Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease.

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.

Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis.

OBJECT: Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model. METHODS: HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression. RESULTS: Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease. CONCLUSIONS: This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders.

Neural stem cell engraftment and myelination in the human brain.

Pelizaeus-Merzbacher disease (PMD) is a rare leukodystrophy caused by mutation of the proteolipid protein 1 gene. Defective oligodendrocytes in PMD fail to myelinate axons, causing global neurological dysfunction. Human central nervous system stem cells (HuCNS-SCs) can develop into oligodendrocytes and confer structurally normal myelin when transplanted into a hypomyelinating mouse model. A 1-year, open-label phase-1 study was undertaken to evaluate safety and to detect evidence of myelin formation after HuCNS-SC transplantation. Allogeneic HuCNS-SCs were surgically implanted into the frontal lobe white matter in four male subjects with an early-onset severe form of PMD. Immunosuppression was administered for 9 months. Serial neurological evaluations, developmental assessments, and cranial magnetic resonance imaging (MRI) and MR spectroscopy, including high-angular resolution diffusion tensor imaging (DTI), were performed at baseline and after transplantation. The neurosurgical procedure, immunosuppression regimen, and HuCNS-SC transplantation were well tolerated. Modest gains in neurological function were observed in three of the four subjects. No clinical or radiological adverse effects were directly attributed to the donor cells. Reduced T1 and T2 relaxation times were observed in the regions of transplantation 9 months after the procedure in the three subjects. Normalized DTI showed increasing fractional anisotropy and reduced radial diffusivity, consistent with myelination, in the region of transplantation compared to control white matter regions remote to the transplant sites. These phase 1 findings indicate a favorable safety profile for HuCNS-SCs in subjects with PMD. The MRI results suggest durable cell engraftment and donor-derived myelin in the transplanted host white matter.

Transplantation of human central nervous system stem cells - neuroprotection in retinal degeneration.

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.

Resolution of syringomyelia after release of tethered cord.

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.

Congenital glioblastoma multiforme: case report and review of the literature.

Congenital glioblastoma multiforme is a rare primary brain tumor that has a unique biology distinct from pediatric and adult variants. In this report, we present a case of congenital glioblastoma with complicated management course. A literature review of previously reported cases is included to illustrate the epidemiology and natural history of this disease. A 9-month-old male infant developed acute lethargy, hemiparesis and unilaterally dilated pupil. Imaging studies revealed a large hemispheric tumor, resulting in significant midline shift suggestive of impending herniation. Emergent tumor cystic fluid drainage was performed at initial presentation. A frontotemporoparietal craniotomy was performed on the following day to attempt a gross total resection. Adjuvant chemotherapy consisting of oral temozolomide was administered. The patient eventually succumbed 4 months later due to aggressive tumor progression. Congenital glioblastoma should be included in the differential diagnosis of infants with large intracranial tumors. Although surgical intervention may increase survival, the overall outcome remains poor despite maximal multimodal treatment.

Central nervous system therapy for lysosomal storage disorders.

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.

Cellular therapy for childhood neurodegenerative disease. Part I: rationale and preclinical studies.

Successful cellular replacement in the diseased human central nervous system (CNS) faces numerous hurdles. In this first installment of a 2-part review, the authors report on the preclinical challenges involved in preparing for a major Phase I trial investigating the safety of human neural stem cell transplantation in a lysosomal storage disorder. Specifically, they discuss choice of the ideal disease for treatment, best donor cell type and source for implantation, the in vitro and in vivo methods used to estimate safety and efficacy, the challenges to noninvasive tracking of cells after transplantation, and the unique issues related to the immunology of CNS cellular transplantation.

Cellular therapy for childhood neurodegenerative disease. Part II: clinical trial design and implementation.

Cellular replacement therapy attempts to improve functioning of the diseased human central nervous system (CNS). In this second installment of a 2-part review, the authors discuss the major challenges to the translation of in vitro and animal studies of neural stem cell (NSC) therapy in the clinical setting. This analysis details the problems unique to the design of clinical trials using human NSCs, outlines patient selection practices, describes surgical techniques for cellular transplantation, and reviews the regulatory issues and ethical concerns in trials involving neurologically impaired children.

Cerebral myiasis associated with angiosarcoma of the scalp: case report.

