Per Kristian Eide

• Eide, Per Kristian; Sherwani, Alexander Gul; Romundstad, Luis; Fjeld, Jan Gunnar; Eriksson, Amanda & Hjørnevik, Trine [Vis alle 7 forfattere av denne artikkelen] (2026). Ventricular CSF-to-blood water transport kinetics in adult hydrocephalus. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. doi: 10.1177/0271678X261466792. Fulltekst i vitenarkiv
• Dejgaard, Magnhild S.; Eide, Per Kristian; Tangen, Gro Gujord; Skovlund, Eva; Selbæk, Geir & Wyller, Torgeir Bruun (2026). Cognitive profiles in idiopathic normal pressure hydrocephalus and Alzheimer's disease. Journal of Alzheimer's Disease. ISSN 1387-2877. s. 1–9. doi: 10.1177/13872877261478264. Fulltekst i vitenarkiv Vis sammendrag

  Background Idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer's disease (AD) are neurodegenerative disorders with partly overlapping clinical features. Since the treatment is different, we need better knowledge about how the cognitive profile differs between these conditions. Objective We aimed to compare the cognitive profile of iNPH patients with that of a large cohort of confirmed AD patients. Methods Patients diagnosed with iNPH and accepted for shunt surgery were compared with patients with biomarker verified Alzheimer's disease in The Norwegian Register of Persons Assessed for Cognitive symptoms (NorCog). All patients underwent a standardized cognitive assessment with age and education adjusted z-scores. We used the Clinical Dementia Rating Scale (CDR) to adjust for disease severity. Since the cognitive score distributions were highly skewed, we used nonparametric analyses stratified by CDR stage combined with multinomial logistic regression. Results In total, 276 iNPH patients were compared to 1113 AD patients. iNPH patients performed significantly poorer on phonemic fluency [median z-score difference (AD—iNPH) 0.30, 95% confidence interval (CI) 0.20 to 0.50], but significantly better on other cognitive tests, in particular immediate (median difference −0.35, 95% CI −0.49 to −0.20) and delayed recall (median difference −0.46, 95% CI −0.59 to −0.34). The differences persisted after adjustment for CDR and were most pronounced in early stages of the disease. Conclusions iNPH seems to affect phonemic fluency more and memory less than AD. As the disease progresses, the cognitive profiles become more similar, and the conditions cannot be distinguished by cognitive tests.

• Eide, Per Kristian; Lashkarivand, Aslan; Hernes, Susanne Miriam Sørensen; Ringstad, Geir Andre & Hovd, Markus (2026). Estimation of human brain fluid clearance using intrathecal imaging contrast agents. Fluids and Barriers of the CNS. 23(1). doi: 10.1186/s12987-026-00826-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Extra-vascular brain fluid dynamics, including exchange through glymphatic and meningeal lymphatic pathways, has been proposed essential for waste clearance and solute transport in the central nervous system. Although animal studies provide evidence for these pathways’ role in clearing neurotoxic proteins and distributing solutes delivered to cerebrospinal fluid (CSF), translation to humans is limited. Quantitative, in vivo measures of inter-individual variability in brain fluid clearance in clinical populations are largely lacking. This study investigated the feasibility of estimating brain fluid clearance indices using intrathecal imaging contrast agents. Methods In a prospective and observational study, iodixanol (Visipaque, GE Healthcare, USA, 270 mg I/mL, 3 mL) was administered intrathecally as a CSF tracer and its clearance from CSF to blood was quantified using population pharmacokinetic modeling. Intracranial tracer enrichment in CSF was assessed by its radiodensity (Hounsfield units) within predefined regions of interest (cisterna magna, Sylvian fissure and vertex) on cranial computed tomography (CT) performed 2-, 4- and 24-hours post-injection. These results were compared with brain fluid clearance indices derived from a separate population pharmacokinetic model using intrathecal gadobutrol (Gadovist, Bayer AG, GE, 1.0 mmol/mL, 0.50 mL), with its enrichment in CSF defined as gadobutrol-induced T1 signal increase from baseline within corresponding subarachnoid spaces on magnetic resonance imaging (MRI). Results The study included 52 subjects receiving intrathecal iodixanol and 45 individuals receiving intrathecal gadobutrol. Marked inter-individual variability was observed in brain fluid clearance to blood for both contrast agents, as well as their distribution in CSF as assessed by CT and MRI. Brain fluid clearance from iodixanol and gadobutrol were significantly correlated. Notably, clearance indices showed stronger correlations with intracranial distribution in CSF for gadobutrol-derived MRI metrics than for iodixanol-derived CT metrics. Conclusions These findings demonstrate the feasibility of estimating brain fluid clearance in humans using intrathecal imaging contrast agents as CSF tracers. Brain fluid clearance capacity exhibits pronounced inter-individual variability and correlates with the degree of contrast enrichment in intracranial subarachnoid spaces, particularly when assessed by MRI. The results underscore the importance of individualized assessment of brain fluid clearance, with implications for studies on pathogenetic mechanisms of neurodegeneration and optimization of intrathecal drug delivery.

