Neuroprotective and behavioral efficacy of nerve growth factor-transfected hippocampal progenitor cell transplants after experimental traumatic brain injury.

OBJECT: Immortalized neural progenitor cells derived from embryonic rat hippocampus (HiB5), were transduced ex vivo with the gene for mouse nerve growth factor (NGF) to secrete NGF (NGF-HiB5) at 2 ng/hr/10(5) cells in culture. METHODS: Fifty-nine male Wistar rats weighing 300 to 370 g each were anesthetized with 60 mg/kg sodium pentobarbital and subjected to lateral fluid-percussion brain injury of moderate severity (2.3-2.4 atm, 34 rats) or sham injury (25 rats). At 24 hours postinjury, 2 microl (150,000 cells/microl) of [3H]thymidine-labeled NGF-HiB5 cells were transplanted stereotactically into three individual sites in the cerebral cortex adjacent to the injury site (14 rats). Separate groups of brain-injured rats received nontransfected (naive [n])-HiB5 cells (12 animals) or cell suspension vehicle (eight animals). One week postinjury, animals underwent neurological evaluation for motor function and cognition (Morris water maze) and were killed for histological, autoradiographic, and immunocytochemical analysis. Viable HiB5 cell grafts were identified in all animals, together with reactive microglia and macrophages located throughout the periinjured parenchyma and grafts (OX-42 immunohistochemistry). Brain-injured animals transplanted with either NGF-HiB5 or n-HiB5 cells displayed significantly improved neuromotor function (p < 0.05) and spatial learning behavior (p < 0.005) compared with brain-injured animals receiving microinjections of vehicle alone. A significant reduction in hippocampal CA3 cell death was observed in brain-injured animals receiving transplants of NGF-HiB5 cells compared with those receiving n-HiB5 cells or vehicle (p < 0.025). CONCLUSIONS: This study demonstrates that immortalized neural stem cells that have been retrovirally transduced to produce NGF can markedly improve cognitive and neuromotor function and rescue hippocampal CA3 neurons when transplanted into the injured brain during the acute posttraumatic period.

Postoperative epilepsy in patients undergoing craniotomy for glioblastoma multiforme.

Glioblastoma multiforme (GBM) has associated with it one of the poorest prognoses among brain tumors. Postoperative seizures and the side effects of anticonvulsants, routinely given for prophylactic purposes, add to patient morbidity. The primary goal of this study was to determine who, of those undergoing craniotomy for GBM resection, is at risk for epilepsy. We studied 72 consecutive patients who underwent craniotomy and palliative resection for GBM. Twenty-nine presented with seizures and 17 had postoperative seizures. All patients were treated with a postoperative anticonvulsant for at least six months; anticonvulsants were continued longer if there was a postoperative seizure. Patient factors examined for an association with risk for postoperative seizure included age, sex, tumor size, tumor location, adjuvant therapy, postoperative complications and history of preoperative seizures. The majority of patients with no prior seizure history and who seized postoperatively had their first seizure after withdrawal from their anticonvulsant medication. All, but one, of the patients with both pre- and postoperative seizures had their first postoperative seizure while still on anticonvulsants. Smaller tumor size and frontal resection were associated with an increased risk of postoperative seizures. Our data suggests that those who do not present with seizures and undergo GBM resection may still be prone to seize but more easily protected from postoperative seizures with anticonvulsant therapy than patients who present with seizures; resection of frontal tumors and smaller tumors seemed to indicate an increased risk for postoperative seizures.

Results and risk factors for anterior cervicothoracic junction surgery.

OBJECT: Stabilization of the cervicothoracic junction (CTJ) requires special attention to the operative approach and biomechanical requirements of the fixation construct. In this study the authors assess the morbidity associated with the anterior approach to the CTJ and define risks that may lead to construct failure after anterior CTJ surgery. METHODS: Data obtained for 14 patients (six men and eight women, mean age 50.1 years) who underwent surgical stabilization of the CTJ via an anterior cervical approach were retrospectively reviewed to assess the anterior approach-related morbidity and the risks of construct failure. The mean follow-up period was 21.1 months. Four patients (29%) had previously undergone CTJ surgery; in 11 patients (64%) more than one motion segment was involved (two levels, six patients; three levels, four patients; four levels, one patient); allograft was placed in three (21%) of 14 graft sites; and anterior plates were used for reconstruction augmentation in eight patients (57%). Postoperatively all patients improved, although four patients had residual deficits or pain. Graft/plate failure, requiring surgical revision and/or halo placement, occurred in five patients (36%). One patient experienced transient recurrent laryngeal nerve palsy. Postoperatively, the authors classified patients into one of two groups: those in whom surgery was successful (nine cases) and those in whom it had failed (five cases). Analysis of the characteristics of these two groups revealed that male sex (p < 0.0365), multiple levels of involvement (p < 0.0378), and the use of allograft as compared with autograft (p < 0.0088) were significant risk factors for construct failure. Prior CTJ surgery (p < 0.053) tended to be associated with graft failure. CONCLUSIONS: Findings of this study, in the setting of these factors, indicate that anterior reconstruction alone may not meet the biomechanical needs of this spinal region and that supplementary fixation may be considered to augment stabilization for fusion success.

The rotating pole test: evaluation of its effectiveness in assessing functional motor deficits following experimental head injury in the rat.

Neurological motor dysfunction is often an integral component of the neurological sequelae of traumatic brain injury (TBI). In experimental TBI, neurological motor testing is an outcome measure used to monitor severity of injury, and the response to treatment. This study evaluates the effectiveness and sensitivity of the rotating pole test (RP) to characterize and evaluate the temporal course of motor deficits after lateral fluid percussion (FP) injury to the rat brain. The results are compared with the previously characterized and widely used composite neuroscore of motor function (NS). The animals were required to walk across an elevated wooden pole that was either stationary or rotating to left or right directions at different speeds. Male Wistar rats underwent lateral FP injury of moderate severity (mean 2.4 atm, n = 9) or sham surgery (n = 9), and were tested at 48 h and 7 days post-injury using the NS and RP. The results of the NS directly correlated to the results of the RP, showing a significant injury effect at both 48 h and 7 days. This is the first study to show that the RP-test detects neurological motor deficits after lateral FP injury, and suggests that this technique is a reliable behavioral tool for evaluating neurological motor function in the acute period after experimental TBI.

Endovascular thrombolysis for symptomatic cerebral venous thrombosis.

OBJECT: The authors sought to treat potentially catastrophic intracranial dural and deep cerebral venous thrombosis by using a multimodality endovascular approach. METHODS: Six patients aged 14 to 75 years presented with progressive symptoms of thrombotic intracranial venous occlusion. Five presented with neurological deficits, and one patient had a progressive and intractable headache. All six had known risk factors for venous thrombosis: inflammatory bowel disease (two patients), nephrotic syndrome (one), cancer (one), use of oral contraceptive pills (one), and puerperium (one). Four had combined dural and deep venous thrombosis, whereas clot formation was limited to the dural venous sinuses in two patients. All patients underwent diagnostic cerebral arteriograms followed by transvenous catheterization and selective sinus and deep venous microcatheterization. Urokinase was delivered at the proximal aspect of the thrombus in dosages of 200,000 to 1,000,000 IU. In two patients with thrombus refractory to pharmacological thrombolytic treatment, mechanical wire microsnare maceration of the thrombus resulted in sinus patency. Radiological studies obtained 24 hours after thrombolysis reconfirmed sinus/vein patency in all patients. All patients' symptoms and neurological deficits improved, and no procedural complications ensued. Follow-up periods ranged from 12 to 35 months, and all six patients remain free of any symptomatic venous reocclusion. Factors including patients' age, preexisting medical conditions, and duration of symptoms had no statistical bearing on the outcome. CONCLUSIONS: Patients with both dural and deep cerebral venous thrombosis often have a variable clinical course and an unpredictable neurological outcome. With recent improvements in interventional techniques, endovascular therapy is warranted in symptomatic patients early in the disease course, prior to morbid and potentially fatal neurological deterioration.

Survival and integration of transplanted postmitotic human neurons following experimental brain injury in immunocompetent rats.

OBJECT: Limitations regarding cell homogeneity and survivability do not affect neuronlike hNT cells, which are derived from a human teratocarcinoma cell line (Ntera2) that differentiates into postmitotic neurons with exposure to retinoic acid. Because NT2N neurons survive longer than 1 year after transplantation into nude mice brains, the authors grafted these cells into the brains of immunocompetent rats following lateral fluid-percussion brain injury to determine the long-term survivability of NT2N cell grafts in cortices damaged by traumatic brain injury (TBI) and the therapeutic effect of NT2N neurons on cognitive and motor deficits. METHODS: Seventy-two adult male Sprague-Dawley rats, each weighing between 340 and 370 g, were given an anesthetic agent and subjected to lateral fluid percussion brain injury of moderate severity (2.2-2.5 atm in 46 rats) or to surgery without TBI (shamoperation, 26 rats). Twenty-four hours postinjury, 10(5) NT2N cells (24 injured animals) or 3 microl of vehicle (22 injured and 14 control animals) was stereotactically implanted into the periinjured or control cerebral cortex. Motor function was assessed at weekly intervals and all animals were killed at 2 or 4 weeks after their posttraumatic learning ability was assessed using a Morris water maze paradigm. Viable NT2N grafts were routinely observed to extend human neural cell adhesion molecule-(MOC-1)immunoreactive processes into the periinjured cortex at 2 and 4 weeks posttransplantation, although no significant improvement in motor or cognitive function was noted. Inflammation identified around the transplant at both time points was assessed by immunohistochemical identification of macrophages (ED-1) and microglia (isolectin B4). CONCLUSIONS: Long-term survival and integration of NT2N cells in the periinjured cortex of immunocompetent rats provides the researcher with an important cellular system that can be used to study maturation, regulation, and neurite outgrowth of transplanted neurons following TBI.

