Umeå University Medical Dissertations, New Series No 1613 Analysis of ICP pulsatility and CSF dynamics The pulsatility curve and effects of postural changes, with implications for idiopathic normal pressure hydrocephalus Sara Qvarlander Department of Radiation Sciences and Department of Pharmacology and Clinical Neuroscience, Umeå University Umeå, Sweden, 2013 Responsible publisher under swedish law: the Dean of the Medical Faculty This work is protected by the Swedish Copyright Legislation (Act 1960:729) ISBN: 978-91-7459-762-2 ISSN: 0346-6612 Electronic version available at http://umu.diva-portal.org/ Printed by: Print & Media Umeå, Sweden 2013 “Prediction is very difficult, especially if it's about the future.” Niels Bohr Abstract The volume defined by the rigid cranium is shared by the brain, blood and cerebrospinal fluid (CSF). With every heartbeat the arterial blood volume briefly increases and venous blood and CSF are forced out of the cranium, leading to pulsatility in CSF flow and intracranial pressure (ICP). Altered CSF pulsatility has been linked to idiopathic normal pressure hydrocephalus (INPH), which involves enlarged cerebral ventricles and symptoms of gait/balance disturbance, cognitive decline and urinary incontinence that may be improved by implantation of a shunt. The overall aim of this thesis was to investigate the fluid dynamics of the CSF system, with a focus on pulsatility, and how they relate to INPH pathophysiology and treatment. Mathematical modelling was applied to data from infusion tests, where the ICP response to CSF volume manipulation is measured, to analyse the relationship between mean ICP and ICP pulse amplitude (AMP) before and after shunt surgery in INPH (paper I-II). The observed relationship, designated the pulsatility curve, was found to be constant at low ICP and linear at high ICP, corresponding to a shift from constant to ICP dependent compliance (paper I). Shunt surgery did not affect the pulsatility curve, but shifted baseline ICP and AMP along the curve towards lower values. Patients who improved in gait after surgery had significantly larger AMP reduction than those who did not, while ICP reduction was similar, suggesting that improving patients had baseline ICP in the linear zone of the curve before surgery. Use of this phenomenon for outcome prediction was promising (paper II). The fluid dynamics of an empirically derived pulsatility-based predictive infusion test for INPH was also investigated, with results showing strong influence from compliance (paper III). Clinical ICP data at different body postures was used to evaluate three models describing postural effects on ICP. ICP decreased in upright positions, whereas AMP increased. The model describing the postural effects based on hydrostatic changes in the venous system, including effects of collapse of the jugular veins in the upright position, accurately predicted the measured ICP (paper IV). Cerebral blood flow and CSF flow in the aqueduct and at the cervical level was measured with phase contrast magnetic resonance imaging, and compared between healthy elderly and INPH (paper V). Cerebral blood flow and CSF flow at the cervical level were similar in INPH patients and healthy elderly, whereas aqueductal CSF flow differed significantly. The pulsatility in the aqueduct flow was increased, and there was more variation in the net flow in INPH, but the mean net flow was normal, i.e. directed from the ventricles to the subarachnoid space (paper V). In conclusion, this thesis introduced the concept of pulsatility curve analysis, and provided evidence that pulsatility and compliance are important aspects for successful shunt treatment and outcome prediction in INPH. It was further confirmed that enhanced pulsatility of aqueduct CSF flow was the most distinct effect of INPH pathophysiology on cerebral blood flow and CSF flow. A new model describing postural and hydrostatic effects on ICP was presented, and the feasibility and potential importance of measuring ICP in the upright position in INPH was demonstrated. Table of Contents Original Papers iii Abbreviations iv Introduction 1 Background 3 CSF circulation 3 Intracranial blood circulation 4 Intracranial pulsatility 5 Idiopathic Normal Pressure Hydrocephalus 6 Mathematical modelling of CSF dynamics 7 Infusion tests 10 Hydrostatic pressure gradients and posture 12 Phase-Contrast Magnetic Resonance Imaging 13 Aims 17 Materials and methods 19 General overview 19 Ethical approval 19 Subjects 19 Infusion test protocols 23 ICP data quality 25 Post processing of ICP data 25 Mathematical modelling and derivations 29 Magnetic Resonance Imaging 38 Post processing of MRI data 39 Statistics 41 Results 43 The pulsatility curve 43 Response to shunt surgery 45 AMPmean – Mean pulse