Cerebrospinal Fluid Flow Rate Research Articles

Reduced Brain Delivery of Homovanillic Acid to Cerebrospinal Fluid During Human Aging

Markers of human brain dopamine metabolism are reported to decline with age. However, the cerebrospinal fluid (CSF) concentration of homovanillic acid (HVA), a major dopamine metabolite, is reported to not change or to increase in elderly individuals. To estimate the rate of delivery of HVA from the brain to CSF, taking into account the HVA concentration gradient in the spinal subarachnoid space and CSF flow. Homovanillic acid concentrations were measured in 5 serial 6-mL aliquots of CSF removed from the L3-4 or L4-5 interspaces of 7 healthy young (mean +/- SD age, 28.7 +/- 4.6 years) subjects and 7 healthy elderly (mean +/- SD age, 77.1 +/- 6.3 years) subjects. Cisterna magna HVA concentrations were estimated from the slopes of the HVA concentrations along the spinal subarachnoid space. The products of cisternal HVA concentrations and published values for CSF flow were used to estimate lower limits for brain delivery of HVA to CSF, according to the Fick principle. The mean +/- SD HVA concentration in the initial lumbar CSF sample in the young subjects, 116 +/- 66 pmol/mL, did not differ significantly from 140 +/- 86 pmol/mL in the elderly subjects. Estimated cisternal HVA concentrations equaled 704 and 640 pmol/mL, respectively, in the young and elderly subjects. Multiplying these concentrations by CSF flow rates of 591 and 294 mL/d, respectively, gave lower limits for rates of delivery of HVA from the brain to CSF. These rates equaled 416 and 175 nmol/d, respectively. A 50% decline in the lower limit for the rate of HVA delivery from the brain to CSF in elderly individuals is consistent with other evidence that brain dopaminergic neurotransmission declines with age.

760 Management of Hydrocephalus Using a Noninvasive Magnetic Resonance Imaging Method for Measurement of Intracranial Compliance and Pressure

INTRODUCTION: Measurements of intracranial compliance (ICC) and intracranial pressure (ICP) are clinically important in the management of patients with hydrocephalus, especially when treating patients with possible shunt malfunction. In this work, we present a noninvasive magnetic resonance imaging (MRI) technique for determination of ICP and ICC. Using standardized measurements obtained from normal patients and patients with severe head trauma (with ICP monitors) we now applied this method to patients with hydrocephalus. METHODS: The compliance index is derived from the measured changes in the ICP and volume of blood and cerebrospinal fluid (CSF) in the intracranial space that occur naturally during each cardiac cycle, obtained with a motion-sensitive MRI scan. Intracranial volume and ICP changes are calculated from MRI measurements of CSF flow and blood volumetric flow rates. The change in pressure is derived from the pressure gradient calculated from velocity. Twenty patients presenting with symptoms suggestive of symptomatic hydrocephalus were studied to determine the need for surgery. RESULTS: The clinical cases included congenital hydrocephalus (some of which had no shunt surgery for >10 yr), tumor, toxoplasmosis, slit ventricles, aqueductal stenosis, and Chiari malformation. Patients presented with a variety of symptoms, including headaches, visual blurring, seizures, neck pain, nausea/vomiting, gait disturbances, and lethargy. This technique correctly identified three patients requiring surgery, and ICP measured at surgery correlated with MRI-ICP. Two patients with third ventriculostomies and enlarged ventricles avoided surgery because extraventricular drain (EVD) measurements correlated with normal MRI-ICP. In three patients with EVDs, pressures correlated with low MRI-ICP measurements. Nonsurgical cases were closely observed and have remained stable. CONCLUSION: These results suggest MRI-ICP sensitivity sufficient to differentiate between normal and elevated ICP in patients with a variety of subtypes of hydrocephalus. Noninvasive MRI-ICP may be a useful tool in the determination of the need for a shunt or shunt revision and may enable patients to avoid unnecessary surgery or invasive monitoring procedures.

