3T magnetic resonance arteriography in pediatric cerebrovascular disease.

Based on a series of 20 cases, eight with 1.5T and 3T MRA's, 3T MRA provides improvement over 1.5T MRA in imaging the vessels of the circle of Willis in pediatric patients with vascular disease. Dephasing artifact is reduced and laminal stenosis or occlusions become better depicted.

Non-accidental brain trauma in infants: diffusion imaging, contributions to understanding the injury process.

Analysis of MRI diffusion images from 33 infants suffering from non-accidental trauma reveals five patterns of injury. These are diffuse supratentorial hypoxic ischemic, watershed hypoxic ischemic, venous infarction, diffuse axonal injury and contusion.

Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome.

BACKGROUND AND PURPOSE: The clinical outcome of acute necrotizing encephalopathy of childhood (ANEC), an encephalopathy characterized by symmetrical involvement of the thalami, has historically been poor, but recent studies have reported better outcomes. By devising a MR imaging scoring system, we determined the relationship between characteristic MR findings and clinical outcome of patients with ANEC. METHODS: MR studies of 12 patients with ANEC were retrospectively reviewed. A MR imaging score was calculated for each patient according to the presence of hemorrhage, cavitation, and location of lesions. Clinical outcome of the patients was assessed, yielding outcome categories based on health state utility value. Spearman rank test was used to correlate the MR imaging score with clinical outcome of the patients. RESULTS: Statistically significant correlation (r = 0.76, P = .001) was found between the MR score and the outcome category. The thalami were involved in all 12 patients, brain stem in 10, cerebral white matter in 8, and cerebellar white matter in 4. Hemorrhage was present in 5 patients and cavitation in 4. Clinical outcome category was 1 in 2 patients, 2 in 8 patients, and 3 in 2 patients. No patients were in category 4. CONCLUSION: There is a significant and positive correlation between the clinical outcome and the MR imaging score in patients with ANEC. The relation between clinical outcome and each individual MR feature remains to be determined. Patients with ANEC may have a better clinical outcome than has been previously reported.

Primary intracranial atypical teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes.

BACKGROUND AND PURPOSE: Primary atypical teratoid/rhabdoid tumors (AT/RTs) are rare malignant intracranial neoplasms, usually occurring in young children. The objectives of this study were to characterize the MR imaging features and locations of primary intracranial AT/RTs, to determine the frequency of disseminated disease in the central nervous system (CNS) at diagnosis and postoperatively, and to assess patient outcomes. METHODS: The preoperative cranial MR images of 13 patients with AT/RTs were retrospectively reviewed for evaluation of lesion location, size, MR signal intensity and enhancement characteristics, and the presence of disseminated intracranial tumor. Postoperative MR images of the head and spine for 17 patients were reviewed for the presence of locally recurrent or residual tumor and disseminated neoplasm. Imaging data were correlated with patient outcomes. RESULTS: Patients ranged in age from 4 months to 15 years (median age, 2.9 years). Primary AT/RTs were intra-axial in 94% of patients. The single primary extra-axial lesion was located in the cerebellopontine angle cistern. AT/RTs were infratentorial in 47%, supratentorial in 41%, and both infra- and supratentorial in 12%. A germ-line mutation of the hSNF5/INI1 tumor-suppressor gene was responsible for the simultaneous occurrence of an intracranial AT/RT and a malignant renal rhabdoid tumor in a 4-month-old patient. Mean tumor sizes were 3.6 x 3.8 x 3.9 cm. On short TR images, AT/RTs typically had heterogeneous intermediate signal intensity, as well as zones of low (54%), high (8%), or both low and high (31%) signal intensity from cystic and/or necrotic regions, hemorrhage, or both, respectively. On long TR/long TE images, solid portions of AT/RTs typically had heterogeneous intermediate-to-slightly-high signal intensity with additional zones of high (54%) or both high and low signal intensity (38%), secondary to cystic and/or necrotic regions, edema, prior hemorrhage, and/or calcifications. AT/RT had isointense and/or slightly hyperintense signal intensity relative to gray matter on fluid-attenuated inversion-recovery (FLAIR) and long TR/long TE images, and showed restricted diffusion. All except 1 AT/RT showed contrast enhancement. The fraction of tumor volume showing enhancement was greater than two thirds in 58%, between one third and two thirds in 33%, and less than one third in 9%. Disseminated tumor in the leptomeninges was seen with MR imaging in 24% of patients at diagnosis/initial staging and occurred in another 35% from 4 months to 2.8 years (mean, 1.1 years) after surgery and earlier imaging examinations with negative findings. The overall 1-year and 5-year survival probabilities were 71% and 28%, respectively. Patients with MR imaging evidence of disseminated leptomeningeal tumor had a median survival rate of 16 months compared with 149 months for those without disseminated tumor (P < .004, logrank test). CONCLUSION: AT/RTs are typically intra-axial lesions, which can be infra- and/or supratentorial. The unenhanced and enhanced MR imaging features of AT/RT are often variable secondary to cystic/necrotic changes, hemorrhage, and/or calcifications. Poor prognosis is associated with MR imaging evidence of disseminated leptomeningeal tumor.

Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.

PURPOSE: This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS: Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS: Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION: The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.

A prospective longitudinal brain morphometry study of children with sickle cell disease.

BACKGROUND AND PURPOSE: Age-related changes in brain morphology are crucial to understanding the neurobiology of sickle cell disease. We hypothesized that the growth trajectories for total GM volume, total WM volume, and regional GM volumes are altered in children with sickle cell disease compared with controls. MATERIALS AND METHODS: We analyzed T1-weighted images of the brains of 28 children with sickle cell disease (mean baseline age, 98 months; female/male ratio, 15:13) and 28 healthy age- and sex-matched controls (mean baseline age, 99 months; female/male ratio, 16:12). The total number of MR imaging examinations was 141 (2-4 for each subject with sickle cell disease, 2-3 for each control subject). Total GM volume, total WM volume, and regional GM volumes were measured by using an automated method. We used the multilevel-model-for-change approach to model growth trajectories. RESULTS: Total GM volume in subjects with sickle cell disease decreased linearly at a rate of 411 mm(3) per month. For controls, the trajectory of total GM volume was quadratic; we did not observe a significant linear decline. For subjects with sickle cell disease, we found 35 brain structures that demonstrated age-related GM volume reduction. Total WM volume in subjects with sickle cell disease increased at a rate of 452 mm(3) per month, while the trajectory of controls was quadratic. CONCLUSIONS: There was a significant age-related decrease in total GM volume in children with sickle cell disease. The GM volume reduction was spatially distributed widely across the brain, primarily in the frontal, parietal, and occipital lobes. Total WM volume in subjects with sickle cell disease increased at a lower rate than for controls.

Primitive neuroectodermal tumors of the central nervous system.

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscientists and pathologists. Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medulloblastomas ([MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum. The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses. Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.

Transient global amnesia due to a dominant hemisphere tumor.

Transient global amnesia is generally regarded as a benign syndrome of probable vascular etiology. We describe a man who experienced a single episode of transient global amnesia and subsequently developed a progressive dominant hemispheric syndrome. Neuroradiologic investigations and the patient's subsequent death strongly suggest that his disease was due to a left temporal-parietal mass lesion. Although the syndrome is most often benign, such patients should be examined for mass lesions.

Focal encephalopathy following methotrexate therapy. Administration via a misplaced intraventricular catheter.

Two patients with lymphoreticular malignant neoplasms and leptomeningeal tumor spread were treated with intraventricular administration of methotrexate via an Ommaya reservoir. The intraventricular instillation of methotrexate resulted in focal CNS damage in brain parenchyma inadvertently pierced by the shunt. Disorientation, aphasia, and right hemiparesis developed in both patients. Computed tomography disclosed a contrast-enhancing, low-density mass in the left cerebral cortex where the distal shunt tip was lodged. In one case the lesion was pathologically consistent with chronic inflammation. A lesion occurred in one patient despite repositioning of the shunt prior to methotrexate instillation. Shunt removal and administration of systemic corticosteroids resulted in resolution of symptoms in one patient.

