Circle of Willis abnormalities in children with neurofibromatosis type 1

Background and purposeThe aim of the study was to assess anatomical variants and abnormalities in cerebral arteries on magnetic resonance angiography in 67 children with neurofibromatosis type 1 (NF1).Materials and methodsThe study included 67 children aged 9 months to 18 years (mean 6.6 years). Control group comprised 90 children aged 2–18 years (mean: 11.8 years). All patients were examined at 1.5 T scanner.ResultsWe found cerebral arteriopathy (moyamoya disease) in one child (1.5%) in the study group. No aneurysms were found. Twenty-nine NF1 children (43.3%) had arterial anatomical variants. In 13 of them, more than one variant was diagnosed (44.8% of group with variants, 19.4% of study group). In control group, 19 children (21.1%) had variants, including four children with more than one variant (21% of group with variants, 4.4% of control group). Arterial variants were more common in NF1 patients compared with control group (p = 0.026, binomial test for two proportions). Percentage of multiple variants was higher in study group than in control group, but this difference was not significant. Variants were more frequent on left side than on the right one (significant difference in control group; p = 0.022, McNemara test). In study group, the number of left-sided anomalies (25) was similar to that of right-sided ones (22). There was no correlation between gender and variants, unidentified bright objects and variants or between optic gliomas and variants.ConclusionsOccurrence of arterial variants in NF1 patients was twofold higher than in control group. Multiple variants were more frequent in the study group although the difference did not reach statistical significance. Features of cerebral arteriopathy were found in one child with NF1.     

Motor cortical excitability and plasticity in patients with neurofibromatosis type 1

ObjectiveNeurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1.MethodsWe included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS).ResultsThe SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009).ConclusionsIndividuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients.SignificanceThese findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.     

Brain gliomas,hydrocephalus and idiopathic aqueduct stenosis in children with neurofibromatosis type 1

PurposeTo evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis.Subjects and methodsWe analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery.ResultsWe have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas.Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause.ConclusionsThe total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up.     

Infantile spasms in patients with neurofibromatosis type 1

The authors report two patients with neurofibromatosis type 1 who were affected by infantile spasms. The infantile spasms were severe and unresponsive to anticonvulsant treatment. The authors maintain that infantile spasms may belong to the clinical features of neurofibromatosis type 1.     

Quantitative microstructural cerebral changes in neurofibromatosis type 1

Objectives

To evaluate microstructural cerebral changes in children with neurofibromatosis type 1 (NF1) based on T₂ relaxation time measurements at 3Tesla.

Social functioning in adults with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common single-gene disorder characterised by a diverse range of cutaneous, neurological and neoplastic manifestations. It is well recognised that children with NF1 have poor peer interactions and are at risk for deficits in social skills. Few studies, however, have examined social functioning in adults with NF1. We aimed to determine whether adults with NF1 are at greater risk for impairment in social skills and to identify potential risk factors for social skills deficits. We evaluated social skills in 62 adults with NF1 and 39 controls using self-report and observer-report measures of social behaviour. We demonstrate that adults with NF1 exhibit significantly less prosocial behaviour than controls. This deficit was associated with social processing abilities and was more evident in males. The frequency of antisocial behaviour was comparable between the two groups, however was significantly associated with behavioural regulation in the NF1 group. These findings suggest that poor social skills in individuals with NF1 are due to deficits in prosocial behaviour, rather than an increase in antisocial behaviour. This will aid the design of interventions aimed at improving social skills in individuals with NF1.     

Ⅰ型神经纤维瘤病基因GRD区突变研究

目的 对39例Ⅰ型神经纤维瘤病（NF1）患者基因的部分GTP酶活化蛋白相关功能区（GRD区）的cDNA突变进行研究。方法 应用反转录聚合酶链反应（RT-PCR）分段扩增GRD区域上的cDNA序列,用单链构象多态性（SSCP）及直接测序法对RT-PCR产物进行突变分析。结果 仅发现1例点突变G3918T颠换,导致1306精氨酸（R）变成亮氨酸（L）。结论NF1基因的GRD区可能不是NF1基因突变的热点区域。     

Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects

Objective

To investigate the relationship between intracranial lesions and epileptic seizures in neurofibromatosis type 1 (NF1) patients.

Background

NF1 is one of the most common autosomal dominant neurocutaneous disorders, and epilepsy is more prevalent in NF1 patients than in the general population. Epileptic seizures were found to be related to various types of intracranial lesions in NF1 patients.

