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: Det har i vissa fall varit märkbart att patienter med idiopatisk normaltrycks hydrocefalus (iNPH) upplever att förväntat shuntbehandlingsresultat inte uppnåtts och de rapporterar försämring vid den postoperativa uppföljningen trots att standardiserade tester inte visar i den riktningen. Det har också visat sig att rehabiliteringsinsatserna varierat för patienterna allt från strukturerade rehabiliteringsperioder på exempelvis geriatrisk rehabiliteringsenhet till i princip ingen rehabilitering alls. Syfte: Att beskriva vilka förväntningar personer med iNPH har på behandling med shunt och hur de ser på sin egen roll i rehabiliteringsprocessen. Metod: Kvalitativ, deskriptiv design med manifest och induktiv ansats. Datainsamlingen skedde genom semistrukturerade intervjuer med sju patienter med iNPH preoperativt. Resultat: Det fanns en samstämmighet bland informanterna kring förväntningar på shuntbehandlingsresultatet. De rörde den symtomtriad (gång och balansstörning, överaktiv urinblåsa samt kognitiv nedsättning) som ofta finns vid iNPH. Varierade beskrivningar gavs på hur symtomen påverkade informanterna. Det fanns också en uppfattning bland informanterna att de hade ett eget ansvar i rehabiliteringsprocessen och förslag framkom på vad de själva kunde bidra med i processen men också olika hinder för att utöva fysisk aktivitet beskrevs. Slutsats: Förväntningar på shuntbehandlingsresultat behöver diskuteras med patienten (ibland även anhörig) inför shuntbehandling redan vid beslut om operation men också då patienten läggs in för behandlingen. Rehabiliteringsprocessen behöver också diskuteras med patienten såväl före shuntoperation som tidigt postoperativt. Detta är troligtvis mycket viktigt för att uppnå ett så optimalt behandlingsresultat som möjligt. / Background: It has been noticeable that some patients with idiopathic normal pressure hydrocephalus (iNPH) find the expected result of shunt treatment not  achieved and they report detoriation at postoperative follow-up even though standardized tests do not show results in that direction. It has also been shown that rehabilitation possibilities for patients varied, ranging from structured rehabilitation periods, e.g. at geriatric rehabilitation units to basically no rehabilitation at all. Objective: To describe what expectations patients with iNPH have on treatment with shunt and how they view their own role in the rehabilitation process. Method: A quality, descriptive design with manifest and inductive approach. The data collection was done by semi-structured interviews with seven patients with iNPH preoperative. Results: There was consensus among informants regarding the expectations on the result of shunt treatment. The expectations concerned the symptom triad (gait-and balance disturbance, urgency bladder and cognitive dysfunction) which often occurs in iNPH. Varied descriptions were given on how the symptoms had affected the informants. There was also an opinion among the informants that they had own responsibility for the rehabilitation process and suggestions were given on what they could contribute with in the process but also different obstacles for performing physical activities were described. Conclusion: Expectations on shunt treatment results need to be discussed with the patient (sometimes together with a relative) prior to shunt treatment, already when the patient is offered a shunt operation and also on the day before operation when the patient is in the neurosurgery clinic. The rehabilitation process also needs to be discussed with the patient before the shuntoperation as well as early postoperative. This is probably very important in order to achieve as optimal treatment results as possible.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22636号 / 医博第4619号 / 新制||医||1044(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 古川 壽亮, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background. CoGNIT is a computerized test battery for cognitive assessment, used in diagnosing and treating patients with idiopathic normal pressure hydrocephalus (INPH). The disorder causes symptoms of dementia, among other things. Apart from other diseases with similar symptoms, like Alzheimer’s, INPH can be countered. CoGNIT is performed by a patient before and after drainage of cerebrospinal fluid. If a significant improvement in cognition is detected after the extraction, the patient receives shunt surgery which reduces all symptoms. The test battery is long and tedious, which makes it difficult for people with cognitive impairments to complete. Objectives. The objectives of this study are to rework original CoGNIT with carefully selected game design elements and analyze the effects of the alteration on performance and user experience. If users perform better in a gamified environment, the validity of gathered data will have improved as the data should better reflect their cognitive capabilities. Another objective is to introduce gamification to the medical field. Methods. Game design elements were picked and designed based on suitability for elderly people and with the impairments of INPH patients in mind. A gamified prototype was developed and put to test with healthy individuals against the original version in an experiment. The effects of gamification on performance was examined by comparing resulting score values from both versions of the test. Participants also filled in a questionnaire as proxy for the test’s target group, meaning that questions were answered with how the participants expected a cognitively impaired person to answer. Answers were used to investigate the effect of gamification ofuser experience. Results. The gamified version of CoGNIT shows an improvement in test segments regarding attention, psychomotor speed, executive function, and manual dexterity, but a negative inclination in segments regarding memory. Results from the user experience questionnaire indicates that the gamified version feels less dramatic, more playful, less "test-like" and less tedious compared to the non-gamified version. This suggests that the added game elementsare affecting the user experience in the desired way. Conclusions. An overall positive impact on both performance and user experience from gamification is concluded. The negative effect on memory tests could not be determined to be a cause of the gamification per se. / Bakgrund. CoGNIT är ett datoriserat testbatteri för kognitiv bedömning som används vid diagnos och behandling av patienter med idiopatisk normaltryckshydrocefalus (INPH). Sjukdomen orsakar bland annat symptom som demens. Till skillnad från andra sjukdomar med liknande symptom, som Alzheimers, kan INPH motverkas. CoGNIT utförs av en patient före och efter dränering av cerebrospinalvätska. Om en förbättring av patientens kognitiva förmågor upptäcks efter dräneringen, shuntoperaras patienten och alla symptom minskas. Testbatteriet är långt och tråkigt, vilket gör det svårt för personer med kognitiva nedsättningar att slutföra. Syfte. Syftet med denna studie är att omarbeta CoGNIT med noggrant utvalda speldesignelement och analysera hur prestation och användarupplevelse påverkas av förändringen. Om användare presterar bättre i en spelifierad miljö kommer validiteten av insamlad data att förbättras eftersom datan borde bättre återspegla deras kognitiva förmågor. Ett annat mål är att introducera spelifiering till det medicinska området. Metod. Speldesignelement valdes ut och utformades baserat på dess lämplighet för äldre och med de funktionsnedsättnigar som INPH-patienter har i åtanke. En spelifierad prototyp utvecklades och testades med friska individer mot originalversionen i ett experiment. Effekterna av spelifiering på prestation undersöktes genom att jämföra poängvärden från båda versionerna av testet. Deltagarna fyllde också i ett frågeformulär som "proxy" för testets målgrupp, vilket innebär att frågorna besvarades med hur deltagarna förväntade sig att en kognitivt nedsatt person hade svarat. Svaren användes för att undersöka effekten av spelifiering på användarupplevelsen. Resultat. Den spelifierade versionen av CoGNIT visar en förbättring i testsegmenten som utvärderar uppmärksamhet, psykomotorisk hastighet, exekutiva funktioner och fingerfärdighet, men en försämring i segmenten som utvärderar minne. Resultat från frågeformuläret indikerar att den spelifierade versionen upplevs mindre dramatisk, mer lekfull, mindre "testliknande" och mindre tråkig jämfört medden icke-spelifierade versionen. Detta visar att de tillagda spelelementen påverkar användarupplevelsen som önskat. Slutsatser. En övergripande positiv inverkan på både prestanda och användarupplevelse från spelfiering fastställs. Den negativa effekten på minnestesterna kunde inte bedömas vara en orsak av spelifiering i sig.

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.