760 Management of Hydrocephalus Using a Noninvasive Magnetic Resonance Imaging Method for Measurement of Intracranial Compliance and Pressure

INTRODUCTION: Measurements of intracranial compliance (ICC) and intracranial pressure (ICP) are clinically important in the management of patients with hydrocephalus, especially when treating patients with possible shunt malfunction. In this work, we present a noninvasive magnetic resonance imaging (MRI) technique for determination of ICP and ICC. Using standardized measurements obtained from normal patients and patients with severe head trauma (with ICP monitors) we now applied this method to patients with hydrocephalus. METHODS: The compliance index is derived from the measured changes in the ICP and volume of blood and cerebrospinal fluid (CSF) in the intracranial space that occur naturally during each cardiac cycle, obtained with a motion-sensitive MRI scan. Intracranial volume and ICP changes are calculated from MRI measurements of CSF flow and blood volumetric flow rates. The change in pressure is derived from the pressure gradient calculated from velocity. Twenty patients presenting with symptoms suggestive of symptomatic hydrocephalus were studied to determine the need for surgery. RESULTS: The clinical cases included congenital hydrocephalus (some of which had no shunt surgery for >10 yr), tumor, toxoplasmosis, slit ventricles, aqueductal stenosis, and Chiari malformation. Patients presented with a variety of symptoms, including headaches, visual blurring, seizures, neck pain, nausea/vomiting, gait disturbances, and lethargy. This technique correctly identified three patients requiring surgery, and ICP measured at surgery correlated with MRI-ICP. Two patients with third ventriculostomies and enlarged ventricles avoided surgery because extraventricular drain (EVD) measurements correlated with normal MRI-ICP. In three patients with EVDs, pressures correlated with low MRI-ICP measurements. Nonsurgical cases were closely observed and have remained stable. CONCLUSION: These results suggest MRI-ICP sensitivity sufficient to differentiate between normal and elevated ICP in patients with a variety of subtypes of hydrocephalus. Noninvasive MRI-ICP may be a useful tool in the determination of the need for a shunt or shunt revision and may enable patients to avoid unnecessary surgery or invasive monitoring procedures.

Use of Cerebrospinal Fluid Flow Rates Measured by Phase-Contrast MR to Predict Outcome of Ventriculoperitoneal Shunting for Idiopathic Normal-Pressure Hydrocephalus

To determine whether favorable clinical response and magnitude of improvement are associated with increased aqueductal cerebrospinal fluid (CSF) flow rates in patients who undergo ventriculoperitoneal shunting (VPS) for idiopathic normal-pressure hydrocephalus (NPH). Between January 1995 and June 2000, 49 patients (14 men and 35 women; mean age, 72.9 years; range, 54-88 years) underwent magnetic resonance quantification of aqueductal CSF flow followed by VPS for presumed idiopathic NPH at the Mayo Clinic, Rochester, Minn. Logistic regression models for the odds of any improvement in score as a function of aqueductal CSF flow and separate models for any improvement in gait, incontinence, cognition, and total score were constructed. Forty-two patients (86%) had improvement in gait at postoperative follow-up (mean, 10 months). Of the 32 patients with incontinence, 27 (69%) improved. Of the 36 patients with cognitive impairment, 16 (44%) improved. In univariate and fully adjusted models, increased CSF flow through the aqueduct was not significantly associated with improvement or the magnitude of improvement in gait, cognition, or incontinence. Thirty-six patients underwent high-volume lumbar puncture preoperatively, of whom 5 (14%) had no response. The aqueductal CSF flow rates of these 5 patients were significantly higher than those of the patients who improved after lumbar puncture. Postoperative complications occurred in 15 patients. The aqueductal CSF flow rates in these 15 patients were not significantly different from those of patients who experienced no complications. Among patients who underwent VPS for the treatment of NPH, measurement of CSF flow through the cerebral aqueduct did not reliably predict which patients would improve after shunting or the magnitude of improvement.

Dynamics of brain-derived proteins in cerebrospinal fluid

Background: The recent theory of blood–cerebrospinal fluid (CSF) barrier function and dysfunction connects molecular flux and CSF flow rate. A reduced CSF flow rate is sufficient to account for the observed hyperbolic relation between different blood-derived protein concentrations in CSF in cases of a blood–CSF barrier dysfunction. Methods: The dynamics of brain-derived proteins in CSF are investigated with reference to the CSF flow rate measured by CSF/serum albumin concentration quotient. Results: Proteins from neurons or glial cells, tau protein, neuron-specific enolase, S-100 protein, all enter CSF primarily in the ventricular and cisternal space. Their concentration between normal ventricular and lumbar CSF is decreasing (in contrast to blood-derived proteins), and in the case of pathologically decreasing CSF flow rate, the concentration in lumbar CSF remains invariantly constant. Concentrations of the primarily leptomeningeal proteins, β-trace protein and cystatin C, increase between normal ventricular and lumbar CSF, and in the case of pathologically decreased CSF flow rate they increase linearly in lumbar CSF (concentrations of blood-derived proteins increase non-linearly). Conclusions: A satisfactory physiological explanation can now be given for the dynamics of proteins in CSF consisting of both brain- and blood-derived fractions (transthyretin, soluble intercellular adhesion molecule (s-ICAM)), as well as the disputed decrease of leptomeningeal protein concentrations (β-trace protein, cystatin C) in cases of bacterial meningitis is also explained. The biophysical treatment of dynamics in the ventricular and lumbar CSF extends the new theory and shows that CSF flow rate is the most relevant parameter for understanding the pathological changes of both blood- and brain-derived proteins in CSF. The impact on diagnosis of neuro-degenerative diseases is discussed.

CEREBROSPINAL FLUID FLOW IN CHILDREN WITH NORMAL AND DILATED VENTRICLES STUDIED BY MR IMAGING

. To quantify the cerebrospinal fluid (CSF) dynamics in the aqueduct of children with normal and dilated ventricles using MR phase-contrast technique. Eighteen patients (6 months to 17 years of age) with various neurological symptoms underwent routine brain MR imaging and CSF flow measurement in the aqueduct. Nine patients had normal ventricles, 5 had dilated ventricles and 4 had a ventriculoperitoneal shunt. The CSF velocity and flow rates in the aqueduct in patients with normal and dilated ventricles showed marked inter-individual variation and clear overlap. In a patient with tight aqueductal stenosis and increased ventricular pressure, pronounced CSF flow in the aqueduct was measured. Absence of flow in another patient with aqueductal stenosis was detected. Measurable although low flow in the aqueduct in 4 patients with a ventriculoperitoneal shunt was found. Quantitative phase MR flow measurement in the aqueduct demonstrated aqueductal stenosis; these patients had either pronounced flow or no flow in the aqueduct.

MR-Intracranial pressure (ICP): a method to measure intracranial elastance and pressure noninvasively by means of MR imaging: baboon and human study.

To develop a noninvasive method for intracranial elastance and intracranial pressure (ICP) measurement. Intracranial volume and pressure changes were calculated from magnetic resonance (MR) imaging measurements of cerebrospinal fluid (CSF) and blood flow. The volume change was calculated from the net transcranial CSF and blood volumetric flow rates. The change in pressure was derived from the change in the CSF pressure gradient calculated from CSF velocity. An elastance index was derived from the ratio of pressure to volume change. The reproducibility of the elastance index measurement was established from four to five measurements in five healthy volunteers. The elastance index was measured and compared with invasive ICP measurements in five patients with an intraventricular catheter at MR imaging. False-positive and false-negative rates were established by using 25 measurements in eight healthy volunteers and six in four patients with chronically elevated ICP. The mean of the fractional SD of the elastance index in humans was 19.6%. The elastance index in the five patients with intraventricular catheters correlated well with the invasively measured ICP (R:(2) = 0.965; P: <.005). MR imaging-derived ICPs in the eight healthy volunteers were 4.2-12.4 mm Hg, all within normal range. Measurements in three of the four patients with chronically elevated ICP were 20.5-34.0 mm Hg, substantially higher than the normal limit. MR imaging-derived elastance index correlates with ICP over a wide range of ICP values. The sensitivity of the technique allows differentiation between normal and elevated ICP.

