Extensive Central Nervous System Research Articles

Prolonged remission in patients with extensive central nervous system metastasis treated with erlotinib

Prolonged remission in patients with extensive central nervous system metastasis treated with erlotinib

Lethal Silver-Haired Bat Rabies Virus Infection Can Be Prevented by Opening the Blood-Brain Barrier

Silver-haired bat rabies virus (SHBRV) infection induces a strong virus-specific immune response in the periphery of the host, but death is common due to the failure to open the blood-brain barrier (BBB) and deliver immune effectors to central nervous system (CNS) tissues. Mice with an SJL background are less susceptible to lethal infection with rabies viruses. In addition, these animals are known to have reduced hypothalamus-pituitary-adrenal (HPA) axis activity and an elevated capacity to mediate CNS inflammatory responses. We show here that approximately one-half of PLSJL mice survive an SHBRV infection that is invariably lethal for 129/SvEv mice. This difference is associated with the elevated capacity of PLSJL mice to mediate BBB permeability changes in response to the infection. The induction of more extensive BBB permeability and CNS inflammation in these animals results in greater virus clearance and improved survival. On the other hand, treatment of SHBRV-infected PLSJL mice with the steroid hormone dehydroepiandrosterone reduced BBB permeability changes and caused greater mortality. We conclude that the infiltration of immune effectors across the BBB is critical to surviving a rabies virus infection and that HPA axis activity may influence this process.

Neurophysiologic assessment of mucopolysaccharidosis III

Objective To describe finding of various neurophysiologic tests in patients with mucopolysaccharidosis III (MPS III) early in the disease course. Methods Patients were evaluated with flash visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), electroencephalography (EEG), and nerve conduction studies (NCS) before they underwent hematopoietic stem cell transplantation (HSCT). Results Thirteen children underwent at least one neurophysiologic test before HSCT. The mean age at testing was 2.7 years. Ten of 11 (91%) patients had a normal flash VEP, and all 9 who had BAEP had normal central conduction. EEG was normal in 7/13 (54%), with the others showing diffuse slowing. NCS was normal in 10/11 (91%) patients. Conclusions Despite extensive central nervous system involvement in MPS III, flash VEP and BAEP are almost always normal. EEG is often abnormal early in the disease. Significance This is the first report of neurophysiologic tests in a large series of MPS III patients.

A 65-Year-Old Woman With a Left Occipital Lobe Tumor

A 65-Year-Old Woman With a Left Occipital Lobe Tumor

Cerebral amyloid angiopathy presenting with vasculitic pathology

We present an elderly patient with an unusual extensive multifocal central nervous system mass lesion, with dramatic imaging changes but only minor disturbance of cerebral function. Cerebral biopsy revealed an unexpected finding of severe cerebral amyloid angiopathy with secondary florid vasculitic appearances, which is a very rare but recognised association. Immunosuppression has produced significant sustained clinical and radiological remission.

Cervical spinal cord delivery of a rabies G protein pseudotyped lentiviral vector in the SOD-1 transgenic mouse. Invited submission from the Joint Section Meeting on Disorders of the Spine and Peripheral Nerves, March 2004.

Lentiviral vectors may constitute a vehicle for long-term therapeutic gene expression in the spinal cord. In amyotrophic lateral sclerosis, spinal cord sclerosis and altered axonal transport pose barriers to therapeutic gene distribution. In the present study the authors characterize gene expression distribution and the behavioral impact of the rabies G (RabG) protein pseudotyped lentiviral vector EIAV.LacZ through cervical spinal cord injection in control and Cu/Zn superoxide dismutase-1 (SOD-1) transgenic mice. Seven-week-old SOD-1 transgenic mice and their wild-type littermates underwent exposure of the cervicomedullary junction and microinjection of RabG.EIAV.LacZ or vehicle. The Basso-Beattie-Bresnahan locomotor score, grip strength meter, and Rotarod assays were used to assess the effects of disease progression, spinal cord microinjection, and lentiviral gene expression. Spinal cords were removed when the mice were in the terminal stage of the disease. The distribution of LacZ gene expression was histologically evaluated and quantified. Direct cervical spinal cord microinjection of RabG.EIAV.LacZ results in extensive central nervous system uptake in SOD-1 transgenic mice; these findings were statistically similar to those in wild-type mice (p > 0.05). Gene expression lasts for the duration of the animal's survival (132 days). The SOD-1 mutation does not prevent retrograde axonal transport of the vector. Three behavioral assays were used to demonstrate that long-term gene expression does not alter sensorimotor function. In comparison with normative data, vector injection and transgene expression do not accelerate disease progression. Direct spinal cord injection of RabG.EIAV vectors represents a feasible method for delivering therapeutic genes to upper cervical spinal cord and brainstem motor neurons. Distribution is not affected by the SOD-1 mutation or disease phenotype.

