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CSF omeprazole concentration and albumin quotient following high dose intravenous omeprazole in dogs
Abstract
Clinical signs of syringomyelia and hydrocephalus occur secondary to cerebrospinal fluid (CSF) accumulation within the central nervous system. Omeprazole is recommended to treat these conditions despite little evidence of its capacity to decrease CSF production in the dog. Studies into new treatments are hampered by difficulties in measuring CSF production. The albumin quotient (QAlb), the ratio between CSF and serum albumin concentrations, may reflect CSF production and any decrease in CSF production should be associated with an increase in QAlb.
The primary objective of this study was to determine CSF omeprazole concentration after administration of a high intravenous dose of omeprazole and to evaluate its impact on QAlb in the dog. The second aim was to validate QAlb as a surrogate marker of CSF production.
Eighteen dogs were included in this prospective crossover placebo-controlled study. Each dog received omeprazole (10 mg/kg), acetazolamide (50 mg/kg) combined with furosemide (1 mg/kg) and saline. Blood and CSF samples were obtained on day 0 and then every 7 days, one hour after drug administration.
Omeprazole concentrations (2.0 ± 0.4 μmol/L) reached in CSF after high dose omeprazole were lower than the concentrations previously described as decreasing CSF production in dogs. There was no significant increase in QAlb following administration of acetazolamide/furosemide, prohibiting validation of QAlb as a surrogate marker for CSF production. Several dogs presented transient mild side effects after injection of acetazolamide/furosemide. High dose omeprazole was well tolerated in all dogs.
Background: Chiari-like malformation (CM) is a developmental condition, characterised by a conformational change and overcrowding of the brain and cranial cervical spinal cord. CM-associated pain (CM-P) and syringomyelia are increasingly being diagnosed, due to the rising popularity of predisposed brachycephalic breeds and the availability of MRI in veterinary practices.
Aim of the article: This article aims to update the veterinary profession on these conditions, and provides a guide to diagnosis and treatment of clinically relevant disease.
Acetazolamide is recommended for the reduction of cerebrospinal fluid production in canine internal hydrocephalus. The efficacy of the drug in terms of alleviation of the clinical symptoms and the restoration of normal ventricular volume has not been documented. We hypothesize that acetazolamide inadequately improve clinical signs and has no effect on the ventricular volume. Six dogs with internal hydrocephalus underwent neurological examination and were examined by magnetic resonance imaging, on the day of the diagnosis, after treatment with acetazolamide directly before surgery, and 6 weeks after implantation of a vetriculo-peritoneal shunt due to lack of improvement after medical therapy with 10 mg/kg acetazolamide three times daily (TID). The ventricular volume in relation to the total brain volume was determined on each occasion. The changes in relative ventricular volume and of the neurological status were assessed and compared.
McNemar's test revealed no significant differences in clinical symptoms before and after medical treatment (P > 0.05). However, clinical symptoms changed significantly after surgical treatment (P = 0.001). The ventricle-brain ratio was not significantly changed after therapy with acetazolamide (P > 0.05); however, after subsequent shunt implantation, it was significantly reduced (P = 0.001).
Acetazolamide (10 mg/kg TID) showed no effects on clinical signs or ventricular volume in dogs with internal hydrocephalus. After subsequent ventriculo-peritoneal shunting, the dogs had a significantly reduced cerebral ventricular volume and five out of six dogs had no abnormal findings in neurological examination.
Previous reports suggest an association between the degree of optic nerve head edema and CSF pressure (CSFp) in idiopathic intracranial hypertension (IIH). We hypothesized that CSFp would be associated with Frisén papilledema grade (FPG) and other clinical features, and that FPG would modify the CSFp response to acetazolamide in participants in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). In the IIHTT, eligible patients underwent lumbar puncture (LP) prior to enrollment and were randomly assigned to one of two treatment groups: acetazolamide plus supervised diet or placebo plus supervised diet. Trial eligibility required baseline CSFp ≥250 mm H2O or ≥200 mm H2O with compelling clinical or imaging IIH findings. Associations between CSFp and FPG and other clinical features were examined at baseline. The effect of acetazolamide on 6-month change in CSFp was examined in those with low FPG (grades I-III) and those with high FPG (grades IV-V) at baseline. All 165 enrolled subjects had a baseline LP and 85 had an LP at 6 months. There was an association between CSFp and FPG at baseline: CSFp was more elevated in subjects with high FPG (378 ± 90 mm H2O, n = 50) than in subjects with low FPG (331 ± 77, n = 115, p = 0.002). At 6 months, acetazolamide had a similar effect on CSFp in subjects with high FPG (-79.9 mm H2O) and in subjects with low FPG (-50.9 mm H2O, p = 0.50). We found a modest association between CSFp and FPG. Acetazolamide had a beneficial effect on CSFp regardless of baseline FPG.
Paraplegia is a rare but devastating complication, which may follow thoracoabdominal aortic surgery. Many adjuncts have been developed to reduce this risk including cerebrospinal fluid (CSF) drainage. Acetazolamide (carbonic anhydrase inhibitor) is a drug used to counteract mountain sickness and one of its effects is to reduce CSF production. Here, we report its first postoperative application in thoracoabdominal surgery with the aim of reducing cerebrospinal cord perfusion pressure and reducing risk of paraplegia.
