Fractional Flow on TOF-MRA as a Measure of Stroke Risk in Children with Intracranial Arterial Stenosis.

BACKGROUND AND PURPOSE: Conventional angiography is the criterion standard for measuring intracranial arterial stenosis. We evaluated signal intensity ratios from TOF-MRA as a measure of intracranial stenosis and infarct risk in pediatric stroke. MATERIALS AND METHODS: A retrospective study was undertaken in children with intracranial arterial stenosis, who had TOF-MRA and conventional angiography performed within 6 months. Arterial diameters were measured for percentage stenosis. ROI analysis on TOF-MRA measured signal intensity in pre- and poststenotic segments, with post-/pre-signal intensity ratios calculated. The Pearson correlation was used to compare percentage stenosis on MRA with conventional angiography and signal intensity ratios with percentage stenosis; the point-biserial correlation was used for infarcts compared with percentage stenosis and signal intensity ratios. Sensitivity, specificity, and positive and negative predictive values were calculated for determining severe (≥70%) stenosis from MRA and signal intensity ratios against the criterion standard conventional angiography. P < .05 was considered statistically significant. RESULTS: Seventy stenotic segments were found in 48 studies in 41 children (median age, 11.0 years; range, 5 months to 17.0 years; male/female ratio, 22:19): 20/41 (48.8%) bilateral, 11/41 (26.8%) right, and 10/41 (24.4%) left, with the most common site being the proximal middle cerebral artery (22/70, 31%). Moyamoya disease accounted for 27/41 (65.9%). Signal intensity ratios and conventional angiography stenosis showed a moderate negative correlation (R = -0.54, P < .001). Receiver operating characteristic statistics showed an area under the curve of 0.86 for using post-/pre-signal intensity ratios to determine severe (≥70%) carotid stenosis, yielding a threshold of 1.00. Sensitivity, specificity, and positive and negative predictive values for severe stenosis were the following-MRA: 42.8%, 58.8%, 30.0%, and 71.4%; signal intensity ratio >1.00: 97.1%, 77.8%, 71.7%, and 97.4%; combination: 75.5%, 100%, 100%, and 76.8%, respectively. Signal intensity ratios decreased with increasing grade of stenosis (none/mild-moderate/severe/complete, P < .001) and were less when associated with infarcts (0.81 ± 0.52 for arteries associated with downstream infarcts versus 1.31 ± 0.55 for arteries without associated infarcts, P < .001). CONCLUSIONS: Signal intensity ratios from TOF-MRA can serve as a noninvasive measure of intracranial arterial stenosis and allow identification of high-risk lesions in pediatric stroke.

Predicting Ischemic Risk Using Blood Oxygen Level-Dependent MRI in Children with Moyamoya.

BACKGROUND AND PURPOSE: Moyamoya is a progressive steno-occlusive arteriopathy. MR imaging assessment of cerebrovascular reactivity can be performed by measuring the blood oxygen level-dependent cerebrovascular reactivity response to vasoactive stimuli. Our objective was to determine whether negative blood oxygen level-dependent cerebrovascular reactivity status is predictive of ischemic events in childhood moyamoya. MATERIALS AND METHODS: We conducted a retrospective study of a consecutive cohort of children with moyamoya who underwent assessment of blood oxygen level-dependent cerebrovascular reactivity. The charts of patients with written informed consent were reviewed for the occurrence of arterial ischemic stroke, transient ischemic attack, or silent infarcts. We used logistic regression to calculate the OR and 95% CI for ischemic events based on steal status. Hazard ratios for ischemic events based on age at blood oxygen level-dependent cerebrovascular reactivity imaging, sex, and moyamoya etiology were calculated using Cox hazards models. RESULTS: Thirty-seven children (21 female; median age, 10.7 years; interquartile range, 7.5-14.7 years) were followed for a median of 28.8 months (interquartile range, 13.7-84.1 months). Eleven (30%) had ischemic events, 82% of which were TIA without infarcts. Steal was present in 15 of 16 (93.8%) hemispheres in which ischemic events occurred versus 25 of 58 (43.1%) ischemic-free hemispheres (OR = 19.8; 95% CI, 2.5-160; P = .005). Children with idiopathic moyamoya were at significantly greater risk of ischemic events (hazard ratio, 3.71; 95% CI, 1.1-12.8; P = .037). CONCLUSIONS: Our study demonstrates that idiopathic moyamoya and the presence of steal are independently associated with ischemic events. The use of blood oxygen level-dependent cerebrovascular reactivity could potentially assist in the selection of patients for revascularization surgery and the direction of therapy in children with moyamoya.