Treatment of xanthoma disseminatum with cyclophosphamide

Xanthoma disseminatum is a rare non-Langerhans cell (class II) histiocytosis, which is often resistant to treatment. We describe an illustrative case with extensive mucocutaneous, ocular, laryngeal, pituitary and central nervous system involvement, which responded to treatment with cyclophosphamide. The presentation, course and treatment of the condition are reviewed. Many of the non-Langerhans cell histiocytoses represent a spectrum of diseases of dermal dendrocytes ranging from self-limiting and benign conditions to multisystem progressive diseases that respond poorly to treatment and severely impair quality of life. We suggest that chemotherapy should be considered at an early stage in the more aggressive subtypes of non-Langerhans cell histiocytoses.

The status of hematopoietic stem cell transplantation in lysosomal storage disease

Lysosomal storage diseases are a group of disorders which have in common an inherited defect in lysosomal function—in most cases, a missing intralysosomal enzyme. Research into potential treatment options for this group of disorders has focused on enzyme replacement. Over the past two decades, hematopoietic stem cell transplantation has been used with increasing frequency to treat patients with lysosomal storage disease by providing a population of cells with the capacity to produce the missing enzyme. The success of marrow transplantation depends on the specific enzyme deficiency and the stage of the disease. Generally, visceral symptoms can be improved, whereas skeletal lesions remain relatively unaffected. The effect on neurologic symptoms varies. Hematopoietic stem cell transplantation remains a viable treatment option in those lysosomal storage diseases where data supportive of disease stabilization or amelioration are known. Early transplantation is the goal so that enzyme replacement may occur before extensive central nervous system injury becomes evident. When inadequate clinical data are available, the decision to perform transplantation requires experimental data demonstrating that the enzyme in question is both excreted from normal cells and taken up by affected cells as evidenced by elimination of storage material in vitro.

Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema.

Taiwan experienced several epidemics of enterovirus 71 (EV71) infections, which were associated with brainstem encephalitis (BE) and pulmonary edema (PE). To elucidate the role of immune mechanisms in the pathogenesis of BE caused by EV71 and its fatal complication, PE, we analyzed the laboratory findings, cytokine, and immunophenotypes of 73 EV71-infected patients with BE. Patients were stratified by disease: PE (n=14), autonomic nervous system (ANS) dysregulation (n=25), and isolated BE (n=34). The mortality rate for PE was 64.3%. Leukocytosis and thrombocytosis were significantly more frequent among patients with PE. A significant elevation of plasma interleukin (IL)-10, IL-13, and interferon (IFN)-gamma levels observed in patients with PE. Patients with PE also had lower circulating CD4(+) T cells, CD8(+) T cells, and natural killer (NK) cells. An extensive peripheral and central nervous system inflammatory response with abnormal IL-10, IL-13, and IFN-gamma cytokine production and lymphocyte depletion appears to be responsible for the pathogenesis of EV71-associated PE.

