CSF analysis of IgH gene rearrangement in CNS lymphoma: relationship to the disease course

PURPOSE: To assess whether clonal IgH genes in CSF of patients with CNS lymphoma correlates with the disease course. BACKGROUND: It has been shown that the PCR technique, which offers a sensitive test for diagnosis of systemic lymphoproliferative malignancies, can be applied to the CSF. METHODS: Seventy-three CSF specimens from 32 patients (27 with primary CNS lymphoma and 5 with an isolated parenchymal CNS relapse of systemic lymphoma) were examined. The results were evaluated retrospectively and compared to conventional cytology, clinical and imaging data, and course of the disease. CNS disease was defined as active when leptomeningeal and/or parenchymal brain involvement was evident on neuroimaging. Patients were considered to have a complete response when imaging confirmed absence of a tumor mass or leptomeningeal seeding. RESULTS: Sixty-three of 73 samples had adequate genetic material for testing. Of the 63, 15 (24%) were positive for clonal IgH rearrangement. In nine (60%) of the 15 patients with active disease, PCR results were positive, while negative results were observed in 19 (95%) of the 20 patients showing clear response to treatment. The sensitivity and specificity of the PCR evaluation were 54% and 97%, respectively. The predictive values of positive and negative tests were 93% and 74%, respectively. CONCLUSIONS: The integrated results of both PCR and cytology evaluations increase the sensitivity of CSF analysis. The PCR study has high specificity and positive results are indicative for the presence of active disease, even when the tumor seems confined to the brain parenchyma.     

Electrolytes in the CSF of hydrocephalic patients (author's transl)]

The concentrations of Na+, K+, Cl-, Ca++, and Mg++ were measured in the CSF and serum of controls and in those of patients with hydrocephalus. Hydrocephalus was proved with pneumoencephalography. The amounts of Na+, K+, Ca++, and Mg++ were significantly higher in the CSF of patients with hydrocephalus than in the CSF of controls. The changes in the electrolyte concentration gradients seem to indicate that it is not the blood-brain barrier but the brain-CSF barrier which is disturbed in hydrocephalus.     

On the relationship of CSF pleocytosis to immunoglobulin levels as estimated by different techniques

One might expect a positive correlation between the number of CSF lymphocytes and the relative amount of CSF IgG, especially in cases of local synthesis of IgG within the CNS. However, previous attempts at correlating the number of CSF lymphocytes with IgG levels have yielded varying results. Since it is known that the estimation of CSF IgG levels can vary according to the method of immunoglobulin determination used, we decided to perform the analyses by three separate methods: (1) the commonly used, immunoprecipitation technique of radial immunodiffusion; (2) physico-chemical separation on the basis of hydrated size/charge using alkaline electrophoresis through the molecular sieving effects of polyacrylamide gels, followed by densitometry of the gamma region of Coomassie Blue-stained proteins; (3) separation into constituent Ig heavy chains and light chains on the basis of unfolded chain lengths by molecular sieving using sodium dodecyl sulphate (SDS), followed by densitometry of heavy chains of immunoglobulins having been labelled with the fluorescent dye dansyl chloride. Our results show a correlation of white count with the latter two techniques but not the former. Possible reasons for discrepancies in the literature are discussed with regard to the peculiar physical properties of the selected CSF IgG molecules.     

Humoral CSF parameters in the differential diagnosis of hematologic CNS neoplasia

Cerebrospinal fluid (CSF) and serum samples of 20 patients with central nervous system manifestations of hematological malignancies including primary cerebral lymphoma (n = 5) and disseminated non-Hodgkin lymphoma (n = 7) were examined for albumin, IgG, IgM, fibronectin, beta 2-microglobulin, interleukin-6, soluble interleukin-2 receptor, tumor necrosis factor alpha, and oligoclonal immunoglobulin bands. Although a broad range of abnormalities were detected, no reliable CSF parameter for the diagnosis of leptomeningeal spread from hematological neoplasias could be identified. An analysis of 61 repeat lumbar punctures added little to the findings of the first CSF examinations. Currently, immunochemical studies of CSF cell surface markers and early biopsy have probably more clinical value than the determination of the humoral CSF parameters included in this study. However, analysis of cytokine synthesis by single CSF cells using molecular biology techniques may improve the differential diagnosis of hematological neoplasia of the brain and spinal cord in the future.     