Morphological alterations of the choroid plexus in late-onset Alzheimer's disease.

Anomalies of the cerebrospinal fluid flow rate and composition that have been reported in patients suffering from Alzheimer's disease (AD) could be related to alterations of the choroid plexuses (CD). Here we report a photonic and electron morphometric study in which we compared the height of CP epithelial cells and the thickness of their basement membrane on post-mortem samples from AD patients, age-matched controls and two newborns. Ageing appeared associated with epithelial atrophy and basement membrane thickening, but these features were significantly accentuated in AD. These data suggest that a dramatic alteration of the secretion and filtration could be involved in the multiparametric pathogenesis of late-onset AD.

頭蓋内圧脈波の振動解析に関する研究 ２ シミュレーションによる動物実験データの解析

To understand the relation between arterial pressure (AP) waves and intracranial pressure (ICP) pulse waves, animal experiments using adult cats and computer simulation using linear vibration model are conducted. In animal experiments, hypercapnias are performed. Equivalent compliance and equivalent mass are estimated by computer simulation using AP and ICP wave data measured by animal, experiment. During the increase of ICP at the beginning of experiments, the equivalent compliance decreases to low value and equivalent mass increases to high value. And when ICP returns to the initial low levels, the equivalent compliance and equivalent mass recover to the initial value. However, after several experiments, although ICP returns to low level, the equivalent compliance remains low value but equivalent mass recovers to low one. These results suggest that the compliance estimated by the computer simulation is available for the indicator of pathological changes in intracranial functions. And the increase of the equivalent mass is caused by that the flow rate of cerebrospinal fluid, which flows through narrow crevices in cranium, increases due to the rise of ICP. This phenomenon is verified by a vibration analysis of experimented results based on a dynamic model.

Elucidating the pathophysiology of syringomyelia.

Syringomyelia causes progressive myelopathy. Most patients with syringomyelia have a Chiari I malformation of the cerebellar tonsils. Determination of the pathophysiological mechanisms underlying the progression of syringomyelia associated with the Chiari I malformation should improve strategies to halt progression of myelopathy. The authors prospectively studied 20 adult patients with both Chiari I malformation and symptomatic syringomyelia. Testing before surgery included the following: clinical examination; evaluation of anatomy by using T1-weighted magnetic resonance (MR) imaging; evaluation of the syrinx and cerebrospinal fluid (CSF) velocity and flow by using phase-contrast cine MR imaging; and evaluation of lumbar and cervical subarachnoid pressure at rest, during the Valsalva maneuver, during jugular compression, and following removal of CSF (CSF compliance measurement). During surgery, cardiac-gated ultrasonography and pressure measurements were obtained from the intracranial, cervical subarachnoid, and lumbar intrathecal spaces and syrinx. Six months after surgery, clinical examinations, MR imaging studies, and CSF pressure recordings were repeated. Clinical examinations and MR imaging studies were repeated annually. For comparison, 18 healthy volunteers underwent T1-weighted MR imaging, cine MR imaging, and cervical and lumbar subarachnoid pressure testing. Compared with healthy volunteers, before surgery, the patients had decreased anteroposterior diameters of the ventral and dorsal CSF spaces at the foramen magnum. In patients, CSF velocity at the foramen magnum was increased, but CSF flow was reduced. Transmission of intracranial pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was partially obstructed. Spinal CSF compliance was reduced, whereas cervical subarachnoid pressure and pulse pressure were increased. Syrinx fluid flowed inferiorly during systole and superiorly during diastole on cine MR imaging. At surgery, the cerebellar tonsils abruptly descended during systole and ascended during diastole, and the upper pole of the syrinx contracted in a manner synchronous with tonsillar descent and with the peak systolic cervical subarachnoid pressure wave. Following surgery, the diameter of the CSF passages at the foramen magnum increased compared with preoperative values, and the maximum flow rate of CSF across the foramen magnum during systole increased. Transmission of pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was normal and cervical subarachnoid mean pressure and pulse pressure decreased to normal. The maximum syrinx diameter decreased on MR imaging in all patients. Cine MR imaging documented reduced velocity and flow of the syrinx fluid. Clinical symptoms and signs improved or remained stable in all patients, and the tonsils resumed a normal shape. The progression of syringomyelia associated with Chiari I malformation is produced by the action of the cerebellar tonsils, which partially occlude the subarachnoid space at the foramen magnum and act as a piston on the partially enclosed spinal subarachnoid space. This creates enlarged cervical subarachnoid pressure waves that compress the spinal cord from without, not from within, and propagate syrinx fluid caudally with each heartbeat, which leads to syrinx progression. The disappearance of the abnormal shape and position of the tonsils after simple decompressive extraarachnoidal surgery suggests that the Chiari I malformation of the cerebellar tonsils is acquired, not congenital. Surgery limited to suboccipital craniectomy, C-I laminectomy, and duraplasty eliminates this mechanism and eliminates syringomyelia and its progression without the risk of more invasive procedures.

