Assessment of Lactate Production and Proteoglycans Synthesis by the Intact and Degenerated Intervertebral Disc Cells under the Influence of Activated Macrophages: an In Vitro Study.

The effects of proinflammatory cytokines on the secretion of glycosaminoglycans and lactate production by normal and degenerated intervertebral disk cells were studied on the model of their co-culturing with activated macrophage-like cells. It was found that proinflammatory cytokines produced a direct effect on intervertebral disk cells in a 3D culture reducing the rate of glycolysis and synthetic activity of both normal and degenerated cells of annulus fibrosus and nucleus pulposus, which is an important factor in progression of intervertebral disk degeneration.

Development of an In Vitro Model of Inflammatory Cytokine Influences on Intervertebral Disk Cells in 3D Cell Culture Using Activated Macrophage-Like THP-1 Cells.

We developed a new model for evaluation of the influence of proinflammatory cytokines on intervertebral disc cells in a 3D culture based on co-culturing of these cells with activated macrophage-like THP-1 cells. The levels of TNFα, IL-1ß, IL-6, IL-8, IL-10, and IL-12p70 production were assessed by flow cytofluorometry using microspheres. Considerable differences in the level of spontaneous cytokine secretion by normal and degenerated intervertebral disc cells were revealed. A significant increase in the level of IL-1ß and IL-8 was observed during co-culturing, which confirms consistency of the developed model.

Role of computer technology in neurosurgery.

In the clinical office, during surgical planning, or in the operating room, neurosurgeons have been surrounded by the digital world either recreating old tools or introducing new ones. Technological refinements, chiefly based on the use of computer systems, have altered the modus operandi for neurosurgery. In the emergency room or in the office, patient data are entered, digitally dictated, or gathered from electronic medical records. Images from every modality can be examined on a Picture Archiving and Communication System (PACS) or can be seen remotely on cell phones. Surgical planning is based on high-resolution reconstructions, and microsurgical or radiosurgical approaches can be assessed precisely using stereotaxy. Tumor resection, abscess or hematoma evacuation, or the management of vascular lesions can be assisted intraoperatively by new imaging resources integrated into the surgical microscope. Mathematical models can dictate how a lesion may recur as well as how often a particular patient should be followed. Finally, virtual reality is being developed as a training tool for residents and surgeons by preoperatively simulating complex surgical scenarios. Altogether, computerization at each level of patient care has been affected by digital technology to help enhance the safety of procedures and thereby improve outcomes of patients undergoing neurosurgical procedures.

Virtual glioblastoma: growth, migration and treatment in a three-dimensional mathematical model.

OBJECTIVES: Glioblastomas are aggressive primary brain cancers that are characterized by extensive infiltration into the brain and are highly resistant to treatment. Through mathematical modelling, we model the process of invasion and predict the relative importance of mechanisms contributing to malignant invasion. Clinically, we predict patterns of tumour recurrence following various modes of therapeutic intervention. MATERIALS AND METHODS: Our mathematical model uses a realistic three-dimensional brain geometry and considers migrating and proliferating cells as separate classes. Several mechanisms for infiltrative migration are considered. Methods are developed for simulating surgical resection, radiotherapy and chemotherapy. RESULTS: The model provides clinically realistic predictions of tumour growth and recurrence following therapeutic intervention. Specific results include (i) invasiveness is governed largely by the ability of glioblastoma cells to degrade and migrate through the extracellular matrix and the ability of single migrating cells to form colonies; (ii) tumours originating deeper in the brain generally grow more quickly than those of superficial origin; (iii) upon surgery, the margins and geometry of resection significantly determine the extent and pattern of postoperative recurrence; (iv) radiotherapy works synergistically with greater resection margins to reduce recurrence; (v) simulations in both two- and three-dimensional geometries give qualitatively similar results; and (vi) in an actual clinical case comprising several surgical interventions, the model provides good qualitative agreement between the simulated and observed course of the disease. CONCLUSIONS: The model provides a useful initial framework by which biological mechanisms of invasion and efficacy of potential treatment regimens may be assessed.

Modified cervical laminoforaminotomy based on anatomic landmarks reduces need for bony removal.