Differential diagnosis of malignant and benign lymphomas of the CNS (author's transl)]

The following results were obtained from 37 cases of malignant lymphomas, including 8 eosinophilic granulomas: 1. Localisation: a. Plasmocytomas occur with approximately the same frequency in the spine and skull, but there is an exceptionally high incidence of multiple myelomas in the thoracic spine. Only in a few cases plasmocytomas of the skull lead to neurological symptoms; particularly when they are localised in the base of the skull. b. Lymphogranulomatosis affects only the thoracic vertebral column and leads less frequently to neurological complications compared with the multiple myelomas. c. Eosinophilic granulomas often attack the calvaria, but can also be found in the spine, the base of the cranium and the flat bones of the pelvis and the scapula. d. Leukaemias showed mainly intracerebral and intramedullary alterations: haemorrhages, leukaemic infiltrations and signs of degeneration. 2. Clinical findings: a. Whenever the calvarium was affected than repeated complaints of headaches prevailed and only very few neurological signs or symptoms were complained. b. Tumors in the base of the cranium caused eye symptoms and various cranial nerve palsies but less frequently increased intracranial pressure. c. Tumors localised in the region of the spinal cord caused early signs like root-irritations (intercoastal neuralgia), diffuse dorsal pain and/or lumbalgia. Symptoms of spinal compression generally of an ascending character then developed within a few weeks. d. Neurological symptoms were the first to manifest themselves in all cases of plasmocytoma in half of our patients with Hodgkin's disease. 3. History and course: a. Generally in the cases of cranial involvement the previous history was less than half a year (visible changes or clear cut symptoms). Spinal tumors on the average had longer histories as did other extra-medullar spinal new growth. Similar courses were seen in multiple myelomas and granulomas. b. Solitary plasmocytomas were very rare but seem to have a considerably better prognosis than in case of multiple occurrence.     

Evidence for the production of peroxynitrite in inflammatory CNS demyelination

Peroxynitrite, which is generated by the reaction of nitric oxide (NO) with superoxide, is a strong oxidant that can damage subcellular organelles, membranes and enzymes through its actions on proteins, lipids, and DNA, including the nitration of tyrosine residues of proteins. Detection of nitrotyrosine (NT) serves as a biochemical marker of peroxynitrite-induced damage. In the present studies, NT was detected by immunohistochemistry in CNS tissues from mice with acute experimental autoimmune encephalomyelitis (EAE). NT immunoreactivity was displayed by many mononuclear inflammatory cells, including CD4+ cells. It was also observed in astrocytes near EAE lesions. Immunostaining for the inducible isoform of NO synthase (iNOS) was also observed, particularly during acute EAE. These data strongly suggest that peroxynitrite formation is a major consequence of NO produced via iNOS, and implicate this powerful oxidant in the pathogenesis of EAE.     

中枢神经系统炎性脱髓鞘损伤髓鞘再生的细胞学治疗

多发性硬化（MS）损伤的病理特征是髓鞘脱失。髓鞘再生近年来被认为是自身免疫性脱髓鞘疾病，尤其是MS治疗中非常有前景的方向。髓鞘再生治疗可分为内源性和外源性，所以大量的临床和实验研究都集中于通过外源性移植细胞或通过促进内源性再生机制来获得中枢神经系统脱髓鞘区域的髓鞘再生，并均取得一定的成功。本文对近年来MS髓鞘再生的细胞学治疗的现状和神经科学背景及再生髓鞘治疗的将来可能发展方向进行了评述。     

Immunologic diagnostic of blood CSF barrier in the course of delirium tremens (author's transl)

Fifty chronic alcoholics with acute withdrawal (in the state of delirium tremens) were examined initially and in the following weeks by quantitatively testing immunoglobulins in the serum and in the cerebrospinal fluid to study the dynamics of the blood-CSF barrier. Compared -to other persons of the same age, acutely delirious patients show a pathologic IgG-IgA constellation in the CSF which does not depend on the serum. That points to an infrastructural barrier function disorder. After 2--4 weeks, delirium tremens, normally in the process of recovering, shows distinct sanitation of the immunologic spectrum of the CSF. With regard to their dynamic proceedings, the results confirm other findings on brain metabolism, biochemistry, neurophysiology, and pathologic anatomy during delirium tremens. The totally and progressively disturbed blood-CSF barrier system of complicated cases of delirium tremens (e.g., Korsakov's and Wernicke's syndromes) seems to provide the possibility of deterioration of the clinical syndrome. The method, simple to implement in the laboratory, permits not only an overall evaluation of the dynamic blood-CSF barrier function in acute and postdelirious state, but also provides both the possibility to diagnose a persistent infrastructural residual syndrome and to indicate a pathophysiologic complication of the clinical course.     

IgM immunoglobulin in cerebrospinal fluid in cases of multiple sclerosis (preliminary report)]

In cases of multiple sclerosis, central nervous system syphilis and other neurological diseases the IgM was determined in the cerebrospinal fluid by means of radial diffusion. The control group comprised patients with neurosis. It was found that IgM determinations must be done in concentrated fluid when this method is used. Raised total and percent level of IgM in the cerebrospinal fluid was observed in 8 out of 29 cases of multiple sclerosis in the acute phase of the disease.     

New tools to trace populations of inflammatory cells in the CNS

Cells of the central nervous system (CNS) and immune system communicate regularly. There is a constant surveillance of the intact, healthy CNS by activated T-cells, and massive infiltration of the CNS by immune cells under pathological conditions such as neurodegeneration or neuroinflammation. Labeling CNS-infiltrating T-cells is an essential tool to identify the signals and mechanisms, which mediate the interaction between immune cells and cells of the CNS. In this article, we will present an overview describing currently used cellular markers and demonstrate how these markers have contributed to our current knowledge of CNS inflammation and immune surveillance.