OBJECTIVE: Primary human cerebral myiasis is an exceedingly rare condition and is almost never encountered by physicians in developed countries. The case report summarizes a case of extensive cerebral myiasis in a periurban community in the United States. CLINICAL PRESENTATION: After a minor motor vehicle accident, police brought a 75-year-old man to the emergency room because he was observed to have a large cranial lesion. Examination revealed a 15 x 17 cm frontal bone defect with eroded frontal dura, exposed cortex, and massive cortical maggot infestation. INTERVENTION: The patient was empirically treated with intravenous antibiotics for meningitis. Maggots (Phaenicia sericata, or the green bottle fly) were removed by suction, attrition, and gentle contact exposure to a mild bleach solution. Biopsy of the scalp and cranium revealed angiosarcoma, for which operative treatment was refused. The patient was transferred to a skilled nursing facility for palliative care where he died 3 months later. CONCLUSION: This is the first published case of cerebral myiasis in the United States. Although human cerebral myiasis is rare, conditions do exist in this country that permit myiasis.

Glutaric acidemia type I: a neurosurgical perspective. Report of two cases.

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.

Identification of phenotypic neural stem cells in a pediatric astroblastoma.

OBJECT: The goal of this study was to illustrate the findings of a significant subpopulation of cells within a pediatric astroblastoma that have the specific cell surface phenotype found on known human neural stem cells. METHODS: Cells with a cell surface marker profile characteristic of human neural stem cells were isolated using fluorescence-activated cell sorting from a mostly nonmitotic astroblastoma removed from the brain of an 11-year-old girl. An unusually high proportion (24%) of the cells were CD133 positive and CD24, CD34, and CD45 negative (CD133(+)CD24(-)CD34(-)CD45(-) cells), the phenotypic antigenic pattern associated with neural stem cells; very few CD133-positive cells were not also CD24, CD34, and CD45 negative. Some cells (12%) were CD34 positive, indicating the presence within the tumor of hematopoietic stem cells. Cells formed cytospheres that resembled neurospheres when seeded into stem cell media and coexpressed beta-tubulin and glial fibrillary acidic protein (GFAP) but did not express the oligodendrocyte marker O4. Cell proliferation was demonstrated by incorporation of bromodeoxyuridine. The cells lost their capacity for self-renewal in vitro after four to six passages, although they continued to coexpress beta-tubulin and GFAP. The cells did not differentiate into neurons or astrocytes when placed in differentiation medium. CONCLUSIONS: Although this astroblastoma contained a high proportion of phenotypic neural stemlike cells, the cells had limited proliferative capacity and multipotency. Their role in astroblastoma formation and growth is unknown.

Paradoxical cerebral herniation secondary to lumbar puncture after decompressive craniectomy for a large space-occupying hemispheric stroke: case report.

OBJECTIVE AND IMPORTANCE: The risk of transtentorial herniation after removal of cerebrospinal fluid from the lumbar cistern in the setting of a supratentorial lesion with significant mass effect, increased cerebrospinal fluid pressure, or midline shift is well known. We report a case of cerebral herniation from intracranial hypotension (so-called paradoxical herniation) secondary to a lumbar puncture 1 month after decompressive hemicraniectomy for a large right hemispheric stroke. CLINICAL PRESENTATION: A 50-year-old woman was transferred to our neurosurgical service for obtundation 4 days after a lumbar puncture to rule out meningitis and 1 month after decompressive craniectomy for a large right hemispheric stroke. INTERVENTION: Eighty grams of mannitol was administered before transfer. On arrival at our hospital, the patient was intubated and a computed tomographic scan was performed. The patient was diagnosed with low-pressure herniation after review of the computed tomographic scan. Rehydration was initiated, and the patient was placed in the Trendelenburg position. She became easier to arouse, but her pupils remained dilated. She experienced a sudden severe cardiac arrhythmia leading to a cardiac arrest. Attempted resuscitation was unsuccessful, and the patient was pronounced dead. CONCLUSION: Lumbar punctures may result in lethal intracranial hypotension in patients after hemicraniectomy and are thus contraindicated unless care is taken to remove the pressure gradient of atmospheric air across the lumbar cistern.

Profile of daily life in children with brain tumors: an assessment of health-related quality of life.

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.

Free latissimus dorsi flap used in treatment of cerebral aspergillosis: a case report and review of the literature.

Cerebral aspergillosis infection is a rare disease in children that carries extremely high morbidity and mortality. Although occurring most commonly in the immunosuppressed patient, cerebral aspergillosis infection has been reported after trauma or neurosurgical procedures. Amphotericin B is the main medical therapy for cerebral aspergillosis. However, surgical treatment is often required for cases of abscess or granuloma formation. Despite aggressive antifungal treatment and surgical intervention, aspergillosis of the central nervous system is often fatal. We present a case report in which a free latissimus dorsi muscle flap was used in conjunction with antifungal medication and surgical debridement to treat intracranial and epidural aspergillosis in a young male following complex craniofacial trauma.

Cortical ependymoma. A case report and review.

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.

Radiation therapy for intracranial germ cell tumors.

PURPOSE: To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model. RESULTS: Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS. CONCLUSION: CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.

Spontaneous resolution of a prepontine arachnoid cyst. Case report and review of the literature.

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.