We describe a modified keyhole laminoforaminotomy (LF) using anatomic landmarks on the posterior aspect of the cervical vertebral body to decompress the intervertebral foramen with minimal bone removal. Twenty-four procedures were performed at C3-4, C4-5, and C5-6; 12 at C6-7; and 3 at C7-Tl. Facets and laminae structures were identified based on relative surgical perspectives. Bony resection was limited as follows: 1) inferior limit; inferior border of the superior facet; 2) superior limit, superior border of the superior facet; 3) lateral limit, a vertical line linking the junction of the lamina-facet to the lateral end of the superior limit; and 4) lateral aspect of the dural sac. Fluoroscopy was used to confirm that the intervertebral space was reached. The amount of bony removal was quantified for the superior and inferior laminae and facets. The length of the exposed nerve root was measured. The intervertebral foramen was exposed and the intervertebral disc reached in all specimens. Fluoroscopy showed that the center of the exposure remained at the same height with the intervertebral space. The mean length of the nerve root was 4.6 mm; the mean percentage of bony resection was 21.8%, 7.5%, 11.3%, and 11.5% for the superior and inferior laminae and facets, respectively. Opening the intervertebral foramen posteriorly consistently exposed sufficient nerve root length and allowed access to the intervertebral disc. The technique offers the most direct and safest method of decompressing the intervertebral foramen while minimizing bony resection. This simple surgical procedure may help reduce postoperative morbidity.

Effects of intravascular perfusion of cooled crystalloid solution on cold-induced brain injury using an extracorporeal cooling-filtration system.

BACKGROUND: We evaluated cerebral metabolic change during brain hypothermia with intravascular perfusion of cooled crystalloid solution using an extracorporeal cooling-filtration system and cerebroprotective effects of this hypothermia on brain injury in an animal model. METHOD: Microdialysis probes were implanted into the bilateral parietal cortices. A cold-induced brain injury was produced behind the microdialysis probe on the right parietal cortex. Immediately after injury in the cooled group (n=9), Ringer's solution cooled to 5 degrees C was infused into the right vertebral artery after occlusion of the bilateral common carotid and the left vertebral arteries. Excessive fluid was ultrafiltrated by a dialyzer. Brain temperature was maintained at about 20 degrees C for 60 minutes. In 7 dogs, three neck arteries were occluded for 60 minutes after injury without cooled fluid infusion. The extracellular concentrations of glutamate, lactate, and pyruvate were measured serially for 180 minutes after injury. FINDINGS: Extracellular glutamate concentrations in the cooled group did not increase, while there was a significant increase in the injured hemisphere as compared to the uninjured hemisphere in the non-cooled group ( P<0.05). Extracellular lactate concentrations increased slightly after occlusion in both groups. The depth of cortical injury was limited in the cooled group, but extended into the white matter in the non-cooled group up to 240 minutes after injury. INTERPRETATION: Occlusion of three main arteries induced ischaemia under critical threshold in canine brains. Under this condition, intravascular cooling with crystalloid solution suppressed accumulation of extracellular glutamate and reduced tissue damage in the early phase after cold-induced brain injury, as cerebroprotective effects. This information suggests that a method employing brain hypothermia via intra-arterial cooling with an extracorporeal cooling-filtration system has potential to achieve successful, safe, selective brain cooling.

Endolymphatic sac tumor: unique features of two cases and review of the literature.

Endolymphatic sac tumors (EST) are rare intracranial tumors originating from the pars rugosa of the endolymphatic sac. Although typically described as histologically nonaggressive lesions, nevertheless they are termed adenocarcinomas and often become locally invasive. We report two patients with histologically proven EST with unique clinical features: the first pediatric case of an EST in an 11-year-old patient whose complaints started at the age of seven; and, a second patient, a 43-year-old man, the first report of metastatic EST which appeared in a remote location from the original site of surgery. Both patients underwent gamma-knife radiosurgery for recurrent tumor. This treatment has not been described previously for these tumors. Both patients have a follow-up of 7 years. Although not disease free they remain neurologically stable. We review the literature on EST.

"The art is long and the life short": the letters of Wilder Penfield and Harvey Cushing.

Wilder Penfield and Harvey Cushing created legacies to neurosurgery, both in terms of those they trained and in their philosophical approach to the field. Their biographies provide only brief comments on their relationship without any thorough examination of their personal correspondence. In this article the Penfield-Cushing relationship is examined through an analysis of their unpublished personal letters. The Penfield-Cushing correspondence is a treasure for neurosurgery: it provides remarkable insight into the embryonic period of the discipline and into the relationship of two of the most influential figures in modern neurosurgery.

Historical considerations of the diagnosis and treatment of facial pain.

