Mary Edwards-Brown

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.

Treatment of posttransplant lymphoproliferative disease in the central nervous system of a lung transplant recipient using allogeneic leukocytes

Posttransplant Epstein-Barr virus-related lymphoproliferative disease (PT-LPD) is a common and often fatal complication following solid organ and hematopoietic stem cell transplantation. PT-LPD following solid organ transplantation generally occurs in B cells of recipient origin in contrast to PT-LPD in marrow transplant recipients, which is exclusively of donor origin. The efficacy of adoptive immunotherapy using donor leukocytes to treat PT-LPD in bone marrow transplant recipients has recently been reported. Because PT-LPD in solid organ transplant recipients is generally of recipient origin, the potential application of adoptive immunotherapy of PT-LPD in solid organ recipients obligates the use of either autologous or allogeneic HLA identical leukocytes, with the attendant risk of organ rejection if cells mismatched with the transplanted organ are used. Nonirradiated allogeneic mononuclear cells from an Epstein-Barr virus (EBV)-seropositive, HLA-identical normal sibling were used to treat a monoclonal EBV lymphoma of recipient origin in the central nervous system of a child who had undergone an HLA-mismatched cadaveric lung transplant. The patient received three separate mononuclear cell infusions over a 9-month period, each containing 1 x 10(6) CD3+ mononuclear cells per kilogram. Complete clinical, radiological, and pathological remission was achieved with this treatment regimen. The response correlated with in vivo reconstitution of normal EBV-specific cytotoxic activity and cytotoxic T lymphocyte precursor frequency. Use of allogeneic HLA-compatible mononuclear cells may thus offer an additional mode of therapy for EBV-related lymphoproliferative disease in selected solid organ transplant recipients refractory to conventional therapies.

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.

Arachnoid Cyst Rupture with Concurrent Subdural Hygroma

Arachnoid cysts (ACs) are relatively common intracranial mass lesions, which occur most often in the middle cranial fossa. While these lesions can present as a mass lesion, many are asymptomatic. Rarely, posttraumatic or spontaneous rupture of ACs can result in intracystic hemorrhage, subdural hematoma or subdural hygroma. We have encountered two cases of ruptured arachnoid cysts that resulted in subdural hygromas. Both patients harbored middle cranial fossa cysts and suffered mild closed head injuries. The presentation, radiographic findings and surgical management of these patients as well as the association between ACs and subdural hygromas are described.

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 Childrens 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. (J Child Neurol 2002;17:245-249).

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 Fishers 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.

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.

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.

Midwest experience with Moyamoya disease

A review of the cases of Moyamoya disease at two large Mid-Western United States Universities was undertaken for the purpose of assessing the epidemiology of Moyamoya disease. A total of 51 cases of Moyamoya disease were identified, with 12 cases classified as akin Moyamoya disease, nine cases of probable Moyamoya disease, and 30 cases of classic or definite Moyamoya disease. The conditions associated with akin Moyamoya were sickle cell disease, Downs syndrome, trauma, radiation, and neurofibromatosis. The mean age of presentation for probable and classic Moyamoya disease was 22 years. The sex predilection was approximately equal, with a slight female predominance. The racial background was identified in 22 of the definite cases, and included six patients with oriental inheritance, three with American Indian inheritance, one black, and the remainder Caucasian. Of some interest, there were five Caucasian patients with names identifiable as Eastern European in origin. The mean age of presentation of the definite Moyamoya disease was 14 years, the probable Moyamoya disease was 4 years, and the akin Moyamoya disease was 5 years.

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.