Cerebrospinal fluid (CSF) infusion tests can be used to estimate the dynamic properties of the CSF system. Idiopathic normal pressure hydrocephalus (INPH) is a syndrome signified by a disturbance to the CSF system, where the cause is unknown and the diagnosis is difficult to determine. As an aid in identifying patients with INPH who will improve after shunt surgery, infusion tests are commonly used to determine the outflow conductance (Cout), or outflow resistance (Rout=1/Cout), of the CSF system. The tests are also used to determine shunt function in vivo. The general aim of this thesis was to develop and validate CSF infusion methods, to investigate the dynamics of the CSF system. The methods should be applicable to patients with INPH, to aid in the quest to further improve the diagnosis and management of this syndrome. An existing mathematical model describing the dynamics of the CSF system was further developed. The characteristics of the model were verified and the effect of expanding intracranial air on the intracranial pressure (ICP) was simulated. The simulations supported the recommendation to maintain sea-level pressure during air ambulance transportation of patients with suspected intracranial air. A recently developed infusion apparatus was evaluated, on an experimental model as well as on a patient material. The repetitiveness in estimating Cout was found to be good. A statistically significant difference was found between the repeated Cout estimations in the patient group, indicating that there might have been a small physiological change introduced during the infusion test. A parameter, ∆Cout, was proposed and evaluated. It proved to reflect the reliability of individual Cout investigations in a clinically useful way, as well as to provide easily interpreted information. An adaptive algorithm for assessment of Cout was developed and evaluated on a patient group. The new algorithm was shown to reduce the investigation time, from 60 minutes, by 14.3 ± 5.9 minutes (mean ± SD), p<0.01, without reducing the reliability of the estimated Cout below clinically relevant levels. The relationship between ICP and CSF outflow was studied in a group of patients investigated for INPH. It was found that in the range of moderate increase from baseline pressure, the assumption of a pressure independent Rout was confirmed (p=0.5). However, at larger pressure increments, the relationship had a non-linear tendency (p<0.05). This indicates that the traditional view of a pressure independent Rout might have to be questioned in the region where ICP exceeds baseline pressure too much. Infusion tests can be performed in different ways, where three main categories may be distinguished. The bolus infusion method was compared to the constant pressure and constant flow infusion methods, on an experimental model as well as on a patient material. When physiological pressure fluctuations were added to the model, significant differences were found in the determination of Cout in the range of clinical importance, i.e. low Cout (p<0.05). The finding was supported by the patient investigations, the difference was however not significant. With the application of the new methods developed in this thesis, and the increased knowledge concerning relationships between CSF dynamic parameters, the CSF infusion test was further improved with the ability to increase measurement reliability in a reduced time. This constitutes a good basis to perform a large multi-centre study with the main goal to determine the predictive value of the parameter Cout.

Bakgrund: Normaltryckshydrocefalus (NPH) är ett neurologiskt tillstånd som innefattar psykiska funktionsnedsättningar, demenssymtom, inkontinens samt problem med gång. Behandlingen för detta är via shuntoperation. Gångförmågan undersöks via gångtester innan och efter ett tapptest, som sedan ligger till grund för att diagnos ska kunna ställas.   Syfte: Syftet med arbetet var att undersöka gångförmågan hos patienter med NPH genom att jämföra gångtesters resultat mätt i sekunder innan tapptest och shuntoperation med resultat efter shuntoperation, samt jämföra skillnader mellan män och kvinnor.    Metod: För studien valdes en kvantitativ metod med en deskriptiv komparativ design. Data som bearbetats i den aktuella studien kommer från ett pågående forskningsprojekt på ett universitetssjukhus där det samlats in resultat av tre gångtester innan shuntoperation och tre månader efter. Totalt var det 161 patienter med NPH i forskningsstudien varav 129 inkluderades i den aktuella studien. Av dessa var 65 stycken män och 64 stycken kvinnor. Gångtesterna som jämförs är Timed up and go (TUG), 10 meter walk test (10 MWT) och 3 meter backwards walk (3 MBW).   Resultat: Resultatet visade på en signifikant förbättring i alla gångtester tre månader efter shuntoperation jämfört med innan operation, samt att det inte förelåg någon signifikant skillnad mellan män och kvinnor. TUG förbättrades med 5 sekunder, 10 MWT förbättrades med 4 sekunder samt att 3 MBW förbättrades med 4 sekunder.   Konklusion: Resultaten visar på att det sker en signifikant förbättring i gångtester för patienter med NPH som genomgått en shuntoperation. Vidare forskning krävs för att säkerställa att gångtesterna är relevanta för personer med NPH, samt för att uppnå ett standardiserat testbatteri som går att applicera över hela populationen. / Background: Normal pressure hydrocephalus (NPH) is a neurological condition that causes cognitive symptoms, dementia, incontinence and difficulties with walking. The treatment for this is shunt surgery. The ability to walk is examined with walking tests before and after a tap test, which then forms the basis for a diagnosis.   Purpose: The purpose of the study was to examine patients with NPH ability to walk through comparison of the results of walking tests measured in seconds before lumbar puncture test and shunt surgery with the results three months after shunt surgery, as well as comparing differences between men and women.   Method: A quantitative method with a descriptive and comparative design was chosen for this study. Data in the current study comes from an ongoing research project at a university hospital that has c ollected data of results of three walking tests before and three months after shunt surgery. In total data from 161 patients with NPH was collected of which 129 patients was included in the current study. Of these were 65 men and 64 women. The walking tests compared are Timed up and go (TUG), 10 meter walk test (10MWT) and 3 meter backwards walk (3MBW)  Results: The results showed a significant improvement in all walking tests before compared to three months after shunt surgery and that there was no significant difference between men and women. The results of TUG improved by 5 seconds, 10MWT by 4 seconds and 3MBW by 4 seconds.  Conclusion: The results show that there is a significant improvement in walking tests for patients with NPH who have undergone shunt surgery. Further research is required to ensure that the walking tests are relevant for people with NPH, as well as to achieve a standardized test battery that can be applied to the entire population.