Silent infarcts in children with sickle cell anemia and abnormal cerebral artery velocity.

BACKGROUND: A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infarction as seen on magnetic resonance imaging (MRI). OBJECTIVES: To determine if transfusion therapy affects the rate at which silent infarcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler (TCD) ultrasonography. STUDY DESIGN: Children with elevated TCD ultrasonographic velocity were randomized to receive long-term transfusion therapy or standard care. Magnetic resonance imaging of the brain was obtained at randomization, annually, and with clinical neurologic events. The risk for new silent lesions and/or stroke was compared for each treatment arm. RESULTS: Among the 37% of subjects with silent infarcts, those receiving standard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy. For subjects receiving standard care, those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality. CONCLUSIONS: Transfusion therapy lowers the risk for new silent infarct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infarct. However, those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infarct or stroke than are those whose initial MRI showed no abnormality. The finding of a silent infarct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen. Similarly, elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infarct or stroke.

Comparison of myelography with CT follow-up versus gadolinium MRI for subarachnoid metastatic disease in children.

We evaluated 17 children with primary intracranial neoplasms for subarachnoid metastatic disease (SAMD) using myelography with computed tomographic follow-up (Myelo + CT) and cerebrospinal fluid (CSF) histopathologic examination, as well as magnetic resonance imaging with gadolinium DTPA (MRI + Gd), between December 1988 and December 1989. There were 12 boys, and the median age was 5.7 years (range, 0.8 to 21.8 years). Tumor histology included 8 primitive neuroectodermal tumors (PNETs), 3 ependymomas, 2 low-grade astrocytomas, 1 anaplastic astrocytoma, 1 glioblastoma multiforme, 1 atypical rhabdoid tumor, and 1 malignant fibrous histiocytoma. Thirteen tumors originated in the posterior fossa, 2 were supratentorial, and 2 were in the spinal cord. The median interval between the 2 diagnostic tests was 2 days. MRI + Gd was positive in 11 (65%), Myelo + CT in 8 (47%), and CSF in 5 (29%) cases. MRI + Gd was superior in delineating spinal cord nodules and "sugar coating" whereas Myelo + CT more readily revealed nerve root sleeve filling defects. There was no case in which Myelo + CT was positive that MRI + Gd did not reveal SAMD. MRI + Gd is a safe, noninvasive test that should be used as the initial imaging modality for the presence of SAMD.

Spectrum of disorders associated with enlarged sylvian fissures in infancy.

Disproportionate enlargement of the sylvian fissures (ESF) on MRI of an infant's CNS suggests underdevelopment of the cortical operculum. We reviewed charts of infants with isolated ESF. Conditions associated with ESF included feeding difficulties and facial dysmorphism (syndromic or nonsyndromic). There may be an embryologic link between growth of the opercular cortex and development of the face.

Evolution of cerebral abscess: correlation of clinical features with computed tomography. A case report.

Computed tomography demonstrated the evolution of a cerebral abscess. Intravenous contrast material was essential for visualization of the abscess capsule. Computed tomography was more specific than technetium 99 brain scanning and cerebral angiography, and is the only diagnostic tool so far capable of differentiating acute focal encephalitis (cerebritis) from a well-developed abscess.

Brainstem gliomas of childhood: magnetic resonance imaging.

We compared magnetic resonance imaging (MRI) and CT on 16 children with brainstem gliomas. MRI demonstrated masses of decreased signal intensity, which enlarged and distorted brainstems in all patients with active disease and showed brainstem abnormalities in 21 of 23 studies (91%). In one-half of the patients, MRI showed more extensive disease than did CT. Exophytic portions of tumors were shown well on MRI. MRI was more sensitive than CT in demonstrating disease relapse.

