Timothy B. Mapstone

Ventral brain stem compression in pediatric and young adult patients with Chiari I malformations.

OBJECTIVE The purposes of this study were as follows: 1) to determine the incidence and degree of ventral brain stem compression (VBSC) in pediatric and young adult patients with Chiari I malformations, and 2) to correlate VBSC with other imaging and clinical factors to help determine what amount of VBSC is successfully treated with a posterior decompressive procedure alone. METHODS The magnetic resonance images and clinical histories of 40 pediatric and young adult patients with Chiari I malformations were analyzed for subjective grade of VBSC, distance of tonsillar descent, odontoids relation to Chamberlains and Wackenheims line, clival length, foramen magnum diameter, syringomyelia, scoliosis, hydrocephalus, presenting clinical status, treatment, and outcome. To objectively measure the amount of ventral cervicomedullary encroachment by the odontoid and its investing tissues into the rostral spinal canal, a line (B-C2) was drawn between the basion and posteroinferior aspect of the C2 body on a sagittal magnetic resonance image. A line perpendicular to this line, pB-C2, was drawn through the odontoid tip to the ventral dura, and a distance (representing the amount of ventral canal encroachment) was measured. RESULTS Flattening and distortion of the ventral brain stem were present in 48 and 28% of the patients, respectively. Only two patients had basilar invagination by traditional definitions. pB-C2 measurements correlated with the subjective grade of VBSC (P < 0.05), age, and distance of tonsillar descent (P < 0.05). Eye motion abnormalities and upper cervical osseous anomalies were associated with higher pB-C2 measurements. All patients with a pB-C2 measurement of less than 9 mm were treated successfully with posterior fossa decompression alone despite any subjective VBSC. Some patients with pB-C2 measurements greater than 9 mm had either preoperative neurological deficits or neurological worsening after posterior fossa decompression referable to VBSC. CONCLUSION Patients with a pB-C2 measurement of less than 9 mm do not require treatment directed at VBSC. In select patients with pB-C2 measurements of 9 mm or greater, reduction of VBSC may be prudent before posterior fossa decompression.

Nonaccidental Pediatric Head Injury: Diffusion-weighted Imaging Findings

OBJECTIVEDiffusion-weighted imaging (DWI) reveals nonhemorrhagic posttraumatic infarction hours to days before conventional computed tomographic scanning or magnetic resonance imaging (MRI). We evaluated the diagnostic utility of DWI in children with nonaccidental head trauma. METHODSThe medical records and imaging examinations obtained between January 1998 and May 2000 for all children less than 2 years of age with presumed or suspected nonaccidental head injury were reviewed retrospectively. Twenty children who had undergone DWI within 5 days of presentation were included in the study. Computed tomographic scans, conventional MRI sequences, and DWI combined with apparent diffusion coefficient (ADC) maps were evaluated. RESULTSEleven girls and nine boys (median age, 5 mo) were studied. Eighteen children had presumed nonaccidental head trauma, and two children had suspected nonaccidental head trauma. Of the 18 children with presumed nonaccidental trauma, 16 (89%) demonstrated abnormalities on DWI/ADC, as compared with neither of the two children with suspected nonaccidental trauma. In 13 (81%) of 16 positive cases, DWI revealed more extensive brain injury than was demonstrated on conventional MRI sequences or showed injuries not observed on conventional MRI. DWI combined with ADC maps allowed better delineation of the extent of white matter injury. DWI/ADC abnormalities in the nonaccidental head-injured children were likely to involve posterior aspects of the cerebral hemispheres, with relative sparing of the frontal and temporal poles. Severity on DWI correlated significantly with poor outcome (P < 0.005). CONCLUSIONDWI has broad applications in the early detection of infarction in children with nonaccidental head injury and enhances the sensitivity of conventional MRI. In the patients in this study, early DWI provided an indicator of severity that was more complete than any other imaging modality. The use of DWI may help to identify children at high risk for poor outcome and to guide management decisions.

