results were obtained under an autosomal recessive model with heterogeneity (multipoint lod score 3.56 with 70% of families linked to the locus). These markers are localized in direct vicinity to the alpha 7 subunit gene of the AChR. CONCLUSIONS: We found evidence for linkage of BECTS to a region on chromosome 15q14. Either the alpha 7 AChR subunit gene or a closely linked gene are implicated in pedigrees with BECTS. The disorder is genetically heterogeneous. Surprisingly, the same chromosomal area has been reported to be linked to the phenotype in families with an auditory neurophysiologic deficit as well as in families with juvenile myoclonic epilepsy, another idiopathic but generalized epilepsy syndrome.

Preponderance of female sex in the transmission of seizure liability in idiopathic generalized epilepsy.

BACKGROUND: the predominance of the female sex in the transmission of seizure liability is a known phenomenon. However, all hitherto published genetic studies are based on reported seizure frequencies only. The aim of this investigation was to reexamine this problem by combining clinical and family EEG data. METHODS: families of 82 index cases fulfilling the following core criteria were ascertained; (1) definite clinical and EEG diagnosis of idiopathic generalized epilepsy with absences and/or myoclonic astatic seizures; (2) obtainable history and EEG recordings from both the parents and one or more siblings. EEG recordings were evaluated for different genetic traits of epileptiform EEG activity (EPA), as well as genetic characteristics of background activity. RESULTS: of the 164 parents 9% suffered from seizures. EPA was detected in 24% of probands' mothers versus 12% in fathers. Altogether 28% of probands' mothers were positive for seizures or EPA versus 16% of the fathers. Of parents with EPA in the EEG only about 50% showed seizures. Twenty one percent of all the parents and 60% of the mothers with EPA showed generalized alpha-activity (9% in controls). In contrast, in mothers without EPA a 'non alpha-EEG' was overrepresented. In probands' siblings, 14% showed seizures and 23% showed seizures or EPA. In probands' siblings with EPA seizure risk was 50 versus only 8% in siblings without EPA. The highest siblings risk was conferred by SW and an affected mother. If a father was affected, risk for the siblings of probands was almost equal to that in families with both the parents unaffected. Siblings of female probands were more often affected than those of male probands (19 vs. 8%; P<0.05). Generalized SW occurred in 17% of probands' siblings, in girls siblings significantly more often than in boys siblings (25 vs. 9%; P<0.01). CONCLUSION: clinical history and family EEG equally contribute information contents. Female preponderance in transmission of seizure liability is the result of a complex of genetic interactions that include the generalized alpha-EEG.

Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy.

Genetic predisposition plays a major role in the etiology of idiopathic epilepsies. The common epilepsy syndromes display a complex pattern of inheritance, with an unknown number of genes contributing to seizure susceptibility. During the last decade linkage studies have narrowed down several candidate regions for susceptibility loci of idiopathic epilepsies. Several lines of evidence point to the existence of an epilepsy susceptibility gene on chromosome 15q14. Evidence for linkage to this region has thus been reported for juvenile myoclonic epilepsy, common subtypes of idiopathic generalized epilepsy (IGE), in addition to the EEG trait 'centrotemporal spikes' in families with rolandic epilepsy. The chromosomal region 15q14 harbours several candidate genes that are involved in the regulation of neuronal excitability. One of the most promising candidate genes is the brain-expressed potassium chloride cotransporter KCC3, given that this class of ion transporter has been implicated in the regulation of neuronal chloride activity. We therefore performed a mutation analysis of KCC3 in the index patients of 23 IGE-families as well as of 16 families with rolandic epilepsy which where selected by positive evidence for linkage to D15S165. Four novel single nucleotide exchanges (SNPs) were identified, none of which change the coding sequence. These results do not support a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.

Neuroborreliosis and isolated trochlear palsy.

We report here for the first time a child with isolated trochlear palsy and neuroborreliosis. IgG and IgM antibodies against Borrelia burgdorferi were highly positive in serum and cerebrospinal fluid respectively. The symptoms resolved completely after initiation of antibiotic treatment with ceftriaxone.

The genetics of rolandic epilepsy.

Focal spikes and sharp waves with predominantly centrotemporal localization are the electroencephalograhic hallmark of Rolandic epilepsy (or BECTS). This EEG trait, but not BECTS itself, has been reported to follow an autosomal dominant mode of inheritance with incomplete penetrance and age dependency. CTS therefore may represent a neurobiological marker for the increased risk of developing BECTS. Several linkage studies exploring candidate loci have rendered negative results. The first positive evidence for linkage in families with centrotemporal spikes was found on chromosome 15q14.

The concept of hereditary impairment of brain maturation.