Most forms of facial pain remain neurologic disorders that, although not life threatening, can be debilitating. Modern descriptions of the various forms of facial pain according to their clinical and anatomic patterns did not develop until after the contributions of the early modern neuroanatomists and physiologists in the first quarter of the nineteenth century. These contributions allowed the recognition of relatively distinct painful afflictions of the face, and permitted surgeons in the late nineteenth century to embark confidently on a variety of approaches to cranial and peripheral nerves using decompressive or destructive procedures to alleviate facial pain.

A history of brain imaging technology in neurosurgery.

In the closing decades of the nineteenth century, diagnosis of cerebral lesions was based on the clinical examination, and often the localization and operative approaches were based on observation of seizures. The attribution of certain symptoms and signs to dysfunction arising at an identifiable focal point in the brain was the basis for clinicopathologic correlation and rational treatment. As beautiful as brain anatomy was and as skillful as clinical examination could be, there was no means to produce images of a living patient that could be used to diagnose and treat that same patient. On November 8, 1895, all of this changed with Wilhelm Röntgen's discovery of X-rays. This article aims to elucidate seminal points in the history of medical imaging as applied to the brain that have had a major impact on neurosurgery.

Using proton magnetic resonance spectroscopic imaging to predict in vivo the response of recurrent malignant gliomas to tamoxifen chemotherapy.

OBJECTIVE: Most patients with a malignant glioma spend considerable time on a treatment protocol before their response (or nonresponse) to the therapy can be determined. Because survival time in the absence of effective therapy is short, the ability to predict the potential chemosensitivity of individual brain tumors noninvasively would represent a significant advance in chemotherapy planning. METHODS: Using proton magnetic resonance spectroscopic imaging (1H MRSI), we studied 16 patients with a recurrent malignant glioma before and during treatment with high-dose orally administered tamoxifen. We evaluated whether 1H MRSI data could predict eventual therapeutic response to tamoxifen at the pretreatment and early treatment stages. RESULTS: Seven patients responded to tamoxifen therapy (three with glioblastomas multiforme; four with anaplastic astrocytomas), and nine did not (six with glioblastomas multiforme; three with anaplastic astrocytomas). Responders and nonresponders exhibited no differences in their age, sex, tumor type, mean tumor volume, mean Karnofsky scale score, mean number of weeks postradiotherapy, or mean amount of prior radiation exposure. Resonance profiles across the five metabolites measured on 1H MRSI spectra (choline-containing compounds, creatine and phosphocreatine, N-acetyl groups, lactate, and lipids) differed significantly between these two groups before and during treatment. Furthermore, linear discriminant analyses based on patients' in vivo biochemical information accurately predicted individual response to tamoxifen both before and at very early treatment stages (2 and 4 wk). Similar analyses based on patient sex, age, Karnofsky scale score, tumor type, and tumor volume could not reliably predict the response to tamoxifen treatment at the same time periods. CONCLUSION: It is possible to accurately predict the response of a tumor to tamoxifen on the basis of noninvasively acquired in vivo biochemical information. 1H MRSI has potential as a prognostic tool in the pharmacological treatment of recurrent malignant gliomas.

Mercury water and cauterizing stones: Nicolas André and tic douloureux.

In his 1756 text, Observations pratiques sur les maladies de l'urèthre et sur plusiers faits convulsifs, Nicolas André coined the term "tic douloureux." He believed that this pain originated from compression of facial sensory peripheral nerves. Using scientific observation and experimentation to confirm this hypothesis, he reproduced the tic pain and treated it by using careful efforts to remove adhesions from the nerve with a caustic solution of mercury water. Believing that recurrence of the pain was a result of early closure of the wound, with recompression of the nerve being the direct cause, André prevented recompression by ensuring open wound drainage. André's surgical technique of using cauterizing stones ensured that there was minimal blood loss and little danger of rebleeding and recompression of the nerve by an accumulated blood clot. His case reports include lengthy follow-up periods that documented the benefits of his procedures, which were confirmed by testimonials from uninvolved colleagues. Although remembered for the two words, "tic douloureux," Nicolas André has long been ignored for his prescient treatment and scientific analysis of a disease for which the modern standard of care has only been defined during the last generation.

Using pattern analysis of in vivo proton MRSI data to improve the diagnosis and surgical management of patients with brain tumors.