Purification of Schwann cells by selection of p75 low affinity nerve growth factor receptor expressing cells from adult peripheral nerve

The intrinsic capacity of Schwann cells to promote regeneration after limited peripheral nerve lesions has been successfully transferred to extensive peripheral nerve injuries and central nervous system lesions by autologous transplantation strategies. However, both the intrinsic ability of axotomized neurons to regenerate and the permissiveness of the parenchyma surrounding the acute injury site diminish over time. Therefore, the autologous transplantation mode requires a fast and effective method to isolate Schwann cells from peripheral nerve biopsies. Here, we report a method to purify p75 low affinity nerve growth factor receptor (p75LNGFr) expressing Schwann cells from peripheral nerve biopsies in adult rats using magnetic-activated cell separation (MACS). After 1 week of nerve degeneration in culture, nerve fragments were dissociated resulting in mixed cultures containing Schwann cells and fibroblasts. After incubation with specific anti-p75LNGFr antibodies and secondary magnetic bead conjugated antibodies followed by one cycle of MACS, 95% pure Schwann cell cultures were generated as confirmed by flow-cytometry and immunocytochemistry. In contrast to established methods, MACS separation of p75LNGFr expressing cells allows the reliable purification of Schwann cells within 9 days after biopsy employing direct selection of Schwann cells rather than fibroblast depletion assays. Therefore, this method represents an effective and fast means to generate autologous Schwann cells for clinical transplantation strategies aiming for axon repair and remyelination.

Reexamination of Amphotropic Murine Leukemia Virus Neurovirulence: Neural Stem Cell-Mediated Microglial Infection Fails to Induce Acute Neurodegeneration

The 4070A amphotropic murine leukemia virus (A-MuLV) has been variably reported to harbor neurovirulence determinants within its env gene. In this report we reexamined this issue by applying two approaches previously demonstrated to amplify murine leukemia virus neurovirulence. The first approach involved introducing the 4070A env gene into the background of Friend virus clone FB29 to enhance peripheral virus replication kinetics and central nervous system entry. The resulting chimeric virus, FrAmE, exhibited widespread vascular infection throughout the central nervous system (CNS); however, parenchymal infection was quite limited. Neither clinical neurological signs nor spongiform neurological changes accompanied FrAmE CNS infection. To overcome this CNS entry limitation, 4070A and FrAmE were delivered directly into the CNS via transplantation of infected C17.2 neural stem cells (NSCs). Significantly, NSC dissemination of either 4070A or FrAmE resulted in widespread, high-level amphotropic virus expression within the CNS parenchyma, including the infection of microglia, the critical target required for inducing neurodegeneration. Despite the extensive CNS infection, no associated clinical neurological signs or acute neuropathological changes were observed. Interestingly, we observed the frequent appearance of circulating polytropic (MCF) virus in the serum of amphotropic virus-infected animals. However, neither peripheral inoculation of an amphotropic/MCF virus mixture nor transplantation of NSCs expressing both amphotropic and MCF viruses induced acute clinical neurological signs or spongiform neuropathology. Thus, the results generated in this study suggest that the 4070A env gene is not inherently neurovirulent. However, the frequent appearance of endogenous MCF viruses suggests the possibility that the interactions of amphotropic viruses with endogenous retroviral elements could contribute to the development of retrovirus-induced neurodegenerative disease.

Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis.

Experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, can be induced by immunization with a number of myelin antigens. In particular, myelin oligodendrocyte glycoprotein, a central nervous system (CNS)-specific antigen expressed on the myelin surface, is able to induce a paralytic MS-like disease with extensive CNS inflammation and demyelination in several strains of animals. Although not well understood, the egress of immune cells into the CNS in EAE is governed by a complex interplay between pro and antiinflammatory cytokines and chemokines. The hematopoietic growth factor, granulocyte macrophage colony-stimulating factor (GM-CSF), is considered to play a central role in maintaining chronic inflammation. The present study was designed to investigate the previously unexplored role of GM-CSF in autoimmune-mediated demyelination. GM-CSF(-/)- mice are resistant to EAE, display decreased antigen-specific proliferation of splenocytes, and fail to sustain immune cell infiltrates in the CNS, thus revealing key activities for GM-CSF in the development of inflammatory demyelinating lesions and control of migration and/or proliferation of leukocytes within the CNS. These results hold implications for the pathogenesis of inflammatory and demyelinating diseases and may provide the basis for more effective therapies for inflammatory diseases, and more specifically for multiple sclerosis.

