Intracranial neoplasms in infants.

Fifty-four primary intracranial neoplasms occurred in infants (18 months of age or younger) in Connecticut during a 40-year period, 1935 to 1974. Thirty percent were medulloblastomas and 16% were ependymal neoplasms. An equal number of males and females were affected. Forty percent were located in the cerebellum, 37% in the cerebral hemispheres, and 17% in the brain stem. The most common symptom was vomiting. Abnormally large head circumference was the most common physical finding. Average survival was 43 months. Survival relative to histopathologic type and location of the neoplasm is discussed. Eighteen patients survived longer than one year and the level of neurological function of these longer survivors is presented.

A method for characterizing subgroups and related survivals in cancer patients. Application to brain tumors.

It has long been known that if the probability of dying of a given cancer remains constant over time, the logarithmic plot of survival of a group of patients with that cancer will be a straight line. More frequently, however, the probability of dying varies with time and the logarithmic survival plot is a curve. We believe that in some cases a population of patients with one type of neoplasm may be composed of several subgroups, each of which has a simple predictable course with a rectilinear survival plot. This article describes a method for partitioning such survival plots and identifying and characterizing the subgroups and applies the method to a group of patients with brain tumors. The value of being able to identify these subgroups and their relative proportions, the observations that can be made with this analysis regarding the nature of the various subgroups of brain tumors, and the implications of changes in the half-lives as well as the proportions of the subgroups with time are discussed.

Increased cerebral blood flow after external carotid artery revascularization.

Ten patients with symptoms of cerebral ischemia were found to have totally occluded internal carotid arteries with significant external carotid artery stenosis or occlusion. Eight patients underwent external carotid endarterectomy, and two patients underwent saphenous vein bypass to the external carotid artery from the subclavian artery. Cerebral blood flow was measured with 133Xe in six patients preoperatively and in five postoperatively. Four of the six patients had diminished mean flow on the affected side, and three had diminished flow in the contralateral side. All patients had abnormalities in regional cerebral blood flow. Postoperatively, all patients had significant improvement in mean blood flow on the side treated with operation (15% to 39%), and four had improvement of blood flow on the contralateral side (12% to 52%). All had improvement in regional cerebral blood flow. Nine of the 10 patients were relieved of their symptoms. One patient, despite improvement in cerebral blood flow, continued to have diminished cerebral flow and symptoms postoperatively. Subsequent extracranial-intracranial bypass relieved his symptoms and his cerebral blood flow returned to normal. Thus external carotid artery revascularization is effective in increasing total and regional cerebral blood flow and in relieving symptoms of internal carotid artery occlusion and external carotid stenosis. Cerebral blood flow measurement with 133Xe is useful in preoperative patient selection and objective assessment of operative results.

Molecular biology of brain tumors.

Through the technical advances in molecular biology during the past decade, important new insights into the fundamental chromosomal changes associated with brain tumors have been gained. The pace of such research is accelerating, and most of the published reports have appeared outside the neurosurgical literature. Furthermore, many neurosurgeons may not be sufficiently familiar with the terminology and techniques involved to remain abreast of the field. In this review, we discuss through specific examples of recent work on brain tumors the basic techniques of molecular biology, including the Southern and Northern blots, restriction enzyme digestion of DNA, molecular cloning of genes, and mapping of chromosomal deletions. Gene amplification and rearrangements are discussed through review of recent work on the N-myc gene in neuroblastoma and the epidermal growth factor receptor (EGFR) gene in glioblastoma. The molecular cloning of the gli gene from a glioblastoma illustrates the powerful analytic nature of these laboratory techniques and the investigative potential of a cloned gene. The concept of the "recessive oncogene" is discussed through a summary of recent work analyzing restriction fragment length polymorphisms (RFLPs) in families of patients with meningioma, acoustic neurinoma, and bilateral acoustic neurofibromatosis (BANF; NF-2). Throughout this article, emphasis is placed on ways in which molecular biology may soon affect clinical practice.