We have used pattern analysis of proton magnetic resonance spectroscopic imaging (1H MRSI) data in a variety of situations related to the clinical management of patients with brain tumors and other cerebral space-occupying lesions (SOLs). Here, we review how 'leave-one-out' linear discriminant analyses (LDAs) of in vivo 1H MRSI spectral patterns have enabled us to quickly, accurately, and non-invasively: (1) discriminate amongst tissue arising from the five most common types of supratentorial tumors found in adults, and (2) use the metabolic heterogeneity of cerebral SOLs to predict certain pathological characteristics that are useful in guiding stereotaxic biopsy and selective tumor resection. These findings suggest that pattern analysis of 1H MRSI data can significantly improve the diagnostic specificity and surgical management of patients with certain cerebral SOLs.

In vivo differentiation of astrocytic brain tumors and isolated demyelinating lesions of the type seen in multiple sclerosis using 1H magnetic resonance spectroscopic imaging.

We used computer pattern recognition of proton magnetic resonance spectroscopic image data to differentiate between brain tumors and large, isolated, demyelinating lesions of the type seen in multiple sclerosis. Leave-one-out linear discriminant analyses correctly classified resonance profiles from five acute demyelinating lesions, 20 low-grade astrocytomas, 22 anoplastic astrocytomas, and 24 glioblastomas. Classification of nonacute lesions will require further development, as the metabolic profiles of demyelinating lesions evolve over time.

Intracranial aneurysms and sickle cell anemia: multiplicity and propensity for the vertebrobasilar territory.

OBJECTIVE: We describe a case of sickle cell anemia and multiple intracranial aneurysms and review the English-language-reported cases of sickle cell disease associated with intracranial aneurysms proven angiographically or by autopsy, to assess whether there are associations with aneurysm multiplicity and sites of aneurysm occurrence. CLINICAL PRESENTATION: A 28-year-old woman with sickle cell disease and a subarachnoid hemorrhage underwent successful clipping of three intracranial aneurysms. RESULTS: Among 44 reviewed cases, 57% of patients demonstrated multiple aneurysms, and aneurysms from patients with multiple aneurysms comprised nearly 80% of the total number of aneurysms. There were, on average, three aneurysms per patient for patients with multiple aneurysms. There was a predominance of female patients (female/male ratio, 1.6:1), although there existed no significant differences in age or gender for patients with single or multiple aneurysms. None of the patients with multiple aneurysms was older than 40 years of age at the time of presentation. Patients with multiple aneurysms and sickle cell disease showed a significant difference in the distribution of the aneurysm sites, with a significantly large number occurring in the vertebrobasilar axis. Multiple aneurysms associated with sickle cell disease showed a higher rate of simultaneous occurrence in the posterior and anterior circulation, compared with multiple aneurysms in the general population. CONCLUSION: There are strong statistical associations for aneurysm multiplicity and sites of aneurysm occurrence among reported patients with sickle cell disease. Patients with sickle cell anemia and neurological symptoms should undergo magnetic resonance angiography or four-vessel angiography to detect potentially harmful, but neurosurgically treatable, pathological conditions.

Magnetic resonance spectroscopy guided brain tumor resection: differentiation between recurrent glioma and radiation change in two diagnostically difficult cases.

BACKGROUND: It is often difficult to differentiate a recurrent glioma from the effects of post-operative radiotherapy by means of conventional neurodiagnostic imaging. Proton magnetic resonance spectroscopic imaging (1H-MRSI), that allows in vivo measurements of the concentration of brain metabolites such as choline-containing phospholipids (Cho), may provide in vivo biochemical information helpful in distinguishing areas of tumor recurrence from areas of radiation effect. PATIENTS AND METHODS: Two patients who had undergone resection and post-operative radiotherapy for a cerebral glioma became newly symptomatic. Computed tomographic (CT) and magnetic resonance imaging (MRI) performed after the intravenous infusion of contrast material, and in one case, [18F]fluorodeoxyglucose positron emission tomography (PET), could not differentiate between the possibilities of recurrent glioma and radiation effect. The patients underwent 1H-MRSI prior to reoperation and the 1H-MRSI results were compared to histological findings originating from the same locations. RESULTS: A high Cho signal measured by 1H-MRSI was seen in areas of histologically-proven dense tumor recurrence, while low Cho signal was present where radiation changes predominated. CONCLUSIONS: The differentiation between the recurrence of a cerebral glioma and the effects of post-operative irradiation was achieved using 1H-MRSI in these two patients whose conventional neurodiagnostic imaging was equivocal for such a distinction. Where these two conditions are present, metabolite images from 1H-MRSI, such as that based on Cho, can be co-registered with other imaging modalities such as MRI and may also be integrated with functional MRI or functional PET within a multimodal imaging-guided surgical navigation system to assure maximal resection of recurrent tumor while minimizing the risk of added neurological damage.