Predictive Value of MRI in Diagnosing Brain AVM Recurrence after Angiographically Documented Exclusion in Children.

BACKGROUND AND PURPOSE: MRI is routinely performed following brain AVM after treatment in children. Our aim was to determine the predictive values of contrast-enhanced MR imaging and TOF-MRA for brain AVM recurrence in children, compared with conventional angiography and the role of 3D rotational angiography-MR imaging fusion in these cases. MATERIALS AND METHODS: We included all pediatric patients with brain AVMs during an 18-year period with angiographically documented obliteration after treatment. Patients underwent 3T MR imaging, including contrast-enhanced MR imaging, TOF-MRA, and conventional angiography, with a subset undergoing 3D rotational angiography. The predictive values of contrast-enhanced MR imaging and TOF-MRA for brain AVM recurrence were determined. CTA sections reconstructed from 3D rotational angiography were coregistered with and fused to 3D-T1WI for analysis. RESULTS: Thirty-nine children (10.8 ± 3.9 years of age; range, 2-17 years; male/female ratio, 19:20; mean Spetzler-Martin grade, 1.9 ± 0.6) met the inclusion criteria. Of these, 13 had angiographically confirmed brain AVM recurrence, 8 following surgery and 5 following embolization. Sensitivity, specificity, and positive and negative predictive values for recurrence were the following: contrast-enhanced MR imaging: 84.6%, 38.5%, 40.7%, 81.8%; TOF-MRA: 50.0%, 96.1%, 85.7%, 79.3%; both: 75.0%, 90.9%, 85.7%, 83.3%. 3D rotational angiography-MR imaging fused images confirmed or excluded recurrence in all available cases (13/13). Embolization-only treatment was a significant predictor of recurrence (OR = 32.4, P = .006). MR imaging features predictive of recurrence included a tuft of vessels on TOF-MRA and nodular juxtamural/linear enhancement with a draining vein on contrast-enhanced MR imaging. CONCLUSIONS: MR imaging is useful for surveillance after brain AVM treatment in children, but conventional angiography is required for definitive diagnosis of recurrence. TOF-MRA and contrast-enhanced MR imaging provide complementary information for determining brain AVM recurrence and should be interpreted in conjunction. 3D rotational angiography-MR imaging fusion increases the diagnostic confidence regarding brain AVM recurrence and is therefore suited for intraoperative neuronavigation.

Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease.

BACKGROUND AND PURPOSE: There is a critical need for a reliable and clinically feasible imaging technique that can enable prognostication and selection for revascularization surgery in children with Moyamoya disease. Blood oxygen level-dependent MR imaging assessment of cerebrovascular reactivity, using voluntary breath-hold hypercapnic challenge, is one such simple technique. However, its repeatability and reliability in children with Moyamoya disease are unknown. The current study sought to address this limitation. MATERIALS AND METHODS: Children with Moyamoya disease underwent dual breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging of cerebrovascular reactivity in the same MR imaging session. Within-day, within-subject repeatability of cerebrovascular reactivity estimates, derived from the blood oxygen level-dependent signal, was computed. Estimates were associated with demographics and intellectual function. Interrater reliability of a qualitative and clinically applicable scoring scheme was assessed. RESULTS: Twenty children (11 males; 12.1 ± 3.3 years) with 30 MR imaging sessions (60 MR imaging scans) were included. Repeatability was "good" on the basis of the intraclass correlation coefficient (0.70 ± 0.19). Agreement of qualitative scores was "substantial" (κ = 0.711), and intrarater reliability of scores was "almost perfect" (κ = 0.83 and 1). Younger participants exhibited lower repeatability (P = .027). Repeatability was not associated with cognitive function (P > .05). However, abnormal cerebrovascular reactivity was associated with slower processing speed (P = .015). CONCLUSIONS: Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease.

