Terminal deoxynucleotidyl transferase (TdT)-positive cells in cerebrospinal fluid and development of overt CNS leukemia: a 5-year follow-up study in 113 children with a TdT-positive leukemia or non-Hodgkin's lymphoma.

We investigated whether an indirect nuclear terminal deoxynucleotidyl transferase (TdT) immunofluorescence (IF) assay on single cells present in the cerebrospinal fluid (CSF) is more effective than conventional cytomorphology for early detection or exclusion of (minimal) meningeal leukemic infiltration in patients with a TdT+ malignancy. During a 5-year follow-up study, 1,661 consecutive CSF samples from 113 children with a TdT+ acute lymphoblastic leukemia (ALL) (n = 100), a TdT+ acute nonlymphoblastic leukemia (ANLL) (n = 8), or a TdT+ non-Hodgkin's lymphoma (NHL) (n = 5) were analyzed. In 1,511 (91.9%) of 1,643 evaluable CSF samples, the positive and negative findings of both cytomorphology and the TdT-IF assay were concordant. In 47 (2.9%) samples from 28 patients, the cytomorphology was suspect while the TdT-IF assay was negative; follow-up as long as 58 months revealed no CNS leukemia in any patient. In 85 (5.2%) samples, cytomorphology was negative (n = 70) or suspect (n = 15) but TdT+ cells were detected. RBC contamination seriously hampered evaluation in 31 of these 85 samples. From the remaining 54 TdT+ samples from 29 patients, 40 samples preceded overt CNS leukemia in 20 patients. Two consecutive findings of TdT+ cells in the CSF were always followed by overt CNS leukemia. At initial diagnosis, 11 children had TdT+ cells in their RBC-free CSF. In one of these children, morphology was suspect; a repeated lumbar puncture was positive on both assays. Thus, initial CNS leukemia was diagnosed. In the other ten children, morphology was negative. In six of them, CNS leukemia was diagnosed 2 to 20 months later. In 32 other children examined at initial diagnosis, neither TdT+ cells nor blasts were observed in the CSF. In none of these patients was a CNS leukemia diagnosed after a follow-up of 2.5 to 57 months (median 24 months). In 207 control CSF samples from 58 children with TdT- oncologic, hematologic, or infectious diseases, no TdT+ cells could be detected. The TdT-IF assay is easy to perform and is a more reliable diagnostic tool for detection of CNS leukemia at an early stage than is cytomorphology. At initial diagnosis, the finding of Tdt+ cells in a RBC-free CSF sample with a negative cytomorphology is highly predictive for development of overt CNS leukemia.

Tumor necrosis factor inhibits the development of viral meningitis or induces rapid death depending on the severity of inflammation at time of administration.

Administration of human rTNF to both male and female mice with severe, but clinically inapparent, lymphocytic choriomeningitis caused death within 2 to 3 h. The development of fatal symptoms was accompanied by a two- to threefold reduction in the number of cells present in the cerebrospinal fluid, with this effect being more apparent in female mice. Giving the same dose of rTNF earlier in the course of the disease was not fatal and reduced the level of subsequent meningitis. In addition, prior exposure to rTNF protected against the acute development of lethal disease when a second dose of the cytokine was given later. The extent of this "tolerance" to rTNF was directly related to the degree of reduction of the inflammatory process resulting from the primary exposure to the cytokine.

Cerebrospinal fluid manifestations of the neurologic complications of human immunodeficiency virus infection.

Cerebrospinal fluid (CSF) cytology, white blood cell (WBC) count and protein were evaluated in 32 human immunodeficiency virus (HIV)-infected patients with the acquired immune deficiency syndrome (AIDS) or an AIDS-related complex who manifested a variety of neurologic symptoms. Of 17 patients with AIDS-related encephalitis (ARE), 13 had hypocellular CSFs; elevated WBCs and pleocytosis were noted in 4, multinucleated giant cells in 2 and elevated CSF protein was found in 4 of 8 specimens tested. Three patients with central nervous system (CNS) toxoplasmosis had unremarkable CSF cytology findings, but all had elevated CSF proteins. In five patients with cryptococcal meningitis, cytologic examinations demonstrated organisms in four and elevated proteins in three. Of five patients with primary CNS lymphomas, one had cytology positive for large cell lymphoma; two showed suspicious cells and two manifested "atypical lymphocytes." Elevated CSF protein was present in four. Other conditions observed included progressive multifocal leukoencephalopathy, tubercular meningitis and cytomegaloviral (CMV) meningitis or encephalitis. Twenty-five percent of patients with ARE manifested pleocytosis with multinucleated giant cells; pleocytosis with CMV inclusions was noted in a CMV viral radiculitis. The CSF cytologic examination in HIV-infected patients with neurologic complications seems helpful in diagnosing cryptococcal meningitis and lymphoma, but less so for diagnosing toxoplasmosis.