Methods

The clinical characteristics of NF1 (1986–2006 in Chung-Gung Memorial Hospital), diagnosed on the basis of the criteria of the National Institutes of Health Consensus Conference (1988), were reviewed by 2 neurologists. We diagnosed epileptic seizures of NF1 patients on the basis of clinical appearances and a history of antiepileptic drugs. Magnetic resonance images were also evaluated by 2 neuroradiologists to confirm the locations of brain tumors or neurofibromatosis bright objects (NBOs). The locations of NBOs were classified into 4 categories: cortex and hippocampus, subcortical white matter, basal ganglia, and infratentorial area. The association between the location of the lesions and the occurrence of seizure in NF1 patients was analyzed statistically.

Results

The medical records of 630 NF1 patients were reviewed. In this cohort, 37 (5.87%) NF1 patients had epileptic seizures. The patients include 22 males (59.5%) and 15 females (40.5%). The mean seizure onset age was 14.8 years (2 months to 72 years). The most common seizure pattern was partial onset seizures, 3 simple partial seizures, and 14 complex partial seizures. Other seizure types found include 15 primary generalized seizures (2 absence seizures and 13 generalized tonic–clonic seizures), 2 infantile spasms, and 3 unclassified.A total of 172 (23 with epilepsy and 149 without epilepsy) NF1 patients underwent MRI examinations. NBOs were identified in 16 (69.6%) epilepsy patients and in 108 (72.5%) patients without epilepsy. The location or the number of these intracranial lesions does not show significant correlation with the occurrence of epilepsy in our cohort. Among 11 NF1 patients with intracranial tumors, 4 patients had seizures (36.36%), vs. 19 out of 161 NF1 patients (11.80%) without tumors.

Conclusion

The occurrence of epileptic seizures in NF1 patients is related to intracranial tumors but not to NBOs.     

Glial clusters and perineuronal glial satellitosis in the basal ganglia of neurofibromatosis type 1

Recent biochemical studies demonstrated that astrocytic differentiation and growth regulation are impaired in neurofibromatosis type 1 (NF1). However, non-neoplastic morphological abnormalities of glial cells in the NF1 brain have been hardly explored. We describe here characteristic glial lesions in the basal ganglia in three NF1 cases (age at death in cases 1-3: 77, 6.5, and 11 years). Clusters of 3-10 dysplastic cells similar to reactive astrocytes were observed in the amygdala, caudate nucleus, putamen, thalamus in cases 1 and 2. Gigantic astrocyte-like glial cells were noted in case 2. Perineuronal glial satellitosis was observed in the amygdala in case 1. Many glial clusters were encountered in case 3 as well, but the round nuclei of the glial cells were more hyperchromatic and showed more remarkable variation in size than those in the other cases. Glial clusters in all cases were glial fibrillary acidic protein- and/or vimentin-positive, but synaptophysin-, myelin basic protein-, and olig2-negative. The glial lesions in cases 1 and 3 were excitatory amino acid transporters 1 (EAAT1)- and EAAT2-negative, and those in case 2 EAAT1- and EAAT2-weakly positive. Proliferation markers Ki-67, proliferation cell nuclear antigen, and cyclin D1 were not expressed in any lesion. Glial clusters in case 3 showed weak to intense immunoreactivity to nestin, a stem cell marker protein. The brains of 19 cases including 14 with various degenerative diseases and five normal brains used as controls lacked the glial lesions observed in NF1 cases. Given these findings, glial clusters and perineuronal glial satellitosis may be histopathological features of the NF1 brain and are probably associated with altered regulation of astrocyte growth in NF1.     

Deficient motor timing in children with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common single-gene disorders affecting fine and visual-motor skills. This case–control study investigated motor timing as a possible related performance deficit in children with NF1. A visual-motor reaction time (VRT) test was administered in 20 NF1 children (mean age 9 years 7 months) and 20 age- and gender-matched typically developing (TD) children. Copying and tracing performance were evaluated using the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI). Children with NF1 responded with an increased reaction time (RT) to temporally predictive stimuli compared to TD children, whereas RT at unpredictive stimuli did not differ between groups. Motor timing indexed by the RT decrease at predictive stimuli significantly associated with the Beery VMI copy and tracing outcomes. Deficient motor timing as an actual symptom may add to further research on the pathogenesis of NF1-associated motor impairment and the development of more effective treatment.     