Cerebrospinal fluid (CSF) fills a system of cavities at the centre of the brain, known as ventricles, and the subarachnoid space surrounding the brain and the spinal cord. In addition, CSF is in free communication with the interstitial fluid of the brain tissue. Disturbances in CSF dynamics can lead to diseases that cause severe brain damage or even death. So-called infusion tests are frequently performed in the diagnosis of such diseases. In this type of test, changes in average CSF pressure are related to changes in CSF volume through infusion of known volumes of additional fluid. Traditionally, infusion tests are analysed with single compartment models, which treat all CSF as part of one compartment and balance fluid inflow, outflow and storage through a single ordinary differential equation. Poroelastic models of the brain, on the other hand, have been used to simulate spatial changes with disease, particularly of the ventricle size, on larger time scales of days, weeks or months. Wirth and Sobey (2008) developed a two-fluid poroelastic model of the brain in which CSF pressure pulsations are linked to arterial blood pressure pulsations. In this thesis, this model is developed further and simulation results are compared to clinical data. At first, the functional form of the compliance, which governs the storage of CSF in single compartment models, is examined by comparison of two different compliance models with clinical data. The derivations of a single-fluid and a two-fluid poroelastic model of the brain in spherical symmetry are laid out in detail and some of the parameters are related to the compliance functions considered earlier. The finite element implementation of the two-fluid model is described and finally simulation results of the average CSF pressure response and the pressure pulsations are compared to clinical data.

BACKGROUND: Idiopathic normal pressure hydrocephalus (INPH) is still a syndrome generating more questions than answers. Today, research focuses mainly on two areas: understanding the pathophysiology – especially how the malfunctioning CSF system affects the brain parenchyma – and finding better methods to select patients benefiting from a shunt operation. This thesis targets the aspect of finding better selection methods by investigating the measurability of intracranial pressure via lumbar space, and determining if intraparenchymal measurement of long-term ICP-oscillations (B-waves) could be replaced by short-term measurements of CSF pulse pressure waves via lumbar space. Furthermore, I look into the interaction between the CSF system and the parenchyma itself by investigating how the cortical activity of the brain changes after long-term CSF drainage, and if there is any regress in the suggested ischemia after this intervention. Finally, I examine if the neuronal integrity in the INPH brain is impaired, and if this feature is relevant for the likeliness of improvement after CSF diversion. METHODS: The comparison of intracranial and lumbar pressure was made over a vast pressure interval using our unique CSF infusion technique, and it included ten INPH patients. Pressure was measured via lumbar space and in brain tissue, and the pressures were compared using a general linear model. Short-term lumbar pressure waves were quantified by determining the slope between CSF pulse pressure and mean pressure, defined as the relative pulse pressure coefficient (RPPC). The correlation between RPPC, B-waves and CSF outflow resistance was investigated. In a prospective study, functional MRI was used to assess brain activity before and after long-term CSF drainage of 400 ml of CSF in eleven INPH patients. The functionalities tested included finger movement, memory, and attention. The results were benchmarked against the activity in ten healthy controls to identify the brain areas improving after drainage. The ischemia (Lactate) and neuronal integrity (NAA and Choline) were measured in a similar manner in 16 patients using proton MR spectroscopy, and the improvement of the patients after CSF drainage was based on assessment of their gait. RESULTS: There was excellent agreement between ICP measured in brain tissue and via lumbar space (regression coefficient = 0.98, absolute difference < 1 mm Hg). Adjusting for the separation distance between the measuring devices slightly worsened the agreement, indicating other factors influencing the measured difference as well. RPPC measured via lumbar space significantly correlated to the presence of B-waves, but not to outflow resistance. In the prospective study, controls outperformed patients on clinical tests as well as tasks related to the experiments. Improved behaviour after CSF drainage was found for motor function only, and it was accompanied by increased activation in the supplementary motor area (SMA). No lactate was detected, either before or after CSF drainage. NAA was decreased in INPH patients compared to controls, and the NAA levels were higher in the patients improving after drainage. CONCLUSIONS: ICP can be accurately measured via lumbar space in patients with communicating CSF systems. The close relation between RPPC and B-waves indicates that B-waves are primarily related to intracranial compliance, and that measurement of RPPC via lumbar space could possibly substitute B-wave assessment as selection method for finding suitable patients for shunt surgery. Improvement in motor function after CSF drainage was associated to enhanced activity in SMA, supporting the involvement of the cortico-basal ganglia-thalamo-cortical loop in the pathophysiology of INPH. There was no evidence indicating a widespread low-graded ischemia in INPH; however, there was a neuronal dysfunction in frontal white matter as indicated by the reduced levels of NAA. In addition, the level of neuronal dysfunction was related to the likeliness of improvement after CSF removal, normal levels of NAA predisposing for recovery.