Systemic Hyperosmolality Improves β-Glucuronidase Distribution and Pathology in Murine MPS VII Brain Following Intraventricular Gene Transfer

Mucopolysaccharidosis VII, a classical lysosomal storage disease, is caused by deficiency of the enzyme β-glucuronidase. Central nervous system (CNS) manifestations are severe with accumulations of storage vacuoles in all cell types. Intraventricular gene transfer can lead to transduction of the ependyma, with production and secretion of β-glucuronidase into the cerebral spinal fluid and underlying cortex resulting in reversal of disease pathology restricted to the periventricular areas. We tested if systemic hyperosmolality would increase the distribution of β-glucuronidase in brain parenchyma after intraventricular virus injection. Mice were administered mannitol, intraperitoneally, 20 days after gene transfer and 1 day prior to sacrifice. Mannitol-induced systemic hyperosmolality caused a marked penetration of β-glucuronidase into the brain parenchyma. If mannitol was administered at the time of the intraventricular injection of virus, there was penetration of vector across the ependymal cell layer, with infection of cells in the subependymal region. This also resulted in increased β-glucuronidase activity throughout the brain. Sections of brains from β-glucuronidase-deficient mice showed correction of cellular pathology in the subependymal region plus cortical structures away from the ventricular wall. These data indicate that virus-mediated gene transfer to the brain via the ventricles, coupled with systemic mannitol administration, can lead to extensive CNS distribution of β-glucuronidase with concomitant correction of the storage defect. Our findings have positive therapeutic implications for the treatment of CNS disorders with gene transfer vectors and recombinant proteins.

Antigen presenting capacity of brain microvasculature in altered peptide ligand modulation of experimental allergic encephalomyelitis

Co-immunization with an altered peptide ligand (LR) partially protects SJL mice from proteolipid protein peptide 139–151-induced experimental allergic encephalomyelitis [Kuchroo, V.K., Greer, J.M., Kaul, D., Ishioka, G.Y., Franco, A., Sette, A., Sobel, R.A., Lees, M.B., 1994. A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire. J. Immunol. 153, 3326-3336; Santambrogio, L., Lees, M.B., Sobel, R.A., 1998. Altered peptide ligand modulation of experimental allergic encephalomyelitis: immune responses within the CNS. J. Neuroimmunol. 81, 1-13]. Clinical protection was noted despite extensive central nervous system inflammation observed after co-immunization with native and altered peptides. To extend our previous reports on this model, we now compare MHC class II expression and antigen presenting cell activity of cells associated with the blood–brain barrier in diseased and protected mice. Immunohistochemical studies identified MHC class II products on both the endothelial and microglial/macrophage populations. Ex vivo experiments suggested a correlation between the reduced clinical disease observed in the co-immunized mice and the antigen presenting activity of cells at the blood–brain barrier. The results suggest that antigen presenting activity is primarily mediated by macrophage-lineage cells of the central nervous system.

Late-Onset Chronic Inflammatory Encephalopathy in Immune-Competent and Severe Combined Immune-Deficient (SCID) Mice with Astrocyte-Targeted Expression of Tumor Necrosis Factor