Malignant Glioma Physiology: Cellular Response to Hypoxia and Its Role in Tumor Progression

Clinical Principles Malignant gliomas occur primarily in patients 40 to 70 years of age. Clinical presentation depends on tumor location and can include headache, seizures, or mental status changes. Age, functional status at presentation, and seizures are important predictors of outcome. Therapeutic options include aggressive surgery, but since resection alone is not often curative, adjunctive therapy is warranted. Patients with glioblastoma multiforme have a median survival of 50 weeks. Pathophysiologic Principles Microvascular proliferation in glioblastoma multiforme is a form of angiogenesis associated with neoplastic progression. Vascular proliferation is often noted in hypoxic regions associated with necrosis and is due at least in part to hypoxia-inducible factormediated expression of vascular endothelial growth factor in hypoxic zones. Losses of tumor suppressor genes, such as TP53 and PTEN, and activation of oncogenes, including EGFR and PDGFR, may directly or indirectly modulate hypoxia-inducible factor-1mediated gene expression in a manner favoring new vessel growth. Angiogenesis and hypoxia-inducible factor-1mediated gene expression are natural targets for interventions since they consistently occur during the progression of glioblastoma multiforme. You are asked to fit a patient into your clinic. He is a 54-year-old man, has been a generally healthy patient of yours for more than 20 years, and is a member of your church. He has been married for over 25 years, and has two children in college. He is employed as a partner at a reputable accounting firm. For the past 6 months, he has felt somewhat confused and dazed at the end of a long workday. He also reports headaches that can usually be controlled with aspirin. He continues to be an active tennis player but feels that his shot placement has deteriorated recently. After playing a long match the previous weekend, he noted some twitching of his right hand, which resolved soon after. His neurologic examination uncovered a mild right-sided weakness and rare word-finding problems. Findings on a Mini-Mental Status Examination were normal. You refer him for magnetic resonance imaging. Images reveal an intra-axial ring-enhancing mass in the left frontoparietal region with surrounding edema that extends to the corpus callosum (Figure 1) . The patient is scheduled for neurosurgery. A craniotomy is performed, and the tumor is subtotally resected. Pathologic examination of tissue reveals an infiltrating astrocytoma with extensive microvascular hyperplasia and necrosis, fulfilling criteria for glioblastoma multiforme (Figure 2) . The patient returns home after an uneventful recovery. Postoperative treatment includes 5400-cGy of external-beam radiation therapy. The tumor initially responds to treatment but shows radiologic evidence of regrowth at 6 months. The patient dies of tumor progression 9 months after surgery. Figure 1. Axial magnetic resonance image demonstrating the features of glioblastoma multiforme. arrow Figure 2. Histopathologic and immunohistochemical features of glioblastoma multiforme. A C long arrows A C short arrows bottom B C Brain tumors are diverse and range widely in their clinical presentation, biological aggressiveness, histologic differentiation, and response to therapy (1). The most common tumors are the infiltrative gliomas, which can be oligodendroglial or astrocytic in differentiation (2). Anaplastic astrocytoma and glioblastoma multiforme are the highest-grade astrocytic neoplasms; they can occur at any age but most frequently affect elderly persons. Their incidenceabout 7 per 100 000 tumors, with a slight male predominance in the United Statesincreases in the fifth decade of life and peaks at about 65 years of age (3). High-grade astrocytomas can progress from lower-grade precursor lesions or can develop de novo. Astrocytomas that develop from a lower grade usually occur in younger patients and have a longer clinical course. De novo lesions, such as the example in the reported case, generally develop after the fifth decade of life with rapidly progressing symptoms (1, 2). In either case, high-grade astrocytomas display an accelerated growth of new blood vessels that seem to be required for progressiona biological feature that is physiologically intriguing and provides a target for developing more effective therapies. Because the diffusely invasive properties of malignant gliomas make them nearly impossible to totally resect, most physicians agree that the best hope for long-term control lies with adjunctive therapies. After surgery for diagnosis and variable tumor debulking, radiation therapy is a mainstay (4). Specific chemotherapeutic agents, especially agents based on nitrosourea, can also be effective. Despite this, median duration of survival of patients with glioblastoma is only 50 weeks. The dismal prognosis of malignant gliomas warrants continued investigation of new therapeutic