Validation of Davson's equation in patients suffering from idiopathic normal pressure hydrocephalus.

INTRODUCTION: The so-called Davson's equation relates baseline intracranial pressure (ICP) to resistance to cerebrospinal fluid outflow (Rout), formation of cerebrospinal fluid (If) and sagittal sinus pressure (PSS) There is a controversy over whether this fundamental equation is applicable in patients with normal pressure hydrocephalus (NPH). We investigated the relationship between Rout and ICP and also other compensatory, clinical and demographic parameters in NPH patients. METHOD: We carried out a retrospective study of 229 patients with primary NPH who had undergone constant-rate infusion studies in our hospital. Data was recorded and processed using ICM+ software. Relationships between variables were sought by calculating Pearson product correlation coefficients and p values. RESULTS: We found a significant, albeit weak, relationship between ICP and Rout (R = 0.17, p = 0.0049), Rout and peak-to-peak amplitude of ICP (AMP) (R = 0.27, p = 3.577e-05) and Rout and age (R = 0.16, p = 0.01306). CONCLUSIONS: The relationship found between ICP and Rout provides indirect evidence to support disturbed Cerebrospinal fluid circulation as a key factor in disturbed CSF dynamics in NPH. Weak correlation may indicate that other factors-variable PSS and formation of CSF outflow-contribute heavily to linear model expressed by Davson's equation

CSF Dynamics for Shunt Prognostication and Revision in Normal Pressure Hydrocephalus.

BACKGROUND: Despite the quantitative information derived from testing of the CSF circulation, there is still no consensus on what the best approach could be in defining criteria for shunting and predicting response to CSF diversion in normal pressure hydrocephalus (NPH). OBJECTIVE: We aimed to review the lessons learned from assessment of CSF dynamics in our center and summarize our findings to date. We have focused on reporting the objective perspective of CSF dynamics testing, without further inferences to individual patient management. DISCUSSION: No single parameter from the CSF infusion study has so far been able to serve as an unquestionable outcome predictor. Resistance to CSF outflow (Rout) is an important biological marker of CSF circulation. It should not, however, be used as a single predictor for improvement after shunting. Testing of CSF dynamics provides information on hydrodynamic properties of the cerebrospinal compartment: the system which is being modified by a shunt. Our experience of nearly 30 years of studying CSF dynamics in patients requiring shunting and/or shunt revision, combined with all the recent progress made in producing evidence on the clinical utility of CSF dynamics, has led to reconsidering the relationship between CSF circulation testing and clinical improvement. CONCLUSIONS: Despite many open questions and limitations, testing of CSF dynamics provides unique perspectives for the clinician. We have found value in understanding shunt function and potentially shunt response through shunt testing in vivo. In the absence of infusion tests, further methods that provide a clear description of the pre and post-shunting CSF circulation, and potentially cerebral blood flow, should be developed and adapted to the bed-space

Effect of resting pressure on the estimate of cerebrospinal fluid outflow conductance

<p>Abstract</p> <p>Background</p> <p>A lumbar infusion test is commonly used as a predictive test for patients with normal pressure hydrocephalus and for evaluation of cerebrospinal fluid (CSF) shunt function. Different infusion protocols can be used to estimate the outflow conductance (<it>C</it>_out) or its reciprocal the outflow resistance (<it>R</it>_out), with or without using the baseline resting pressure, <it>P</it>_r. Both from a basic physiological research and a clinical perspective, it is important to understand the limitations of the model on which infusion tests are based. By estimating <it>C</it>_out using two different analyses, with or without <it>P</it>_r, the limitations could be explored. The aim of this study was to compare the <it>C</it>_out estimates, and investigate what effect <it>P</it>_rhad on the results.</p> <p>Methods</p> <p>Sixty-three patients that underwent a constant pressure infusion protocol as part of their preoperative evaluation for normal pressure hydrocephalus, were included (age 70.3 ± 10.8 years (mean ± SD)). The analysis was performed without (<it>C</it>_{excl Pr}) and with (<it>C</it>_{incl Pr}) P_r. The estimates were compared using Bland-Altman plots and paired sample <it>t</it>-tests (<it>p </it>< 0.05 considered significant).</p> <p>Results</p> <p>Mean <it>C</it>_out for the 63 patients was: <it>C</it>_{excl Pr}= 7.0 ± 4.0 (mean ± SD) μl/(s kPa) and <it>C</it>_{incl Pr} = 9.1 ± 4.3 μl/(s kPa) and <it>R</it>_out was 19.0 ± 9.2 and 17.7 ± 11.3 mmHg/ml/min, respectively. There was a positive correlation between methods (r = 0.79, n = 63, <it>p </it>< 0.01). The difference, Δ<it>C</it>_out= -2.1 ± 2.7 μl/(s kPa) between methods was significant (<it>p </it>< 0.01) and Δ<it>R</it>_outwas 1.2 ± 8.8 mmHg/ml/min). The Bland-Altman plot visualized that the variation around the mean difference was similar all through the range of measured values and there was no correlation between Δ<it>C</it>_outand <it>C</it>_out.</p> <p>Conclusions</p> <p>The difference between <it>C</it>_outestimates, obtained from analyses with or without <it>P</it>_r, needs to be taken into consideration when comparing results from studies using different infusion test protocols. The study suggests variation in CSF formation rate, variation in venous pressure or a pressure dependent <it>C</it>_outas possible causes for the deviation from the CSF absorption model seen in some patients.</p