amplitude 47 Postural effects on ICP 49 Cerebral blood flow and CSF flow 51 Discussion 53 Intracranial pulsatility 53 Treatment and outcome prediction in INPH 54 Pathophysiology of INPH 56 Extension of the mathematical model of CSF dynamics 59 Modelling of postural and hydrostatic effects on ICP 60 Future research 62 Conclusion 65 Acknowledgements 67 References 69 i ii Original Papers This thesis is based on the following papers, which are referred to by their Roman numerals in the text: I. Qvarlander S, Malm J, Eklund A. The pulsatility curve – the relationship between mean intracranial pressure and pulsation amplitude. Physiological Measurement 31(11):1517-28, 2010* II. Qvarlander S, Lundkvist B, Koskinen L-O D, Malm J, Eklund A. Pulsatility in CSF dynamics: pathophysiology of idiopathic normal pressure hydrocephalus. Journal of Neurology, Neurosurgery, and Psychiatry 84(7):735-41, 2013* III. Qvarlander S, Malm J, Eklund A. CSF dynamic analysis of a predictive pulsatility-based infusion test for normal pressure hydrocephalus. Medical and Biological Engineering and Computing 2013 Oct 23. [Epub ahead of print]* IV. Qvarlander S, Sundström N, Malm J, Eklund A. Postural effects on intracranial pressure: modeling and clinical evaluation. Journal of Applied Physiology 2013 Sep 19. [Epub ahead of print]* V. Qvarlander S, Ambarki K, Wåhlin A, Jacobsson J, Birgander R, Malm J, Eklund A. Differences in cerebral blood flow and CSF flow between INPH and healthy elderly. In manuscript. * Reprinted with permission. iii Abbreviations ΔV Intracranial arterial volume expansion at systole ρ Density of cerebrospinal fluid/blood (approximated as water) AMP Pulse amplitude of intracranial pressure AMPmean Mean pulse amplitude of intracranial pressure during first 10 minutes of constant flow infusion AMPnorm Normalized pulse amplitude of intracranial pressure AMPr Baseline/resting pulse amplitude of intracranial pressure ANOVA Analysis of variance C Compliance of the cerebrospinal fluid system CBF Cerebral arterial blood flow CFI Constant flow infusion CPI Constant pressure infusion CSF Cerebrospinal fluid Cout Conductance of cerebrospinal fluid outflow (1/Rout) CVP Central venous pressure ECG Electrocardiogram FFT Fast Fourier transform g Gravitational acceleration HIPCSF Hydrostatic indifference point of the cerebrospinal fluid system HIPvein Hydrostatic indifference point of the venous system ICA Internal carotid artery ICP Intracranial pressure ICPnorm Normalized intracranial pressure ICPr Baseline/resting intracranial pressure ICPstart Intracranial pressure at start of external infusion Ia Absorption rate of cerebrospinal fluid If Formation rate of cerebrospinal fluid Iext Rate of external infusion IJV Internal jugular vein INPH Idiopathic normal pressure hydrocephalus k Elastance coefficient of the cerebrospinal fluid system (=1/0.4343PVI) Lheart Distance from auditory canal to the centre of the sternum (as an anatomical reference for the heart) Lheart-HIPvein Distance from the heart to the hydrostatic indifference point of the venous system Lcollapse Distance from top of collapsed venous segment to the auditory canal iv MRI Magnetic resonance imaging NPH Normal pressure hydrocephalus P0 Pressure constant of the mathematical model of the cerebrospinal fluid system PC-MRI Phase contrast magnetic resonance imaging Pd Venous pressure in the dural venous sinus PHIPvein Venous pressure at the venous hydrostatic indifference point PVI Pressure volume index (=1/0.4343k) ROC Receiver operating characteristic ROI Region of interest Rout Resistance to cerebrospinal fluid outflow/absorption (1/Cout) RPPC Relative pulse pressure coefficient, slope of linear relationship between pulse amplitude and mean intracranial pressure SD Standard deviation SV Stroke volume VA Vertebral artery Venc Maximum velocity measured without aliasing in phase contrast magnetic resonance imaging sequence v vi Introduction The adult cranium is rigid, and encloses a fixed volume that is shared by the brain, blood and cerebrospinal fluid (CSF). The Monro-Kelli doctrine postulates that, as these constituents are considered essentially incompressible, the increases in the volume of one of the constituents must be compensated for by reduction in the others (82). The doctrine was defined for slow processes, such as a mass lesion, e.g. an intracranial haemorrhage, but can also be applied to interpret fast, cardiac-related pulsatility. Thus, with every heartbeat, when the intracranial arterial blood volume briefly increases, venous blood and CSF is forced out of the intracranial compartment (53, 54). The intracranial flow of blood and CSF is thus pulsatile, as is the intracranial pressure (ICP). This cardiac-related pulsatility has become the focus of several hypotheses