Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.

BACKGROUND: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research.

Early cognitive and behavioral problems in children with nodular heterotopia.

Adults with periventricular nodular heterotopia (PNH) have epilepsy and dyslexia, but most have normal intelligence. It is not known whether PNH-related reading difficulty can be detected earlier in childhood or whether associated behavioral problems are present. We studied 10 children with PNH, 3 of whom did not have seizures, and 10 matched controls with neuropsychological testing and parental rating instruments at two time points separated by about 1 year. Children with PNH performed significantly worse than controls on a task related to reading fluency. In addition, those with PNH showed significantly worse adaptive skills, and a measure of conduct problems significantly worsened over time. Mood and behavioral problems were reported more commonly, though not significantly so, in children with PNH. These findings demonstrate that reading dysfluency can be evident in children with nodular heterotopia, even in the absence of epilepsy, but also highlight difficulties with behavior in this population.

Very early arterial ischemic stroke in premature infants.

Early stroke in the premature infant has rarely been described. Presented here are the cases of 23 infants, born between 23 and 35 weeks gestational age, with focal arterial ischemic stroke occurring before 44 weeks gestational age. Ten (43%) were male. Five children (22%) were half of a twin pair; no co-twin died. The most commonly affected territory was the middle cerebral artery territory. Three children with extreme prematurity (< or =26 weeks) had cerebellar infarcts. Twelve children had unilateral or bilateral intraventricular hemorrhages (grade 3 or higher in 8 of the 12). Twelve children had white matter injury: periventricular leukomalacia, hypoxic-ischemic encephalopathy, or both. Most children had multiple comorbidities, and the median neonatal intensive care unit stay was 63 days (range, 14-365). One child died in the neonatal intensive care unit (age 123 days). All 22 survivors were left with disabilities. Seventeen (77%) had cerebral palsy, 10 (45%) had epilepsy, and 17 (77%) had cognitive impairment. Arterial ischemic stroke appears to add to the neurologic disabilities commonly associated with prematurity.

Neonatal sinovenous thrombosis: presentation and association with imaging.

Few studies have examined when children with neonatal sinovenous thrombosis come to medical attention, risk factors associated with time of presentation, what clinical presentations are more likely to occur early or late, or whether the timing of presentation or severity of clinical presentation correlate with radiographic findings. Chi-square and Fisher's exact tests were used to explore associations in a cohort of 59 neonates with sinovenous thrombosis. Most (66%) came to medical attention within 48 hours of birth (defined as early presentation). Most (88%) had multiple comorbidities. Respiratory distress (P = 0.005), hypoxia (P = 0.02), poor tone (P = 0.05), fetal distress (P < 0.001), preterm delivery (P = 0.044), and low Apgar score (P = 0.018) were associated with early presentation. Infant dehydration was associated with late presentation (P < 0.001). Time of presentation was not associated with radiographic severity. Presentation with difficult-to-control seizures was marginally associated with hemorrhage (P = 0.096) but no other measure of radiographic severity. Neonates with sinovenous thrombosis often present within 48 hours, with multiple comorbidities and presenting signs, some of which are associated with time of presentation. Neither timing of presentation nor presence or absence of severe seizures can be used to predict findings on radiographic imaging.

Carotid dissection and stroke after tonsillectomy and adenoidectomy.

Carotid dissection and cerebral infarction are extremely rare complications of tonsillectomy and adenoidectomy. We describe a 12-year-old boy who presented with a right internal carotid dissection and right middle cerebral artery infarction, associated with tonsillectomy and adenoidectomy. We discuss the risk factors that may predispose patients to these complications.

A 10-year-old girl with coexistent moyamoya disease and Graves' disease.

There are rare reports of young women with moyamoya disease associated with Graves' disease; we are unaware of any previous reports of this association in prepubescent girls. We report a 10-year-old girl who presented with multiple bilateral strokes. Cerebral angiography demonstrated moderate to severe stenosis of her bilateral distal internal carotid arteries and proximal anterior and middle cerebral arteries, which was greater on the right. Thyroid function tests demonstrated suppressed thyroid-stimulating hormone and elevated thyroid hormone levels. Serum antiphospholipid antibody screen demonstrated mild elevations of antiocardiolipin IgG. Possible mechanisms predisposing individuals to concurrent moyamoya and Graves' disease are discussed.

Neuroimaging in autistic spectrum disorder (ASD).

Autistic spectrum disorder (ASD) is a lifelong developmental disorder characterized by impairment in socialization and communication. Neuroimaging research has shown abnormalities in the frontal lobes, limbic systems, and cerebella of individuals with ASD. Recently, abnormal developmental trajectories of brain growth have been reported, with increases in brain volume (in both gray and white matter) seen in younger rather than older individuals with this disorder. Despite 30 years of research, a reliable marker for ASD has not been identified. Therefore, routine neuroimaging for individuals with ASD is not recommended.