Aqueductal cerebrospinal fluid pulsatility in healthy individuals is affected by impaired cerebral venous outflow.

To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius (AoS) in chronic cerebrospinal venous insufficiency (CCSVI)-positive and -negative healthy individuals using cine phase contrast imaging.Fifty-one healthy individuals (32 CCSVI-negative and 19 age-matched CCSVI-positive subjects) were examined using Doppler sonography (DS). Diagnosis of CCSVI was established if subjects fulfilled ≥2 venous hemodynamic criteria on DS. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and routine 3T MRI outcomes.CCSVI was associated with increased CSF pulsatility in the AoS. Net positive CSF flow was 32% greater in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.008). This was accompanied by a 28% increase in the mean aqueductal characteristic signal (ie, the AoS cross-sectional area over the cardiac cycle) in the CCSVI-positive group compared with the CCSVI-negative group (P = 0.021).CSF dynamics are altered in CCSVI-positive healthy individuals, as demonstrated by increased pulsatility. This is accompanied by enlargement of the AoS, suggesting that structural changes may be occurring in the brain parenchyma of CCSVI-positive healthy individuals

Cerebrospinal fluid pulse pressure amplitude during lumbar infusion in idiopathic normal pressure hydrocephalus can predict response to shunting

<p>Abstract</p> <p>Background</p> <p>We have previously seen that idiopathic normal pressure hydrocephalus (iNPH) patients having elevated intracranial pressure (ICP) pulse amplitude consistently respond to shunt surgery. In this study we explored how the cerebrospinal fluid pressure (CSFP) pulse amplitude determined during lumbar infusion testing, correlates with ICP pulse amplitude determined during over-night ICP monitoring and with response to shunt surgery. Our goal was to establish a more reliable screening procedure for selecting iNPH patients for shunt surgery using lumbar intrathecal infusion.</p> <p>Methods</p> <p>The study population consisted of all iNPH patients undergoing both diagnostic lumbar infusion testing and continuous over-night ICP monitoring during the period 2002-2007. The severity of iNPH was assessed using our NPH grading scale before surgery and 12 months after shunting. The CSFP pulse was characterized from the amplitude of single pressure waves.</p> <p>Results</p> <p>Totally 62 iNPH patients were included, 45 of them underwent shunt surgery, in whom 78% were shunt responders. Among the 45 shunted patients, resistance to CSF outflow (R_out) was elevated (≥ 12 mmHg/ml/min) in 44. The ICP pulse amplitude recorded over-night was elevated (i.e. mean ICP wave amplitude ≥ 4 mmHg) in 68% of patients; 92% of these were shunt responders. In those with elevated overnight ICP pulse amplitude, we found also elevated CSFP pulse amplitude recorded during lumbar infusion testing, both during the opening phase following lumbar puncture and during a standardized period of lumbar infusion (15 ml Ringer over 10 min). The clinical response to shunting after 1 year strongly associated with the over-night ICP pulse amplitude, and also with the pulsatile CSFP during the period of lumbar infusion. Elevated CSFP pulse amplitude during lumbar infusion thus predicted shunt response with sensitivity of 88 and specificity of 60 (positive and negative predictive values of 89 and 60, respectively).</p> <p>Conclusions</p> <p>In iNPH patients, shunt response can be anticipated in 9/10 patients with elevated overnight ICP pulse amplitude, while in only 1/10 with low ICP pulse amplitude. Additionally, the CSFP pulse amplitude during lumbar infusion testing was elevated in patients with elevated over-night ICP pulse amplitude. In particular, measurement of CSFP pulse amplitude during a standardized infusion of 15 ml Ringer over 10 min was useful in predicting response to shunt surgery and can be used as a screening procedure for selection of iNPH patients for shunting.</p

