Creation of an international registry to support discovery in schwannomatosis.

Schwannomatosis is a tumor suppressor syndrome that causes multiple tumors along peripheral nerves. Formal diagnostic criteria were first published in 2005. Variability in clinical presentation and a relative lack of awareness of the syndrome have contributed to difficulty recognizing affected individuals and accurately describing the natural history of the disorder. Many critical questions such as the mutations underlying schwannomatosis, genotype-phenotype correlations, inheritance patterns, pathologic diagnosis of schwannomatosis-associated schwannomas, tumor burden in schwannomatosis, the incidence of malignancy, and the effectiveness of current, or new treatments remain unanswered. A well-curated registry of schwannomatosis patients is needed to facilitate research in field. An international consortium of clinicians and scientists across multiple disciplines with expertise in schwannomatosis was established and charged with the task of designing and populating a schwannomatosis patient registry. The International Schwannomatosis Registry (ISR) was built around key data points that allow confirmation of the diagnosis and identification of potential research subjects to advance research to further the knowledge base for schwannomatosis. A registry with 389 participants enrolled to date has been established. Twenty-three additional subjects are pending review. A formal process has been established for scientific investigators to propose research projects, identify eligible subjects, and seek collaborators from ISR sites. Research collaborations have been created using the information collected by the registry and are currently being conducted. The ISR is a platform from which multiple research endeavors can be launched, facilitating connections between affected individuals interested in participating in research and researchers actively investigating a variety of aspects of schwannomatosis. © 2016 Wiley Periodicals, Inc.

Lorazepam for seizure prophylaxis during high-dose busulfan administration.

Seizure is a recognized complication of high-dose busulfan (BU) therapy and phenytoin (DPH) is widely used as prophylaxis. A number of adverse effects have been associated with DPH and it may also interfere with BU metabolism. We used lorazepam (median dose 0.022 mg/kg) i.v. or p.o. before each dose and for 24 h after the last dose of BU as seizure prophylaxis to 29 children undergoing hematopoietic stem cell transplantation. The regimen was well tolerated and drowsiness was the only significant side-effect. Twelve patients were able to receive the entire prophylaxis by mouth. No seizure developed during and within 48 h of BU. Concomitant pharmacokinetic studies showed no alternation of the absorption and clearance of BU during lorazepam administration. Lorazepam can be used as an alternative for seizure prophylaxis during high-dose BU treatment.

The role of surgery in children with neurofibromatosis.

BACKGROUND/PURPOSE: Neurofibromatosis frequently is complicated by the development of symptomatic lesions such as optic gliomas and plexiform neurofibromas that require operative resection. Although characteristically benign, these neoplasms have often devastating functional and cosmetic effects and must be monitored for malignant transformation. The purpose of this study is to identify and describe the surgical considerations in the care of children with neurofibromatosis. METHODS: The authors reviewed the charts of all children (<21) at our institution with neurofibromatosis who underwent an operative procedure from 1979 to 1999. Patient demographics, symptomatic lesions, malignant transformation, form of surgical intervention, type of anesthesia, and outcome were collected. RESULTS: A total of 249 patients with either neurofibromatosis 1 or 2 were identified. Of these, 50 (20%) underwent a total of 93 operations. The average age at operation was 9.4 years (1.2 to 21 years). There were 40 soft tissue procedures, 21 intracranial, and 32 miscellaneous. The soft tissue masses typically were treated with wide local excision, and in 8 of these procedures multiple resections were performed. Fourteen of the 50 patients had malignancies. Five of the tumors were soft tissue sarcomas, and 9 were intracranial malignancies. Three patients died, 2 from malignancy and 1 from acute, obstructive hydrocephalus after operation. There were 3 patients alive with malignancy and 8 others living with varying levels of disability. CONCLUSIONS: Neurofibromatosis in the pediatric patient frequently requires surgical intervention, often because of symptoms such as pain or cosmetic deformity, or for malignancy. Children should be watched carefully for signs of malignant transformation and undergo biopsy for neurofibromas that exhibit rapid growth. Management of sarcomas should be aggressive with consideration given to re-excision, placement of brachytherapy catheters, metastectomy, and limb salvage with adjuvant therapy when possible. Preoperatively, children should receive clinical and radiographic (computed tomography or magnetic resonance imaging) evaluation for hydrocephalus.