Hippocampal sclerosis and associated focal cortical dysplasia-related epilepsy in neurofibromatosis type I

Neurofibromatosis type I (NF1) is a relatively common disorder associated with a range of neurologic sequelae. Refractory epilepsy occurs in 4–13% of NF1 patients. Hippocampal sclerosis and focal cortical dysplasia, both well-defined epilepsy-related entities, have been described in a subset of cases. To our knowledge, there has been only one other series describing coexistent focal cortical dysplasia and hippocampal sclerosis in the setting of NF1. We report two such patients who presented with intractable seizures requiring epilepsy surgery. Histologically, the hippocampal sclerosis specimen met criteria for the International League Against Epilepsy (ILAE) hippocampal sclerosis subtypes Ia and II respectively. The associated focal cortical dysplasia observed within the resected temporal lobe were both consistent with ILAE focal cortical dysplasia type IIIa (e.g. associated with a secondary lesion). Post-operatively, both patients had recurrence of habitual seizures, with one case continuing to have intractable seizures following two subsequent temporal lobectomies. Although hippocampal sclerosis association with focal cortical dysplasia is well document in epilepsy, it has been rarely described in the setting of neurofibromatosis type I. Although prior surgical series have shown good epilepsy surgery outcomes within neurofibromatosis type I, these two cases did not.     

Behavioural, academic and neuropsychological profile of normally gifted Neurofibromatosis type 1 children

In the present study the neuropsychological, academic and social-emotional profiles were examined in Neurofibromatosis type 1 (NF1) children Subjects 17 NF1 children (ages 7–11) with NF1 without serious medical problems and with a full scale IQ (FSIQ) above 70. Methods Wechsler Intelligence Scale for Children-Revised (WISC-R), academic tests and an exhaustive neuropsychological test battery were administered in all children. Parents and teachers filled out the Child Behavioural Checklist (CBCL) and Teacher Report Form (TRF), respectively, the NF1 children the Experienced Competence Scale for Children (ECSC). Results and discussion Nearly 50% (8/17) of the children showed learning disabilities, when corrected for IQ in the academic evaluations. Isolated impaired literacy skills, particularly spelling problems, were most frequent (4/8), whereas a pure arithmetic learning disability was rare (1/8). Three children presented both learning disabilities. Results on academic and neuropsychological tests did not fit the well-known types of learning disabilities – nonverbal learning disability (NLD) and dyslexia. Nearly all NF1 children showed visual perceptual and executive dysfunctions. In this study, teachers more frequently reported behavioural problems in NF1 children than parents, as opposed to literature data in a general population. The correspondence of the perception of internalizing problems between the children and teachers was greater than between children and their parents. No correlation was found between the performances on the WISC-R, specific neuropsychological results, academic performances and behavioural problems. The Deficiency in Attention, Motor and Perception (DAMP) concept seems most appropriate in order to describe the neuropsychological deficits and their repercussions on behavioural and academic performances seen in NF1 children.     

Neuropsychological evaluation and parental assessment of behavioral and motor difficulties in children with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder, with large inter and intrafamilial clinical variability and uncertain prognosis. In children with NF1 cognitive disorders, learning difficulties and behavioral problems are common.The present study aims to establish the neuropsychological and behavioral profiles of 78 patients with NF1, aged between 5 and 18 years, and to examine the relationship between these profiles and the transmission of NF1 (sporadic vs. familial), clinical manifestations, and environmental factors.We used several questionnaires completed by parents and neuropsychological tests.The results confirmed specific neuropsychological disabilities in children with NF1, especially involving visuospatial and fine motor skills, learning difficulties and behavioral problems. Cognitive difficulties were significantly more frequent in patients with familial than in those with sporadic NF1. All parental questionnaires were correlated with each other, but parental reports were not associated with FSIQ, SES, school status, and clinical manifestations of the disease.Neuropsychological tests were poorly related to parental reports of cognitive and behavioral difficulties.     

Neurofibromatosis type 1 and type I Chiari malformation: an unusual association

We report an 11-year-old boy with neurofibromatosis type 1 (NF₁) and asymptomatic type I Chiari malformation. This association may be considered a pure coincidence, due to the relative frequency of the two conditions, but recent reports describing the same association suggest that type I Chiari malformation probably should be added to the list of abnormalities of the central nervous system reported in patients affected by NF₁.     