Epstein-Barr virus-related lymphoproliferative disorders following bone marrow transplantation: an immunologic and genotypic analysis.

Four patients from 1.5 to 18 yr of age who had received partially matched T-cell-depleted bone marrow transplants for acute leukemia succumbed to a widespread lymphoproliferative disorder (LPD) at 56 to 147 days after transplant. Premortem diagnosis of LPD was suggested in two because plasmacytoid cells were observed in the blood and bone marrow, and in the cerebrospinal fluid of one of these patients. Serum clonal immunoglobulins (Igs) were also demonstrated in these two patients premortem, while the other two had clonal Igs in serum obtained at autopsy. Autopsies revealed a plasmacytoid infiltrate or immunoblastic lymphoma involving lymph nodes, spleen, liver, lungs, gastrointestinal tract, and kidneys. Immunoglobulin gene rearrangement studies performed in three revealed B-cell clonality. Both immunohistochemical and DNA gene rearrangement studies were useful in differentiating the LPD from the pretransplant leukemia. Epstein-Barr virus (EBV) genome was found in the tissues of the three patients studied. The diagnosis of EBV-induced LPD must be considered in bone marrow transplant patients who deteriorate and who exhibit serum clonal Igs or prominent plasmacytoid cells in laboratory specimens.

Cerebrospinal fluid lymphocytes from HIV-infected patients synthesize HIV-specific antibody in vitro.

Cerebrospinal fluid lymphocytes from six human immunodeficiency virus (HIV)-infected and three seronegative patients were studied for in vitro synthesis of HIV-specific antibody by means of Western blot analysis of lymphocyte culture supernatants. All the HIV-positive subjects showed in vitro production of HIV-specific IgG, regardless of neurological involvement, while no specific antibody synthesis was detected in seronegative individuals. These data provide the first direct evidence that HIV-specific antibody in cerebrospinal fluid is due to intrathecal synthesis.

Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis.

We have investigated the T cell populations in the cerebrospinal fluid (CSF) of chronic progressive multiple sclerosis (MS) patients. Individual T cells from the CSF and blood were cloned before expansion and their clonotypes were defined by analysis of rearranged T cell receptor beta chain and gamma chain genes. 87 T cell clones from blood and CSF of two patients with chronic progressive MS were examined for common TCR gene rearrangement patterns. In one patient, 18 of 28 CSF-derived T cell clones demonstrated common TCR gene rearrangements indicating oligoclonal T cell populations; in the blood, two patterns were found twice among 26 T cell clones. In another patient, 5 of 27 CSF-derived clones had common TCR gene rearrangement patterns. In contrast, no common beta chain rearrangement pattern was found among 67 T cell clones derived from the blood or CSF of a patient with subacute sclerosing panencephalitis, among 20 clones from the CSF of a patient with herpes zoster meningoencephalitis, or among 66 clones from a normal subject. A subject with atypical, fatal MS of 8-mo duration was also studied and did not have oligoclonal T cells in the CSF or blood. These results demonstrate that distinct oligoclonal T cell populations can be found in the CSF immune compartment of subjects with nonmalignant inflammatory disease and they can create a new avenue for the investigation of the specificity of the T cell response within the central nervous system.

Fast three-dimensional imaging of cerebrospinal fluid.

The RARE method is based on the principle of echo imaging to generate images with high T2 contrast. Since RARE is a fast imaging method, it can be used to acquire a high-resolution three-dimensional data set in less than 15 min. Thin slices from such a three-dimensional data set provide detailed information about the ventricular system.

Negative cultures of cerebrospinal fluid in partially treated bacterial meningitis.

Admission cerebrospinal fluid and serum were examined for antimicrobial activity in 296 Egyptian patients hospitalized with signs of meningitis. Assays were positive in 92%; 60% had large levels of antimicrobial activity in cerebrospinal fluid. Bacterial meningitis was diagnosed in 102 patients. The negative cerebrospinal fluid cultures in 58 of these patients were in part due to the antimicrobial activity in the cerebrospinal fluid. Mortality in patients with bacterial meningitis was greatest when cultures were positive and moderate levels of antimicrobial activity were present in the cerebrospinal fluid. Survival in these patients appeared to be enhanced if their prehospitalization antimicrobial use suppressed bacterial growth in the cerebrospinal fluid.

The behavior of Pantopaque on MR: in vivo and in vitro analysis.