Vermian hypoplasia and arrested cerebral myelination in two sisters: variant of Joubert's syndrome or a new syndrome?

Two adult sisters have vermian hypoplasia, ataxia, nystagmus, pontine divergence insufficiency, and mild to moderate intellectual disability, with an arrest of cerebral myelination resembling the pattern of a 4-month-old infant. Other abnormalities include high myopia, optic nerve hypoplasia, decreased bone density, hypoplasia of the secondary teeth, and amenorrhea. We did not find matching patients described in the literature. The sisters could represent a variant of one of the described syndromes of the cerebellocerebro-oculorenal spectrum, such as a variant of Joubert's syndrome, or a disorder sui generis within the spectrum.

Hydrogen proton magnetic resonance spectroscopy in autism: preliminary evidence of elevated choline/creatine ratio.

Hydrogen proton magnetic resonance spectroscopy is only beginning to be studied in autistic individuals. We report an association between hydrogen proton magnetic resonance spectroscopy choline/creatine ratios and severity of autism as measured by the Children's Autistic Rating Scale (Pearson r = .657, P = .04) in 10 autistic children. Hydrogen proton magnetic resonance spectroscopy choline/creatine ratio measures the concentration of cytosolic choline including free choline used in the synthesis of acetylcholine. Elevation in this ratio has been interpreted as a result of membrane degradation such as caused by a tumor or, alternatively, as a result of choline synthesis associated with increased cellular proliferation. Recent neuropathologic evidence has implicated disruption of acetylcholine transmission in the brains of autistic adults. A case-controlled study of hydrogen proton magnetic resonance spectroscopy choline/creatine ratios is warranted.

Tacrolimus (FK506)-induced mutism after liver transplant.

Tacrolimus (FK506), an immunosuppressant, has been associated with mutism in adults after liver transplant. Speech arrest, agitation, tremor, ataxia, and downward gaze deviation in a 5-year-old female 13 days after orthotopic liver transplant are reported. FK506, which began to be administered 12 days earlier, rose to a level of 44 ng/mL (normal range, 10-20 ng/mL) 1 day before neurologic abnormalities began. FK506 dose level was maintained and then reduced. Three days later the patient could say a few single words and extra-ocular movement returned to normal. Four months later, she continued to exhibit decreased fluency and dysarthria with ataxia. One year later, decreased fluency and mild ataxia persists. Rapid identification of speech loss linked to FK506 may be important because reduction or cessation of the drug may be associated with reverse of speech loss.

From swelling to sclerosis: acute change in mesial hippocampus after prolonged febrile seizure.

Mesial temporal sclerosis (MTS) has been linked to prolonged febrile seizures. The sequence of changes in the temporal lobe/hippocampus following prolonged febrile seizures and status epilepticus is beginning to be elucidated. We obtained repeated magnetic resonance imaging (MRI) volumetric analysis of the hippocampi in a 23-month-old boy after a prolonged focal febrile seizure. Three days after a prolonged left focal febrile seizure, brain MRI showed increased T2 weighted signal and increased volume (swelling) of the right hippocampus. Repeat MRI 2 months later demonstrated sclerosis of the right hippocampus. Review of the literature shows four other children with prolonged focal seizures associated with the MRI sequence of temporal lobe swelling followed by sclerosis. All had left focal seizures followed by right MTS. Our patient demonstrates a shorter interval for the radiologic development of hippocampal sclerosis compared to other reports.

Like father, like son: periventricular nodular heterotopia and nonverbal learning disorder.

Periventricular nodular heterotopia is a common malformation of cortical development in which the migration of developing neurons destined for the cerebral cortex is abbreviated. Bilateral periventricular nodular heterotopia is most commonly an X-linked disorder that involves mutations in the filamin A (FLNA) gene, but an autosomal recessive form and sporadic forms have been identified. To our knowledge, autosomal dominant transmission of isolated periventricular nodular heterotopia has not been reported. Periventricular nodular heterotopia has a heterogeneous phenotype, associated commonly with seizure disorder, and more recently with reading deficits and visual-spatial deficits in some patients. We present a father and son with bilateral periventricular nodular heterotopia and similar visual-spatial learning deficits, consistent with nonverbal learning disability.

Malignant transformation of a chiasmatic pilocytic astrocytoma in a patient with diencephalic syndrome.

Chiasmatic gliomas with metastatic spread are rare in children and are usually associated with diencephalic syndrome. They are mostly pilocytic astrocytomas and their transformation to high-grade astrocytomas has never previously been reported in the pediatric population. We report leptomeningeal spread of a chiasmatic pilocytic astrocytoma in a child presenting with diencephalic syndrome. He was treated with chemotherapy and radiation. The tumor recurred with transformation into a high-grade astrocytoma. Radiation therapy may have played a role in transformation of the tumor, but more research is needed to further clarify the biological behavior of this tumor.