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Summary Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. At year 2, all subjects exhibited diffusion MRI changes at the implantation sites as well as in more distant brain regions. There were persistent, increased signal changes in the three patients who were studied up to year 5. Two of four subjects developed donor-specific HLA alloantibodies, demonstrating that neural stem cells can elicit an immune response when injected into the CNS, and suggesting the importance of monitoring immunologic parameters and identifying markers of engraftment in future studies., Highlights • Neural stem cell transplantation has a safe long-term safety profile • Donor-specific alloantibodies develop after stem cell transplantation into the CNS • Diffusion MR imaging is a potential surrogate for CNS myelination, Gupta and colleagues show that transplantation with allogeneic central nervous system stem cells can be performed safely in humans with minimal morbidity. Immunologic data, however, show that neural stem cells can elicit an immune response following transplantation, suggesting the importance of monitoring immunologic parameters.

Background Human central nervous system stem cells (HuCNS-SC) are multipotent adult stem cells with successful engraftment, migration, and region-appropriate differentiation after spinal cord injury (SCI). Objective To present data on the surgical safety profile and feasibility of multiple intramedullary perilesional injections of HuCNS-SC after SCI. Methods Intramedullary free-hand (manual) transplantation of HuCNS-SC cells was performed in subjects with thoracic (n = 12) and cervical (n = 17) complete and sensory incomplete chronic traumatic SCI. Results Intramedullary stem cell transplantation needle times in the thoracic cohort (20 M HuCNS-SC) were 19:30 min and total injection time was 42:15 min. The cervical cohort I (n = 6), demonstrated that escalating doses of HuCNS-SC up to 40 M range were well tolerated. In cohort II (40 M, n = 11), the intramedullary stem cell transplantation needle times and total injection time was 26:05 ± 1:08 and 58:14 ± 4:06 min, respectively. In the first year after injection, there were 4 serious adverse events in 4 of the 12 thoracic subjects and 15 serious adverse events in 9 of the 17 cervical patients. No safety concerns were considered related to the cells or the manual intramedullary injection. Cervical magnetic resonance images demonstrated mild increased T2 signal change in 8 of 17 transplanted subjects without motor decrements or emerging neuropathic pain. All T2 signal change resolved by 6 to 12 mo post-transplant. Conclusion A total cell dose of 20 M cells via 4 and up to 40 M cells via 8 perilesional intramedullary injections after thoracic and cervical SCI respectively proved safe and feasible using a manual injection technique.

Purpose The loss of retinal pigment epithelial (RPE) cells is a feature common to age-related macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate. Methods Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 × 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy. Results RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods. Conclusions These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated. Translational relevance Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.

Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

Purpose The survival of children with CNS tumors approaches 70%, yet health-related quality of life (HRQOL) has not been investigated rigorously in this population. We aimed to show that universal assessment of HRQOL could be obtained easily by using the PedsQL 4.0 and to provide a composite profile of their daily lives. Patients and Methods The PedsQL was administered to all patients seen in the neuro-oncology clinic at Lucile Packard Children's Hospital (Palo Alto, CA) from December 2001, to September 2002. Patients were compared with healthy controls by using two-sided t tests to evaluate statistically significant differences. Results One hundred thirty-four patients (73 male; mean age ± standard deviation, 11.8 ± 5.4 years; 55 had low-grade glioma, 32 had medulloblastoma/primitive neuroectodermal tumor/embryonal tumor, 17 had malignant astrocytoma, nine had germ-cell tumor, and 21 had other types of tumors) were assessed, each in less than 20 minutes. Scores on both child and parent-proxy reports for the total HRQOL, psychosocial, physical, emotional, social, and school-functioning scales were all significantly lower than controls (P < .01). Patients with low-grade glioma were reported to have the highest total HRQOL. Children receiving radiation therapy (XRT) but no chemotherapy had significantly lower total, psychosocial, emotional, and social functioning than those receiving other treatments, including XRT plus chemotherapy. Conclusion The PedsQL can be used to assess HRQOL rapidly and easily in children with CNS tumors, who have significantly worse HRQOL than healthy children. Children receiving XRT fare worse overall; chemotherapy added to XRT does not seem to worsen HRQOL. Assessment of HRQOL should be included as an outcome in future clinical trials.