Central nervous system imaging in reevaluation of patients with neurofibromatosis type 1

We report the results of the reevaluation of 24 patients with neurofibromatosis type 1 (NF1) using central nervous system (CNS) imaging techniques. The first examination by computed tomography (CT) or magnetic resonance imaging (MRI) indicated the presence of optic glioma in three cases, unidentified bright objects (UBOs) in six, and a suspected right frontal tumor in one. In two patients optic glioma and UBOs were both present and in one of them a bulbar tumor was also suspected. Later imaging examinations revealed the appearance of optic glioma in three more cases and UBOs in nine. In two of these patients both optic glioma and UBOs were present. This study indicates that the likelihood of detecting imaging abnormalities in patients with NF1 increases when systematic follow-up is performed. Optic gliomas are characteristic of pediatric patients; they rarely give rise to clinical manifestations (1/6 cases) and in general progress very slowly. For these reasons, therapeutic strategy must be carefully considered and individually decided. UBOs are very frequent findings in pediatric patients with NF 1 and therefore they must be considered diagnostically relevant. They are not related to clinical manifestations and spontaneous regression has been observed. The nature of these imaging abnormalities is still unknown, but because they do not behave like tumors, useless and dangerous therapeutic procedures should not be employed.     

Activity and participation in children with neurofibromatosis type 1

We describe activity and participation in children and youth with neurofibromatosis type 1 (NF1), and compared an intervention and control group after a strengthening program using the Pediatric Outcomes Data Collection Instrument (PODCI) and the Children's Assessment of Participation and Enjoyment (CAPE). Questionnaires were filled out by parents at baseline, 12-weeks, and 1-year. The intervention group performed a strengthening program twice a week for ten weeks, followed by a 9-month independent program. Thirty-six participants (18 control, 18 intervention) between the ages of 5- and 18-years (mean 10.6 years, SD 4.6 years) were enrolled, and 34 completed the 1-year assessment. There were significant differences between formal and informal participation (p < 0.0001) in baseline CAPE scores for the entire cohort. At 12 weeks, PODCI upper extremity function improved in intervention and decreased in controls (p = 0.040), while happiness declined in intervention and increased in control (p = 0.003). There were no significant differences between control and intervention groups in any of the CAPE or PODCI change scores from baseline to 1-year. Upper extremity function, sport and physical function, comfort/pain and happiness PODCI scores were lower than normative values. The NF1 cohort had low participation in formal active physical and skill-based activities. The companionship and location dimensions suggest participation occurs with family and other relatives in the home or a relative's home and reflects a pattern of social isolation from peers.     

Malignant intracerebral giant nerve sheath tumor in a 14-month-old girl with neurofibromatosis type 1: a case report

Introduction  Malignant intracerebral nerve sheath tumor (MINST) is extremely rare and the origin is still unclear. The authors present the clinical, radiological, and pathological features of a malignant intracerebral giant nerve sheath tumor. Case report  A giant tumor in the right frontotemporoparietal lobes causing a midline shift was detected in a 14-month-old girl who presented with developmental delay, vomiting, and lethargy. The physical examination was consistent with neurofibromatosis type 1 (NF-1). Subtotal resection was performed and the histopathological examination revealed the diagnosis of MINST. Discussion  There are only six cases of malignant intracerebral nerve sheath tumor in the literature. The presented case is the youngest and the occurrence of MINST in a 14-month-old girl may support the hypothesis of multipotent mesenchymal stem cell origin; however, the tumors which arise from multipotent mesenchymal stem cells may be seen in later stages of life. Another important feature of the presented case is the occurrence of MINST in NF-1. Conclusion  MINSTs are extremely rare tumors with unknown origin. The location, the degree, and the size of the tumor and the general condition of the patient are prognostic factors in MINSTs, like in other malignant tumors.     

Glioblastoma in adults with neurofibromatosis type I: A report of two cases

Neurofibromatosis type I (NF1) is a familial tumor syndrome with an autosomal‐dominant inheritance. NF1‐associated tumors often include neurofibromas, malignant peripheral nerve sheath tumors and pilocytic astrocytomas of the optic nerve. The presentation of NF1 patients with glioblastoma is a rare occurrence, with only a handful of cases reported in the literature. We report two cases of glioblastomas occurring in adults with NF1 and briefly review the relevant literature.