Comparison of metrizamide computed tomography and magnetic resonance imaging in the evaluation of lesions at the cervicomedullary junction.

We compared intrathecal metrizamide-enhanced CT (metrizamide-CT) and magnetic resonance imaging (MRI) in the evaluation of 17 patients with clinical suspicion of lesions at the cervicomedullary junction. MRI was superior in imaging the position of the cerebellar tonsils and the size and extent of mass lesions. MRI and metrizamide-CT were equal in detecting syringomyelia. CT with and without IV contrast enhancement was necessary to detect calcium or defects in the blood-brain barrier within neoplasms.

Gadolinium-DTPA-enhanced magnetic resonance imaging in childhood brain tumors.

Gadolinium DTPA (Gd-DTPA) is a paramagnetic blood-brain barrier contrast agent for MRI that has been used primarily in adults. During May through October 1987, 17 children between the ages of 3 and 18 years with brain tumors underwent MRI examinations, before and after Gd-DTPA (11 gliomas, 4 medulloblastomas, 1 craniopharyngioma, and 1 child with neurofibromatosis and no pathologic diagnosis). We compared T1 and T2 Gd-DTPA-enhanced MRI with concurrent unenhanced MRI and enhanced CT, and then correlated this with the clinical and pathologic findings. Gd-DTPA enhanced tumors in all 7 patients with newly diagnosed tumors and enhanced tumors in 7 of 10 patients without clinical evidence of progressive disease at the time of the study. In the 7 new patients, Gd-DTPA defined tumor margins in all, and demonstrated internal tumor architecture (vessels, necrosis, and cysts) in 5. Areas believed to represent surgical scars showed varying degrees of enhancement. Leptomeningeal tumor spread, including spinal, not seen on pre-Gd-DTPA MRI or on contrast CT, was evident in 2 patients. Gd-DTPA enhancement obscured hemorrhage within the tumor (methemoglobin) in 2 patients. There were no significant side effects. These results suggest that Gd-DTPA-enhanced MRI (1) is safe in children, (2) demonstrates the extent and character of tumors better than unenhanced MRI and enhanced CT, and (3) may allow for noninvasive imaging of leptomeningeal disease, including the spine, not previously demonstrated by any other noninvasive neuroimaging technique.

Plexiform neurofibromas in NF1: toward biologic-based therapy.

Neurofibromatosis type 1 (NF1) is one of the most common neurogenetic diseases affecting adults and children. Neurofibromas are one of the most common of the protean manifestations of NF1. Plexiform neurofibromas, which will frequently cause cosmetic abnormalities, pain, and neurologic deficits, are composed of "neoplastic" Schwann cells accompanied by other participating cellular and noncellular components. There is increasing evidence that loss of NF1 expression in neoplastic Schwann cells is associated with elevated levels of activated RAS, supporting the notion that the NF1 gene product, neurofibromin, acts as a growth regulator by inhibiting ras growth-promoting activity. In addition, there is increasing evidence that other cooperating events, which may be under cytokine modulation, are important for neurofibroma development and growth. Treatment of plexiform neurofibromas has been empiric, with surgery being the primary option for those with progressive lesions causing a major degree of morbidity. The efficacy of alternative treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic drugs, has been questionable. More recently, biologic-based therapeutic approaches, using drugs that target the molecular genetic underpinnings of plexiform neurofibromas or cytokines believed important in tumor growth, have been initiated. Evaluation of such trials is hindered by the unpredictable natural history of plexiform neurofibromas and difficulties in determining objective response in tumors that are notoriously large and irregular in shape. Innovative neuroimaging techniques and the incorporation of quality-of-life scales may be helpful in evaluation of therapeutic interventions. The ability to design more rational therapies for NF1-associated neurofibromas is heavily predicated on an improved understanding of the molecular and cellular biology of the cells involved in neurofibroma formation and growth.

Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients.

OBJECTIVE: To determine the number of primary laminin alpha2 gene mutations and to conduct genotype/phenotype correlation in a cohort of laminin alpha2-deficient congenital muscular dystrophy patients. BACKGROUND: Congenital muscular dystrophies (CMD) are a heterogeneous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin alpha2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD. Laminin alpha2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins. METHODS: Seventy-five CMD patients were tested for laminin alpha2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin alpha2 coding sequence of 22 completely laminin alpha2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test (PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin alpha2-deficient patients were collected. RESULTS: Thirty laminin alpha2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin alpha2 mutations. Clinical features of laminin alpha2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin alpha2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed. CONCLUSIONS: Our data suggest that the large majority of laminin alpha2-deficient patients show laminin alpha2 gene mutations.

Magnetic resonance imaging of cranial radiation lesions.

Fifty-six patients who previously received therapeutic cranial irradiation (CRT) were imaged by a 1.5 Magnetic Resonance (MR) System 0.1-11 years following CRT. Abnormal MR findings within the treatment volume unrelated to tumor, prior to surgery, or coexisting conditions were reviewed for an association with CRT. Twenty-four patients had MR abnormalities considered to be attributable to CRT. These were scored as mild (Grade I) in 6, moderate (Grade II) in 9, and severe (Grade III) in 9. Eight of these 24 patients with CRT findings on MR had CT abnormalities that correlated with the MR. Six lesions seen on computed tomography (CT) were Grade III abnormalities; all were judged as being visualized better by MR. Eight patients had significant neurologic dysfunction attributable to their CRT lesions, and 7 of these had Grade III lesions. Whereas the clinical significance of mild or moderate CRT effects seen on MR is uncertain, Grade III (severe) MR lesions correlate well with important clinical findings.

Desmoplastic primitive neuroectodermal tumor with divergent differentiation. Broadening the spectrum of desmoplastic infantile neuroepithelial tumors.

We report an unusual large, multicystic, posterior fossa neuroepithelial neoplasm involving the cerebellum, brain-stem, and quadrigeminal cistern of a 9-month-old girl. The neoplasm consisted of variably sized, sharply demarcated nests of small cells with a high nuclear-cytoplasmic ratio and moderately basophilic nuclei, embedded in a desmoplastic, immature-appearing, mesenchymal stroma. The nests contained mitoses but none were seen in the stroma. Glial fibrillary acidic protein (GFAP), neurofilament protein, synaptophysin, and cytokeratin (AE-1) were expressed in the nests. Mesenchymal cells were negative for neural markers but positive for vimentin and desmin. The neoplasm was interpreted as a mixed mesenchymal and primitive neuroectodermal tumor (PNET) with histologic features reminiscent of a recently described intraabdominal desmoplastic small cell tumor. The tumor responded poorly to chemotherapy and a second operation was performed 1 year later. The second specimen bore no resemblance to the original and consisted of epithelial-like nests and clusters of neoplastic cells frequently interrupted by sinusoidal vessels. Tumor cells had medium-sized vesicular nuclei with small nucleoli, and a granular cytoplasm. Occasional less cellular islands of neuropil-like tissue contained larger cells having eccentric, vesicular nuclei with prominent nucleoli and abundant pink cytoplasm. Mitoses were not conspicuous. Many cells expressed synaptophysin, neurofilament protein, and GFAP. Neurofilament protein was strongly positive in the larger, neuron-like cells and synaptophysin stained the neuropil-like areas strongly but was less prominent in the neuronal perikarya. Unexpectedly, the neuropil-like areas expressed epithelial membrane antigen, whereas the neuronal cells were negative for chromogranin A. The peculiar histologic picture, combination of phenotypic markers, and remarkable biologic behavior of this unusual tumor defies classification according to existing nomenclature and exemplifies the broad range of phenotypes expressed by primitive neuro-epithelial neoplasms.