Growth hormone deficiency in children with neurofibromatosis type 1 without suprasellar lesions.

Risk factors for shortness of stature in children with neurofibromatosis type 1 (NF-1) include suprasellar lesions, which can lead to growth hormone deficiency (GHD), skeletal deformities, nutritional insufficiency, and methylphenidate use. At our Neurofibromatosis Clinic, we have observed short children growing poorly without these risk factors. This study investigated whether GHD occurs in children with NF-1 in the absence of suprasellar lesions. Of 251 children with NF-1, 112 were at or below the 25th percentile for height (68 were at or below the 10th). Of these, 51 children, 5-16 years of age were short, growing poorly, and without medical or radiologic findings to explain the poor growth. In 19 of 51, we evaluated GH secretion; 15 of 19 had GHD (peak GH level less than 5 ng/mL in most cases). These findings suggest that GHD may be relatively common in short children with NF-1 without suprasellar abnormalities, suggesting an association with NF-1 independent of organic, pituitary damage. Larger cohorts of NF-1 children should be evaluated to clarify whether NF-1 represents a novel etiology of GHD. Also, a careful assessment of GH secretion in children with NF-1 who are growing poorly in the absence of another clinical explanation is warranted.

Quantitative morphology of the corpus callosum in children with neurofibromatosis and attention-deficit hyperactivity disorder.

Neurofibromatosis-1 is a common autosomal-dominant genetic disorder associated with numerous physical anomalies and an increased incidence of attention-deficit hyperactivity disorder (ADHD). Studies of children with idiopathic ADHD have suggested a link between corpus callosum size and symptom severity. This study examines the contribution of corpus callosum morphology to symptoms of ADHD in children with neurofibromatosis. Eighteen control subjects and 36 children with neurofibromatosis underwent magnetic resonance imaging of the brain. Twelve subjects with neurofibromatosis had evidence of ADHD and 24 did not. Subjects with neurofibromatosis had significantly larger total corpus callosum area and significantly larger regional measurements in three of seven areas. However, there were no differences between the neurofibromatosis alone and neurofibromatosis plus ADHD groups. Increased severity of attention problems was associated with smaller total callosal areas. These results suggest that some features of ADHD in children with neurofibromatosis could be linked to quantifiable differences in brain morphology, but the nature of the genetic mutation in neurofibromatosis suggests that neurochemical effects also could be important.

Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status.

OBJECTIVE: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. BACKGROUND: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. METHODS: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. RESULTS: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual-spatial and motor skills were associated with greater regional corpus callosum size. CONCLUSIONS: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

Magnetic resonance angiography of primary varicella vasculitis: report of two cases.

Two patients with onset of hemiparesis 3 weeks following primary varicella infection demonstrated contralateral temporal lobe and basal ganglia infarctions on magnetic resonance imaging. In both cases, magnetic resonance angiography (MRA) was performed and demonstrated flow abnormalities ipsilateral to the infarcts. Digital subtraction angiography was performed in one case; however, the findings were significantly less conspicuous than those of the MRA. MRA proved to be sensitive to the diagnosis of varicella-induced vasculitis in two consecutive cases and provided a noninvasive means of following the progression of the disease process in response to therapy.

Brain tumors in children with neurofibromatosis: additional neuropsychological morbidity?

Neurofibromatosis type 1 is a common autosomal dominant genetic disorder associated with numerous physical anomalies and an increased incidence of neuropsychological impairment. Tumors of the CNS occur in approximately 15% of children with neurofibromatosis, presenting additional risk for cognitive impairment. This study examines the impact of an additional diagnosis of brain tumor on the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological tests was administered to 149 children with neurofibromatosis. Thirty-six of these children had a codiagnosis of brain tumor. A subset of 36 children with neurofibromatosis alone was matched with the group of children diagnosed with neurofibromatosis and brain tumor. Although mean scores of the neurofibromatosis plus brain tumor group were, in general, lower than those of the neurofibromatosis alone group, these differences were not statistically significant. Children in the neurofibromatosis plus brain tumor group who received cranial irradiation (n = 9) demonstrated weaker academic abilities than did children with brain tumor who had not received that treatment. These results suggest that neurofibromatosis is associated with impairments in cognitive functioning, but the severity of the problems is not significantly exacerbated by the codiagnosis of a brain tumor unless treatment includes cranial irradiation.