We retrospectively reviewed 6 patients who have been treated with this drug between 2011 and 2012 who were undergoing thoracoabdominal aortic surgery. Our indications were decided to include: (i) patients in whom a spinal drain could not be positioned; (ii) patients with blood-stained CSF; (iii) patients in whom the volume of CSF drained was outside guidelines; (iv) patients in whom CSF pressure was elevated; (v) patients with excessive vasopressor usage and (vi) patients with postoperative neurological dysfunction as measured by motor-evoked potentials or clinical examination. All were given 500 mg intravenous acetazolamide, not more than eight hourly, for a duration dependent on response.
In the 6 patients, 2 received a single dose of the drug and responded by an immediate drop in intracranial pressure (ICP) pressure. Of the 4 who received multiple doses of the drug, 1 had an immediate decline in ICP after each of the first six doses, while 3 had no discernable response.
This is the first report of the efficacy of acetazolamide in reducing CSF production and lowering ICP during thoracoabdominal aortic surgery. We believe that its use will be beneficial in the 6 patient groups described. Our experience suggests there are 'responders' and 'non-responders', the characteristics of whom are yet to be defined. Its efficacy in reducing not just CSF volume and ICP but also clinically relevant morbidity such as paraplegia, is the subject of a planned randomized controlled trial. This report serves to raise awareness of the possible efficacy of this drug when normal management strategies are limited or exhausted.
Cerebrospinal fluid (CSF) routine analysis for diagnosis of neurological diseases is based on the concepts for discrimination of blood-derived and brain-derived immunoglobulin fractions in CSF. The actual molecular flux/CSF flow theory of the blood/CSF barrier function, which founded the hyperbolic discrimination lines in quotient diagrams, is derived from the laws of molecular diffusion combined with CSF flow rate. It emerged from this theory that the decrease of CSF flow rate is sufficient to explain quantitatively the increase of CSF protein concentrations as observed in many neurological diseases. With this concept of CSF flow rate as the modulator of the normal and pathological blood-CSF barrier function, we got for the first time a theoretical frame work to explain also quantitatively the dynamics of brain-derived proteins and their source related (neurons and glial cells or leptomeningal cells) differences. The review of the anatomical, physiological and biophysical knowledge points to the new interpretations: The changing albumin quotient is an indicator of changing CSF flow rate and not for a morphological "leakage" of the blood-brain barrier. As an application of these concepts the dynamics of brain-derived molecules in blood are discussed with two examples: beta trace protein, flowing with CSF into venous blood, and neuron-specific enolase, passing from tissue into blood the opposite direction of serum proteins, again a gradient-dependent protein diffusion across the intact blood vessel wall.
Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used and best-studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide's efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects. This review summarizes the known systemic effects of acetazolamide and incorporates them into a model encompassing several factors that are likely to play a key role in the drug's efficacy. Such factors include not only metabolic acidosis resulting from renal CA inhibition but also improvements in ventilation from tissue respiratory acidosis, improvements in sleep quality from carotid body CA inhibition, and effects of diuresis.
Idiopathic intracranial hypertension (IIH) is uncommon in the paediatric population. Papilloedema is the hallmark sign and patients can suffer permanent vision loss as a consequence. We describe the role of optical coherence tomography (OCT) in the follow-up of two paediatric patients with newly diagnosed IIH. Patient A presented with vomiting and examination showed ophthalmoplaegia and papilloedema. She was treated with acetazolamide, furosemide and therapeutic lumbar punctures. Patient B presented with incidental papilloedema and was treated with acetazolamide and she reported intermittent headache during follow-up. Fundoscopic examinations for both patients showed persistent blurred disc margins but OCT examinations documented improvement of average retinal nerve fibre layers. OCT may be of value in monitoring for recurrence in paediatric IIH.
Idiopathic intracranial hypertension is a disorder characterised by raised intracranial pressure that predominantly affects young, obese women. Pathogenesis has not been fully elucidated, but several causal factors have been proposed. Symptoms can include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable. Although few studies have been done to support evidence-based management, several recent advances have the potential to enhance understanding of the causes of the disease and to guide treatment decisions. Investigators of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) reported beneficial effects of acetazolamide in patients with mild visual loss. Studies have also established weight loss as an effective disease-modifying treatment, and further clinical trials to investigate new treatments are underway. The incidence of idiopathic intracranial hypertension is expected to increase as rates of obesity increase; efforts to reduce diagnostic delays and identify new, effective approaches to treatment will be key to meeting the needs of a growing number of patients.