Respiratory patterns in human brain tumors.

It has been recognized for some time that malignant cells have a diminished respiratory rate coupled with an excessive rate of aerobic glycolysis. Subsequent studies indicated, however, that this pattern was neither unique to malignant tumors nor an essential characteristic of all varieties of cancer. In attempting to synthesize the data on oxygen consumption of human brain tumors, it is difficult to relate activity to malignancy, and the integrity of the mitochondrial electron transport chain has not been systematically examined. In this study, oxygen consumption was measured using a whole cell mixture and subsequently with isolated mitochondria prepared by routine differential centrifugation from a variety of human brain tumors. It is clear from these data that low oxidative respiration is not uniquely characteristic of malignant tumors, but that a number of benign tumors such as meningiomas and pituitary adenomas display very low levels of oxygen consumption. Many of these tumors have normal respiration, with isolated mitochondria using substrates that enter at different points in the electron transport pathway. However, several of the tumors in this series showed defects in respiration at various points in the electron transport pathway. These data suggest that both benign and malignant brain tumors have depressed respiratory capacities secondary to either a decrease in mitochondria per cell or defects in electron transport activities.

Cytokine gene expression by human gliomas.

Two glioma tumor lines and specimens from five patients with gliomas were analyzed to determine genic expression of four growth factors found in human brain. Messenger RNA encoding for interleukin-1 beta, interleukin-6, and basic fibroblast growth factor was found to be expressed in significant amounts in some of these tumors, while mRNA for interleukin-3 was found in small quantities in only the tumor lines. Multiple species of mRNA for basic fibroblast growth factor were found. Expression of growth factor genes may play a role in the growth of human gliomas.

Oxidative metabolism and glycolysis in benign brain tumors.

Glucose utilization in vivo and hexokinase activity and mitochondrial oxygen consumption in vitro were measured in a series of human brain tumors. Several relatively slow-growing tumors appeared to have depressed electron-transport activities coupled with a compensatory elevated glucose utilization. These data suggest that a decrease in oxidative metabolism and a corresponding increase in glycolysis are not necessarily correlated with malignancy in certain human brain tumors.

A cannula for use in ultrasonically guided biopsies of the brain. Technical note.

The authors describe a cannula that has been modified to improve its visibility during ultrasonically guided biopsies of the brain. To enhance the echogenicity of the tip of the cannula, six parallel rings, 0.25 to 0.30 mm deep and 0.40 to 0.50 mm apart, were etched into the tip of the cannula. The cannula was also lengthened to approximately 19 cm to permit its unencumbered passage through any biopsy guidance device that may be employed. Detailing the precise location of the tip of the biopsy cannula is most important. The tip of this modified probe is much more echogenic and hence more easily seen ultrasonically than it would be otherwise, both in vivo and in vitro. This modified cannula is useful in any ultrasonically guided intracranial biopsy procedure.

Choroid plexus carcinoma.

The authors report a case of carcinoma of the choroid plexus and review the 22 cases reported since 1844 that adhere to the criteria for primary choroid plexus carcinoma. Two-thirds of the tumors are found in children and all of these are located in the lateral ventricles. In adults most of the tumors are present in the fourth ventricle. Differentiation of this neoplasm from papillary ependymomas, choroid plexus papillomas, secondary carcinomas, and "collision tumors" is discussed.

Late results of cervical disc surgery.

Late results of cervical disc surgery have been reported and statistically studied in 383 cases: 83% were lateral discs, 13% were central spondylosis discs, and 4% central soft discs. Central spondylosis occured at a higher spinal level, and caused cord compression with or without weakness of the hands, but no pain. A posterior approach was used in all lateral discs, and either an anterior or a posterior approach, with or without fusion, for central discs. Preoperative myelography was always done and is recommended postoperatively in central disc surgery to evaluate the results. Our results were good to excellent in 95% of lateral discs, in 64% of central spondylosis discs, and in an unexpected 91% of 11 cases of central soft discs. There were no recurrences and no serious complications, although 20% developed other cervical or lumbar disc herniations.