Arthur Roland Elvidge (1899-1985): contributions to the diagnosis of brain tumors and cerebrovascular disease.

The contributions of Arthur Elvidge (1899-1985), Wilder Penfield's first neurosurgical recruit, to the development of neurosurgery have been relatively neglected, although his work in brain tumors extended the previous work of Percival Bailey and Harvey Cushing. He published rigorous correlations of clinical and histological information and formulated a revised, modern nosology for neuroepithelial tumors, including a modern histological definition of glioblastoma multiforme. Well ahead of his time, he believed that glioblastoma was not strictly localized and was the first to comment that the tumor frequently showed "satellitosis." He was the first neurosurgeon in North America to use angiography as a radiographic aid in the diagnosis of cerebrovascular disease. Having studied with Egas Moniz, he was the first to detail the use of angiographic examinations specifically for demonstrating cerebrovascular disorders, believing that it would make possible routine surgery of the intracranial blood vessels. Seeking to visualize all phases of angiography, he was the impetus behind the design of one of the first semi-automatic film changers. Elvidge and Egas Moniz made the first observations on thrombosis of the carotid vessels independently of each other. Elvidge elucidated the significance of embolic stroke and commented on the ischemic sequelae of subarachnoid hemorrhage. Besides his contributions to neurosurgery, he codiscovered the mode of transmission of poliomyelitis. Elvidge's soft-spoken manner, his dry wit and candor, mastery of the understatement, love of exotic travel, and consummate dedication to neurosurgery made him a favorite of patients, neurosurgery residents, nurses, and other hospital staff. His accomplishments and example as teacher and physician have become part of neurosurgery's growing legacy.

Function and organization in dysgenic cortex. Case report.

Cerebral dysgenesis is a subject of interest because of its relationship to cerebral development and dysfunction and to epilepsy. The authors present a detailed study of a 16-year-old boy who underwent surgery for a severe seizure disorder. This patient had dysgenesis of the right hemisphere, which was composed of a giant central frontoparietal nodular gray matter heterotopia with overlying large islands of cortical dysplasia around a displaced central fissure. Exceptional insight into the function, biochemistry, electrophysiology, and histological structure of this lesion was obtained from neurological studies that revealed complementary information: magnetic resonance (MR) imaging, [18]fluoro-2-deoxy-D-glucose positron emission tomography (PET), functional PET scanning, proton MR spectroscopic (1H-MRS) imaging, intraoperative cortical mapping and electrocorticography, in vitro electrophysiology, and immunocytochemistry. These studies demonstrated compensatory cortical reorganization and showed that large areas of heterotopia and cortical dysplasia in the central area may retain normal motor and sensory function despite strikingly altered cytoarchitectonic organization and neuronal metabolism. Such lesions necessitate appropriate functional imaging studies prior to surgery and cortical mapping to avoid creating neurological deficits. Integrated studies, such as PET, 1H-MRS imaging, cortical mapping, immunocytochemistry, and electrophysiology may provide information on the function of developmental disorders of cerebral organization.

Accurate, noninvasive diagnosis of human brain tumors by using proton magnetic resonance spectroscopy.

Although conventional proton magnetic resonance imaging has increased our ability to detect brain tumors, it has not enhanced to nearly the same degree our ability to diagnose tumor type. Proton magnetic resonance spectroscopy is a safe, noninvasive means of performing biochemical analysis in vivo. Using this technique, we characterized and classified tissue from normal brains, as well as tissue from the five most common types of adult supratentorial brain tumors. These six tissue types differed in their pattern across the six metabolites measured. 'Leaving-one-out' linear discriminant analyses based on these resonance profiles correctly classified 104 of 105 spectra, and, whereas conventional preoperative clinical diagnosis misclassified 20 of 91 tumors, the linear discriminant analysis approach missed only 1. Thus, we have found that a pattern-recognition analysis of the biochemical information obtained from proton magnetic resonance spectroscopy can enable accurate, noninvasive diagnosis of the most prevalent types of supratentorial brain tumors.

Chemical pathology of acute demyelinating lesions and its correlation with disability.

We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline-containing compounds, lactate, and myo-inositol inside the lesion acutely. Decreases in relative resonance intensities of N-acetylaspartate and creatine were seen both in and around the magnetic resonance imaging-detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo-inositol resonance intensities normalized during the follow-up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N-acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N-acetylaspartate resonance intensities and both brain lesion volumes (r = -0.80, p < 0.0001) and clinical disability (r = -0.73, p < 0.0001). As N-acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.