MR imaging is considered by many to be the procedure of choice in imaging the spinal cord; yet we encountered an important pitfall of this procedure in the form of a patient with retained intraspinal Pantopaque. The results of this case are presented as well as those obtained in another patient with retained Pantopaque. Also described is the behavior of this contrast material when using in vitro imaging data obtained from a CSF/Pantopaque phantom. When T1-weighted imaging sequences are used, Pantopaque gives a high signal and CSF gives a low signal. With long repetition time, (e.g., 4000 ms), the CSF signal is high and the Pantopaque signal is not. With repetition time around 1000 to 2000, both may be isointense. The implications of these findings are discussed.

Cyclosporin-A treatment of experimental allergic encephalomyelitis: changes in immunological regulation and blood-CSF barrier function.

Strain 13 guinea pigs at 18-21 days of age were sensitised with spinal cord and Freund's complete adjuvant to induce experimental allergic encephalomyelitis (EAE). Treatment with cyclosporin-A (CS-A) from one day before sensitisation until from 12 to 39 days after sensitisation resulted in a suppression of the disease. Suppression was indicated by an absence or reduction in severity of clinical signs together with a lack of increase in blood-cerebrospinal fluid (CSF) barrier permeability to proteins and a lower white cell count in the CSF from treated animals. When CS-A treatment was withdrawn, clinical disease reappeared but changes in IgG concentration in the CSF indicated that intrathecal synthesis of IgG had occurred, which was not the case in the untreated disease. Modification by CS-A of the immunoregulatory processes involved in the development of EAE, provides a model to study the special conditions which operate in neuroimmunological disorders.

[Clinico-pathological studies of CSF dissemination of glioblastoma and medulloblastoma].

Clinico-pathological findings of CSF dissemination which was diagnosed on CT scan, were studied on 13 cases of glioblastoma and 9 cases of medulloblastoma. The type of CSF dissemination and the prognosis of patients were both different between glioblastoma and medulloblastoma. In the former, the dissemination was predominantly in ventricular walls and in the latter, in basal cisterns. The mean survival time after the diagnosis of dissemination is 6 months of glioblastoma as compared with 13 months of medulloblastoma. The Pathological studies show that subependymal and/or subpial infiltration of tumor cells, and thickness of arachnoid membrane by marked mesodermal reaction were demonstrated in cases of glioblastoma. On the contrary, tumor cells of medulloblastoma grow markedly in the subarachnoid space and/or on the ependymal layers. From these pathological findings of CSF dissemination, it will be resulted that the prognosis of glioblastoma is much more poor that of medulloblastoma.

Cerebrospinal fluid cytopathology.

Cerebrospinal fluid (CSF) evaluations represent important diagnostic procedures for many pathologic conditions of the central nervous system, such as meningitis, encephalitis, and brain tumors. The authors' discussion of CSF cytopathology includes specimen collection and cytopreparation, microscopic evaluation, cell differential and cell counting methods, and the cellular composition of pathologic CSF. The accuracy of CSF cytopathology is indicated and future trends are noted.

Unusual presentations of inflammatory conditions in cerebrospinal fluid.

Unusual inflammatory reactions in cerebrospinal fluid (CSF) in five patients were explicable by the type of intracranial injury or surgical intervention that they had received or by their basic disease process. Lumbar puncture fluid from a 64-year-old man with multiple facial fractures contained neutrophils, bacteria, Candida sp. and ciliated columnar cells, findings consistent with a basilar skull fracture allowing paranasal sinus contents to enter the subarachnoid space. A 59-year-old man with angioimmunoblastic lymphadenopathy developed meningitis and suffered a respiratory arrest; a ventricular fluid contained acute inflammatory cells as well as numerous corpora amylacea. Lumbar CSF obtained during surgery from a 26-year-old man with a pontine glioma contained numerous histiocytes clustered around polarizable filaments, probably strands of gauze introduced during surgery. A specimen of CSF obtained intraoperatively from a 54-year-old man with an acoustic neuroma undergoing a second craniotomy contained multinucleated giant cells bearing suture material. A 19-year-old girl with systemic sarcoidosis had noncaseating granulomas in the right temporal lobe and multinucleated giant cells in her CSF.

The use of C-reactive protein from cerebrospinal fluid for differentiating meningitis from other central nervous system diseases.

C-reactive protein (C-RP) determinations were performed by using the latex slide agglutination test on cerebrospinal fluid (CSF) from 235 patients. The patients were categorized into the following groups: bacterial meningitis (n = 74); viral meningitis (n = 10); fever without bacterial meningitis (n = 80); neurological symptoms without infection (n = 25); intracranial hemorrhage (n = 10); increased intracranial pressure that was secondary to pseudotumor cerebri or hydrocephalus (n = 16); and malignancies (n = 20). On the initial lumbar puncture, the C-RP was positive in 97% (72 of 74) of the patients in group 1, as compared with 0% (0 of 10), 6% (5 of 80), 20% (5 of 25), 50% (5 of 10), 6% (1 of 16), and 30% (6 of 20) in groups 2-7, respectively (P less than .0001). The C-RP test was able to detect bacterial meningitis with a sensitivity of 97% (72 of 74), a specificity of 86% (139 of 161), a positive predictive value of 77% (72 of 94), and a negative predictive value of 99% (139 of 141). These data indicate that C-RP determinations performed on CSF are useful and rapid clinical tests for the exclusion of the presence of bacterial meningitis in a patient.

The induction of meningeal inflammation by components of the pneumococcal cell wall.

Pneumococcal cell wall induces meningeal inflammation in rabbits injected intracisternally with greater than 10(5) cell equivalents. Both of the major cell wall components, teichoic acid and peptidoglycan, contribute to this inflammatory activity although responses differ depending on the chemical nature, size, and complexity of these fractions. Challenge with teichoic acid (membrane or wall associated) results in greater inflammation at 5 hr than at 24 hr. Degraded teichoic acid is inactive. In contrast, the inflammation caused by whole cell wall or high-molecular-weight peptidoglycan-containing fractions increases in intensity from 5 to 24 hr. Peptidoglycan fractions lose activity at 24 hr when hydrolyzed to disaccharide-stem peptide moieties. Generation of free cell wall components in cerebrospinal fluid as, for example, during treatment with antibiotics that are bacteriolytic as well as bactericidal, could contribute to increased inflammation in the subarachnoid space.

Lack of validity of standard corrections for white blood cell counts of blood-contaminated cerebrospinal fluid in infants.

An evaluation of the validity in infants of standard computations for the correction of white cell counts in blood-contaminated cerebrospinal fluid (traumatic lumbar puncture) was undertaken. In 39 infants with significant blood contamination (greater than 10(4) red blood cells/microL) and no evidence of bacterial meningitis, both calculated corrections based on simultaneously obtained complete blood counts and estimated corrections based on average values resulted in overcorrection in a majority of cases (33 of 39 and 25 of 39, respectively). The mechanism of this overcorrection could not be defined. In eight infants with significant blood contamination and proven bacterial meningitis, correction computations normalized or overcorrected the white cell count in one case. It appears that standard computations frequently overcorrect white cell counts in blood-contaminated cerebrospinal fluid and that the magnitude of the overcorrection may obscure pathologic states in some cases.

Immunocytochemical identification and quantitation of the mononuclear cells in the cerebrospinal fluid, meninges, and brain during acute viral meningoencephalitis.

The mononuclear cells of the central nervous system (CNS) inflammatory response were characterized in cerebrospinal fluid (CSF), meningeal exudate, and brain parenchyma of mice 3-14 d after infection with Sindbis virus. The inflammatory infiltrate in CSF peaked and resolved before that of the parenchyma or meningeal exudate. Immunoperoxidase staining with monoclonal antibodies identified CSF inflammatory cells to be almost exclusively T cells, while inflammatory cells in the brain parenchymal perivascular cuffs and the meninges were a mixture of T cells, B cells, and macrophages. The percentage of B cells and macrophages increased at the later time points. Approximately 20% of CSF and 50% of the cells present early in the perivascular cuffs were not identified, suggesting that another subset of inflammatory cells may be present. We concluded that significant differences exist in the time course and cellular composition of the inflammatory responses in different compartments of the CNS during an acute viral infection.

Cytologic findings in homosexual males with acquired immunodeficiency.

During a three-year period (1979 to 1982), 248 cytology specimens were obtained from 38 homosexual males who were admitted for treatment and had a variety of nonspecific symptoms, such as general malaise and weight loss. Twenty patients had Kaposi's sarcoma. Exfoliative and aspiration/brush specimens were prepared mainly from cerebrospinal fluids and tracheobronchial secretions. One hundred twenty-four specimens were of diagnostic value, exhibiting cytologic abnormalities: acute inflammation (11 specimens), marked cellular atypia (39 specimens), increased number of mature and immature lymphoreticular elements (31 specimens) and organisms such as parasites and fungi (43 specimens). Awareness of an epidemic of acquired immuno-deficiency-associated disease among male homosexuals, in conjunction with special processing and careful interpretation of cytologic specimens, contributed to the identification of organisms and the ruling out of malignancy. Despite prompt treatment, a swiftly progressive clinical course resulted in the death of 20 patients.