Pathological changes from acute to chronic in experimental spinal cord trauma.

The pathological changes occurring in the thoracic spinal cords of 41 cats were studied by light microscopy at 4 hours, 4 weeks, and 4 months after graded transdural trauma. Alterations characteristic of a vascular injury proportionate to the magnitude of the original trauma which results in tissue hypoxia, destruction, and reparation were identified at each interval studied. In more severely injured animals these changes consisted of an initial hemorrhagic infarction followed by the removal of necrotic parenchyma and the development of an adhesive arachnoiditis and intramedullary carvitation. A comparison of the findings in the present investigation with what has been described in postmortem studies of spinal cord injured patients indicates that the response of the spinal cord to non-disruptive trauma is similar in both cases.

The microvasculature in transitory traumatic paraplegia. An electron microscopic study in the monkey.

Fine structural alterations in the microvasculature, primarily of the gray matter, occur as one aspect of experimental spinal cord contusion. A force of 300 gm-cm, shown by the authors to produce a transitory paraplegia, was applied to the T-10 level of exposed primate spinal cord. At 5 min post-contusion, the muscular venules of the central gray matter were distended with erythrocytes. Erythrocytes were seen within the perivascular spaces of the post-capillary venules and muscular venules at 15 and 30 min post-contusion, and there was hemorrhage into the gray matter at 1 hour post-contusion. The appearance of erythrocytes within the perivenular spaces was apparently due to small ruptures in the walls of the muscular venules, which were first demonstrated by electron microscopy 15 min after contusion. Alterations in capillary and post-capillary venule endothelium of both gray and white matter were present at 4 hours post-contusion and consisted of vacuolation and endothelial swelling. In conclusion, following experimental contusion of the spinal cord sufficient to cause a transitory paraplegia, the principal changes were early perivascular and parenchymal hemorrhages followed by later evidence of ischemic endothelial injury in the microvasculature.

Histopathology of transitory traumatic paraplegia in the monkey.

The microscopic appearance of the primate spinal cord within a 4-hour interval following the delivery of a direct force sufficient to produce a transitory paraplegia was investigated by light microscopy. The resulting hemorrhagic lesion involved primarily the central gray matter and was attributed to the direct effect of the trauma on the vessels in the gray matter with a consequent impairment of blood supply to the injured area. Chromatolysis, vacuolation, and alterations in cytoplasmic density and stainability were observed within the neurons. The edematous changes in the white matter, which were more marked in the internal layers relative to the external layers, appeared minimal and explain in part why the paraplegia was transient.

Intraoperative ultrasonic evaluation of spinal cord motion.

The spinal canals of 11 patients with various pathological conditions, both benign and malignant, were examined intraoperatively using real-time ultrasonography. The spinal cords in eight of these patients with lesions causing cord compression were seen to oscillate rhythmically over each mass with a frequency corresponding to the patient's arterial pulsations. The majority of the observed motion was transmitted or extrinsically induced from compression of the anterior spinal artery. In one case, after resection of an anterior cervical neurofibroma, these oscillations diminished markedly. Spinal cord motion, as described, has important implications for neurosurgery, since it contradicts the previously held belief that oscillations of the spinal cord or dura mater imply a "free" or noncompressed spinal cord. Furthermore, spinal cord motion may play a role in the degradation of computerized tomography images of the cord, since these movements are maximized at the areas with the most severe pathology.

Medulloblastoma in childhood: an epidemiological study.