options, with early introduction of promising agents into clinical trials. One emerging field of basic and clinical investigation attempts to counteract the vascular proliferation that is a physiologic response to hypoxia within malignant gliomas. Vascular Properties in Astrocytomas It has been estimated that solid tumors cannot grow larger than 1 to 2 mm without forming new blood vessels (angiogenesis; see Glossary) (5). These estimations may not precisely apply to infiltrative astrocytomas, since neoplastic cells can migrate within the brain toward preexisting vascular supplies. However, considering the various histologic subtypes and molecular pathways of astrocytomas, the features of angiogenesis are remarkably consistent and suggest that new blood vessels are necessary for high-grade progression (6). The lowest-grade infiltrative, or diffuse, astrocytomas (World Health Organization [WHO] grade II) typically present clinically in the third and fourth decades of life and are seen by magnetic resonance imaging as variably expansile, T2-bright, nonenhancing cerebral hemispheric lesions (1, 2). In histologic sections, individual astrocytoma cells percolate through the central nervous system parenchyma but show little tendency to aggregate around blood vessels (Figure 3). Vascular density and structure in these lesions are similar to those of a normal brain. Figure 3. Progression of infiltrating astrocytoma (World Health Organization [ WHO ] grade II, left ) to glioblastoma multiforme (WHO grade IV, right ). far left black arrows white arrow Anaplastic astrocytoma (WHO grade III) represents the transition from a low-grade infiltrative tumor to glioblastoma. As such, they are more expansile, and a substantial percentage will show contrast enhancement by neuroimaging studies because of emerging vascular changes. Pathologically, anaplastic astrocytomas show increased cellularity and elevated proliferation rates. The density of blood vessels increases noticeably, and many vessels are physically distorted, with dilated lumens or thickened walls. Moreover, neoplastic aggregation around small and medium-sized blood vessels becomes evident. A dramatic sequence of vascular changes occurs in transition from anaplastic astrocytoma to glioblastoma, resulting in the most highly vascularized of all neoplasms. Altered vascular properties are reflected on neuroimaging studies as intense, often ring-like, contrast enhancement of the rapidly growing mass (Figure 1). Glioblastomas are defined as highly cellular astrocytic neoplasms displaying either microvascular hyperplasia or necrosis with pseudopalisading of tumor cells or both. The pseudopalisading appearance is due to dense packing of neoplastic cells around necrotic centers. As noted in the reported case, necrosis within a glioblastoma is often seen immediately adjacent to microvascular hyperplasia (Figures 2 and 3). The latter is a structurally distinct form of angiogenesis that consists of rapidly dividing endothelial cells and pericytes, which form tufted microaggregates at the leading edge of parent blood vessels. Not infrequently, foci of vascular hyperplasia resemble renal glomeruli and are called glomeruloid bodies (7, 8). These examples of accelerated angiogenesis are believed to influence the biological behavior of malignant astrocytomas, signaling the beginning of an aggressive growth phase. Angiogenic Triggers in Astrocytomas The biological steps of angiogenesis are complex and, normally, tightly regulated by the opposing influences of pro- and antiangiogenic factors (Table 1) (9). Investigations of the vascular response to exogenous growth factors, such as vascular endothelial growth factor (VEGF), have shown a consistent pattern. Initially, mature vessels demonstrate increased permeability, leading to extravasation of plasma and plasma proteins and deposition of proangiogenic matrix proteins (10, 11). Basement membranes and extracellular matrices are modified by limited proteolytic digestion to accommodate the budding of new vessels. Endothelial cells begin to divide and migrate along the chemotactic gradient within the extracellular matrix that has been modified for their entrance. They then form a central lumen, elaborate a new basement membrane, and recruit pericytes and smooth-muscle cells to surround the mature vessels. Eventually, a tightly controlled signaling cascade results in a stable, new vasculature. Table 1. Angiogenic and Antiangiogenic Factors The accelerated rate of vascular proliferation in glioblastomas suggests that tight regulation of angiogenesis is altered to favor neoplastic growth (12). One of the main triggers for tumoral angiogenesis is believed to be the physiologic response to hypoxia. This is evident in glioblastomas, in which the close temporal and spatial relationship between microvascular hyperplasia and necrosis can be explained best by an angiogenic response to low oxygen levels in nearby necrotic zones (13). Indeed, tumor cells palisading around necrosis express hi