Elucidating the pathophysiology of syringomyelia

Object Syringomyelia causes progressive myelopathy. Most patients with syringomyelia have a Chiari I malformation of the cerebellar tonsils. Determination of the pathophysiological mechanisms underlying the progression of syringomyelia associated with the Chiari I malformation should improve strategies to halt progression of myelopathy. Methods The authors prospectively studied 20 adult patients with both Chiari I malformation and symptomatic syringomyelia. Testing before surgery included the following: clinical examination; evaluation of anatomy by using T1-weighted magnetic resonance (MR) imaging; evaluation of the syrinx and cerebrospinal fluid (CSF) velocity and flow by using phase-contrast cine MR imaging; and evaluation of lumbar and cervical subarachnoid pressure at rest, during the Valsalva maneuver, during jugular compression, and following removal of CSF (CSF compliance measurement). During surgery, cardiac-gated ultrasonography and pressure measurements were obtained from the intracranial, cervical subarachnoid, and lumbar intrathecal spaces and syrinx. Six months after surgery, clinical examinations, MR imaging studies, and CSF pressure recordings were repeated. Clinical examinations and MR imaging studies were repeated annually. For comparison, 18 healthy volunteers underwent T1-weighted MR imaging, cine MR imaging, and cervical and lumbar subarachnoid pressure testing. Compared with healthy volunteers, before surgery, the patients had decreased anteroposterior diameters of the ventral and dorsal CSF spaces at the foramen magnum. In patients, CSF velocity at the foramen magnum was increased, but CSF flow was reduced. Transmission of intracranial pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was partially obstructed. Spinal CSF compliance was reduced, whereas cervical subarachnoid pressure and pulse pressure were increased. Syrinx fluid flowed inferiorly during systole and superiorly during diastole on cine MR imaging. At surgery, the cerebellar tonsils abruptly descended during systole and ascended during diastole, and the upper pole of the syrinx contracted in a manner synchronous with tonsillar descent and with the peak systolic cervical subarachnoid pressure wave. Following surgery, the diameter of the CSF passages at the foramen magnum increased compared with preoperative values, and the maximum flow rate of CSF across the foramen magnum during systole increased. Transmission of pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was normal and cervical subarachnoid mean pressuree and pulse pressure decreased to normal. The maximum syrinx diameter decreased on MR imaging in all patients. Cine MR imaging documented reduced velocity and flow of the syrinx fluid. Clinical symptoms and signs improved or remained stable in all patients, and the tonsils resumed a normal shape. Conclusions The progression of syringomyelia associated with Chiari I malformation is produced by the action of the cerebellar tonsils, which partially occlude the subarachnoid space at the foramen magnum and act as a piston on the partially enclosed spinal subarachnoid space. This creates enlarged cervical subarachnoid pressure waves that compress the spinal cord from without, not from within, and propagate syrinx fluid caudally with each heartbeat, which leads to syrinx progression. The disappearance of the abnormal shape and position of the tonsils after simple decompressive extraarachnoidal surgery suggests that the Chiari I malformation of the cerebellar tonsils is acquired, not congenital. Surgery limited to suboccipital craniectomy, C-1 laminectomy, and duraplasty eliminates this mechanism and eliminates syringomyelia and its progression without the risk of more invasive procedures.