The authors have reviewed 143 cases of medulloblastoma in children aged 19 years or younger who were treated in a 42-year period and reported in the Connecticut Tumor Registry. About 20 cases have occurred in each 5-year period since 1950, but 31 were seen between 1955 and 1959. Correspondingly, an excessive number of children born in the period 1954 to 1958 have developed medulloblastomas. A relationship to polio vaccine contaminated with SV40 virus may exist. Children with medulloblastomas had an increased number of immediate family members with brain tumors, leukemia, and childhood cancer when compared to controls. In this series, the male to female ratio was 1.33:1. Average age at diagnosis was 6 1/2 years, with most children being diagnosed at 3 years old and fewer cases appearing in each successive hemidecade from birth to 20 years of age. Probability of survival at 6 months was 0.687; at 1 year, 0.444; at 2 years, 0.314; and at 5 years, 0.222. Survival probability was statistically significantly better in the years 1968 to 1977 than in previous decades, in part due to fewer autopsy diagnoses and lowered operative mortality, but also due to a decreased mortality rate in children several years after diagnosis. Fifty-one percent were treated with operation and irradiation, 17% with operation alone, 12% with irradiation alone, and 5% with operation, irradiation, and chemotherapy. Fifteen percent were not treated. One- and 5-year survival rates in patients with operation and irradiation were, respectively, 0.615 and 0.307; with operation, 0.125 and 0.042; with irradiation, 0.688 and 0.277; and with operation, irradiation, and chemotherapy, 0.857 and 0.643. All seven children who received chemotherapy were diagnosed after 1968, and five are still alive. Perhaps due to short follow-up time, the course and mortality rate of children treated with all three modalities were not statistically significantly different from those of children treated since 1968 with operation and radiation therapy.

Glioblastoma multiforme in children.

Of 488 children with central nervous system neoplasms, 43 (8.8%) had glioblastomas, 22 of which were in the cerebral hemispheres, 16 in the brain stem, two in the cerebellum, and three in the spinal cord. The male to female ratio was 3:2. Glioblastoma multiforme of the cerebral hemispheres occurred at a mean age of 12.7 years, and the frontal lobe was the most commonly involved. Main presenting symptoms included headache (85%), nausea or vomiting (65%), and seizures (35%). Papilledema (45%) was the most common physical finding. The longest survivals were achieved by a combination of operation and radiation (22 months). Brain stem glioblastomas occurred at a mean age of 6.7 years, with the pons as the most frequent site. Nausea or vomiting (50%) and headache (36%) were the main presenting symptoms; the major physical findings were ataxia (43%), cranial nerve palsies (28%), and paresis (28%). The length of survival was greatest with radiation alone (10.5 months). The period of survival of children with glioblastoma multiforme was significantly increased with steroid therapy. Glioblastoma multiforme behaves similarly in children and adults. Intracranial glioblastomas have a more rapidly fatal course than that of other similarly situated gliomas in childhood.

Ependymomas and ependymoblastomas in children.

The authors analyze histologically verified cases of ependymoma and ependymoblastoma (malignant ependymoma) occurring in children in Connecticut from 1935 to 1973. Of the 488 central nervous system tumors diagnosed in that period, 44 (9%) of the 467 intracranial neoplasms and five (24%) of the 21 intraspinal tumors were of ependymal origin. An increase in the incidence of ependymomas was noted since the mid-1950's. The mean ages at diagnosis of ependymomas and ependymoblastomas were 5.6 and 5.0 years respectively. The male to female ratio was 0.6:1 for ependymomas and 1.7:1 for ependymoblastomas. Epencymomas were found above and below the tentorium with similar frequency; however, viturally all of the epencymoblastomas occurred supratentorially. Presenting symptoms and physical findings were reviewed. A significant difference (p less than 0.05) was noted in the seizure rates of supratentorial ependymomas (9%) and ependymoblastomas (38%). A significantly increased survival (p less than 0.05) was associated with supratentorial ependymal neoplasms relative to infratentorial from 42 months following diagnosis onward. Contrary tp the reports of no clinical difference between ependymomas and ependymoblastomas, children with supratentorial ependymomas were noted to have a significantly longer survival (p less than 0.05) than those with similarly situated ependymoblastomas, with the difference noted from 18 months following diagnosis onward. The children treated by operation and irradiation had a significantly greater survival (p less than 0.05) than those treated by other methods; furthermore, with this treatment, longer survivals were noted in the ependymoma patients as compared to those with epencymoblastomas. This difference became significant (p less than 0.05) at 27 months after diagnosis. Operative mortality decreased from 40% to 17% in the last decade of the study as compared to the previous decade. Steroid therapy may have contributed to this decreased operative mortality, but it had no statistically significant effect on length of survival. The clinical course of intracranial ependymal neoplasms in adults and children was compared and appeared to be essentially the same.