Surface Expression of ASIC2 Inhibits the Amiloride-sensitive Current and Migration of Glioma Cells

Gliomas are primary brain tumors with a complex biology characterized by antigenic and genomic heterogeneity and a propensity for invasion into normal brain tissue. High grade glioma cells possess a voltage-independent, amiloride-inhibitable, inward Na+ current. This current does not exist in normal astrocytes or low grade tumor cells. Inhibition of this conductance decreases glioma growth and cell migration making it a potential therapeutic target. Our previous results have shown that the acid-sensing ion channels (ASICs), members of the epithelial Na+ channel (ENaC)/degenerin (DEG) family of ion channels are part of this current pathway. We hypothesized that one member of the ENaC/DEG family, ASIC2, is retained intracellularly and that it is the lack of functional expression of ASIC2 at the cell surface that results in hyperactivity of this conductance in high grade gliomas. In this study we show that the chemical chaperone, glycerol, and the transcriptional regulator, sodium 4-phenylbutyrate, inhibit the constitutively activated inward current and reduce cell growth and migration in glioblastoma multiforme. The results suggest that these compounds induce the movement of ASIC2 to the plasma membrane, and once there, the basally active inward current characteristic of glioma cells is abolished by inherent negative regulatory mechanisms. This in turn compromises the ability of the glioma cell to migrate and proliferate. These results support the hypothesis that the conductance pathway in high grade glioma cells is comprised of ENaC/DEG subunits and that abolishing this channel activity promotes a reversion of a high grade glioma cell to a phenotype resembling that of normal astrocytes.

Death in Shunted Hydrocephalic Children in the 1990s

Using a combined search of the Children’s Hospital (Birmingham, Ala., USA) medical records and the Jefferson County Health Department death records, we reviewed all shunt-related deaths that occurred between January 1990 and July 1996. Of these, we excluded patients who died of nonhydrocephalus-related reasons, such as bronchopulmonary dysplasia, as well as patients who had other serious neurological illnesses such as brain tumor and hydranencephaly. Twenty-eight patients died of shunt-related causes in the 6.5-year period. A survival analysis showed that 96% survived 32 months after first shunting. Of 28 patients, 23 were beyond help prior to medical evaluation. However, at least 10 of these patients had symptoms suggestive of shunt failure at least 24 h and as long as 2 weeks prior to their demise. We conclude that hydrocephalic children still die of shunt failure despite the modern technology of the 1990s. Some of these causes may be avoidable through early detection of symptoms. Guidelines to patients, families, and primary caregivers should be emphasized.

Neonatal ventriculosubgaleal shunts.

OBJECTIVE We report on 32 neonates treated with ventriculosubgaleal (VSG) shunts to determine VSG shunt survival and associated complications. METHODS Between 1993 and 1997, 37 VSG shunts were placed in 32 neonates when the cerebrospinal fluid (CSF) or the abdomen was considered unsuitable for ventriculoperitoneal shunt placement. In each child, a ventricular catheter was attached to 3 cm of a closed-end peritoneal tube via a right-angle connector, which drained into a surgically created subgaleal pocket. RESULTS The causes of hydrocephalus were as follows: intraventricular hemorrhage (IVH) in 20 neonates, meningitis/ventriculitis in 6, IVH and infection in 2, and other causes in 4. The mean postconception age at the time of VSG shunt insertion was 37.2 weeks (33.1 wk in the IVH group), and the mean weight was 2227 g (1724 g in the IVH group). The average preoperative head circumference was 33.6 cm. The average survival of these 37 VSG shunts (five children had two VSG shunts) was 35.1 days. The complications were as follows: one CSF leakage occurred when sutures were removed; one catheter fell into the ventricle and required removal, and one child died immediately after VSG shunt revision. There were no VSG shunt infections. All surviving children followed for a minimum of 4 months after insertion of a VSG shunt (n = 24) have required a ventriculoperitoneal shunt. Mean follow-up from the time of first VSG shunt insertion was 21.6 months. Four children died as a result of causes unrelated to the VSG shunt. CONCLUSION VSG shunts offer a simple, effective, and relatively safe means of temporizing hydrocephalus, and they avoid the need for external drainage or frequent CSF aspiration in these medically unstable infants until the CSF characteristics and abdomen are acceptable for ventriculoperitoneal shunting.

Expression of platelet-derived growth factors, transforming growth factors, and the ros gene in a variety of primary human brain tumors.