Elevated cerebrospinal fluid pressure in patients with Alzheimer's disease

BACKGROUND: Abnormalities in cerebrospinal fluid (CSF) production and turnover, seen in normal pressure hydrocephalus (NPH) and in Alzheimer's disease (AD), may be an important cause of amyloid retention in the brain and may relate the two diseases. There is a high incidence of AD pathology in patients being shunted for NPH, the AD-NPH syndrome. We now report elevated CSF pressure (CSFP), consistent with very early hydrocephalus, in a subset of AD patients enrolled in a clinical trial of chronic low-flow CSF drainage. Our objective was to determine the frequency of elevated CSFP in subjects meeting National Institutes of Neurological and Communicative Diseases and Stroke – Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for AD, excluding those with signs of concomitant NPH. METHODS: AD subjects by NINCDS-ADRDA criteria (n = 222), were screened by history, neurological examination, and radiographic imaging to exclude those with clinical or radiographic signs of NPH. As part of this exclusion process, opening CSFP was measured supine under general anesthesia during device implantation surgery at a controlled pCO(2 )of 40 Torr (40 mmHg). RESULTS: Of the 222 AD subjects 181 had pressure measurements recorded. Seven subjects (3.9%) enrolled in the study had CSFP of 220 mmH(2)0 or greater, mean 249 ± 20 mmH(2)0 which was significantly higher than 103 ± 47 mmH(2)O for the AD-only group. AD-NPH patients were significantly younger and significantly less demented on the Mattis Dementia Rating Scale (MDRS). CONCLUSION: Of the AD subjects who were carefully screened to exclude those with clinical NPH, 4% had elevated CSFP. These subjects were presumed to have the AD-NPH syndrome and were withdrawn from the remainder of the study

Dynamics of cerebral fluids in patients suffering from hydrocephalus and pseudotumour cerebri