The authors report a rare case of a cortical ependymoma in a 10-year-old boy. The patient presented with complex partial seizures and a well-circumscribed, right frontal cortical mass. Routine microscopy showed a glial tumor with diverse histologic features. Immunohistochemistry and electron microscopy were required to establish the definitive diagnosis of cortical ependymoma. Cortical-based pediatric brain tumors range from World Health Organization grade I to III lesions and require significantly different treatment and follow-up. This case illustrates the importance of establishing an accurate neuropathologic tissue diagnosis of all pediatric cortical tumors.

Object. The goal of this study was to determine the effect of hydrocephalus on cerebrospinal fluid (CSF) production rates in patients with acute and chronic hydrocephalus. Methods. The authors studied CSF production both in patients presenting with acute and chronic hydrocephalus, and patients with Parkinson disease (PD) of a similar mean age, whose CSF production was known to be normal. A modification of the Masserman method was used to measure CSF production through a ventricular catheter. The CSF production rates (means ± standard deviations) in the three groups were then compared. The patients with PD had a mean CSF production rate of 0.42 ± 0.13 ml/minute; this value lies within the normal range measured using this technique. Patients with acute hydrocephalus had a similar CSF production rate of 0.4 ± 0.13 ml/minute, whereas patients with chronic hydrocephalus had a significantly decreased mean CSF production rate of 0.25 ± 0.08 ml/minute. Conclusions. The authors postulate that chronic increased intracranial pressure causes downregulation of CSF production.

Objective: This prospective, randomized, controlled study was designed to investigate the safety, feasibility, and preliminary efficacy of long-term CSF drainage via a low-flow ventriculoperitoneal shunt in subjects suffering from AD. Methods: Twenty-nine subjects selected for probable AD (National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer’s Disease and Related Dementias Association criteria) were screened to exclude normal pressure hydrocephalus or other etiologies of dementia and randomized to treatment (shunt) or no treatment groups. The study endpoint was the comparison of group performance on psychometric testing at quarterly intervals for 1 year. Shunted subjects had CSF withdrawn for MAP-tau and Aβ (1-42) assays at the same time intervals. Results: There was no mortality from the surgical procedure, and no patient sustained a subdural hematoma. Five notable postoperative adverse events, which resolved without permanent neurologic deficit, were reported in the shunt group. Group mean Mattis Dementia Rating Scale total scores showed little change over the year in the shunt-treatment group, in contrast to a decline in the control group ( p = 0.06). Mini-Mental State Examination mean scores supported a trend in favor of shunt treatment ( p = 0.1). There was a concomitant decrease in ventricular CSF concentrations of AD biomarkers MAP-tau and Aβ (1-42) . Conclusions: The surgical procedure and the device are reasonably safe. Adverse events were consistent with shunt procedures for hydrocephalus in this older population. The endpoint data show a trend in favor of the treated group. A larger, randomized, double-blinded, controlled, clinical trial is underway.

Prepontine arachnoid cysts are rare developmental anomalies that occur almost exclusively in children. The symptomatic child typically suffers from hydrocephalus, visual impairment, endocrine dysfunction and/or cranial neuropathies. Some cysts, however, are discovered incidentally upon prenatal or postnatal imaging for other indications. While there is little doubt that surgical treatment should be initiated to help the symptomatic child, appropriate therapy for the asymptomatic patient is unclear. Although arachnoid cysts are often managed conservatively using serial imaging, the consequences of injury to surrounding structures with prepontine cysts often lowers the threshold for intervention. The natural history of asymptomatic prepontine arachnoid cysts is unknown. It has been reported that some cysts enlarge and cause symptoms, whereas others are stable for years. This report describes an index case of spontaneous resolution of a prepontine arachnoid cyst in a female infant over a 5-year period.