Complexity of gap junctions between horizontal cells of the carp retina.

In the vertebrate retina, horizontal cells (HCs) reveal homologous coupling by gap junctions (gj), which are thought to consist of different connexins (Cx). However, recent studies in mouse, rabbit and zebrafish retina indicate that individual HCs express more than one connexin. To provide further insights into the composition of gj connecting HCs and to determine whether HCs express multiple connexins, we examined the molecular identity and distribution of gj between HCs of the carp retina. We have cloned four carp connexins designated Cx49.5, Cx55.5, Cx52.6 and Cx53.8 with a close relationship to connexins previously reported in HCs of mouse, rabbit and zebrafish, respectively. Using in situ hybridization, Cx49.5 expression was detected in different subpopulations of retinal neurons including HCs, whereas the Cx52.6 transcript was localized exclusively in HCs. Using specific antibodies, Cx55.5 and Cx53.8 were detected on dendrites of all four HC subtypes and axon terminals. Immunoelectron microscopy confirmed the presence of Cx55.5 and Cx53.8 in gap junctions between these processes and Cx55.5 was additionally observed in HC dendrites invaginating cone pedicles, suggesting its participation in the modulation of photoreceptor output in the carp retina. Furthermore, using single-cell RT-PCR, all four connexins were detected in different subtypes of HCs, suggesting overlapping expression patterns. Thus, the composition of gj mediating homologous coupling between subtypes of carp HCs appears to be more complex than expected. Moreover, BLAST searches of the preliminary carp genome, using novel sequences as query, suggest that most of the analyzed connexin genes are duplicated in carp.

Decreased Superior Sagittal Sinus Diameter and Jugular Bulb Narrowing Are Associated with Poor Clinical Outcome in Vein of Galen Arteriovenous Malformation.

BACKGROUND AND PURPOSE: Few clinical and imaging findings are known to be associated with poor outcome in neonates and infants with vein of Galen arteriovenous malformations. In the present consecutive series of 35 patients, we evaluated both the diameter of the superior sagittal sinus at onset and the diameter of the jugular bulb on follow-up as potential factors related to poor outcome. MATERIALS AND METHODS: Thirty-five consecutive neonates and infants who were prospectively collected in a single-center data base were included in this review. Outcome was assessed by using the Bicêtre Outcome Score. Both the absolute diameter of the superior sagittal sinus and its ratio to the biparietal diameter were measured at onset, compared with age-matched controls, and correlated to patient outcome. RESULTS: The diameter of the superior sagittal sinus at onset and its ratio to the biparietal diameter were significantly smaller in the vein of Galen arteriovenous malformation population compared with the matched population (P = .0001) and were correlated significantly with a risk of poor clinical outcome (P = .008). Development of jugular bulb narrowing was also related to poor clinical outcome (P < .0001). CONCLUSIONS: Decreased superior sagittal sinus diameter may reflect a decrease of cerebral blood flow due to cerebral arterial steal and intracranial hydrovenous disorders. This finding may be considered cerebral blood flow deterioration and thus taken into consideration in the management decisions for patients with vein of Galen arteriovenous malformations. Likewise, our data suggest that progressive jugular bulb narrowing may indicate earlier intervention to prevent severe narrowing.

Ocular manifestations of crush head injury in children.

AIMS: To review the ocular manifestations of crush head injuries in children. METHODS: Retrospective clinical and pathological reviews. Group 1: A total of 16 children admitted with crush head injuries from television tip over. Group 2: Nine autopsy findings in crush head injury. RESULTS: Group 1: A total of 11 children had fundus examination: three by neurosurgeons, eight by ophthalmologists. Scattered posterior pole preretinal and blot haemorrhages extending to mid equator region observed in one child. No evidence of traumatic retinoschisis or retinal folds in any patient. Group 2: All with multiple skull fractures and six with subdural haemorrhage. Posterior pole retinal haemorrhages in four children, extending to the ora serrata in one after motor vehicle accident. No child had retinal folds. Subinternal limiting membrane haemorrhages in three children. Optic nerve sheath haemorrhage in three children. CONCLUSIONS: Intraretinal and preretinal haemorrhages, predominantly in the posterior pole, can occur in crush injury to the paediatric head. Haemorrhage under the internal limiting membrane or extending to the ora serrata were only seen in situations where crush injury was part of a fatal trauma scenario related to motor vehicles. Retinal folds and the typical macular retinoschisis associated with abusive head injury were not observed.

