Receptor-mediated transfer of IgG and albumin at cerebrospinal fluid interfaces.

Receptor-mediated transfer of IgG and albumin has been suggested to occur also at cerebrospinal fluid interfaces. We point out findings of statistically unchanging IgG/albumin ratios along the lumbar CSF column which propose that such transfer should be absent or very small at cerebrospinal fluid interfaces.

Penetration of ifosfamide and its active metabolite 4-OH-ifosfamide into cerebrospinal fluid of patients with CNS malignancies.

PURPOSE: The aim of this study was to examine the penetration of ifosfamide (IFO) and 4-hydroxy-ifosfamide (4-OH-IFO) into the CSF of human adults and to evaluate the influence of blood-CSF barrier (BCB) function. METHODS: In 12 adult patients with a malignant CNS disease treated with IFO 1,300-2,000 mg/m(2)/d as a 3-hour intravenous infusion, 17 CSF samples were collected within 10 min after the end of IFO infusion. In 8 of these patients, the CSF was obtained in up to 5 sequential 2-ml portions to detect a potential caudocranial concentration gradient. Additionally, blood was collected before treatment and immediately following IFO infusion. RESULTS: IFO was detected in all 17 CSF samples at a median concentration of 79.24 µmol/l (39.27-176.73) and a median CSF/plasma ratio of 0.38 (0.18-0.72). 4-OH-IFO was detected in 11 CSF samples from 7 patients at a median concentration of 4.1 µmol/l (2.44-36.03) and a median CSF/plasma ratio of 3.07 (0.62-29.12). 4-OH-IFO was undetectable in 6 CSF samples from 5 patients and in one plasma sample. Both CSF drug concentrations and their CSF/plasma quotients neither correlated with steroid comedication nor with albumin quotients (QAlb). CONCLUSIONS: Both IFO and 4-OH-IFO can penetrate into the CSF of human adults without a correlation to CSF turnover. In contrast to IFO, 4-OH-IFO CSF penetration is not reliable with levels ranging between undetectable and exceeding those in the corresponding plasma.

Variation of barrier permeability for albumin and immunoglobulin G influx into cerebrospinal fluid.

BACKGROUND: The aim of the present study was to analyze variations in permeability of albumin and immunoglobulin G (IgG) influx into cerebrospinal fluid (CSF) in a clinical setting. METHODS: In a retrospective intra-individual comparison of CSF samples, we used the IgGIndex and its constituents to indicate alterations in IgG/albumin permeability. RESULTS: We found altered IgGIndices in 25/64 patients (range -25% to +44%), with differently altered QAlb and QIgG values (-69% to +549%), unaltered IgG-Indices in a further 25/64 patients with equally altered QAlb and QIgG values (-46% to +107%), and no parameter alteration in 14/64 patients. Parameter alterations in 25/64 patients indicated that permeability of albumin was changed to different extents than for IgG. It changed in the same direction in 20/25 patients, and the opposite in five patients. In further 25/64 patients, equal QAlb and QIgG alterations indicated equally altered permeabilities and/or altered efflux of the proteins. In 14/64 patients, no alteration in permeability or efflux was seen. CONCLUSIONS: Results revealed surprisingly variable intra-individual changes in permeabilities for albumin and IgG in pathologic as well as normal CSF. Differing changes in permeability indicate that the diffusion paths of the two proteins may react to disturbances independently of each other. The details of the influx permeability for albumin and IgG into CSF illustrate the prospect of a more comprehensive insight into the protein exchange between blood and CSF.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis.

BACKGROUND: Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. OBJECTIVE: To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. MATERIALS AND METHODS: The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. RESULTS AND DISCUSSION: Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158-189%, intraindividual range of CV of plasma Mtx levels 35-64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively (r=-0.7), which reflects their largely common elimination from CSF. CONCLUSION: Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

What determines the CSF concentrations of albumin and plasma-derived IgG?