This dissertation is devoted to dynamics of brain liquids in patients with altered CSF circulation and pressure-volume compensation. Since the introduction of intracranial pressure (ICP) monitoring, the studies of CSF dynamics have revealed unique information about the intracranial circulation and opened new opportunities for diagnosis and treatment of hydrocephalus and pseudotumour cerebri. The adaptation of infusion tests in clinical practice over 45 years ago has introduced a practical tool to benefit both patients and research into altered CSF dynamics. Objective testing of intracranial circulation in patients with clinical symptoms constitutes a unique situation, where the discovery of new patterns and reasons for disturbed intracranial circulation can be quantified. Such macroscopic yet practical quantifications can easily be translated to clinically useful information, and back, in real time or alternative past and future synchronicities. The aim of this dissertation is to demonstrate the value of testing CSF dynamics in vivo and how it could provide pathophysiological and clinical insights into hydrocephalus and pseudotumour cerebri syndrome (PTCS). My intention was to describe and reflect the main themes involved in the study of CSF dynamics: a) their role in diagnosis and treatment, b) their use in understanding shunts and shunt malfunction c) the need to optimise our understanding of the contents of ICP, meaning that long-term ICP monitoring or dynamic tests are required in CSF disorders, not snapshot ICP measurements and finally d) the mapping and quantification of the interaction between CSF circulation and cerebral blood flow (CBF). As the above foundations and results of my work lead to the formation of a required, albeit expected, long doctoral treatise, I have structured the later in 9 chapters containing a comprehensive literature review of the Resistance to CSF outflow as well as a systematic literature review of the CBF and autoregulation of the CBF in NPH. I have also dedicated a methods chapter, Chapter 3, into introducing and explaining the variable tested during a CSF infusion test, such as the fundamental amplitude of ICP and the compensatory reserve indices. Following this is the presentation of the data and clinical material used for my original projects. Specifically, my results contain the following: I) Autoregulation of cerebral blood flow in hydrocephalus CSF infusion tests provide a unique setting where both ICP and cerebral blood flow and autoregulation can be measured in ambulatory patients utilising many different methods. Autoregulation has been studied by quantifying the interaction between the CSF and cerebral blood circulation has revealed diagnostic and outcome implications that could perhaps describe the natural course of a CSF disorder, or differentiate between a CSF disorder and a vascular disorder, or the coexistence of the two, opening new chapters to the comprehension of shunt responsive NPH. I have explored the state of global autoregulation in patients undergoing infusion tests, in an attempt to set out a reference for investigations related to NPH, Resistance, autoregulation and their clinical implications. In the 5th chapter, I have: • Described the relationship between Rout, cerebral autoregulation and arterial blood pressure. Rout demonstrates a negative linear relationship with global autoregulation. When I combined these parameters and accounted for the patients’ age, I was able to show a good correlation with outcome, much improved compared to Rout alone. II) CSF dynamics in normal pressure hydrocephalus and pseudotumour cerebri. CSF dynamics in different conditions have shown that parameters such as the Resistance to CSF outflow in NPH and ICP at baseline combined with compensatory reserve indices in PTCS, could provide important diagnostic and management information. This could be a valuable addition of objective evidence to imaging and clinical examination. Using large cohorts of patients, I have explored the Resistance to CSF outflow (Rout) in NPH in the context of different aetiologies of NPH, its relationship with age as well as its overall correlation with outcome after shunting. I have also explored these relationships in relevance to clinical practice. In PTCS, I have described the findings from infusion tests in both adult and paediatric patients and have highlighted the differences with hydrocephalus. In chapter 6, , I have described the following: • Davson’s equation in NPH: The so-called Davson’s equation describes the relationship between ICP, Rout, CSF formation rate and sagittal sinus pressure under physiological circumstances. I have validated the existence of such a linear relationship in NPH. • CSF dynamics in post-traumatic hydrocephalus: Traumatic brain injury, as a cause of secondary NPH, shows some differences in Rout and ICP amplitude compared to idiopathic NPH. I have also described the effect of decompressive craniectomy and of cranioplasty on CSF dynamics. In chapter 7, I have explored the CSF dynamics of PTCS and in particular: • The coupling between CSF pressure and Sagittal sinus pressure (SSp) in PTCS patients at baseline and during infusion tests. I have also shown how this relates to Davson’s equation under an unstable SSp and the possible pathophysiological consequences of this finding. • The CSF dynamics of paediatric patients with PTCS. Those included all patients assessed in Cambridge and classified as definite, probable and not PTCS. III) Shunt testing in vivo. Shunts are currently the mainstay for the management of hydrocephalus, as well as an important part of the management of PTCS. They change CSF dynamic parameters in a way that is easily assessed with shunt infusion tests. The knowledge of the post-shunting CSF circulation contains crucial information on the state of the shunt function, as well as the adequate restoration of the patients’ intracranial circulation. I have described how objective knowledge from shunt testing in vivo impacts clinical practice and patients’ outcomes. In chapter 8, I have presented two studies about testing shunt function in-vivo: • Shunt testing in vivo using infusion tests is important in avoiding unnecessary revisions of patent shunts and allows patients to be managed conservatively, with good outcomes. This also translates to financial benefits for healthcare systems. • In paediatric hydrocephalus, shunt infusion studies are an accurate and useful tool for investigating insidious shunt obstruction. IV) Slow waves of Intracranial Pressure. Reliable, long-term overnight monitoring is the gold standard in monitoring and analysing ICP and its contents. Slow waves, compensatory reserve and relationship with the venous circulation contain reliable information that are again correlated to clinical practice and can be compared and incorporated into the shorter-term infusion test. I have explored the behaviour of slow waves in anaesthetized patients In chapter 9, I have investigated the influence of general anaesthesia on slow waves of ICP in NPH and traumatic brain injury (TBI) patients. Conclusion: Infusion tests are a practical tool for research and possibly diagnosis and treatment in patients with PTCS and NPH. CSF dynamics provide a quantitative description of cerebral pathophysiology in CSF disorders, both for CSF and potentially for cerebral blood flow. After shunting, infusion tests are a reliable and cost-effective tool for identifying or excluding shunt malfunction. Further studies are needed to verify the clinical implications of CSF infusion tests and cerebral blood flow and autoregulation in those patients

Cerebral venous outflow and cerebrospinal fluid dynamics

In this review, the impact of restricted cere- bral venous outflow on the biomechanics of the intracranial fluid system is investigated. The cerebral venous drainage system is often viewed simply as a series of collecting vessels channeling blood back to the heart. However there is growing evidence that it plays an important role in regulating the intracranial fluid system. In particular, there appears to be a link between increased cerebrospinal fluid (CSF) pulsatility in the Aqueduct of Sylvius and constricted venous outflow. Constricted venous outflow also appears to inhibit absorp- tion of CSF into the superior sagittal sinus. The compliance of the cortical bridging veins appears to be critical to the behaviour of the intracranial fluid system, with abnormalities at this location implicated in normal pressure hydrocephalus. The compliance associated with these vessels appears to be functional in nature and dependent on the free egress of blood out of the cranium via the extracranial venous drainage pathways. Because constrict- ed venous outflow appears to be linked with increased aqueductal CSF pulsatility, it sug- gests that inhibited venous blood outflow may be altering the compliance of the cortical bridging veins

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis.

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear