Normal pressure hydrocephalus (NPH) is characterised by a build-up of cerebrospinal fluid (CSF) in the brain despite apparently normal CSF pressure at lumbar puncture. In addition to movement and urinary symptoms, patients commonly display cognitive decline and apathy. NPH is recognised as an important cause of cognitive decline as it is thought be reversible with surgical CSF diversion (e.g. shunt surgery). However, this remains controversial and the neuropsychology of NPH is relatively poorly understood. Further, despite being the most commonly reported neuropsychiatric symptom in NPH, the significance of the symptom of apathy has not yet been elucidated. This thesis aims to expand on the neuropsychological and neuropsychiatric research in NPH, with the main objectives being to investigate neuropsychological outcome, and the significance of the symptom of apathy in NPH. In order to investigate neuropsychological outcome following shunt surgery in NPH, a systematic review and meta-analysis was conducted (Chapter 2). The findings from studies which used a battery of neuropsychological tests to assess cognitive outcome in NPH were combined. Meta-analyses were conducted on pre-operative and difference scores for the most commonly used neuropsychological tests. These were seven tests which spanned global cognitive function, learning and memory, executive function and psychomotor speed. Results for all tests were significant in the direction of improvement. However, the significance of the results for two measures of executive function were deemed not to be robust. This is discussed in line with previous research which suggests that executive function may be less likely to improve following shunt surgery than other neuropsychological domains. Next, the thesis focuses on the symptom of apathy. Chapter 3 investigated whether apathy in NPH relates to cognitive outcome and to a measure of ventricular enlargement. A reduction in apathetic symptoms following treatment was associated with better performance in a measure of global cognitive function. Further, larger ventricles (which may indicate greater disease severity/ brain damage) was associated with more severe apathy. A structural MRI study was then conducted to expand on these findings and to define brain structural correlates of apathy in NPH (Chapter 4). Results from this study suggested a potential role of the caudate nuclei in apathetic symptoms in NPH. Finally, consideration is given to the assessment of apathy in NPH. Since apathy is rarely investigated in patients with NPH it is unclear which assessment method is most appropriate for this patient group. Chapter 5 presents findings from a feasibility study of a novel reward learning task to determine whether it might be useful as an objective measure of motivation and apathy in NPH.

Normal pressure hydrocephalus (NPH), a CSF circulation disorder, is important as a reversible cause of gait and cognitive disturbance in an aging population. The inconsistent response to CSF shunting is usually attributed to difficulties in differential diagnosis or co-morbidity. Improving outcome depends on an increased understanding of the pathophysiology of NPH. Specifically, this thesis examines the contribution of, and inter-relationship between, the brain parenchyma and CSF circulation in the pathophysiology of NPH. Of the four core studies of the thesis, the first quantifies the characteristics of the CSF circulation and parenchyma in NPH using CSF infusion studies to measure the resistance to CSF absorption and brain compliance. The second study assesses cerebral blood flow (CBF) was using O15-labelled positron emission tomography (PET) with MR co-registration. By performing CSF infusion studies in the PET scanner, CBF at baseline CSF pressure and at a higher equilibrium pressure is measured. Regional changes and autoregulatory capacity are assessed. The final study examines the microstructural integrity of the parenchyma using MR diffusion tensor imaging. These studies confirm the importance of the inter-relationship of the brain parenchyma and CSF circulation. NPH symptomatology and its relationship to the observed regional CBF reductions in the basal ganglia and thalamus are discussed. Regional CBF reductions with increased CSF pressure and the implications for autoregulatory capacity in NPH are considered. The reduction in CBF when CSF was increased was most striking in the periventricular regions. In addition, periventricular structures demonstrated increased diffusivity and decreased anisotropy. The relationship between these changes and mechanisms such as transependymal CSF passage are reviewed. The findings of this thesis support a role of both the CSF circulation and the brain parenchyma in the pathophysiology of NPH. The results have implications for the approach to the management of patients with NPH.

Idiopathic normal pressure hydrocephalus (iNPH) is a condition with dilated cerebral ventricles but intracranial pressure within normal limits. The symptoms of gait impairment, cognitive decline and urinary incontinence develop gradually. Treatment with shunt insertion results in improvement in eight out of ten patients. The cerebrospinal fluid tap test (CSF TT) and preoperative magnetic resonance imaging (MRI) are methods used to select patients who may benefit from shunt surgery, but they are performed and interpreted differently in different centers throughout the world. The aim of this thesis was to evaluate the performance of the CSF TT and the underlying mechanisms of improvement in gait function after CSF removal, and to investigate the prognostic value of preoperative MRI scans. Improvement in gait and changes in cerebral blood flow (CBF) after a CSF TT were investigated in two prospective studies that included 39 and 20 patients, respectively. Gait assessment and perfusion MRI were done before and several times during the first 24 hours after a CSF TT. Perfusion was investigated with pseudo-continuous arterial spin labeling. At the group level, gait function was significantly improved at all investigation times, but only one-third of individual CSF TT responders were improved at all investigation times. In patients with increased CBF in lateral and frontal white matter after the CSF TT, gait function improved more than it did in patients with decreased CBF in these regions. However, in the whole sample, there was no significant increase in CBF after CSF removal. Preoperative MRI scans were retrospectively evaluated in 109 patients with iNPH who had undergone shunt surgery. The callosal angle was smaller in shunt responders compared with non-responders. The following findings showed the highest association with a positive outcome after shunting: a small callosal angle, wide temporal horns, and occurrence of disproportionally enlarged subarachnoid space hydrocephalus. In conclusion, CBF in white matter close to the lateral ventricles may play a role in the reversibility of symptoms after CSF removal in patients with iNPH. The CSF TT should be reevaluated if the patient does not initially improve, and preoperative MRI investigations can add prognostic information regarding the selection of shunt candidates.

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.

Normal pressure hydrocephalus (NPH), a CSF circulation disorder, is important as a reversible cause of gait and cognitive disturbance in an aging population. The inconsistent response to CSF shunting is usually attributed to difficulties in differential diagnosis or co-morbidity. Improving outcome depends on an increased understanding of the pathophysiology of NPH. Specifically, this thesis examines the contribution of, and inter-relationship between, the brain parenchyma and CSF circulation in the pathophysiology of NPH. Of the four core studies of the thesis, the first quantifies the characteristics of the CSF circulation and parenchyma in NPH using CSF infusion studies to measure the resistance to CSF absorption and brain compliance. The second study assesses cerebral blood flow (CBF) was using O15-labelled positron emission tomography (PET) with MR co-registration. By performing CSF infusion studies in the PET scanner, CBF at baseline CSF pressure and at a higher equilibrium pressure is measured. Regional changes and autoregulatory capacity are assessed. The final study examines the microstructural integrity of the parenchyma using MR diffusion tensor imaging. These studies confirm the importance of the inter-relationship of the brain parenchyma and CSF circulation. NPH symptomatology and its relationship to the observed regional CBF reductions in the basal ganglia and thalamus are discussed. Regional CBF reductions with increased CSF pressure and the implications for autoregulatory capacity in NPH are considered. The reduction in CBF when CSF was increased was most striking in the periventricular regions. In addition, periventricular structures demonstrated increased diffusivity and decreased anisotropy. The relationship between these changes and mechanisms such as transependymal CSF passage are reviewed. The findings of this thesis support a role of both the CSF circulation and the brain parenchyma in the pathophysiology of NPH. The results have implications for the approach to the management of patients with NPH.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 4 uppsatser.

Yes / 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.

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.

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