OBJECTIVES: To estimate the mean influence of the main determinants of the cerebrospinal fluid (CSF) concentration of albumin and plasma-derived immunoglobulin G (IgG). METHODS: Correlations of serum and CSF concentrations of albumin and IgG and assumptions of the mode of action of the determinants (plasma concentration, barrier permeability, and CSF flow) are used to quantify the determinants' influences in a sample of 1700 patients. RESULTS: We estimated in patients with normal CSF albumin that the serum concentrations of albumin and IgG explained 3.3% and 23% of the variation of the respective CSF concentrations, whereas the barrier permeability accounted for 41.9% and 22.2%, and CSF flow for 54.8%. In patients with pathologic CSF albumin concentration, the serum concentrations were estimated to explain 0.2% and 8.2% of the variation of the respective CSF concentrations, the barrier permeability 19.7% and 11.7%, and CSF flow 80.1%. CONCLUSIONS: CSF flow had the strongest mean influence, especially at elevated CSF albumin levels. The serum concentrations and barrier permeabilities of albumin and IgG influenced the respective CSF concentrations quite differently, which should be due to the different physicochemical properties of the two molecules. Mean influences from large patient samples, as explored here, can give only an overview. Understanding the determinants in individuals will need further specific measurements, especially of CSF flow.

Progressive multifocal leukoencephalopathy with detection of JC virus in a patient with chronic lymphocytic leukemia parallel to onset of fludarabine therapy.

Along with the establishment of more intense chemotherapeutic regimens including fludarabine for the treatment of indolent lymphoproliferative diseases like chronic lymphocytic leukemia (CLL), an increasing amount of cases with progressive multifocal leukoencephalopathy (PML) due to JC virus have been observed. We report a patient with CLL who developed PML parallel to the onset of fludarabine therapy. Spinal fluid was tested positive for JC virus. Despite virostatic treatment with cidofovir, neurologic symptoms were progressive and the disease ultimately fatal. The present case suggests that immunosuppression caused by chronic lymphoproliferative malignancies alone may be a factor in the development of PML. Chemotherapy with fludarabine may act as an additional trigger. The question remains whether serologic screening for JC virus in patients with chronic lymphoproliferative disease undergoing intense chemotherapy might be valuable once sufficient antiviral treatment has been established.

Conditions of iodine contrast transfer from lumbosacral CSF to blood.

PURPOSE: To determine conditions which influence transfer of iopamidol from lumbosacral cerebrospinal fluid (CSF) to blood. METHODS: Iopamidol transfer was measured in 32 patients over 180 min after radiculography and compared with patient variables. RESULTS: Iopamidol transfer began early in 12 patients, more slowly in 13 patients, and was not detected during sample period in 7 patients. Transfer of sequential samples correlated highly with each other (r>0.8). Transfer was more pronounced in patients with prominent nerve root sleeves on radiculogram (p=0.006, t test), and correlated inversely with body weight (r=-0.4258), and with albumin CSF/serum quotient (r=-0.4702). CONCLUSION: Early iopamidol transfer probably indicates transfer through spinal arachnoid villi and granulations with CSF bulk flow. Prominent nerve root sleeves may facilitate access to transfer sites. No transfer during sample period suggests no such spinal transfer, possibly due to sparse access to or presence of spinal transfer sites. Inverse correlation of transfer with body weight may reflect influence of body weight on retroperitoneal venous pressure, which regulates outflow of CSF and of compounds dissolved in it. Awareness of wide interindividual transfer variation and steady intraindividual transfer may help to specify dosage and effect expectation of intrathecal drug therapy.

Determinants of lumbar CSF protein concentration.

OBJECTIVE: To determine factors influencing the wide variation of protein concentration in lumbar cerebrospinal fluid (CSF). METHODS: Patient variables with potential influence on spinal CSF flow and resorption were measured in different patient settings and compared with albumin and IgG CSF/serum quotients. RESULTS: In patients whose diagnostic lumbar puncture produces normal CSF the albumin quotient increased with body mass index (r = 0.408), abdominal circumference (r = 0.399), and body weight (r = 0.317), age-corrected with partial correlation. Body motion before lumbar puncture showed only marginal influence on albumin quotient. In patients with radiculography the albumin quotient decreased with iodine contrast medium elimination from spinal subarachnoid space (r = -0.598) and increased with narrowing of lumbosacral spinal canal (r = 0.515). CONCLUSION: Correlation of albumin quotient with body mass index and related variables may be mediated by spinal CSF resorption, which should be impaired in overweight patients with elevated venous pressure. Negative correlation of albumin quotient with iodine resorption from spinal CSF supports this assumption. Correlation of albumin quotient with narrowing of lumbosacral canal should be due to slowed spinal CSF flow which does increase protein concentration. Tested variables explain part of variation of CSF protein concentration. Other variables like blood-CSF barrier permeability and pulsatile spinal CSF flow should have additional influence.