Our previous studies demonstrated that thrombin is an important factor in brain injury after intracerebral and intraventricular hemorrhage. This study examined the effect of acetazolamide, a carbonic anhydrase inhibitor, on thrombin-induced hydrocephalus. There were two parts in this study. First, rats had an injection of either 50 μl saline or 3 U thrombin into the right lateral ventricle. Second, rats had an injection of 3 U thrombin into the right lateral ventricle and were treated with either vehicle or acetazolamide (30 mg/kg, intraperitoneally (IP)) at 1 h after thrombin infusion. Lateral ventricle volumes were measured in magnetic resonance imaging T2 images and the brains were used for histology analysis at 24 h later. Intraventricular injection of thrombin induced significantly larger ventricle volume (27.8 ± 3.7 vs 8.5 ± 1.3 mm(3), n = 6, p < 0.01) and more ventricular wall damage (the breakdown of the ependymal layer, 20.2 ± 3.1 vs 2.4 ± 0.8 %, n = 6, p < 0.01) compared with saline injection. Acetazolamide treatment (30 mg/kg, IP) markedly attenuated thrombin-induced hydrocephalus (16.1 ± 4.2 mm(3) vs 29.5 ± 5.3 mm(3), n = 6, p < 0.01). These results suggest decreasing CSF production by acetazolamide attenuated thrombin-induced hydrocephalus in rats.
Administration of omeprazole by ventriculo-cisternal perfusion or intravenously has been shown to decrease cerebrospinal fluid (CSF) production in dogs and rabbits. Oral omeprazole has consequently been recommended to reduce CSF production in dogs with conditions in which clinical signs may be attributable to an accumulation of CSF in the central nervous system (e.g. hydrocephalus, syringomyelia). The albumin quotient (QAlb), the ratio between CSF and serum albumin concentration, has been proposed as a reliable means to evaluate CSF production; decreasing CSF production should cause an increase in QAlb.
The aims of this study were to assess the effect of oral administration of omeprazole on QAlb in dogs and to compare two methods to assess CSF albumin concentration. Fifteen healthy Beagle dogs received omeprazole (1.2 mg/kg/day) orally for 14 days; CSF and blood were obtained before and after treatment. CSF albumin concentrations were evaluated by nephelometry and high-resolution protein electrophoresis. Regardless of the method used for measuring albumin, QAlb did not change significantly following oral omeprazole administration, suggesting that CSF production in healthy dogs may not be affected by chronic oral therapy with omeprazole.
Idiopathic intracranial hypertension (IIH) is characterized by an increase of intracranial pressure in the absence of neurologic tumors. The sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor (CAI) acetazolamide (AAZ), a compound developed in the 1950s as a diuretic drug and presently used as an antiglaucoma, antiepileptic and diuretic agent, is effective in the treatment of IIH. AAZ is a low nanomolar inhibitor of CA isoforms involved in cerebrospinal fluid (CSF) secretion. Inhibition of brain/choroid plexus CA II, IV, VA and XII leads to a decreased CSF fluid secretion and control of the intracranial pressure. Although many sulfonamide/sulfamate CAIs are in clinical use for decades, apparently only AAZ is being currently used clinically for IIH. We speculate that more lipophilic CAIs such as methazolamide, zonisamide or topiramate should lead to a more effective control of increased intracranial pressure, thus having the opportunity to become useful in the management of IIH.
To compare the diuretic effects of subcutaneous (SC) administration of furosemide to conventional methods of administration including intravenous (IV), per os (PO), and constant rate infusion (CRI) in healthy dogs.
Prospective, randomized, cross-over study.
Veterinary university research facility.
Seven healthy, adult mongrel dogs (3 males, 4 females).
Each dog in the study was randomly assigned to receive a 2 mg/kg dose of furosemide via a single SC, IV, or PO dose at the beginning (time 0) of an 8-hour study, or via CRI during an 8-hour study period. Urine was collected by emptying the bladder using an indwelling catheter and blood samples were obtained via venipuncture at time 0 for baseline measurements and at 1, 2, 4, 6, and 8 hours into the study. Hourly urine output was calculated in all dogs for each study. Complete blood count, plasma total protein, blood urea nitrogen, creatinine, and renin concentration were measured for each sample.
The SC administration of furosemide resulted in a urine output per hour (UOP/h) that peaked at 1 hour with UOP/h returning to baseline at 4 hours after injection. Following IV administration, UOP/h also peaked at 1 hour but returned more rapidly to baseline levels at 2 hours after injection. With PO administration, UOP/h reached a maximum UOP/h at 2 hours but time to return to baseline levels was prolonged to 6 hours after administration. With CRI administration, the time to the maximum UOP/h was delayed to 4 hours after injection but UOP/h was then maintained throughout the study period.
Total urine output following SC administration of furosemide in healthy dogs was similar when compared to the IV and PO route. Subcutaneous route may be an effective means for administration of furosemide in dogs, particularly when IV access is difficult.
© Veterinary Emergency and Critical Care Society 2015.
