Margaret G. Norman

Cytogenetic analysis of 109 pediatric central nervous system tumors.

Reports of cytogenetic abnormalities in pediatric central nervous system (CNS) tumors are important for collection and comparison of large numbers of karyotypes of primary CNS neoplasms to produce statistically significant correlations. We report cytogenetic results of 119 samples of pediatric CNS tumors from 109 patients. Tumors included 33 low-grade astrocytomas, 18 high-grade astrocytomas, 14 gangliogliomas, 13 ependymomas, 17 primitive neuroectodermal tumors (PNET), three choroid plexus papillomas and carcinomas, and a miscellaneous group of 20 rare primary CNS tumors and metastases. In each group, cytogenetic results were correlated with histologic subtype and survival. The study indicated specific chromosome abnormalities in different groups of tumors. Low-grade astrocytomas showed mostly numeric abnormalities with gains of chromosome 7, high-grade astrocytomas showed differences from karyotypic changes observed in adults in lacking double minutes (dmin) and monosomy 10. The ependymoma group showed the largest proportion of abnormal karyotypes with frequent involvement of chromosome 6 and 16. Chromosome 6 was the single most common abnormal chromosome in this study, closely followed by chromosomes 1 and 11. Pediatric CNS neoplasms differ from adult tumors cytogenetically as well as histologically and biologically.

The growth and development of microvasculature in human cerebral cortex

Sections of the occipital cortex from 31 fetuses, infants and children, ranging in age from 15 weeks gestation to ten years postnatal, were stained to demonstrate alkaline phosphatase activity in intracortical vessels. At 15 weeks gestation intracortical positively staining vessels, assumed to be arterial precursors, were radially oriented, originating from leptomeningeal arteries. Most radial vessels coursed through the cerebral cortex without branching to vascularize the subcortical tissue. By 20 weeks gestation horizontal branches arose from radial vessels, most frequently in the lower half of the cortex. Occasionally, recurrent collaterals ascended from these horizontal branches to more superficial cortex. From 20–27 weeks gestation, the number of horizontal branches and recurrent collaterals increased in the lower half of the cortex, horizontal branches appeared in the upper half. From 27 weeks to term, shorter radial vessels, terminating in the more superficial cortical laminae increased in number. After birth a network of fine vessels, presumably precursors of capillaries, increased, particularly vascular layer 3 (neuronal lamina IV and Va). The number of radially oriented vessels per mm2 of pial surface (NA) decreased throughout development, with the most dramatic decrease occurring prenatally. In five cases of trisomy values of NA decreased less rapidly than in the normal.

Apnea in Patients with Myelomeningocele

Apnea is a known complication of the Chiari II malformation presenting in infancy. Obstructive apnea secondary to bilateral abductor palsy or laryngomalacia and centrally mediated expiratory apnea with cyanosis can occur. Observations of 9 patients suggest that these forms of apnea may represent stages in a continuum of brain stem dysfunction due to the combined effects of the hindbrain malformation and its compression, hydrocephalus and progressive arachnoiditis. Obstructive apnea in some patients may be reversed by optimal control of hydrocephalus with or without cervical decompression. These patients may also develop episodes of cyanotic expiratory apnea of central origin (PEAC). This form of apnea does not respond to surgical or medical treatment and may show progressive worsening over time. Five of 6 patients with this form of apneic spell died suddenly, 2 of these died despite full recuscitative efforts. It is recommended that reports of treatment address results for both forms of apnea.

Nongerminomatous germ cell tumors of the brain

PURPOSE This analysis was performed to determine the clinical outcome of patients with primary nongerminomatous germ cell tumors of the brain. The efficacy of various treatment options was evaluated. METHODS AND MATERIALS A total of 57 patients with primary nongerminomatous germ cell tumors of the brain were identified. Patient-related data were collected and analyzed retrospectively. Follow-up in surviving patients ranged from 3 to 243 months (median follow-up 36). Survival and failure rates were determined using the Kaplan-Meier method, and differences between the survival curves were evaluated using either the log rank test or the Wilcoxon test. RESULTS The 3-year survival rate was 86% for patients with mature teratomas, 67% for patients with immature teratomas, 44% for patients with mixed germ cell tumors, and 13% for patients with the other histologic types (p = 0.02). The 3-year survival rate was 0% for patients having biopsies alone, 32% for patients having subtotal resections, and 73% for patients having gross total resections (p = 0.0001). Patients with tumors other than mature or immature teratomas were evaluated for possible relationships between the administration of chemotherapy or radiotherapy and survival. Patients who received chemotherapy had a 3-year survival rate of 56% compared to 8% for those patients who did not receive chemotherapy (p = 0.0001) Patients who received radiotherapy had a 3-year survival rate of 46% compared to 11% for those patients who did not receive radiotherapy (p = 0.0015). CONCLUSION The survival of patients with primary nongerminomatous germ cell tumors of the brain is dependent on tumor histology and the extent of surgical resection. Patients with tumors other than mature or immature teratomas appear to benefit from the administration of chemotherapy and radiotherapy.

Bilateral encephaloclastic lesions in a 26 week gestation fetus: effect on neuroblast migration.

A 26 week gestation fetus with bilaterally symmetrical encephaloclastic lesions in the cerebral hemispheres is described. Information about gestation allows dating of the cerebral insult to the 3-4th fetal month. The history and morphology in this case suggest that insults occurring at or before the 3-4th fetal month interfere with normal neuroblast migration, producing a cerebral scar containing a band of neuroblasts arranged without order or lamination.

Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesions of patients with tuberous sclerosis.

Tuberous sclerosis (TSC), an autosomal dominant disorder, is characterized by malformations, hamartomas and tumors in various organs including the brain. TSC is genetically linked to two loci: TSC1 on chromosome 9q34 and TSC2 on 16p13.3. TSC2 has been cloned, sequenced and encodes a protein (tuberin) which functions as a tumor suppressor. We have analyzed the distribution of TSC2 mRNA and tuberin in the brains of TSC patients and non‐affected individuals using both autopsy and biopsy material. High levels of transcript and protein expression were observed in choroid plexus epithelium, ependymal cells, most brainstem and spinal cord motor neurons, Purkinje cells and the external granule cell layer of the cerebellum in both TSC and control cases. Individual balloon cells from TSC patients showed very faint expression while other glia showed no expression of either transcript or tuberin. Neocortical and hippocampal neurons expressed high levels of TSC2 transcript, but only modest levels of tuberin. The internal granule cell layer of the cerebellum expressed abundant transcript but low levels of tuberin. These observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in‐situ hybridization recognize different splice variants of the TSC2 gene. In TSC patients, dysmorphic cytomegalic neurons expressed high levels of tuberin and transcript, particularly when in an ‘ectopic’ location. Individual cells within subependymal giant cell astrocytomas (SEGAs) and hamartomas from TSC patients expressed moderate to high levels of TSC2 transcript and tuberin. While the TSC2 transcript is widely expressed primarily within neurons, tuberin is demonstrable primarily within dysplastic/cytomegalic cells of the cortex and subependymal hamartomas/SEGAs. CIMS expression of tuberin is unique in that primarily non‐dividing cells express it in this location, whereas extra‐CNS expression of tuberin is mainly found in actively proliferating cell types such as epithelium.

Primary Ewing's Sarcoma of the Base of the Skull

The authors report a case of primary Ewings sarcoma of the petrous bone. The radiological features, including the computed tomographic scan and angiographic findings, are described in detail.

Sudden infant death syndrome: increased number of synapses in the hypoglossal nucleus.

The medulla was sampled from nine cases of sudden infant death syndrome (SIDS) and from six age-matched control cases without neurological disease. Morphometric analyses were performed on serial Nissl sections through the hypoglossal nucleus on the left side of the medulla. The total volume of the nucleus and both the numerical density (Nv, cells per mm3) and total number of neurons were measured. Tissue from the remaining hypoglossal nucleus was prepared for electron microscopy using the ethanolic phosphotungstic acid method to stain synaptic contacts. Stereological analyses were performed to determine the Nv and total number of synapses. Total volume of the hypoglossal nucleus was significantly greater (36%) in SIDS cases than in controls. The Nv of neurons was significantly less than in controls (28%), although the total number of neurons did not differ significantly. The mean profile area of motor neuron cell bodies was significantly greater (30%) in SIDS cases, with no differences in the mean profile areas for interneurons or glia. The Nvof synapses did not differ significantly between SIDS cases and controls, although the total number of synapses was greater (61%) in SIDS. These abnormalities in growth indicate a greater volume of neuropil in a hypoglossal nucleus containing a normal complement of neurons. The greater number of synapses in SIDS cases is consistent with a failure to eliminate normally extraneous synapses during early development.

Mechanisms of brain damage in twins.

The brains of 18 twins dying in the perinatal period showed a variety of lesions. Eleven had subependymal cell plate hemorrhage which had ruptured into the lateral ventricles in five. Five had periventricular damage. Three had anoxic neuronal damage. One acardiac monster had bilateral cerebral infarction. One pair had unequal sized brains, probably due to unequal intrauterine nutrition. Twins have a high perinatal mortality and morbidity; as well, intrauterine events may alter brain growth and development in each twin unequally, so they are an imperfect model to study the effect of genes and environment on intelligence.

Sudden Infant Death Syndrome: Postnatal Changes in the Numerical Density and Total Number of Neurons in the Hypoglossal Nucleus

Tissue specimens from the medulla were sampled from 28 sudden infant death syndrome (SIDS) victims and from 15 control cases without neurological disease (36–95 postconceptional weeks). Morphometric analyses were performed on serial Nissl sections through the hypoglossal nucleus. The total volume of the hypoglossal nucleus, the numerical density (Nv, cells per mm3) and the total number of motor neurons, interneurons and glia were determined. Normal development was characterized by a linear increase in the volume of the hypoglossal nucleus during the first postnatal year. While the Nv of neurons decreased, the total number of neurons remained relatively constant at approximately 7,600 motor neurons and 3,100 interneurons. In SIDS cases the rate of increase in the volume of the hypoglossal nucleus was significantly greater than in controls (79%). The Nv of neurons was less than in controls (25–30%), although the total number of motor neurons and interneurons did not differ significantly. In SIDS cases the mean profile area of motor neuron cell bodies was significantly greater than in controls (29%), while the mean profile areas of interneurons and glia did not differ. These abnormalities in growth indicate a greater volume of neuropil in a hypoglossal nucleus containing a normal complement of neurons. The disproportionately rapid increase in volume of neuropil in the hypoglossal nucleus of SIDS cases may result from an increased arborization of dendrites on the motor neurons.