Hypothermia pediatric head injury trial: the value of a pretrial clinical evaluation phase.

BACKGROUND: The utility of a pretrial clinical evaluation or run-in phase prior to conducting trials of complex interventions such as hypothermia therapy following severe traumatic brain injury in children and adolescents has not been established. METHODS: The primary objective of this study was to prospectively evaluate the ability of investigators to adhere to the clinical protocols of care including the cooling and rewarming procedures as well as management guidelines in patients with severe traumatic brain injury (Glasgow Coma Scale

Magnetoencephalographic spike sources associated with auditory auras in paediatric localisation-related epilepsy.

OBJECTIVE: To characterise magnetoencephalographic spike sources in paediatric patients with auditory auras and recurrent localisation-related epilepsy. METHODS: Six patients (four boys and two girls (ages 7-14 years) were retrospectively studied. All patients had auditory auras as part of their initial seizure manifestation, including four patients who underwent previous brain surgery. Scalp video electroencephalography and magnetoencephalography (MEG) were carried out in six patients, intraoperative electrocorticography in three patients and extraoperative intracranial video electroencephalography in one patient. MEG auditory-evoked fields (AEFs) were studied in four patients. RESULTS: Three patients had elementary auditory auras, one had complex auditory aura and two had both complex and elementary auras. All six patients had clustered MEG spike sources with coexisting scattered spike sources. MEG clusters were localised in the superior temporal gyrus with surrounding scatters in four patients (two left and two right); two patients had scattered spikes in the superior temporal gyrus in addition to clustered MEG spike sources in the left inferior and middle frontal gyri or parieto-occipital region. AEFs were located within an MEG cluster in one patient and within 3 cm of a cluster in two patients. Surgical resection, including the regions of MEG clusters, was carried out in four patients. Three of four patients who had previous surgeries were seizure free at 2 years after excision of the MEG cluster region. CONCLUSIONS: MEG spike sources clustered in the superior temporal gyrus in six patients with auditory auras. These spike sources were in close proximity or seemed to engulf the magnetic AEF. Areas with MEG spike sources contained the residual or recurrent epileptogenic zone after incomplete cortical excision for lesional epilepsy.

Pituitary stalk thickening and primary central nervous system lymphoma.

We report a 14-year-old girl in whom a diagnosis of primary central nervous system lymphoma was confirmed while receiving growth hormone (GH) for GH deficiency, detected after presenting with short stature. MRI revealed an enhancing and thickened pituitary stalk with absence of the normal bright signal in the posterior pituitary. Regular MRI surveillance detected progression of the neurohypophyseal changes 13 months into GH treatment. Biopsy confirmed this to be B-cell large cell lymphoma. This case highlights the diagnostic and management challenges inherent in treating such children.

A human brain tumor-derived PDGFR-alpha deletion mutant is transforming.