Fabrication and testing of a device capable of reducing the incidence of ventricular shunt promoted metastasis.

Some malignant brain tumors shed cells into the cerebrospinal fluid (CSF). These tumors may implant throughout the neuroaxis via the CSF. With the placement of a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt, tumor cells free-floating in the CSF may be carried through the shunt to the remainder of the body. Mechanical filtration devices to prevent this are not reliable. We report the development of a new device capable of reducing the incidence of shunt promoted metastasis. The device exposes the draining CSF, as it passes through a baffle system, to a localized high-intensity radiation field adequately shielded from surrounding normal tissue. The prototype consists of geometrically fixed iodine-125 (125I) sources. The device accommodates the maximum CSF flow rate of 500 ml/24 hours. Radiation exposure to clonogenic cells occurs as they transit through the baffle system. Since the volume of the prototype device is 14 ml, a tumor cell floating through the device will be exposed to radiation for 40 minutes. Utilizing the human medulloblastoma cell line D425 MED, a limiting dilution clonogenic assay was performed. Suspensions of tumor cells in liquid medium were pumped through the device at the maximum anticipated CSF production rate of 0.35 ml/min. After the cells, with their tissue culture medium, were received from the device, a series of nine 5-fold dilutions were prepared from the suspensions which initially contained 10(6) tumor cell/ml. Plates were then incubated and growth was demonstrated by visual scoring of colonies of more than 20 cells. Limiting dilution data analysis was performed. Radiation surveys of the fully loaded (approximately 1.8 Ci) 125I prototype were conducted. A well calibrator was used to measure the activity of the fully loaded device. When the device was loaded with 125I seeds providing a dose of 364-479 cGy the probability of clonogen survival was 0.033. Radiation exposure levels at the exterior surface of the shielded device were in the range of 2-5 mR/hr and thus fell within guidelines for acceptable normal tissue exposure. Attenuation of radiation by the shielding case for the fully loaded device was 10(-5). The device kills medulloblastoma cells as they are pumped through it. If the risk of metastasis is linearly related to the number of clonogenic cells, then the device would, we infer, reduce the risk of shunt-born metastasis by a factor of 0.033 and merits further investigation.

Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data.

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic parameters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82-0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by "diffusion and flow model" with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.

Flow rate of cerebrospinal fluid (CSF) — A concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases

Many neurological diseases are accompanied by increased protein concentrations in the cerebrospinal fluid (CSF), described as a blood-CSF barrier dysfunction. The earlier interpretation as a “leakage” of the blood-CSF barrier for serum proteins could be revised by introduction of a “population variation coefficient” of the CSF / serum quotients for IgG, IgA and IgM (ΔQ/Q̄) which is evaluated as a function of increasing albumin quotients (Q Alb). The data presented here are based on specimens from 4380 neurological patients. These population variation coefficients were found to be constant over two orders of magnitude of normal and pathological CSF protein concentrations (Q Alb = 1.6 · 10 −3 - 150 · 10 −3). This constancy indicates that there was no change in blood-CSF barrier related structures with respect to diffusion controlled protein transfer from blood into CSF and hence no change in molecular size dependent selectivity. The pathological increase of plasma protein concentrations in CSF in neurological diseases could also be explained quantitatively by a decrease of CSF flow rate due to its bifunctional influence on CSF protein concentration: reduced volume exchange, and as newly stated, increased molecular net flux into CSF without change of permeability coefficients. Again, on the basis of a changing CSF flow rate, the hyperbolic functions, which describe empirically the changing quotient ratios between proteins of different size (e.g. Q IgG : Q Alb) with increasing CSF protein content (Q Alb) can likewise be derived from the laws of diffusion as the physiologically relevant description. The hyperbolic discrimination line between brain-derived and blood-derived protein fractions in CSF in the quotient diagrams for CSF diagnosis can be further improved on the basis of the large number of cases investigated. Other physiological and pathological aspects, such as high CSF protein values in the normal newborn, in spinal blockade, in meningeal inflammatory processes, CNS leukemia or polyradiculitis as well as animal species dependent variations can each be interpreted as due to a difference or change in the CSF flow rate.

