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

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

Priorities for hydrocephalus research: report from a National Institutes of Health-sponsored workshop

Journal ArticleObject. Treatment for hydrocephalus has not advanced appreciably since the advent of cerebrospinal fluid (CSF) shunts more than 50 years ago. Many questions remain that clinical and basic research could address, which in turn could improve therapeutic options. To clarify the main issues facing hydrocephalus research and to identify critical advances necessary to improve outcomes for patients with hydrocephalus, the National Institutes of Health (NIH) sponsored a workshop titled "Hydrocephalus: Myths, New Facts, and Clear Directions." The purpose of this paper is to report on the recommendations that resulted from that workshop. Methods. The workshop convened from September 29 to October 1, 2005, in Bethesda, Maryland. Among the 150 attendees was an international group of participants, including experts in pediatric and adult hydrocephalus as well as scientists working in related fields, neurosurgeons, laboratory-based neuroscientists, neurologists, patient advocates, individuals with hydrocephalus, parents, and NIH program and intramural staff. Plenary and breakout sessions covered injury and recovery mechanisms, modeling, biomechanics, diagnosis, current treatment and outcomes, complications, quality of life, future treatments, medical devices, development of research networks and information sharing, and education and career development. Results. The conclusions were as follows: 1) current methods of diagnosis, treatment, and outcomes monitoring need improvement; 2) frequent complications, poor rate of shunt survival, and poor quality of life for patients lead to unsatisfactory outcomes; 3) investigators and caregivers need additional methods to monitor neurocognitive function and control of CSF variables such as pressure, flow, or pulsatility; 4) research warrants novel interdisciplinary approaches; 5) understanding of the pathophysiological and recovery mechanisms of neuronal function in hydrocephalus is poor, warranting further investigation; and 6) both basic and clinical aspects warrant expanded and innovative training programs. Conclusions. The research priorities of this workshop provide critical guidance for future research in hydrocephalus, which should result in advances in knowledge, and ultimately in the treatment for this important disorder and improved outcomes in patients of all ages

Intracranial Pressure Monitoring in Cerebrospinal Fluid Dynamics Disturbances

There are numerous gaps in the knowledge of Intracranial Pressure (ICP) physiology and Cerebrospinal Fluid (CSF) dynamics. This PhD answers some of the research questions posed by these gaps, through the use of invasive ICP monitoring in patients with suspected CSF dynamics disturbances. Research on CSF dynamics disturbances has mainly focused on conditions that cause high ICP, whilst only sparse attention has been centred on low CSF pressure/volume states. Chapter 3 and chapter 4 of this thesis are focused on Spontaneous Intracranial Hypotension (SIH). Chapter 3 is a comprehensive systematic review and meta-analysis of the clinical presentation, investigation findings and treatment outcomes of this disease. Chapter 4 is an observational study that investigated the utility of invasive ICP monitoring when there is diagnostic uncertainty for SIH. This study demonstrates that, in selected cases, ICP monitoring can be useful and confirm a low-pressure state in 8% of the patients and identify a paradoxical clinical presentation with an underlying high-pressure state in 16% of the patients. Chapters 5 and 6 provide evidence on the way that ICP and brain compliance respond to external variables, such as changes in posture and shunt setting adjustments. Chapter 5 is a retrospective observational study that describes the changes of ICP and pulse amplitude with different postures. Chapter 6 is a retrospective observational study investigating the effect of valve setting adjustments on ICP. This study demonstrates that paradoxical changes in ICP following differential pressure valves setting changes can occur. Chapters 7 and 8 investigate the possibility of replacing invasive ICP monitoring with non-invasive biomarkers of raised ICP. Chapter 7 demonstrated the association between higher ICP measurements and the absence of spontaneous retinal venous pulsations detected with infrared video recordings. Chapter 8 demonstrates the utility of integrating ophthalmic and imaging biomarkers to predict raised ICP

Hydrocephalus 2008, 17–20th September, Hannover Germany: a conference report

Hydrocephalus 2008 was held 17–20 September in Hannover, Germany, at the invitation of Petra M Klinge (President), co-hosted by Joachim K. Krauss (Vice President), and Madjid Samii (Honorary President). This meeting was a successor to Hydrocephalus 2006 held in Göteborg, Sweden, organised by Past-President, Carsten Wikkelso. The conference began with a general introductory session of six talks including three invited lectures, followed by eighteen parallel sessions. Subjects covered were hydrocephalus signs, symptoms and diagnosis, especially in normal pressure hydrocephalus; cerebrospinal fluid (CSF) physics and dynamics; CSF function and modelling of function; dementia and quality of life, economy, health care and rehabilitation; neuropsychology, cognition and outcome assessment; neuroimaging, functional imaging and non-invasive diagnostics; paediatric and adolescent hydrocephalus; intelligent shunt and valve design (e.g. telemetry, adjustable and antimicrobial shunts); endoscopic third ventriculostomy; technical advances and image-guided surgical approaches in the treatment of hydrocephalus; brain metabolism, biomarkers and biophysics; co-morbidity, classification and aetiology; epidemiology, registries and clinical trials; experimental hydrocephalus; and pharmaceutical modulation of central nervous system function (CNS drug delivery). Each session began with introductory talks from the invited chairpersons followed by six to eight submitted oral presentations. Overall, 136 oral presentations and 18 posters were presented, the abstracts of which were published elsewhere [1]. We present here an account of the introductory session, the invited chairperson's talks and the concluding remarks by Anthony Marmarou