Aberrant receptor tyrosine kinase signaling plays an important role in the molecular pathogenesis of brain tumors. We have been studying a previously identified human glioblastoma-derived PDGFR-alpha mutant that has an in-frame deletion in the extracellular domain, causing loss of exons 8 and 9 (PDGFR-alpha(delta8,9)). In the primary tumor, this deletion mutant receptor was shown to be amplified and overexpressed. The purpose of this study was to determine the expression, activity, localization, and transformation properties of this deletion mutant. In the absence of serum, or PDGF-AA, PDGFR-alpha(delta8,9) was phosphorylated on tyrosine residues, indicating ligand-independent autoactivation. Localization by staining and cell surface biotinylation studies revealed expression of the deletion mutant predominantly in the cytoplasm, with very little present on the cell surface. To determine if PDGFR-alpha(delta8,9) was oncogenic, we transfected wild-type and mutant receptors into Rat1 cells and performed analyses of cell growth, in vitro transformation, and subcutaneous growth in the nude mouse. PDGFR-alpha(delta8,9)-expressing cells displayed enhanced cell growth and survival in low serum, and formed foci in monolayer cultures. PDGFR-alpha(delta8,9)-expressing Rat1 cells were also tumorigenic when injected subcutaneously into nude mice. Expression of PDGFR-alpha(delta8,9) was also associated with increased c-Jun phosphorylation in the absence of PDGF ligand, demonstrating also that the mutant receptor is associated with altered intracellular signaling. These data demonstrate that PDGFR-alpha(delta8,9) is transforming, and it is the first demonstration of a naturally occurring tumor-derived mutant PDGFR-alpha with oncogenic properties.

Glioma migration: clues from the biology of neural progenitor cells and embryonic CNS cell migration.

Neural stem cells have recently come to the forefront in neurobiology because of the possibilities for CNS repair by transplantation. Further understanding of the biology of these cells is critical for making their use in CNS repair possible. It is likely that these discoveries will also have spin-offs for neuro-oncology as primary brain tumors may arise from a CNS progenitor cell. An understanding of the normal migratory ability of these cells is also likely to have a very important impact on the knowledge of brain tumor invasion.

Cip/Kip cell-cycle inhibitors: a neuro-oncological perspective.

The cell cycle is a precisely controlled cellular program that ensures normal cellular proliferation and development. The cyclin-dependant kinases (CDK) are molecules central to the continued progression through the cell-cycle checkpoints and as such are regulated by various mechanisms including cyclin levels, phosphorylation/dephosphorylation and cyclin-dependant kinase inhibitors (CKI). The CKIs are grouped into two families based on their structure and function, four lnk4 CKIs and three Cip/Kip CKIs. Abnormalities in these proteins can give rise to developmental defects and cancer. In this review, we will discuss the biochemistry and cell biology of the each of the Cip/Kip CKIs, their role in development as evidenced by targeted mutations in mice, and their role as possible tumor suppressor genes.

The INK4A/ARF locus: role in cell cycle control and apoptosis and implications for glioma growth.

The unique INK4A/ARF locus at chromosome 9p21 encodes two distinct proteins that intimately link the pRB and p53 tumour suppressor pathways. p16INK4A has been identified as an inhibitor of the cell cycle, capable of inducing arrest in G1 phase. p14/p19ARF on the other hand can induce both G1 and G2 arrest due to its stabilizing effects on the p53 transcription factor. In addition to their roles in growth arrest, both proteins are involved in cellular senescence and apoptosis. The frequent mutation or deletion of INK4A/ARF in human tumours as well as the occurence of tumours in the murine knockout models have identified both p16 and ARF as bona fide tumour suppressors.

Cytoskeletal-induced alterations in the adhesion of HT-1080 fibrosarcoma cells to extracellular matrix.

We have investigated the adhesion of the human fibrosarcoma cell line, HT-1080, transfected with glial fibrillary acidic protein (GFAP) to a variety of extracellular matrix macromolecules (ECM) including collagen type IV, laminin, and fibronectin. The GFAP-transfectants demonstrated altered adhesiveness to extracellular matrix substrates when compared to controls. GFAP-positive, heavy metal-induced fibrosarcoma cells were more adherent to plastic and collagen type IV than were the parental or uninduced cells. In contrast, GFAP-positive fibrosarcoma cells were less adherent to laminin- or fibronectin-coated dishes than controls. Time course adhesion studies over 9 days showed that the heavy metal-induced fibrosarcoma cells progressively became more adherent to collagen type IV and less adherent to laminin- or fibronectin-coated dishes than did uninduced cells. However, with the removal of heavy metal from the medium, the HT-1080 fibrosarcoma cells were restored to their original adhesive potential. By phase microscopy, uninduced and induced HT-1080 cells demonstrated different morphological features and remained viable in an anchorage-dependent fashion on collagen type IV as a substrate. By way of contrast, GFAP-induced HT-1080 cells were not particularly viable in monolayer culture and readily detached from laminin as a substrate. The expression of beta1 integrin in GFAP-positive fibrosarcoma cells was decreased following heavy metal induction by Western blot analyses. In contrast, the expression of alpha2 integrin was increased whereas alpha5 integrin was unchanged in HT-1080 cells following the induction of GFAP. Gelatin zymography showed that 72 kDa collagenase was less expressed in GFAP-induced clones than in controls. Our data suggest that the forced expression of the intermediate filament, GFAP, in HT-1080 cells may modulate cell adhesion to different ECM substrates through alterations in expression of integrins.