Terminally differentiated human neurons survive and integrate following transplantation into the traumatically injured rat brain.

The present study evaluated the survival and integration of human postmitotic neurons (hNT) following transplantation into the traumatically injured rodent brain. Anesthetized male Sprague-Dawley rats (n = 47) were subjected to lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Sham animals (n = 28) were surgically prepared, but did not receive brain injury. At 24 h following injury or sham surgery, the rats were re-anesthetized and approximately 100,000 hNT cells (freshly cultured or previously frozen) or vehicle were stereotactically injected into the ipsilateral cortex. Animals were examined for neuromotor function at 48 h, 7 days, and 14 days posttransplantation using a standard battery of motor tests. Animals were sacrificed at 2 weeks postinjury and viability of hNT grafts was assessed by Nissl staining and MOC-1 immunohistochemistry, which recognizes human neural cell adhesion molecules (NCAM) expressed on hNT cells. Transplanted hNT grafts remained viable in 83% of brain-injured animals at 2 weeks following transplantation of either fresh or frozen hNT cells. Glial fibrillary acidic protein (GFAP) immunohistochemistry revealed a marked increase in the number of reactive astrocytes following brain injury in both vehicle and hNT implanted animals. These reactive astrocytes appeared not to impede grafted cells from sending projections into host tissue. Despite the survival of transplanted cells in the traumatically injured brain, hNT cells had no significant effect on posttraumatic neurologic motor function during the acute posttraumatic period. Since hNT cells are transfectable, prolonged survival of these transplanted cells in the posttraumatic milieu suggests that grafted hNT cells may be a suitable means for delivery of therapeutic, exogenous proteins into the CNS for treatment of traumatic brain injury.

Treatment of villous hypertrophy of the choroid plexus by endoscopic contact coagulation.

Villous hypertrophy of the choroid plexus (VHCP) is a condition characterized by overproduction of cerebrospinal fluid by bilaterally symmetric and enlarged, yet histologically normal, choroid plexi. Medical and surgical therapy have been met with variable success. Traditional shunting procedures often result in failure to correct the underlying problem as well as failure to absorb the large volume of fluid produced. Craniotomy for open surgical resection of the choroid is associated with considerable morbidity. The authors describe a technique of endoscopic contact coagulation as an effective and safe treatment of VHCP. A 14-month-old hydrocephalic girl with VHCP who failed ventriculoperitoneal shunting as the sole treatment of her hydrocephalus presented with increasing ascites. She was successfully treated with ventriculoperitoneal shunting and endoscopic Bugby wire-directed monopolar contact coagulation of the hyperplastic choroid plexus. Postoperatively her head circumference and cognitive development is normal for her age, and her ascites has resolved. Endoscopic contact coagulation of the hyperplastic choroid plexus is a minimally invasive surgical method which treats the cause of the CSF production while avoiding the operative complications of open choroid plexus resection.

Ventriculofemoroatrial shunt: a viable alternative for the treatment of hydrocephalus. Technical note.

Children with shunted hydrocephalus often have a myriad of other medical conditions. When these concomitant problems involve the pleura, peritoneum, and/or the venous system, placement of the distal catheter may prove to be problematic. This report presents preliminary results in three hydrocephalic children following ventriculofemoroatrial shunt placement. The peritoneal and pleural cavities in each of these children were compromised and there was no vascular access into the superior vena cava due to intercurrent disease. An alternative technique for ventriculoperitoneal shunt placement was performed via the femoral vein. Fluoroscopic guidance was used to confirm the intraatrial position of the distal end of the shunt catheter. Follow-up review to date shows no complications. This newly described technique provides a feasible alternative to distal shunt catheter placement in patients in whom more traditional sites are unavailable.

Progressive congenital kyphosis: report of five cases and review of the literature.