Objective: To evaluate the production rate of CSF in patients with differing disease states. Methods: The authors measured the production rate of CSF in three groups of patients: five patients with PD below age 60 (aged 51 ± 4 years, mean ± SD), nine with PD over age 60 (aged 69 ± 6 years, mean ± SD), and seven with dementia of the Alzheimer’s type (AD) (aged 72 ± 9 years, mean ± SD). This method, based on the Masserman technique, employs ventricular rather than a lumbar access to the CSF space. Furthermore, the volume of CSF removed during the procedure is only 3 mL rather than 10 mL. Results: These measurements indicate that the mean rate of CSF production in patients with PD under age 60 was 0.47 ± 0.13 mL/minute, in patients with PD aged 60 or older the mean rate was 0.40 ± 0.12 mL/minute, and in patients with AD the mean rate was 0.20 ± 0.06 mL/minute. Conclusion: These results indicate that the rate of CSF production in patients with PD is normal, and that the rate of CSF production in patients with AD is markedly reduced.

Chemotherapeutic regimens in present use for recurrent glioma have substantial toxicity. Activity against recurrent gliomas has been reported for both tamoxifen and interferon alpha, agents that have more acceptable toxicity profiles and that can be administered in an outpatient setting. We tested the efficacy and toxicity of the combination of high-dose tamoxifen and interferon alpha in adults with recurrent glioma in a phase II trial. Eligible patients had radiographically measurable recurrent gliomas of any grade after initial radiation therapy. Interferon-alpha (6 × 106 U subcutaneously three times per week) and tamoxifen (240 mg/m2/day orally) were administered continuously. Treatment response was assessed at 6 week intervals using clinical and radiographic criteria. Eighteen patients (11 males and 7 females) were enrolled. Median age was 41 years (range 23–61 years). All patients had gliomas that progressed after radiation therapy and nitrosourea chemotherapy. The histologic diagnosis of the original tumor was glioblastoma multiforme in 8 patients, anaplastic astrocytoma in 5 patients, astrocytoma in 4 patients and mixed malignant glioma in 1 patient. Reversible moderate to severe neurological toxicity manifested by dizziness and unsteady gait was seen at tamoxifen doses of 240 mg/m2/day. Although the initial tamoxifen dose was reduced to 120 mg/m2/day, moderate neurotoxicity was noted at this dose as well and the trial was closed early. The combination of oral tamoxifen (120 to 240 mg/m2/day) and subcutaneous interferon-alpha (6 × 106 U three times per week) was associated with significant neurotoxicity in this group of recurrent glioma patients, resulting in early study closure. Of 16 evaluable patients, 12 had progressive disease after one cycle of treatment, 3 had stable disease, and there was one minor response. Gradual dose escalation may be required if similar patients are to be treated with high dose tamoxifen in conjunction with interferon.

Patients with primary brain tumors may be considered for several different treatments during the course of their disease. Assessments of disease progression and response to therapy are typically performed by visual interpretation of serial MRI examinations. Although such examinations provide useful morphologic information, they are unable to reliably distinguish active tumor from radiation necrosis. This poses a particular problem in the assessment of response to localized radiation therapies such as gamma knife radiosurgery. In this paper, we present methodology for evaluating changes in tissue morphology and metabolism based on serial volumetric MRI and magnetic resonance spectroscopic imaging (MRSI) examinations. Registration and quantitative analysis of these data provide measurements of the temporal and spatial distributions of gadolinium enhancement and of N-acetylasparate, choline, creatine, and lactate/lipid. The key features of this approach and the potential clinical benefits are illustrated by a detailed analysis of six serial MRI/MRSI examinations and three serial 1-[F-18] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies on a patient with a recurrent anaplastic astrocytoma.