To examine the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of degenerative disorders of the central nervous system (CNS), transgenic mice were developed in which expression of murine TNF-alpha was targeted to astrocytes using a glial fibrillary acidic protein (GFAP)-TNF-alpha fusion gene. In two independent GFAP-TNFalpha transgenic lines (termed GT-8 or GT-2) adult (>4 months of age) animals developed a progressive ataxia (GT-8) or total paralysis affecting the lower body (GT-2). Symptomatic mice had prominent meningoencephalitis (GT-8) or encephalomyelitis (GT-2) in which large numbers of B cells and CD4+ and CD8+ T cells accumulated at predominantly perivascular sites. The majority of these lymphocytes displayed a memory cell phenotype (CD44high, CD62Llow, CD25-) and expressed an early activation marker (CD69). Parenchymal lesions contained mostly CD45+ high, MHC class II+, and Mac-1+ cells of the macrophage microglial lineage with lower numbers of neutrophils and few CD4+ and CD8+ T cells. Cerebral expression of the cellular adhesion molecules ICAM-1, VCAM-1, and MAdCAM as well as a number of alpha- and beta-chemokines was induced or upregulated and preceded the development of inflammation, suggesting an important signaling role for these molecules in the CNS leukocyte migration. Degenerative changes in the CNS of the GFAP-TNFalpha mice paralleled the development of the inflammatory lesions and included primary and secondary demyelination and neurodegeneration. Disease exacerbation with more extensive inflammatory lesions that contained activated cells of the macrophage/microglial lineage occurred in GFAP-TNFalpha mice with severe combined immune deficiency. Thus, persistent astrocyte expression of murine TNF-alpha in the CNS induces a late-onset chronic inflammatory encephalopathy in which macrophage/microglial cells but not lymphocytes play a central role in mediating injury.

Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin’s lymphoma

Chronic carriers of Hepatitis B virus (HBV) infection, who are treated for malignant lymphoma, are at high risk of mortality from reactivated HBV infection. We report a case of a 29-year-old male chronic HBV carrier who developed fulminant reactivated HBV infection following intensive chemotherapy for stage IVB large cell B-cell non-Hodgkin's lymphoma associated with extensive central nervous system and bone marrow involvement. Prior to chemotherapy the patient had normal liver function tests and was negative for HBV DNA by semiquantitative PCR assay. Fulminant HBV reactivation was confirmed following clinical deterioration, massive rises in hepatic transaminases (peak alanine aminotransferase = 2,850 U/l), liver biopsy and rising levels of serum HBV DNA. Following treatment with lamivudine 150 mg bd for 18 weeks dramatic and sustained recovery ensued. Symptoms and liver function tests improved within days and HBV DNA became negative within 12 weeks. Our patient later died from relapsed lymphoma but without evidence of reactivated HBV infection. We advise that lamivudine should be considered during intensive chemotherapy treatment of chronic carriers of HBV.

Recognition of Central Nervous System Metastases in Children with Metastatic Primary Extracranial Neuroblastoma

In children with primary extracranial neuroblastoma (NB), intrinsic central nervous system (CNS) metastases (brain parenchyma or leptomeninges) are thought to occur rarely. This study was done to evaluate our anecdotal experience, which suggested that CNS involvement is becoming more frequent. Reports of computed tomographic (CT) and magnetic resonance (MR) imaging scans, biopsies, cerebrospinal fluid (CSF) cytologies, and autopsies were reviewed for children with stage TV NB diagnosed in 1978-1993 and followed at the Children's Hospital of Pittsburgh. Of 43 children over the age of 1 year, CNS metastases were documented in 7 (16.2%). Six patients developed signs or symptoms best explained by the presence of CNS tumor and had radiographic and/or histologic evidence of parenchymal disease (cortical masses on CT and MR, n = 3; suprasellar mass on CT, n = 1; diffuse leptomeningeal carcinomatosis by MR and/or autopsy, n = 2). CSF cytologies were positive in the one patient so tested. An additional asymptomatic patient had extensive CNS involvement at autopsy. In two of these children, the CNS was the first or only site of recurrent disease. It is concluded that intrinsic CNS disease is not uncommon in children with NB over the age of 1 year and there has been a trend toward its increasing recognition in recent years. Whether this is a function of wider use of diagnostic tools or a true change in natural history over time with increased intensity of chemotherapy is not clear. A study that prospectively monitors children with advanced neuroblastoma, radiographically and with CSF cytologies (prior to treatment and at 6-monthly intervals), is under way and should help to better define the natural history in the context of current therapies.