Cerebrospinal fluid kallikrein in spontaneously hypertensive and desoxycorticosterone acetate-salt hypertensive rats.

To determine whether immunoreactive tissue kallikrein levels in cerebrospinal fluid (CSF) of spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)--salt-treated hypertensive rats are elevated compared with normotensive Wistar-Kyoto (WKY) and Sprague-Dawley rats. The present study was designed to test the hypothesis that the activity of the brain tissue kallikrein-kinin system is enhanced in hypertensive states. Age-matched 18- to 19-week-old SHR and WKY rats, and Sprague-Dawley rats treated for 6 weeks either with 2 mg/kg per day DOCA subcutaneously and 0.9% saline in the drinking water, or with vehicle and tap water to drink, were studied. CSF was collected from a cannula inserted into the cisterna magna, and was frozen until the tissue kallikrein in the samples was measured by radioimmunoassay. Arterial pressure in the SHR and WKY rats was measured directly via a cannula inserted in the femoral artery or by tail-cuff plethysmography. In adult 18- to 19-week-old SHR the CSF kallikrein concentration was higher than in WKY rats. The CSF flow rate in SHR was also higher than in WKY rats. The rate of appearance of kallikrein in the CSF of SHR was twice that in WKY rats. Moreover, CSF kininogenase activity in SHR was significantly higher than that in age-matched WKY rats. In DOCA--salt hypertensive rats the CSF kallikrein concentration was higher than in vehicle-treated control rats. Acute elevation of blood pressure with a 120-min intravenous phenylephrine infusion did not change the CSF kallikrein concentration in 50 rats compared with vehicle-treated control rats. This is the first study to quantitate immunoreactive tissue kallikrein in the CSF of rats and to show elevated levels of CSF kallikrein in hypertensive rats compared with normotensive rats. The present data suggest that higher brain kallikrein activity in hypertensive rats may play a role in the development of elevated blood pressure.

Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. Intrathecal accumulation and CSF flow rate

Concentrations of ascorbate (vitamin C) in cerebrospinal fluid (CSF) from human controls (median 163 μmol/l, n = 63) were found to be in the same range as CSF samples from patients ( n = 56) with various neurological diseases, but excluding those with blood-CSF barrier dysfunction. The CSF/serum concentration ratio in the former group is non-linear, decreasing with increasing serum concentration. Surprisingly, ascorbate concentration in blood (median 41 μmol/l, n = 119) was decreased significantly in cases of neurological diseases with a blood-CSF barrier dysfunction (median 26 μmol/l, n = 30). In this latter group a linear CSF to serum ratio with a mean of 5.7:1 (with CSF/serum albumin quiotients QAlb = 7.8–70.8 · 10 −3, median 10.0 · 10 −3) was observed, approaching a value >12.5:1 in the case of complete stop of CSF flow. Serum ascorbate concentrations decreased with decreasing CSF flow rate (1√QAlb), indicating a CSF flow-dependent constant contribution from high intrathecal ascorbate concentration to the varying diet-dependent concentrations in blood. In the control group the biological coefficient of variation for CSF ascorbate concentrations (C.V. = 21.1%) was smaller than for serum concentrations (C.V. = 42.6%), confirming an efficient ascorbate homeostasis in human brain. This was different from uric acid which was used as a reference molecule with an inversed gradient in the same group of control patients. Similar variations in CSF( y) and serum( x) for urate concentrations are observed due to the strong correlation y = 0.1 x ± 10 μmol/l, including 99% of the cases with an urate serum concentration range from 80 μmol/l to 460 μmol/l.