BACKGROUND It is often assumed that a cerebral lesion that is nonenhancing on a magnetic resonance imaging study with gadolinium contrast is a low grade tumor. Some physicians recommend observation rather than biopsy for such lesions. METHODS The authors prospectively evaluated the incidence of anaplastic tumor histology in a consecutive series of patients who presented to a neuro-oncology service with a nonenhancing mass of the cerebral hemisphere. RESULTS During a 5-month period, the authors evaluated 31 patients who had a nonenhancing lesion in the cerebral hemisphere on initial magnetic resonance images. Thirty patients underwent stereotactic biopsy (27%) or open resection (73%). The median patient age was 36 years (range, 6-63 years). There was no mortality or permanent neurologic morbidity from surgery. Twenty-eight patients had pathologic confirmation of diagnosis while their lesions were still nonenhancing. Of these patients, 9 (32%) had Grade 3 lesions (anaplastic astrocytoma or oligoastrocytoma), 13 (43%) had Grade 2 lesions (astrocytoma, oligodendroglioma, or oligoastrocytoma), and 2 (7%) had Grade 1 lesions (dysembryoplastic neuroepithelial tumors). Two additional patients (ages 33 and 59 years) who developed enhancement within their lesions during preoperative periods of observation had glioblastomas at surgery. Logistic regression was used to relate patient age to the risk of anaplasia in a nonenhancing cerebral mass lesion. Older age predicted a significantly higher risk of anaplasia (P = 0.025). The model predicted that nonenhancing cerebral masses in patients older than 44 years were more likely to be anaplastic tumors than low grade tumors. There was no "safe" age below which low grade histology could be confidently assumed. CONCLUSIONS Magnetic resonance-nonenhancing cerebral lesions may be histologically anaplastic, even in young patients. The risk of anaplasia in magnetic resonance-nonenhancing lesions increases significantly with patient age. Cancer 1997; 80:936-41. © 1997 American Cancer Society.

Human neural stem cell transplants have potential as therapeutic candidates to treat a vast number of disorders of the central nervous system (CNS). StemCells, Inc. has purified human neural stem cells and developed culture conditions for expansion and banking that preserve their unique biological properties. The biological activity of these human central nervous system stem cells (HuCNS-SC®) has been analyzed extensively in vitro and in vivo. When formulated for transplantation, the expanded and cryopreserved banked cells maintain their stem cell phenotype, self-renew and generate mature oligodendrocytes, neurons and astrocytes, cells normally found in the CNS. In this overview, the rationale and supporting data for pursuing neuroprotective strategies and clinical translation in the three components of the CNS (brain, spinal cord and eye) are described. A phase I trial for a rare myelin disorder and phase I/II trial for spinal cord injury are providing intriguing data relevant to the biological properties of neural stem cells, and the early clinical outcomes compel further development.

Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

Cell transplantation offers a novel therapeutic strategy for stroke; however, how transplanted cells function in vivo is poorly understood. We show for the first time that after subacute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human vascular endothelial growth factor (hVEGF), is necessary for cell-induced functional recovery. We correlate this functional recovery to hVEGF-induced effects on the host brain including multiple facets of vascular repair and its unexpected suppression of the inflammatory response. We found that transplanted hCNS-SCns affected multiple parameters in the brain with different kinetics: early improvement in blood-brain barrier integrity and suppression of inflammation was followed by a delayed spatiotemporal regulated increase in neovascularization. These events coincided with a bimodal pattern of functional recovery, with, an early recovery independent of neovascularization, and a delayed hVEGF-dependent recovery coincident with neovascularization. Therefore, cell transplantation therapy offers an exciting multimodal strategy for brain repair in stroke and potentially other disorders with a vascular or inflammatory component.