A simple and reproducible bioanalytical method for the determination of flecainide in human plasma was developed and validated using an ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) to obtain higher sensitivity than the current available methods. After simple protein precipitation, flecainide and a stable isotope-labeled internal standard (IS) were chromatographed on an Acquity UPLC BEH C18 column (2.1 × 100 mm, 1.7 µm) with isocratic elution of mobile phase consisting of 45% methanol containing 0.1% formic acid at a flow rate 0.25 mL/min. Detection was performed in positive electrospray ionization by monitoring the selected ion transitions at m/z 415.4/301.1 for flecainide and m/z 419.4/305.1 for the IS. The method was validated according to current bioanalytical method validation guidelines. The calibration standard curve was linear from 2.5 to 1000 ng/mL using 0.1 mL of plasma. No significant interferences were detected in blank human plasma. Accuracy and precision in the intra- and inter-batch reproducibility study were within acceptance criteria. Neither hemolysis effects nor matrix effects were observed. The UPLC-MS/MS method developed was successfully applied to determine plasma flecainide concentrations to support clinical studies and incurred sample reanalysis also ensured the reproducibility of the method. Copyright © 2015 John Wiley & Sons, Ltd.
Copyright © 2015 John Wiley & Sons, Ltd.
Omeprazole (OME) is a proton pump inhibitor with a 58% bioavailability after a single oral dose. It is subject to marked inter-individual variations and significant drug-drug interactions. The authors developed a simple and rapid method based on liquid chromatography in tandem with mass spectrometry (LC/MS-MS) with solid phase extraction and isotope-labelled internal standard (IS) to monitor plasma levels of OME in pharmacokinetics and drug-drug interaction studies.
OME and its IS (OME-D3) were eluted with a Zorbax Extend C-18 rapid resolution column (4.6 mm x 50 mm, 3.5 μm) at 25°C, under isocratic conditions through a mobile phase consisting of 1 mM ammonium acetate, pH 8.5 (55%), and acetonitrile (45%). The flow rate was 0.8 mL/min, and the chromatogram run time was 1.2 min. OME was detected and quantified by LC-MS/MS with positive electrospray ionization, which operates in multiple-reaction monitoring mode.
The method was linear in the range of 1.5-2000 ng/mL for OME. The validation assays for accuracy and precision, matrix effect, extraction recovery, and stability of the samples for OME did not deviate more than 20% for the lower limit of quantification and no more than 15% for other quality controls.
These findings are consistent with the requirements of regulatory agencies. The method enables rapid quantification of OME concentrations and can be used in pharmacokinetic and drug-drug interaction studies.
Microdialysis is used in vivo for measuring compounds in brain interstitial fluid. The authors describe another application of this technique to the central nervous system, namely microprobe dialysis in the cisterna magna to study the dynamics of ion transport and cerebrospinal fluid (CSF) formation in the rat. The choroid plexus is the major source of CSF, which is produced by active transport of Na from blood into the cerebral ventricles. Formation of CSF is directly proportional to the blood-to-CSF transport of Na. By injecting ²²Na into the systemic circulation and quantifying its movement into CSF by microdialysis, one can reliably estimate alterations in the rate of CSF formation. The sensitivity of this system was determined by administering acetazolamide, a standard inhibitor of CSF production. Because acetazolamide is known to decrease CSF formation by 40% to 50%, the cisternal microdialysis system in animals treated with this drug should detect a corresponding decrease in the amount of ²²Na dialyzed. This hypothesis is supported by the ²²Na uptake curves for control versus treated animals: that is, by the acetazolamide-induced average diminution of about 45% in both the rate and extent of tracer accession to dialysate. Bumetanide, a loop diuretic, reduced by 30% the ²²Na entry into dialysate. Microprobe dialysis of fluid in the cisterna magna is thus a minimally invasive and economical method for evaluating effects of drugs and hormones on the choroid plexus-CSF system.
The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM.
Omeprazole, a specific inhibitor of H+K+-activated ATPase, gave a dose-dependent inhibition of CSF production as determined by cerebroventriculocisternal perfusions in the rabbit. The reduction was 35% when the perfusate concentration of omeprazole was 10−6M and 25% after an intravenous dose of 0.2 mg/kg of omeprazole, respectively. A similarly substituted benzimidazol () without H+K+-ATPase-inhibiting properties did not affect CSF production at a perfusate concentration of 10−5M. Omeprazole in a concentration of 2 × 10−4M and more caused a significant but variable reduction in total and Na+-K+-ATPase activity in choroid plexus homogenates. However, in concentrations of 2 × 10−5M and less, no effect on total or Na+K+-ATPase activity was obtained. Nor did omeprazole (2 × 10−4M) influence HCO3-ATPase. Choline uptake in isolated choroid plexus was significantly reduced by 86% in the presence of acid-pretreated omeprazole 2 × 10−3M, but was not affected by 2 × 10−5M omeprazole (intact or acid-pretreated). Thus, the mechanism for the marked inhibitory influence of omeprazole on CSF production is not yet evident. In doses causing even a 50% reduction of CSF production, no side effects were observed in contrast to Na+K+-ATPase inhibitors such as ouabain.