A Simple Method of Estimating Cerebrospinal Fluid Pressure During Lumbar Puncture

It is often difficult to measure cerebrospinal fluid (CSF) pressure in children. CSF flow through a spinal needle is described by the equation: Flow = pressure/(needle constant x relative viscosity). Thus, CSF flow rate during lumbar puncture can be used to estimate CSF pressure. Because the viscosity of CSF is approximately the same as that of normal saline, 0.9% NaCl was used to model CSF flow in vitro. Flow of saline through various spinal needles was measured as pressure and temperature were varied to determine needle constants and variation in viscosity with temperature. Counting periods for which the number of drops counted equals the pressure (in centimeters of H2O) then were determined for each needle size. At patient temperatures less than 40 degrees C, counting periods were calculated at 21, 39, and 12 seconds, for 22-gauge 1.5-inch, 22-gauge 3.5-inch, and 20-gauge 3.5-inch spinal needles, respectively. Viscosity decreased slightly above 40 degrees C, and counting periods became 20, 37, and 11 seconds. Finally, the method was tested prospectively in 12 patients by comparing drop count (over the calculated counting period) to manometric pressure measurement. Drop counts were within 15% of manometric pressure in all patients. This method allows simple and rapid estimation of CSF pressure during lumbar puncture.

The presence of cocaine and benzoylecgonine in rat cerebrospinal fluid after the intravenous administration of cocaine

Cocaine hydrochloride, in doses of 0.5, 1.0, 2.0 and 4.0 mg/kg, iv, was administered to male Sprague-Dawley rats. Cerebrospinal fluid (CSF) was collected from the cisterna magna over a 20 min period and blood samples were obtained at 20 min after cocaine administration. In addition, blood samples for the 1 mg/kg dose of cocaine were collected at 2, 10, 20 and 30 min following drug injection. Gas chromatography/mass spectrometry was used for the analysis of cocaine and its metabolites in plasma and CSF. The disappearance of cocaine (1 mg/kg) from the plasma exhibited first order kinetics with a half-life of 18.11 ± 3.22 min. Cocaine and benzoylecgonine were found in CSF and the concentrations of cocaine and benzoylecgonine increased in CSF as the doses of cocaine were increased. CSF flow rates were not altered by the iv administration of cocaine or benzoylecgonine. The CSF-to-plasma ratios for cocaine were quite similar to each other over the dosage range of cocaine that was administered; however, the CSF-to-plasma ratios for benzoylecgonine decreased as the concentrations of benzoylecgonine increased in plasma and CSF. When benzoylecgonine (2 mg/kg, iv) was given, the compound was detected in CSF indicating that benzoylecgonine can enter into the central nervous system from the peripheral blood. This investigation shows that cocaine and benzoylecgonine can be assayed in CSF and that the plasma levels of these compounds correlate with their concentrations in CSF.

Clinical studies of cranial and spinal compliance and the craniospinal flow of cerebrospinal fluid.

The cranial compartment contributed 37% and the spinal compartment 63% to the total compliance of the craniospinal space in the horizontal body position. In the erect position the values were almost reversed, the cranial compartment contributing 66% and the spinal compartment 34%. The total compliance was almost unaffected by body position. The pulsatile volume of cerebrospinal fluid (CSF) moving between the cranial and spinal compartments was about 1 ml in the horizontal position. The corresponding pulsatile change in cerebral blood volume was calculated to be 1.6 ml. A craniospinal block increased the intracranial pressure amplitude by 110% in the horizontal position. The volume of CSF moving between the cranial and spinal compartments when sitting up and lying down, was about 3 ml. The pulsatile and postural flow rate of CSF may reach about 200 ml/min. High CSF flow velocity may impair the protective coating of CSF around the brain and thus contribute to herniation.

Motor Activity Increases Tryptophan, 5‐Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.