Expression of p57(KIP2) potently blocks the growth of human astrocytomas and induces cell senescence.

Astrocytic tumors frequently exhibit defects in the expression or activity of proteins that control cell-cycle progression. Inhibition of kinase activity associated with cyclin/cyclin-dependent kinase co-complexes by cyclin-dependent kinase inhibitors is an important mechanism by which the effects of growth signals are down-regulated. We undertook the present study to determine the role of p57(KIP2) (p57) in human astrocytomas. We demonstrate here that whereas p57 is expressed in fetal brain tissue, specimens of astrocytomas of varying grade and permanent astrocytoma cell lines do not express p57, and do not contain mutations of the p57 gene by multiplex-heteroduplex analysis. However, the inducible expression of p57 in three well-characterized human astrocytoma cell lines (U343 MG-A, U87 MG, and U373 MG) using the tetracycline repressor system leads to a potent proliferative block in G(1) as determined by growth curve and flow cytometric analyses. After the induction of p57, retinoblastoma protein, p107, and E2F-1 levels diminish, and retinoblastoma protein is shifted to a hypophosphorylated form. Morphologically, p57-induced astrocytoma cells became large and flat with an expanded cytoplasm. The inducible expression of p57 leads to the accumulation of senescence-associated beta-galactosidase marker within all astrocytoma cell lines such that approximately 75% of cells were positive at 1 week after induction. Induction of p57 in U373 astrocytoma cells generated a small population of cells ( approximately 15%) that were nonviable, contained discrete nuclear fragments on Hoechst 33258 staining, and demonstrated ultrastructural features characteristic of apoptosis. Examination of bax and poly-(ADP ribose) polymerase levels showed no change in bax, but decreased expression of poly-(ADP ribose) polymerase after p57 induction in all astrocytoma cell lines. These data demonstrate that the proliferative block imposed by p57 on human astrocytoma cells results in changes in the expression of a number of cell cycle regulatory factors, cell morphology, and a strong stimulus to cell senescence.

Imaging correlates of successful endoscopic third ventriculostomy.

OBJECT: The goal of this study was to determine and compare imaging correlates in pediatric patients who underwent successful or failed endoscopic third ventriculostomies (ETVs). To this end, the authors measured ventricular size changes and the presence of cerebrospinal fluid (CSF) flow void in both groups of children following ETV. METHODS: Images obtained in children with hydrocephalus immediately before and at least 30 days after having undergone ETV were reviewed by four independent observers (two blinded and two nonblinded). Each observer independently measured the frontal and occipital horn ratio ([FOR], a reliable and valid measure of ventricular size) and provided a subjective assessment of the presence of a flow void at the ETV site, the degree of periventricular edema, and the amount of CSF over the cerebral hemispheres. There were 29 children whose mean age was 6.6 years at the time of ETV and who had a mean postoperative follow-up period lasting 1.6 years. Postoperatively, the mean reduction in ventricular size (as measured using the FOR) was 7% (95% confidence interval [CI] 3-11%) in cases that were deemed failures (eight patients) and 16% (95% CI 12-20%) in clinically successful cases (21 patients). This reduction was significantly greater in cases of clinical success compared with those that were deemed failures (p = 0.03, t-test). There were no substantial differences between blinded and nonblinded assessments. Flow void was present in 94% of successes and absent in 75% of failures (p = 0.01, Fisher's exact test). The other subjective assessments were not significantly different between the groups of successes and failures. CONCLUSIONS: Ventricular size appears to be somewhat reduced in both groups of patients who underwent clinically successful and failed ETV; however, the reduction is significantly greater among clinically successful cases. The presence of a flow void also appears to correlate with clinical success and its absence with clinical failure.