The classification of benign partial epilepsies and related conditions includes (besides rolandic epilepsy) atypical benign partial epilepsy, bioelectrical status epilepticus (ESES) and a variety of other syndromes. The broad overlap of the clinical and bioelectrical symptomatology might reflect a pathogenetic background common to these epilepsies. In order to understand the great phenotypic variability, the clinical symptomatology in 56 sibships with focal sharp waves of genetic origin was analyzed. A genetic determination was assumed if, in addition to the index case, at least one sibling or offspring revealed typical focal sharp waves. The 56 index-cases and their 61 sib/offspring/parents showed a broad spectrum of epileptic and non-epileptic conditions ranging from mild selective performance deficits to severe complex mental retardation, from neonatal seizures, febrile convulsions, and simple rolandic epilepsy to severe epilepsies with minor seizures or ESES. The different conditions are not disease entities but sets of variably weighted symptoms of a complex pathogenetic background, in which a genetic disposition to focal anomalies of brain function is of decisive importance. As can be demonstrated by the data, this genetic liability coincides with other widespread genetic traits, expressed in certain EEG patterns, as well as with lesional pathogenetic factors. The biological background of the genetic focal anomaly is currently unknown. The marked age dependence of the symptoms justifies the assumption of an hereditary impairment of brain maturation.

Multifactorial pathogenesis of neonatal seizures--relationships to the benign partial epilepsies.

Elevated incidence of neonatal seizures (NS) in children with idiopathic partial epilepsies, as well as reports on the transition of NS into benign partial epilepsy, point to pathogenetic relationships between these conditions. Further insight into the nature of these relationships can be expected only from NS patients with long-term follow-up, which includes the age range of maximum manifestation of subsequent seizures or epilepsies (SSE), and age-dependent genetic EEG traits. A sample of such cases will necessarily be selected and thus prohibit any quantitative inferences regarding the incidence of SSE and special EEG characteristics. Nevertheless, the data provide new aspects with regard to a possibly multifactorial pathogenesis of NS and SSE. Children in the present study were selected applying the following inclusion criteria: cerebral seizures during the first 14 days of life; follow up of more than two years with at least two EEG recordings beyond the age of two. Children with metabolic NS or subsequent West syndrome were not included. Seventy-six cases were confirmed, 42 with SSE, 34 without. The incidence of EEG symptoms of a generalized genetic seizure liability (theta rhythms, generalized spikes and waves, photoparoxysmal response) was significantly elevated, equally in children with and without SSE. Beyond the age of two years, 50% of the probands had focal sharp waves foci characteristic of idiopathic partial epilepsy (e.g. rolandic epilepsy). Among SSE, febrile convulsions and partial epilepsies with benign course dominated. Idiopathic generalized epilepsies were not observed. These findings indicate that in a certain proportion of cases, NS have genetic factors in common with idiopathic partial epilepsies. Quantitative representative data cannot be obtained to determine the incidence of such pathogenetic mechanisms in NS and SSE.

Neuropsychological long-term outcome of rolandic EEG traits.

BACKGROUND: Long-term outcome of rolandic epilepsy (RE) is associated with a diversity of neuropsychological deficits in childhood, although RE is historically considered as a benign epileptic disorder. Dyslexia and other developmental disorders are associated with rolandic EEG traits. AIM: To investigate if there is an association between the manifestation of a specific EEG trait of RE and dyslexia. If the EEG traits are causing dyslexia, the cognitive deficits are supposed to be normalised after the EEG trait have resolved. METHOD: Thirty adolescents and young adults, who had previously received a diagnosis of dyslexia by standard criteria, were included. Fifteen probands (mean age = 15.9) with dyslexia and rolandic EEG traits were compared with 15 age- and sex-matched controls (mean age = 16.0) with normal EEG. RESULTS: There were no statistical differences between the groups according to intelligence (Verbal IQ, Performance IQ and Arithmetical IQ) or spelling ability. However, there was a significant difference between the groups in reading ability of non-related words with the group without RE performing better than the group with RE (p < 0.01). Attentional shifts in dichotic listening with forced or directed attention are generally found in 50-60% in normative samples. However, the present date suggest an impaired attentional shift in dichotic listening test for both groups. Only one third was able to modulate their ear-preference. There were no group differences. CONCLUSION: In general, both dyslectic groups did not show significant neuropsychological deficits as compared to standard controls. However, there were more reading errors and a tendency to attention impairments in the group with rolandic EEG trait as compared to the dyslectic group with normal EEG. Possible pathogenic factors are discussed.

Whole-genome linkage scan for epilepsy-related photosensitivity: a mega-analysis.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31). Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets. Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity.

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes.

OBJECTIVE: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies. METHODS: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case-control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls. RESULTS: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004). CONCLUSION: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.