Cell fate decisions in the grasshopper central nervous system

The central nervous system (CNS) of grasshopper embryos is similar in organization to the embryonic Drosophila CNS, but its neurons are much larger. The recent development of a culture system in which extensive CNS development occurs has allowed new types of experiments to be performed, including perturbation of gene expression within single neuroblast lineages.

The role of neurogenetics in Gaucher disease.

Gaucher disease is the most prevalent hereditary metabolic storage disorder, and the most common genetic disease in individuals of Ashkenazic Jewish ancestry. Patients with Gaucher disease have been classified into three clinical phenotypes. Patients with type 1 disease exhibit markedly variable hepatosplenomegaly, anemia, thrombocytopenia, skeletal, and, to a lesser extent, pulmonary and kidney involvement. The central nervous system does not appear to be involved. In patients with type 2 Gaucher disease, hepatosplenomegaly and extensive central nervous system damage are apparent in infancy. These patients usually die between 1 and 2 years of age. Patients with type 3 Gaucher disease have been subclassified into types 3a and 3b. Type 3a patients exhibit mild-to-moderate hepatosplenomegaly and slowly progressive neurologic deterioration. Recurrent myoclonic seizures are common. Patients with type 3b Gaucher disease exhibit splenomegaly along with extensive hepatomegaly that is frequently accompanied by esophageal varices. Horizontal supranuclear gaze paresis is the major neurologic sign. Excessive quantities of glucocerebroside accumulate in the organs of patients with Gaucher disease because of a deficiency of the enzyme glucocerebrosidase. In the vast majority of patients, the reduction of glucocerebrosidase activity is caused by mutations in the gene that codes for glucocerebrosidase. In a few instances, glucocerebroside accumulates due to a lack of saposin C, a cohydrolase that is required in addition to glucocerebrosidase for the catabolism of glucocerebroside. Mutations in the glucocerebrosidase gene are discussed in the context of the severity of disease and the presence or absence of nervous system involvement. Enzyme replacement therapy is highly beneficial for patients with type 1 Gaucher disease. Enzyme replacement is also being investigated for patients with type 3b Gaucher disease. Novel procedures must be developed to deliver glucocerebrosidase to the nervous system so that patients with type 2 and type 3a Gaucher disease can be helped. Exploration of gene therapy for Gaucher disease is under way.

Dose-dependent effects of prenatal ethanol exposure in the guinea pig

The guinea pig is an appropriate animal for studying ethanol central nervous system (CNS) teratogenesis due to its extensive prenatal CNS development. In order to establish an ethanol dosage regimen that produces CNS teratogenesis, the objective of this study was to characterize the dose-dependent effects of chronic ethanol administration on pregnancy outcome and locomotor activity of the offspring. Pregnant guinea pigs received one of the following oral treatments, via intubation into the oral cavity, throughout gestation: 3, 4, 5, or 6 g ethanol/kg maternal body weight/day; isocaloric sucrose and pair feeding; or water. The 5 and 6 g ethanol/kg/day regimens produced maternal death, spontaneous abortion, and perinatal death with at least 75% incidence; the 3 and 4 g ethanol/kg/day regimens produced little or no maternal, embryonic/fetal, or perinatal lethality. The 3 and 4 g ethanol/kg/day regimens did not affect other indices of pregnancy outcome compared with the respective isocaloric-sucrose pair-fed control animals and water-treated animals. The 3, 4, and 5 g ethanol/kg/day regimens increased spontaneous locomotor activity in the offspring, and there was a direct relationship between the magnitude of hyperactivity at days 10 and 60 of age and each of the ethanol dosage regimens and the maternal blood ethanol concentration on day 56 of gestation. The data demonstrate that, in the guinea pig, chronic oral administration of ethanol produces: (a) dose-dependent effects on pregnancy outcome, (b) hyperactivity in the offspring that is dose- (and maternal blood ethanol concentration-) and age-related, and (c) persistent hyperactivity into adulthood with minimal toxicity on pregnancy outcome for the 4 g ethanol/kg/day regimen.