J. Neurochem. (2010) 113 , 1230–1239.
Abstract
Albumin is the most abundant protein in both CSF and plasma, and albumin quotient is often used to assess the functions of brain barriers especially that of the blood‐CSF barrier [i.e. the choroid plexus (CP) which also secretes CSF]. In this study, we took albumin as a model molecule to investigate ageing‐related alterations in the CSF‐CP system in sheep. We found significant ageing‐related increases in the weight of lateral CP [122.4 ± 14.0 mg in the young, 198.6 ± 35.4 mg in the middle aged, 286.1 ± 25.1 mg in the old ( p < 0.05)], in the CSF albumin as well as the albumin quotient. Albumin protein spots in old CSF displayed wider on 2D western immunoblotting images, and had higher densities on images of 2D large gels stained with Pro‐Q Emerald 488 compared to the young samples, suggesting ageing‐related post‐translational modification in the albumin. CSF secretion was reduced with age: 0.148 ± 0.013 mL/min/g in the young, 0.092 ± 0.02 mL/min/g in the middle aged, 0.070 ± 0.013 mL/min/g in the old ( p < 0.05). The ¹²⁵ I‐BSA extraction was not different among the sheep groups, nor was altered by temperature reduction, monensin, nocodazole, anti‐transforming growth factor β receptor II antibody, as well as unlabelled albumins. In conclusion, elevation of albumin in old CSF is associated with reduced CSF secretion by the CP, which size increases with age. ¹²⁵ I‐BSA extract, reflecting the extracellular space rather than the active albumin uptake in the CP, is not different between ages. These early changes in health ageing may result in the accumulation and modifications of CSF proteins leading to neurotoxicity.
Hydrocephalus is distension of the ventricular system of the brain related to inadequate passage of cerebrospinal fluid from its point of production within the ventricular system to its point of absorption into the systemic circulation. Developmental disorders are the most common causes of hydrocephalus, but there are other causes as well. Diagnosis is based on the clinical features and on brain imaging to assess ventricular size and to identify any specific causes. Medical therapy can provide temporary relief but definitive treatment usually involves placement of a ventriculoperitoneal shunt. This article discusses the pathophysiology and management of hydrocephalus.
Adult mongrel dogs, weighing 10-17 kg. were anesthetized with Nembutal and cervical and lumbosacral laminectomy was performed. The spinal subarachnoid space was blocked by extradural ligation at the level of the C4 to interrupt CSF communication between the cranial and spinal space. Polyethylene catheters were placed in the cervical and lumbosacral subarachnoid space, and artificial Mock CSF buffer, pH 7.35-7.40, containing inulin of 25 mg/dl or 14C-inulin of 1.5-2 muCi/dl as a tracer was perfused in the sacro-cervical direction through the catheter. After a steady state of perfusion was acommplished, the CSF was collected from the outlet catheter. Production and absorption rate of the CSF were calculated after Pappenheimer and Heisey's equation. 1) Effects of CSF pressure on the rate of production (Vf) and absorption (Va) of CSF and on the difference between outflow fluid rate (Vo) and inflow fluid rate (Vi) were studied within the pressure range of -100 to +600 mmH2O. Then, regression lines were calculated by means of the least square method. See Article. Vf was little affected by changes in CSF pressure, while Va increased linearly as CSF pressure elevated. This suggests that the spinal subarachnoid space plays an important role as a site of CSF absorption when the intracranial pressure increases. Vo-Vi, that is difference between absorption and production rate, decreased linearly as the CSF pressure increased. 2) Under a constant CSF pressure of +200 mmH2O, the effects of glucocorticoids (dexamethasone, 0.25 mg/kg and hydrocortisone, 4.15 mg/kg) and a carbonic anhydrase inhibitor (acetazolamide, 10 mg/kg) upon the production and absorption rate of CSF were determined 1/2, 1, 2 and 3 hours after intravenous administration. a) Effect of dexamethasone: The rate of CSF production was reduced to 60.5 +/- 2.4% (p less than 0.001) of the control level. The absorption rate of CSF also decreased to 59.2 +/- 6.09% (p less than 0.001) of the control. b) Effect of hydrocortisone: The production rate of CSF decreased to 67.4 +/- 6.61% (p less than 0.001), and the absorption rate to 76.5 +/- 3.94% (p less than 0.001) of the control level. c) Effect of acetazolamide: The production and absorption rate also decreased to 57.2 +/- 5.61% (p less than 0.001) and to 56.9 +/- 7.02% (p less than 0.001), respectively. 3) Pentration of tritiated dexamethasone and tritiated hydrocortisone from plasma to CSF. The penetration of tritiated dexamethasone and tritiated hydrocortisone from plasma to CSF in the spinal and cranial subarachnoid space was observed after the intravenous administration. The CSF/Plasma ratio of dexamethasone was 30.9% at 15 minutes and gradually increased to 91.5% and 93.5%, respectively, in the cranial and spinal CSF at 3 hours after the injection.