Ribonucleic acid was isolated from a wide spectrum of central nervous system tumors to examine the expression of platelet-derived growth factors (PDGF) A and B, tumor growth factors (TGF-beta) 1 and 2, and ros messenger ribonucleic acid. Eight glioblastoma cell lines were examined as well as cell cultures from 22 tumor explants. The explants included 6 glioblastomas, 4 anaplastic astrocytomas, 5 astrocytomas, 3 ependymal tumors, 2 meningiomas, 1 medulloblastoma. and 1 ganglioglioma. For comparison, 2 nontumor glial cell cultures were included. The PDGF B-chain was expressed in 5 of 8 glioblastoma cell lines, 2 of 6 glioblastomas, and in 3 of 4 anaplastic astrocytoma explants. There was no PDGF B expression in 4 astrocytomas, 3 ependymomas of varying malignancy, in the remainder of the tumors, or in the nontumor glial cells. The PDGF A-chain was expressed in all of the tumors, with the exception of the malignant ependymoma and in both nontumor glial cell cultures. TGF-beta 1 was expressed in all of the tumors and in nontumor glial cells. The expression of TGF-beta 2 was expressed in many of the benign and malignant tumors and also in both nontumor glial cell cultures. The ros messenger ribonucleic acid was expressed in 1 of 5 glioblastoma cell lines and in 2 of 6 glioblastoma cell explants, but in none of the other tumors or in the nontumor glial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant human gliomas express an amiloride-sensitive Na+ conductance

Human astrocytoma cells were studied using whole cell patch-clamp recording. An inward, amiloride-sensitive Na+ current was identified in four continuous cell lines originally derived from human glioblastoma cells (CH235, CRT, SKMG-1, and U251-MG) and in three primary cultures of cells obtained from glioblastoma multiforme tumors (up to 4 passages). In addition, cells freshly isolated from a resected medulloblastoma tumor displayed this same characteristic inward current. In contrast, amiloride-sensitive currents were not observed in normal human astrocytes, low-grade astrocytomas, or juvenile pilocytic astrocytomas. The only amiloride-sensitive Na+channels thus far molecularly identified in brain are the brain Na+ channels (BNaCs). RT-PCR analyses demonstrated the presence of mRNA for either BNaC1 or BNaC2 in these tumors and in normal astrocytes. These results indicate that the functional expression of amiloride-sensitive Na+ currents is a characteristic feature of malignant brain tumor cells and that this pathway may be a potentially useful target for therapeutic intervention.

Vagus nerve stimulation: current concepts

Vagus nerve stimulation (VNS) has become an accepted treatment option for pharmacologically resistant epilepsy. Although initially approved for adults, it increasingly has gained acceptance in children. In this article the author reviews the current state of knowledge of VNS therapy and discusses its potential utility.

pH Alterations “Reset” Ca2+ Sensitivity of Brain Na+ Channel 2, a Degenerin/Epithelial Na+ Ion Channel, in Planar Lipid Bilayers

Members of the degenerin/epithelial Na+ channel superfamily of ion channels subserve many functions, ranging from whole body sodium handling to mechanoelectrical transduction. We studied brain Na+ channel 2 (BNaC-2) in planar lipid bilayers to examine its single channel properties and regulation by Ca2+. Upon incorporation of vesicles made from membranes of oocytes expressing either wild-type (WT) BNaC-2 or BNaC-2 with a gain-of-function (GF) point mutation (G433F), functional channels with different properties were obtained. WT BNaC-2 resided in a closed state with short openings, whereas GF BNaC-2 was constitutively activated; a decrease in the pH in the transcompartment of the bilayer activated WT BNaC-2 and decreased its permeability for Na+ over K+. Moreover, these maneuvers made the WT channel more resistant to amiloride. In contrast, GF BNaC-2 did not respond to a decrease in pH, and its amiloride sensitivity and selectivity for Na+ over K+were unaffected by this pH change. Buffering the bathing solutions with EGTA to reduce the free [Ca2+] to <10 nmincreased WT single channel open probability 10-fold, but not that of GF BNaC-2. Ca2+ blocked both WT and GF BNaC-2 in a dose- and voltage-dependent fashion; single channel conductances were unchanged. A drop in pH reduced the ability of Ca2+ to inhibit these channels. These results show that BNaC-2 is an amiloride-sensitive sodium channel and suggest that pH activation of these channels could be, in part, a consequence of H+“interference” with channel regulation by Ca2+.