Idiopathic normal pressure hydrocephalus (iNPH) is a common and treatable neurological disorder in older adults with ventriculomegaly due to disturbed cerebrospinal fluid (CSF) dynamics. The pathophysiology of iNPH is still incompletely understood, and there is growing evidence that neuroinflammation is partly responsible. Ventricular size is radiologically assessed with linear measures such as the Evans index (EI), but these measures are insensitive to clinically relevant changes in ventricular volume, so postoperative monitoring remains challenging. Shunt treatment is frequently complicated by overdrainage, underdrainage and suspected malfunction.

The overall aim of this thesis was to develop and evaluate a clinically feasible quantitative tool for monitoring shunt treatment and apply it in a clinical cohort of iNPH patients with a special focus on the following: 1. Ventricular volumetry based on 3D quantitative MRI (qMRI). 2. Very early postoperative ventricular change in relation to initial valve setting and in vivo MRI resistance of a modern adjustable shunt valve. 3. Long-term relationships between volumetric change, clinical response and overdrainage 4. Inflammatory and neurodegenerative biomarker profiles in iNPH patients across plasma, lumbar CSF and ventricular CSF.

The LiNPH study, a prospective controlled clinical longitudinal cohort study with a randomized controlled trial component, provided the data for the four papers in this thesis. Paper I was a methodological reliability study (45 qMRI examinations from iNPH patients and controls) comparing manual, automated and reviewed ventricular segmentations. Paper II was a randomized, double-blinded clinical study (n=45) with qMRI volumetry preoperatively and ~36 hours post-operatively that compared Certas Plus shunt valve settings 4 (open shunt) versus 8 (virtually closed) and evaluated the in vivo MRI stability of the valve. Paper III was a prospective cohort study (50 enrolled; follow-up at 3, 12 and 36 months) relating ventricular volumetry to clinical outcomes, valve adjustments and complications. Paper IV utilized CSF and plasma samples collected preoperatively from iNPH patients (n=56) and neurologically healthy controls (n=19) to profile 71 inflammatory cytokines, chemokines, growth factors and classical neurodegenerative markers, including paired plasma, lumbar CSF and ventricular CSF, via multiplex immunoassays and multivariate modelling.

qMRI-based ventricular volumetry demonstrated excellent intra- and interrater reliability (intraclass correlation coefficient 0.999--1.000), whereas EI failed to reflect several clinically important volume differences. Early after shunting, ventricular volumes decreased significantly in both randomized groups, but the reduction was greater at setting 4 than at setting 8 (mean 16±9 mL vs 5±5 mL), whereas linear measures were equal except for THC (tight high convexity, the amount of CSF in the parasagittal convexity sulci). There were no inadvertent valve adjustments after 156 MRI examinations were performed. Over three years, the mean ventricular volume decreased from 134±35 mL preoperatively to 97±31 mL at 36 months, whereas gait and the iNPH scale improved markedly early and remained improved at the group level. Compared with nonresponders, responders presented greater reductions, and patients with overdrainage symptoms (orthostatic headaches and more) presented greater reductions than asymptomatic patients did. Biomarker analyses revealed a robust iNPH inflammatory profile compared with that of the controls and strong compartment concentration separation.

In conclusion, qMRI-based ventricular volumetry is a sensitive, reliable and clinically feasible method for longitudinal iNPH follow-up, providing clinically valuable information on shunt effects, valve adjustments, suspicion of malfunction and overdrainage risk. The Codman Certas Plus valve is MRI resistant in vivo. There is a clear inflammatory component in iNPH pathophysiology, and there are substantial differences in cytokine and neurodegenerative biomarker concentrations among ventricular CSF, lumbar CSF and plasma, which are relevant to future study designs.

Idiopatisk normaltryckshydrocefalus (iNPH) är en neurologisk sjukdom hos äldre och kan ge gång- och balanssvårigheter, kognitiv svikt och inkontinensbesvär. Vid sjukdomen är hjärnans vätskefyllda hålrum (ventriklar) vidgade och cirkulationen av cerebrospinalvätska (CSF) är störd. Nya studier tyder på att inflammation i nervsystemet kan bidra till sjukdomsutvecklingen. Många patienter förbättras efter shuntoperation där CSF leds bort. Nuvarande röntgenmetoder är bra för diagnos men är för trubbiga för att följa ventrikelstorlek och shuntfunktion postoperativt. De enkla mått som används på datortomografi och magnetresonanstomografi (MRI), t ex Evans index (EI), missar viktiga förändringar. Samtidigt kan shuntbehandling orsaka komplikationer som överdränage av CSF, underfunktion av shunten samt shuntstopp. Ventrikelvolymmätning kan vara ett bättre och känsligare sätt att följa ventriklarnas storleksförändring.