Fibrinolytic activity in experimental intracerebral hematoma.

In an attempt to investigate the role of tissue fibrinolytic activity in the resolution of intracerebral hematoma, an experimental model of intracerebral hematoma was developed in the rat. The fibrinolytic activity was studied using a histochemical fibrin slide technique. A total of 59 adult male rats were studied. Twenty-nine rats were used for developing the intracerebral hematoma model via injection of autologous whole blood into the left frontal lobe; in the remaining 30 rats, the intracerebral hematomas were studied sequentially. Intracerebral hematoma formation was unsuccessful in six (21%) of 29 rats. Four rats died in the immediate postoperative period and two showed no intraparenchymal clot. Intense fibrinolytic activity was demonstrated in the blood vessel walls of the normal brain, especially in the meninges, choroid plexus, and ependymal cell layer. In the initial stages of hematoma resolution, fibrinolytic activity was not seen in the hematoma or parenchyma except in the preexisting blood vessels. However, 3 to 5 days later, fibrinolytic activity was observed in the capillary buds surrounding the hematoma and among the infiltrating mononuclear cells. This activity increased for 7 to 10 days following formation of the hematoma and decreased after 21 to 28 days. It is concluded that tissue fibrinolytic activity associated with newly formed blood vessels appears to be important in lysis of intracerebral hematomas.

A frameless stereotactic approach to neurosurgical planning based on retrospective patient-image registration. Technical note.

A frameless stereotactic device interfacing an electromagnetic three-dimensional (3-D) digitizer to a computer workstation is described. The patient-image coordinate transformation was found by retrospectively registering a digitizer-derived model of the patient's scalp with a magnetic resonance (MR) imaging-derived model of the same surface. This procedure was performed with routine imaging data, eliminating the need to obtain special-purpose MR images with fiducial markers in place. After patient-image fusion was achieved, a hand-held digitizing stylus was moved over the scalp and tracked in real time on cross-sectional and 3-D brain images on the computer screen. This device was used for presurgical localization of lesions in 10 patients with meningeal and superficial brain tumors. The results suggest that the system is accurate enough (typical error range 3 to 8 mm) to enable the surgeon to reduce the craniotomy to one-half the size advisable with conventional qualitative presurgical planning.

Frameless stereotaxy with real-time tracking of patient head movement and retrospective patient-image registration.

The accuracy of a novel frameless stereotactic system was determined during 10 surgeries performed to resect brain tumors. An array of three charge-coupled device cameras tracked the locations of infrared light-emitting diodes on a hand-held stylus and on a reference frame attached to the patient's skull with a single bone screw. Patient-image registration was achieved retrospectively by digitizing randomly chosen scalp points with the system and fitting them to a scalp surface model derived from magnetic resonance (MR) images. The reference frame enabled continual correction for patient head movements so that registration was maintained even when the patient's head was not immobilized in a surgical clamp. The location of the stylus was displayed in real-time on cross-sectional and three-dimensional MR images of the head; this information was used to predict the locations of small intracranial lesions. The average distance (and standard deviation) between the actual position of the mass and its stereotactically predicted location was 4.8 +/- 3.5 mm. The authors conclude that frameless stereotaxy can be used for accurate localization of intracranial masses without resorting to using fiducial markers during presurgical imaging and without immobilizing the patient's head during surgery.