Capillary hemangioma of the neck: prenatal MR findings.

Prenatal MR findings of a case of extracranial capillary hemangioma simulating an encephalocele at sonography are reported. MR imaging had an adjunctive diagnostic role in excluding the possibility of an encephalocele. The capillary hemangioma had diffuse T2 hypointensity prenatally, which is atypical of postnatal imaging findings.

Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: utilization of a neurological severity score.

Neuropsychological studies of children who have brain tumors have yielded diverse results with respect to identifying factors that contribute to poor intellectual outcome. The purpose of this study was to evaluate the relationship between pre- and perioperative events, tumor-related factors, and the neuropsychological status of children diagnosed with astrocytoma. Events that could potentially be detrimental to neuropsychological outcome were quantified utilizing a new "neurological severity score." The Neurological Severity Score was developed as a research tool to test our hypothesis that ultimate intellectual outcome is a result of cumulative, interactive insults on the central nervous system. This study constitutes a first step in examining the predictive value of the Neurological Severity Score by evaluating its correlation with baseline neuropsychological status. Fifty-nine children who had astrocytoma (36 supratentorial and 23 infratentorial) received complete neurological and neuropsychological evaluations within 3 months of diagnosis. Each child's neurological history and examination results were scored by an independent observer using the Neurological Severity Score. Neuroimages obtained at diagnosis and at the time of neuropsychological testing were evaluated as well. For the group as a whole, memory, attention, and motor abilities were significantly below age-appropriate norms, whereas intelligence, language, and academic skills were preserved. Patterns of deficits were identified and related to tumor site. There were no significant differences in mean neuropsychological domain scores between groups based on gender, pre-versus post-operative status, ethnicity, tumor grade, or abnormalities on magnetic resonance imaging (MRI). The Neurological Severity Score was significantly inversely correlated with visual-spatial skills, memory, attention, performance IQ, and global IQ. In conclusion, among all the medical and neurological factors present at diagnosis, the neurological severity score had the highest correlation with neuropsychological scores. This instrument has promise as a research tool in investigations of the psychological effects of cancer and its treatment on children.

Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis.

Of children with neurofibromatosis (NF), 40% have a cognitive or learning impairment. Approximately 60% also have anomalous areas of high signal intensity on T2-weighted brain MRIs. The association of these hyperintensities and neuropsychological status is not fully understood. We administered a battery of neuropsychological tests and a standard clinical MRI to determine the impact of hyperintensity presence, number, and location on cognitive status in 84 children (8 to 16 years) with NF type 1. These children underwent standard clinical MRI using a GE 1.5-tesla scanner (except one child who was examined with a 1.0-tesla scanner). We conducted three types of analyses: Hyperintensity presence or absence.-Scores of children with (55%) and without hyperintensities (45%) were compared using t tests. No statistically significant differences between groups in intellectual functioning or any neuropsychological variable were found. Number of hyperintensities-The number of hyperintensity locations per child ranged from one to five (mean = 2.22). Pearson correlations revealed no significant association between the number of hyperintensities and neuropsychological performance. Location of hyperintensities-In four of the five locations studied, no statistically significant differences were found between scores of children with a hyperintensity in an area and those with one elsewhere. However, mean scores for IQ, Memory, Motor, Distractibility, and Attention domains for children with hyperintensities in the thalamus were significantly lower than scores for those with hyperintensities elsewhere. These results suggest that the simple presence or absence of hyperintensities, or their total number, is not as important as their anatomic location for detecting their relationship with neuropsychological status. Taking location into account, hyperintensities in the cerebral hemispheres, basal ganglia, brainstem, or cerebellum seem to have no impact on neuropsychological functioning, whereas hyperintensities in the thalamus do.

In vivo microdialysis and gas chromatography/mass spectrometry for studies on release of N-acetylaspartlyglutamate and N-acetylaspartate in rat brain hypothalamus.