Simultaneous implantation of intracerebral depth electrodes and subdural electrode grids is an extension of available techniques for invasive monitoring and seizure localization in epilepsy surgery candidates. This combined approach is described in 10 selected patients with refractory complex partial epilepsy, in whom previous intensive video/EEG monitoring with scalp or depth electrodes had indicated a lateralized seizure onset. All patients required subdural grids for further localization, functional mapping, or both. Ipsilateral depth electrodes were placed in mesial temporal or other regions through the same craniotomy. Four patients had seizures originating in the mesial temporal lobe, and the onsets were first seen in the temporal lobe depth electrodes. The other six patients had seizures beginning in lateral cortical structures, and the onsets were first seen in the subdural grid (overlying known structural lesions in four patients). The information from both electrode sources guided the surgical resections. All patients were improved after surgery; six are seizure-free with at least 12 months of followup. This preliminary experience indicates that simultaneous placement of depth and subdural grid electrodes is useful in localizing the site of seizure onset and in guiding surgical resections.

Background Syringomyelia is an abnormal cystic dilatation of the spinal cord caused by excessive accumulation of CSF. Patients can develop various neurologic deficits secondary to untreated syringomyelia, some of which can be permanent despite surgical intervention. Case Description The authors present a patient with syringomyelia, aortic coarctation, and tethered cord syndrome. Serial radiographic imaging demonstrated initial significant reduction of the thoracic syrinx after coarctation repair and release of tethered cord. However, subsequent follow-up imaging revealed partial recurrence. Conclusion This case provides evidence of a possible cause-effect relationship between syringomyelia and tethered cord. It demonstrates the indication of surveillance imaging of the entire spine to ensure that all potential etiologies of syringomyelia are identified and treated. Furthermore, it illustrates the complex dynamic nature of syrinx physiology and reinforces the importance of serial follow-up studies after surgical intervention.

Cervical instability secondary to fracture/dislocation or traumatic subluxation involving the posterior elements may be treated by a variety of fusion techniques. The rigidity of the stainless steel wires used in posterior cervical fusions often leads to difficulty with insertion, adequate tension, and conformation of the graft construct. This report describes a technique of posterior cervical fusion employing a wire system using flexible stainless steel cables. The wire consists of a flexible, 49-strand, stainless steel cable connected on one end to a short, malleable, blunt leader with the opposite end connected to a small islet. The cable may be used in occipitocervical, atlantoaxial, facet-to-spinous process, and interspinous fusion techniques. The cable loop is secured by using a tension/crimper device that sets the desired tension in the cable. In addition to superior biomechanical strength, the flexibility of the cable allows greater ease of insertion and tension adjustment. In terms of direct operative instrumentation in posterior cervical arthrodesis, involving both the upper and lower cervical spine, the cable system appears to be a safe and efficient alternative to monofilament wires.

Glutaric acidemia type I (GA-I) is a rare, autosomal recessive metabolic disorder that leads to severe dystonia, basal ganglia degeneration, and bilaterally enlarged anterior middle cranial fossae. The current management of this disease includes early diagnosis with newborn screening, prevention of catabolism, carnitine supplementation, and a strict dietary protein restriction. Neurosurgical evaluation and intervention may be necessary in patients with structural lesions associated with this disease. In this report, the authors present two pediatric patients with GA-I and discuss the neurosurgical aspects of this rare medical disorder.

Most lysosomal storage disorders are characterized by progressive central nervous system impairment, with or without systemic involvement. Affected individuals have an array of symptoms related to brain dysfunction, the most devastating of which is neurodegeneration following a period of normal development. The blood‐brain barrier has represented a significant impediment to developing therapeutic approaches to treat brain disease, but novel approaches— including enzyme replacement, small-molecule, gene, and cell-based therapies—have given children afflicted by these conditions and those who care for them hope for the future. (DOI: 10.3171/FOC/2008/24/3-4/E11)