Syftet med denna avhandling var att utveckla och utvärdera en mer exakt och praktiskt användbar metod för att följa shuntbehandling vid iNPH och tillämpa den på patienter. Fokus låg på: 1. automatisk och tillförlitlig mätning av ventrikelvolym med 3D kvantitativ MRI-teknik (qMRI). 2. Tidiga förändringar av ventrikelvolym efter shuntoperation i relation till motståndet på en modern ställbar shuntventil samt dess förmåga att motstå förändringar av motståndet av MRI. 3. Hur ventrikelvolymen förändras i relation till klinisk förbättring, överdränage och förändrat ventilmotstånd under tre års uppföljning av iNPH-patienter. 4. Förekomst av inflammatoriska (cytokiner/kemokiner) och neurodegenerativa proteiner (s k biomarkörer) hos iNPH-patienter jämfört med friska försökspersoner i blod och CSF tagen från ländryggen (L-CSF) samt ventriklarna (V-CSF).

En klinisk studie, LiNPH-studien, genomfördes under tre år och gav upphov till fyra artiklar: Artikel 1 var en metodutvecklingsstudie som jämförde manuell bedömning av ventrikelvolymen med automatiserad och eftergranskad. Artikel 2 var en randomiserad dubbelblind studie med qMRI före och ca 36 timmar efter operation där två motstånd (shunten Certas Plus motstånd 4 (öppen) respektive 8 (virtuellt avstängd)) jämfördes och ventilens MR-stabilitet följdes. Artikel 3 var en prospektiv uppföljningsstudie med kontroller av kliniska tester och ventrikelvolym innan operationen samt vid 3-, 12- och 36 månader efteråt. Artikel 4 analyserade 71 cytokiner/kemokiner samt neurogenerativa biomarkörer hos iNPH-patienter och friska försökspersoner.

qMRI-baserad ventrikelvolym visade mycket hög mätprecision och tydliga skillnader medan EI missade att påvisa dessa. Redan 36 timmar efter shuntoperation sågs en tydlig volymminskning i båda grupperna men större vid motstånd 4 än 8. EI och nästan alla vanligen använda mått var oförändrade. Efter 156 MRI-undersökningar kunde ingen oavsiktlig ventilomställning påvisas. Under tre år minskade ventrikelvolymen tydligt med drygt en fjärdedel samtidigt som iNPH-symtomen förbättrades tydligt, särskilt gång och balans. Patienter som förbättrades på shuntbehandlingen hade oftast större volymsminskning än icke-svarande medan överdränerade patienter hade ännu större volymsminskning. Biomarkörstudien visade tydliga skillnader i proteiners koncentrationer mellan blod, L-CSF samt V-CSF samt mellan patienter och friska försökspersoner. Därtill kunde ett mönster förenligt med neuroinflammation påvisas hos iNPH-patienterna.

Sammanfattningsvis visar avhandlingen att qMRI-baserad ventrikelvolymsmätning är en pålitlig och kliniskt genomförbar metod för långsiktig uppföljning av iNPH-patienter. Metoden kan ge stöd vid bedömning av shunteffekt, ventilmotståndjusteringar, misstänkt shuntstopp och risk för överdränage. Certas Plus-ventilen är motståndskraftig mot MRI i klinisk praxis. Det finns ett tydligt neuroinflammatoriskt inslag vid iNPH:s sjukdomsutveckling och skillnaderna mellan koncentrationer mellan provtagningsställena behöver beaktas i framtida forskningsstudier.

OBJECTIVE

Diffusion tensor imaging (DTI) along the perivascular space (ALPS) (DTI-ALPS)—by calculating the ALPS index, a ratio accentuating water diffusion in the perivascular space—has been proposed as a noninvasive, indirect MRI method for assessing glymphatic function. The main aim of this study was to investigate whether DTI-ALPS would reveal glymphatic dysfunction in idiopathic normal pressure hydrocephalus (iNPH) and whether the ALPS index was associated with disease severity.

METHODS

Thirty iNPH patients (13 men; median age 77 years) and 27 healthy controls (10 men; median age 73 years) underwent MRI and clinical assessment with the Timed Up and Go test (TUG) and Mini-Mental State Examination (MMSE); only the patients were evaluated with the Hellström iNPH scale. MRI data were analyzed with the DTI-ALPS method and Radscale screening tool.