For over 60 years congenital kyphotic deformities of the spine have been categorized into two distinct groups, depending on the developmental defect. Those arising from a failure of formation of the vertebral bodies were classified as type 1, while those arising from a failure of segmentation were referred to as type 2. Recognition of the progressive and unstable nature of the type 1 defects alerted physicians to the need for early operative stabilization through decompression and stabilization through instrumentation. As the embryogenesis of the spinal column was further investigated, and as diagnostic imaging methods of the spine improved, unstable congenital kyphoses were further subdivided. Progressive congenital kyphotic deformities now may accompany a host of vertebral column developmental defects as well as genetically mediated mesenchymal tissue defect syndromes. This paper presents 5 patients from The Children's Hospital of Philadelphia with progressive and symptomatic congenital kyphotic deformities of the spine. Two of these lesions resulted from defects of formation of the vertebral bodies, while one resulted from segmental spinal dysgenesis, maldevelopment of both the anterior and posterior vertebral elements. One patient's kyphotic deformity was a result of caudal regression syndrome, and the final case presented experienced a high thoracic kyphosis from a syndrome associated diffuse midline mesenchymal tissue abnormalities known as cerebrocostomandibular syndrome. All patients showed evidence of progressive cord compression and required neural element decompression, fusion, and instrumentation. The cases are discussed individually, and the developmental and clinical aspects of each are explored.

Intraoperative endovascular surgery for cerebral aneurysms.

The application of a number of procedures that can be considered intraoperative endovascular neurosurgery has enhanced our ability to treat cerebral aneurysms from the abluminal surface. This study identifies a role for these techniques in the management of difficult aneurysms. A review of the last 1202 aneurysms undergoing direct clipping by the authors disclosed that these methods were used in 62 cases. Of these aneurysms, 36 arose from the internal carotid artery, 12 from the middle cerebral artery, eight from the vertebrobasilar distribution, and six from the anterior cerebral artery. The indications for applying these methods were large size (12-60 mm), intraluminal thrombus, broad neck, plaque at the neck, the potential compromise of branches at the base of the aneurysm, or a combination of these problems. The most frequently chosen intraoperative technique was suction decompression with direct removal of plaque and thrombus using suction, dissection, and/or ultrasonic aspiration. The application of temporary clips was required in all cases in which the aneurysm was opened before definitive clipping. No special pharmacological cerebral protective regimen was used. In one case in which a greater occlusion time was anticipated, cardiopulmonary bypass with profound hypothermia was performed. A favorable outcome was achieved in 73% of these difficult cases. An increased neurological deficit after surgery was seen in 11%, and the mortality rate was 8%. These methods should be considered and can be anticipated before surgery for unusual aneurysms. Many cases now being considered for embolization may be more suitable for definitive surgical obliteration.

Increased basic fibroblast growth factor (bFGF) immunoreactivity at the site of focal brain wounds.

Basic fibroblast growth factor (bFGF) is a polypeptide found within the CNS with potent effects on the survival and proliferation of CNS glia and endothelial cells, and on the survival and outgrowth of CNS neurons. Immunohistochemical methods were used to examine relative changes in the levels and distribution of bFGF following focal brain injury. Two monospecific antisera to bFGF were used to immunostain intact mature rat brain, and brain in which a focal mechanical lesion had been made in the dorsolateral cerebral cortex one week previously. In the intact brain, staining was localized primarily in neuronal cell bodies, especially in limbic structures. In injured brain, a marked increase of bFGF immunoreactivity was found at the borders of lesions, localized to the dense accumulation of cells, many of which resembled 'reactive' astroglia. Such increases in local bFGF concentrations may contribute to the cascade of cellular changes--including glial and capillary proliferation, and neural sprouting--that follows focal brain injury.

A factor from the injured lower vertebrate CNS promotes outgrowth from human fetal brain neurons.

Unlike mammals, lower vertebrates retain the capacity to regenerate damaged central nervous system (CNS) pathways throughout life. In previous studies, we have used the goldfish optic nerve (ON) as a model for CNS regeneration, and found that the injured goldfish ON selectively secretes a factor that promotes process outgrowth of cultured neurons, including neurons of the developing rodent CNS. In the current study, we found that a factor similarly obtained from the injured goldfish ON also has potent outgrowth-promoting effects on cerebrocortical neurons of the fetal human brain, and that these effects are dependent on the age of fetal neurons. This factor appeared to be a protein of mol. wt. greater than 12,000, and was associated with a distinctive morphology of neurite outgrowth. The neurite-promoting factor from the injured goldfish ON may be homologous to factors within the developing human brain.