Microdialysis and gas chromatography/mass spectrometry was used for the measurement of extracellular N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) in rat hypothalamus. The sensitivity of the method for each of these compounds was approximately 5 pmol/30 microliters of dialysate. Baseline NAA concentrations in dialysate were estimated to be approximately 25 pmol/36 microliters, while that for NAAG was at or below the detection limit of 5 pmol/ 36 microliters. In vivo and in vitro calibrations of microdialysis probes showed that the recovery for NAA was approximately 10 percent. For NAAG, the in vitro recovery was 6.3%, and in vivo recovery, 11%. Depolarization stimulation using 100 mM KCl in the microdialysis perfusate was employed to measure extracellular NAA and NAAG concentrations. Extracellular NAA was elevated to approximately 70 pmol/36 microliters dialysate following depolarization. No significant elevation of NAAG was observed. By infusing known amounts of stable isotopically labeled NAAG-d3 via the microdialysis probe and measuring the isotopically labeled catabolic product, NAA-d3, in collected microdialysate, we were able to confirm the existence of one or more hydrolytic enzymes active towards NAAG in the hypothalamus. This finding suggest the possible involvement of active metabolic processes in the relationship between NAAG and NAA releases.

Neuropsychological profile of children with neurofibromatosis, brain tumor, or both.

Neurofibromatosis type 1, a common autosomal dominant genetic disorder, is associated with numerous physical and medical anomalies as well as an increased incidence of learning disability. Tumors of the central nervous system have been estimated to occur in 15%, but their contribution to neuropsychological status is unknown. This study examines the relative contribution of neurofibromatosis and brain tumor to the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological and behavioral tests was administered to a group of 65 children with neurofibromatosis type 1. Fourteen were then matched on demographic variables with two other groups of children who had either a brain tumor in addition to neurofibromatosis or a brain tumor alone. The two brain tumor groups were also matched on tumor type, location, and therapy. Mean scores of the neurofibromatosis-brain tumor group were generally the lowest of the three groups; those of the brain tumor group were highest, and performance of the neurofibromatosis group was generally between the other two groups. These results suggest that neurofibromatosis is, by itself, associated with significant cognitive morbidity, but that the severity of the problems is increased somewhat if a brain tumor is also present.

Prenatal diagnosis of unilateral megalencephaly by real-time ultrasonography.

Unilateral megalencephaly is a rare anomaly of neuronal cell migration. We recently diagnosed this condition in a fetus at 20 weeks' gestation with ultrasonography and magnetic resonance imaging. The pregnancy was terminated and postmortem magnetic resonance imaging and autopsy confirmed the diagnosis. To our knowledge this represents the first case to be prenatally diagnosed with certainty.

Proton magnetic resonance imaging and spectroscopic studies of the pathogenesis and treatment of juvenile dermatomyositis.

Juvenile dermatomyositis is an inflammatory disorder of muscle, skin, and connective tissue. Immune vasculopathy is central to the pathophysiology. We studied a 13-year-old boy with juvenile dermatomyositis using proton magnetic resonance imaging (MRI) with short tau inversion recovery (STIR), and proton magnetic resonance spectroscopy (MRS) to quantitate lipid and water in affected regions of muscle. Tissue perfusion was assessed by measuring tissue water concentration changes during isometric exercise of the tibialis anterior muscle. During sequential studies over 3 months of steroid treatment, STIR image abnormalities, resting water concentrations, and diminished perfusion returned to normal. Resting lipid concentrations increased during this period. MRI serves to guide muscle biopsy and monitor progress of the disease state. MRS demonstrates the vasculopathy and provides noninvasive assessment of steroid therapy in juvenile dermatomyositis.

Brain and ocular abnormalities in infants with in utero exposure to cocaine and other street drugs.

We describe 10 infants with developmental delay and congenital cerebral anomalies who were found to have had in utero exposure to vasoactive drugs. Nine infants had ophthalmological abnormalities; these included strabismus, nystagmus, and/or hypoplastic optic discs. Six mothers used cocaine, one used cocaine and heroin, one used only heroin, one used amphetamine, and one used phenylpropanolamine. Each of these cerebral anomalies (agenesis of the corpus callosum, septo-optic dysplasia, schizencephaly, hydranencephaly, congenital hydrocephalus, porencephaly, and cerebral infarctions) can be attributed to insults at different stages of development. There appears to be a relationship between the time of prenatal drug exposure and the type of cerebral anomaly, evoking malformations, disruptions, or fetal strokes. Since many or possibly all of these anomalies are thought to have a vascular origin, it seems appropriate to implicate prenatal exposure to vasoactive drugs.