Molecular biology and neurosurgery in the third millennium.

The application of techniques in molecular biology to human neurosurgical conditions has led to an increased understanding of disease processes that affect the brain and to novel forms of therapy that favorably modify the natural history of many of these conditions. Molecular strategies are currently being either used or sought for brain tumors, stroke, neurodegenerative diseases, vascular malformations, spinal degenerative diseases, and congenital malformations of the central nervous system. Considering that the structure of deoxyribonucleic acid was ascertained by Watson and Crick as recently as 1953, the progress that has been made to implement molecular medicine in clinical practice has been meteoric. More than 2000 patients have been treated in approved gene therapy trials throughout the world. Many of these patients have been treated for neurological diseases for which conventional medical therapies have been of limited utility. As part of this continuing series on advances in neurosurgery in the third millennium, we first reflect on the history of the nascent field of molecular biology. We then describe the powerful techniques that have evolved from knowledge in this field and have been used in many publications in Neurosurgery, particularly within the past decade. These methods include commonly used techniques such as advanced cytogenetics, differential display, microarray technology, molecular cell imaging, yeast two-hybrid assays, gene therapy, and stem cell utilization. We conclude with a description of the rapidly growing field of bioinformatics. Because the Human Genome Project will be completed within 5 years, providing a virtual blueprint of the human race, the next frontier (and perhaps our greatest challenge) will involve the development of the field of "proteomics," in which protein structure and function are determined from the deoxyribonucleic acid blueprint. It is our conviction that neurosurgeons will continue to be at the forefront of the treatment of patients with neurological diseases using molecular strategies, by performing essential research leading to increased understanding of diseases, by conducting carefully controlled studies to test the effects of treatments on disease processes, and by directly administering (by neurosurgical, endovascular, endoscopic, or stereotactic means) the treatments to patients.

Measurement of ventricular size: reliability of the frontal and occipital horn ratio compared to subjective assessment.

INTRODUCTION: The frontal and occipital horn ration (FOR) has recently been described as a simple, linear measurement of ventricular size that correlates very well with ventricular volume. This study further characterizes the measurement properties of the FOR by investigating its interobserver reliability and comparing it to a subjective assessment of ventricular size. METHODS: Axial images (CT and MR) of children with hydrocephalus taken before and after third ventriculostomy were reviewed by 4 independent observers. Two observers were blinded to patient identity and clinical status and 2 observers were nonblinded. Each observer independently recorded linear measurements from which the FOR was calculated for each image. Each reviewer also made a separate subjective assessment of the degree of hydrocephalus on a 9-point adjectival scale. Reliability was calculated using a repeated-measures analysis of variance (ANOVA) and an intraclass correlation coefficient (ICC) with random image and observer effects. RESULTS: There were 120 separate observations (4 observers, 30 images). The FOR ranged from 0.33 to 0.75 (mean 0.55, standard deviation 0.11). The reliability coefficient was 0.93 (95% confidence interval, CI 0.80-0.97) between the 2 blinded observers and 0.98 (95% CI, 0.95-0.99) between the 2 nonblinded observer. The overall interobserver reliability for all 4 observers was 0.95 (95% CI 0.92-0.98). The mean FOR for each observer was very similar, regardless of the observer's blinding status. However, the reliability of the observers' subjective assessment of the hydrocephalus was much lower (ICC = 0.77, 95% CI 0. 60-0.88). CONCLUSIONS: The FOR demonstrates excellent interobserver reliability (>0.9) and was superior to subjective assessments of hydrocephalus. In this study, excellent reliability was maintained regardless of the blinding status of the observers. This further demonstrates the properties of the FOR as a simple and reproducible measure of ventricular size. It is suitable for use in clinical studies, possibly even in situations in which observer blinding is not possible.