CSF and serum was obtained from 216 patients with neurological or psychoneurotic symptoms and the concentrations of albumin and IgG were immunologically determined. The IgG/albumin index, calculated as the quotient of the CSF/serum ratios of IgG and albumin was compared with electrophoresis on agar gel. In "normal" cases, the IgG/albumin index was between 0.26-0.66. Pathological electrophoresis, i.e. with two or more IgG bands in the gamma globulin region was found in 85 per cent of the MS patients; in 29 per cent of the patients with a possible demyelinating disease; in 41 per cent of patients with CNS infection; and in 4 per cent of patients with other neurological disorders; whereas an increased IgG/albumin index ( greater than 0.66) was found in 88 per cent of the MS patients; in 43 per cent of the patients with a possible demyelinating disease; in 50 per cent of the patients with CNS infection; in 11 per cent of patients with immunological disorders; and in 18 per cent of patients with other neurological diseases. The increase of the IgG/albumin index was sometimes moderate (0.67-0.90), except in patients with MS, syphilis and other CNS infections, where a pathological electrophoresis combined with an IgG/albumin index above 1.0 was found to be a valuable support for the clinical diagnosis.
In a prospective study, 24 consecutive patients with pseudotumor cerebri were followed for an average of 49 months with regular neurologic and ophthalmologic examinations. At the first examination the intracranial pressure was between 18 and 45 mm Hg; several patients had pressure waves up to 70 mm Hg and decreased conductance to cerebrospinal fluid outflow. In the majority, medical treatment, usually with diuretics and acetazolamide, induced a rapid relief of symptoms, but about 25% had a more protracted disease course with persistent headache, asthenia and memory disturbances interfering with daily life. Five patients required a shunt operation. Chronic changes of the optic disc developed in nearly half the patients, and one had optic atrophy and severe visual impairment. Repeated measurements of the intracranial pressure and conductance to cerebrospinal fluid outflow showed that abnormalities can persist for a long time, even in cases without symptoms of intracranial hypertension.
Despite its effectiveness, cerebrospinal shunting for hydrocephalus continues to be accompanied by considerable complications and morbidity. Medical therapy with acetazolamide 100 mg/kg/day and furosemide 1 mg/kg/day can be an effective alternative to shunting by halting progression of hydrocephalus until such time as sutures can become fibrosed and spontaneous arrest can occur. In an appropriately selected population older than 2 weeks with hydrocephalus of varied origin, our success rate in avoiding shunting is greater than 50%. The dramatic difference between the number of hospitalizations of patients with shunts and those treated medically, and the potential to avoid shunt dependence would appear to make an initial trial with medical therapy worthwhile.
Summary The concentration ratios of several proteins between serum and cerebrospinal fluid (CSF) can be correlated more easily to hydrodynamic volumes than to molweights. Hydrodynamic radii were calculated from literature diffusion data and determined by analytical column chromatography and gel electrophoresis. Discrepancies between molweight and hydrodynamic volume become evident, especially with the high-molecular proteins because of stronger conformational variability in this size range. The permeability of the blood-CSF-barrier is compared to the blood-lymph-barrier and the results are discussed with reference to current views about capillary permeability. The basement membrane, exposed to the capillary lumen by endothelial fenestrations is considered the most likely site of protein passage at the blood-CSF-barrier.
The effect of acetazolamide and furosemide on choroid plexus (CP) production and electrolyte composition of cerebrospinal fluid (CSF) from the cat CP in situ was investigated. Both drugs decreased CSF production by the CP by 50--90% from a control rate of 0.53 microL . min-1 . mg-1 CP within 1.5--2.5 h after the start of drug treatment. The results were similar whether the drug was administered intravenously or applied directly to the CSF side of the CP. A number of experiments in which the effect of administering drugs via the chamber were studied were continued with the drugs removed by washing the preparation with drug-free artificial CSF and the responses measured. The results demonstrated that the effects of acetazolamide and furosemide were reversed during the 1st h following the washout. Both drugs decreased K concentration of nascent CSF when administered intravenously and furosemide also did so when administered on the CSF side of the CP. It is concluded from these and previous data that acetazolamide and furosemide markedly inhibit the transport mechanism(s) in the cat CP that are responsible for CP secretion which represents about 40--60% of the total CSF production and that K transport is also affected.
Drugs which inhibit carbonic anhydrase (CA) reduce cerebrospinal fluid (CSF) flow. This study relates the inhibition of CSF flow in cats after 1 to 30 mg/kg of methazolamide, acetazolamide or benzolamide (inhibitors of differing pharmacokinetic properties) to plasma and choroid plexus levels of these drugs. From plasma concentrations of unbound drug and the dissociation constants for the interaction of drugs with choroid plexus CA, it is shown that the concentration of residual active CA in choroid plexus of cats must be reduced from approximately 22 microM to the range of 5 to 10 nM to reduce CSF flow significantly. This represents at least 99.95% inhibition of CA of choroid plexus. This level of inhibition was achieved by an i.v. dose of 30 mg/kg of methazolamide, acetazolamide or benzolamide, whereas doses of 10 mg/kg of methazolamide or acetazolamide did not significantly decrease mean residual CSF flow. The data suggest that it is the residual flow after inhibition, not the absolute or percentage of decrease in flow, which should be used to evaluate the effectiveness of CA inhibition, because of the variability in individual control rates. Maximal effects of CA inhibition in cat reduce flow to 9 to 11 microliter/min from a mean of 21.7 microliter/min. In choroid plexus of man, the CA concentration is, at most, 40% that of cat. An attempt has been made to use CA concentration, drug binding data and other pharmacokinetic factors in predicting appropriate choices of drug and dose for man, extrapolating from the data for cats. These predictions are compared to existing data for plasma levels or CSF effects of CA inhibitors in man.