RESULTS

iNPH patients showed significantly lower mean ALPS index scores compared with healthy controls (median [interquartile range] 1.09 [1.00–1.15] vs 1.49 [1.36–1.59], p < 0.001). Female healthy controls showed significantly higher ALPS index scores than males in both hemispheres (e.g., right hemisphere 1.62 [1.47–1.67] vs 1.33 [1.14–1.41], p = 0.001). This sex difference was not seen in iNPH patients. The authors found a moderate exponential correlation between mean ALPS index score and motor function as measured with time required to complete TUG (r = −0.644, p < 0.001), number of steps to complete TUG (r = −0.571, p < 0.001), 10-m walk time (r = −0.637, p < 0.001), and 10-m walk steps (r = −0.588, p < 0.001). The authors also found a positive linear correlation between mean ALPS index score and MMSE score (r = 0.416, p = 0.001). Simple linear regression showed a significant effect of diagnosis (B = −0.39, p < 0.001, R2 = 0.459), female sex (B = 0.232, p = 0.002, R2 = 0.157), and Evans index (B = −4.151, p < 0.001, R2 = 0.559) on ALPS index. Multiple linear regression, including diagnosis, sex, and Evans index score, showed a higher predictive value (R2 = 0.626) than analysis of each of these factors alone.

CONCLUSIONS

The ALPS index, which was significantly decreased in iNPH patients, could serve as a marker of disease severity, both clinically and in terms of neuroimaging. However, it is important to consider the significant influence of biological sex and ventriculomegaly on the ALPS index, which raises the question of whether the ALPS index solely reflects glymphatic function or if it also encompasses other types of injury. Future studies are needed to address potential confounding factors and further validate the ALPS method.

Barnneurokirurgi är en subspecialitet inom neurokir­urgin. Barnens neurokirurgiska sjukdomar skiljer sig från de vuxnas med andra diagnoser, patofysiologiska mekanismer, tumörtyper och inte minst annan prognos.

I denna artikel belyser vi de tre vanligaste barnneurokirurgiska tillstånden: hjärntumörer, hydrocefalus samt neuralrörsdefekter inklusive ryggmärgsbråck.

Vi sammanfattar bakgrund, symtombild och initial handläggning samt ger en översikt av neurokirurgisk behandling av sjukdomarna. 

Prognosen är oftast god, men samtliga tillstånd är allvarliga och både sjukdom och behandling riskerar att ge livslånga konsekvenser för individen och dess anhöriga.

The objective of this research is to detect and extract traces of past human activities on the Etruscan site of San Giovenale (Blera) in Northern Lazio, Italy. Investigations have been conducted by integrating high-resolution satellite data with digital models derived from LiDAR survey and multisensory aerial prospection (traditional, thermal and near infrared pictures). The use of different sensor technologies is requested to cope with (i) different types of surface covers, i.e. vegetated and non-vegetated areas (trees, bushes, agricultural uses, etc), (ii) variety of archaeological marks (micro-relief, crop marks, etc) and (iii) different types of expected spatial/spectral feature patterns linked to past human activities (urban necropoleis, palaeorivers, etc). Field surveys enabled us to confirm remotely sensed features which were detected in both densely and sparsely vegetated areas, thus revealing a large variety of cultural transformations, ritual and infrastructural remains such as roads, tombs and water installations. Our findings clearly point out a connection between the Vignale plateau and the main acropolis (San Giovenale) as well as with the surrounding burial grounds. Our results suggest that the synergic use of multisensory/multisource data sets, including ancillary information, provides a comprehensive overview of new findings. This facilitates the interpretation of various results obtained from different sensors when studied in a larger prospective.

Twenty-seven operated women had postoperative intermittent injections of bupivacaine or saline for 24 hours after reduction mammaplasty. The injections were given five-hourly either subcutaneously along the submammary incision or deep into the wound. The patients were randomised into three groups of nine each: 5 ml bupivacaine 0.25% into the margin, 5 ml bupivacaine 0.25% into the cavity, and 5 ml physiological saline into the cavity. Postoperatively all patients received oral paracetamol and dextropropoxyphene. If additional analgesia was needed morphine was given intravenously. Total morphine consumption was significantly (p <0.03) lower in patients given bupivacaine into the margin (2.0 (0.9) mg) or into the cavity (2.4 (0.8) mg) compared with controls (6.9 (1.5) mg). VAS pain scores and vomiting did not differ among the three groups. Postoperative intermittent infusion of bupivacaine lowered morphine consumption after reduction mammaplasty, and the analgesic effect seemed to be independent of where the infusion was given. © 2005 Taylor & Francis.