The purpose of this study was to investigate the efficacy of combined therapy with acetazolamide and furosemide in normalizing intracranial pressure in children with pseudotumor cerebri. The role of repeated lumbar cerebrospinal fluid pressure monitoring in evaluating the response to therapy is also demonstrated. Continuous 1-hour lumbar cerebrospinal fluid pressure monitoring was done in eight children with pseudotumor cerebri on admission and at weekly intervals until the baseline pressure had normalized. (One child had two episodes of pseudotumor cerebri). All patients were treated with oral acetazolamide and furosemide until papilledema had cleared. Raised intracranial pressure was present on admission in all nine episodes of pseudotumor cerebri. Six children had an increased baseline cerebrospinal fluid pressure, whereas raised intracranial pressure was diagnosed in three children on account of an abnormal pulse wave and/or pressure waves. The mean baseline pressure was significantly lower after the 1st week of treatment than on admission (P = .007) and normalized in all patients within 6 weeks of start of therapy. All children had a rapid clinical response. Combined therapy with acetazolamide and furosemide is an effective first-line method of treating raised intracranial pressure in children with pseudotumor cerebri. The good correlation found between the clinical response and normalization of baseline cerebrospinal fluid pressure suggests that clinical monitoring of treatment is adequate in most children with this condition.
With the hypothesis that the NaCl cotransporter in mammalian choroid plexus (CP) has a role in CSF formation, we postulated that loop diuretic agents would curtail transport of Cl from blood to CSF. Microdialysis in the cisterna magna of Sprague-Dawley rats was used to assess the ability of furosemide and ethacrynic acid (i.e. loop agents that interfere directly with cotransport) to inhibit 36Cl transport from blood to CSF over a 3-h period. Cl uptake by CSF was quantified as % volume of distribution (Vd) of 36Cl, i.e. 100 x cpm/g CSF divided by cpm/ml plasma. Uptake curves of Vd vs. time were constructed for the various treatments; then, to compare drug effects, the curves were analyzed for: (i) the early slope of uptake (Kin), (ii) the steady-state value for Vd, and (iii) the area-under-curve (AUC). Assessment of the curve parameters collectively revealed that at 5 mg/kg, both furosemide (FUR) and ethacrynic acid (EA) reduced Cl penetration into CSF by one quarter; at 50 mg/kg, these loop agents decreased Cl uptake by about a third. On the other hand, 50 mg/kg of the carbonic anhydrase inhibitor, acetazolamide, reduced Cl uptake into CSF by 55-60%. Thus, NaCl cotransport inhibitors maximally reduced Cl transport in the rat by about 35%; this inhibition was less extensive than that brought about by acetazolamide, which interferes with CSF secretion by a different mechanism.
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 (delta Q/Q) which is evaluated as a function of increasing albumin quotients (QAlb). 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 (QAlb = 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. QIgG:QAlb) with increasing CSF protein content (QAlb) 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.
Concentrations of ascorbate (vitamin C) in cerebrospinal fluid (CSF) from human controls (median 163 mumol/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 mumol/l, n = 119) was decreased significantly in cases of neurological diseases with a blood-CSF barrier dysfunction (median 26 mumol/l, n = 30). In this latter group a linear CSF to serum ratio with a mean of 5.7:1 (with CSF/serum albumin quotients QAlb = 7.8-70.8 x 10(-3), median 10.0 x 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 square root of 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 = 0.1x +/- 10 mumol/l, including 99% of the cases with an urate serum concentration range from 80 mumol/l to 460 mumol/l.
We investigated the effects of omeprazole and Sch 28080, a more specific and a more potent inhibitor of K+,H+-ATPase than omeprazole, in canine cerebrospinal fluid (CSF) production. CSF production was measured by ventriculocisternal perfusion (VCP) technique in three groups (n = 10 in each group) of anesthetized, paralyzed and mechanically ventilated dogs. Group I served as control, Sch 28080 (10(-4) mol/l of synthetic CSF) was added to VCP in group II, and omeprazole (10(-5) mol/l of synthetic CSF) was added to VCP in group III, after baseline control CSF production had been determined at 15, 30, 45, and 60 min. Comparing the three groups, the mean baseline values for CSF production did not differ significantly. However, the percent decreases in CSF production in the omeprazole treated group were 26 +/- 17 and 24 +/- 13 at 210 and 225 min, which were significantly more than the respective values in the control group. Percent decrease in CSF production in Sch 28080 was not significantly different from that in the control group. We conclude that in the canine model, physiological doses of omeprazole decrease CSF production by about 26%. However, the effect is independent of the K+,H+-ATPase activity, since Sch 28080 which is more potent than omeprazole did not significantly affect CSF production.
Familial hemiplegic migraine and episodic ataxia type 2 (EA2) are allelic disorders with distinct types of mutations in the CACNA1A gene. EA2 attacks are remarkably sensitive to acetazolamide, a carbonic anhydrase inhibitor. The effectiveness of acetazolamide in migraine prophylaxis is unknown.
To evaluate the efficacy and the tolerability of acetazolamide in migraine prophylaxis.
We compared daily oral 500 mg acetazolamide and placebo in patients with migraine in a multicentre, double-blind, randomised trial of 12 weeks duration after a run-in period of 4 weeks without treatment. Frequency of attacks at the last trial period of 4 weeks was the primary efficacy criterion. Secondary efficacy criteria were the frequency of attacks per 4 weeks, the severity and duration of attacks, the number of hours with migraine as well as the number of responders with more than 50% reduction in attack frequency.
53 patients had been enrolled when the study was prematurely stopped because of a high number of withdrawals (34%), primarily linked to acetazolamide related side effects. Considering the primary and secondary efficacy criteria, among the 53 included patients (27 in the placebo group and 26 in the acetazolamide group), no difference between the 2 study groups could be demonstrated. The most frequent adverse events related to acetazolamide were paresthesias and asthenia.
In this trial, migraine sufferers poorly tolerated acetazolamide given in an oral dose of 500 mg daily. No obvious prophylactic beneficial effect of acetazolamide appeared on migraine attacks.
There is evidence that production and turnover of CSF help to clear toxic molecules such as amyloid-beta peptide (Abeta) from the interstitial-fluid space of the brain to the bloodstream. Two changes in CSF circulatory physiology have been noted as part of ageing: first, a trend towards lower CSF production, hence a decrease in CSF turnover; and second, greater resistance to CSF outflow. Our hypothesis is that, all else being equal, the initially dominant physiological change determines whether CSF circulatory failure manifests as Alzheimer's disease (AD) or as normal-pressure hydrocephalus (NPH). If CSF production failure predominates, AD develops. However, if resistance to CSF outflow predominates, NPH results. Once either disease process takes hold, the risk of the other disorder may rise. In AD, increased deposition of Abeta in the meninges leads to greater resistance to CSF outflow. In NPH, raised CSF pressure causes lower CSF production and less clearance of Abeta. The disorders may ultimately converge in vulnerable individuals, resulting in a hybrid as has been observed in several clinical series. We postulate a new nosological entity of CSF circulatory failure, with features of AD and NPH. NPH-AD may cover an important subset of patients who carry the diagnosis of either AD or NPH.
Furosemide is usually administered by the oral or intravenous route to cardiac patients with hypertension and heart failure, as well as edema. Occasionally, furosemide cannot be administered by these routes.
To evaluate the diuretic/natriuretic efficacy of subcutaneously administered furosemide in healthy volunteers.
This single-center, double-blind, placebo-controlled, randomized, crossover pilot study compared the diuretic effect of subcutaneously administered furosemide and NaCl 0.9% (placebo) in 12 healthy volunteers. The study was conducted over 5 days. Baseline values were determined on day 1. On days 3 and 5, each volunteer was injected with either furosemide 20 mg (2 mL) or 2 mL of placebo subcutaneously. A washout period occurred on day 4. Fluid and dietary intake were controlled on all 3 data collection days. Primary outcome measures consisted of urine volume voided, urine sodium concentration, onset time and volume of initial urine output, and number of voids during 8 hours of urine collection.
All outcomes demonstrated statistically significant differences when treatment and placebo groups were compared (p < 0.05). Adverse effects most commonly reported by the participants were minor and included transient burning and stinging at the injection site.
This study demonstrates that subcutaneously administered furosemide is a viable alternative when the oral or intravenous route of administration is not desirable or possible in humans. However, the results of this study need to be corroborated in various patient populations.
This study was designed to test the hypothesis that pain associated with syringomyelia in dogs is dependent upon size and involvement of the dorsal part of the spinal cord.
Masked observers determined syrinx dimensions and precise location within the spinal cord on magnetic resonance images of 55 cavalier King Charles spaniels with syringomyelia. After removal of masking, syrinx size and location were compared between the cohorts of dogs that exhibited pain with those that did not.
Maximum syrinx width was the strongest predictor of pain, scratching behaviour and scoliosis in dogs with syringomyelia. Both pain and syrinx size were positively correlated with syrinxes located in the dorsal half of the spinal cord.
Large syrinxes associated with damage to the dorsal part of the spinal cord are associated with persistent pain suggesting that the pain behaviour expressed by this group of patients is likely to be "neuropathic pain," resulting from disordered neural processing in the damaged dorsal horn. As such it is likely that conventional analgesic medication may be ineffective.
Accurate analysis of cerebrospinal fluid (CSF) provides a wide range of information about the neurological health of the patient. CSF can be withdrawn from either of two cisterns in dogs and cats using relatively safe techniques. Once CSF has been collected it must be analysed immediately and methodically. Evaluation should consist of macroscopic, quantitative and microscopic analyses. As part of a quantitative analysis, cell counts and infectious disease testing are the most important and potentially sensitive indicators of disease. Although certain pathologies can be described, microscopic analysis will rarely be specific for any disease, emphasising the adjunctive nature of this diagnostic modality.
Syringomyelia: current concepts in pathogenesis, diagnosis, and treatment
- Rusbridge