• Mossige, Ingrid; Valnes, Lars Magnus; Storås, Tryggve Holck; Emblem, Kyrre Eeg; Eide, Per Kristian & Ringstad, Geir Andre (2026). Comparing Glymphatic Function Measures: Diffusion Tensor Image Analysis Along Perivascular Spaces (DTI-ALPS) versus Intrathecal Contrast-Enhanced MRI. Radiology. ISSN 0033-8419. 318(2). doi: 10.1148/radiol.252070. Fulltekst i vitenarkiv Vis sammendrag

  Background Diffusion-tensor image (DTI) analysis along the perivascular space (ALPS) is a noninvasive but not well-validated method proposed to evaluate glymphatic function. Purpose To assess ALPS indexes across participant groups and compare them with measures of cerebrospinal fluid (CSF) tracer enrichment and clearance obtained by intrathecal contrast-enhanced MRI (glymphatic MRI [gMRI]). Materials and Methods This secondary analysis of a prospective observational study included participants who underwent clinical work-up for CSF disorders from September 2015 to December 2019. MRI scans were acquired before injection and 24 and 48 hours after intrathecal injection of 0.5 mmol of gadobutrol. DTI scans were preprocessed and segmented using the FMRIB Software Library. Intrathecal contrast-enhanced MRI (ie, gMRI) scans were registered to the baseline T1-weighted image, and cortex and white matter (WM) were segmented with FreeSurfer. ALPS indexes were compared with relative changes in normalized T1-weighted signal intensity at 24 and 48 hours in regions of the cortex, subcortical WM, and deep WM where the ALPS regions of interest are located by using regression analysis. Results A total of 56 participants were included (mean age, 48 years ± 20 [SD]; 36 women): 16 with idiopathic normal pressure hydrocephalus (iNPH), 10 with arachnoid cysts, 11 with idiopathic intracranial hypertension, and 19 reference participants. The ALPS index was lower in the iNPH group than in the reference group (ALPS index, 1.26 and 1.68, respectively; P < .001). Across groups, the ALPS index and degree of CSF tracer enrichment at 24 hours in deep WM were negatively associated (β = −48; P < .001). However, mean tracer enrichment in the ALPS regions of interest was low (10%), in some participants close to 0, whereas enrichment in the cortex ranged from 68% to 81%. Across groups, there was no evidence of associations between the ALPS index and measures of CSF tracer dynamics at 48 hours in any region (|β| ≤ 8; P ≥ .55). Conclusion CSF tracer enhancement in the ALPS regions of interest was sparse across groups, and the association between the ALPS index and gMRI markers of glymphatic function was limited.

• Eide, Per Kristian; Hovd, Markus; Valnes, Lars Magnus; Pripp, Are Hugo & Ringstad, Geir Andre (2026). When blood hits the brain: altered glymphatic and dural lymphatic function after surface bleeds. Acta Neurochirurgica. ISSN 0001-6268. 168. doi: 10.1007/s00701-025-06760-9. Fulltekst i vitenarkiv Vis sammendrag

  Background The impact of acute subdural hematoma (aSDH) on measures of glymphatic–meningeal lymphatic function has not previously been reported. We present a descriptive observational study including a small case series—one patient following unilateral aSDH, three following unilateral subarachnoid hemorrhage (SAH), and three control subjects—providing new insights into the differential effects of surface intracranial bleeds. Methods The magnetic resonance imaging (MRI) contrast agent gadobutrol (0.5 mmol), administered intrathecally, was used as a cerebrospinal fluid (CSF) tracer. Multiphase contrast-enhanced MRI was performed to assess glymphatic tracer enrichment. CSF tracer clearance to blood, serving as a proxy for dural lymphatic function, was estimated using population pharmacokinetic modeling. All hemorrhagic cases involved unilateral bleeds, allowing within-subject comparison between affected and unaffected hemispheres. Results The series included one patient with aSDH (2.8 months post-event), three patients with unilateral SAH (mean 5.8 months post-event), and three age-matched, near-healthy reference subjects. Compared with controls, glymphatic tracer enrichment 24 h post-injection was slightly increased on the affected hemisphere in the aSDH case, whereas SAH patients showed markedly reduced enrichment on the affected side. Tracer distribution in controls was symmetrical. CSF clearance to blood was notably reduced in the aSDH case compared with references, suggesting impaired dural lymphatic function. Conclusion This small descriptive series suggests that aSDH and SAH may differentially affect glymphatic and dural lymphatic functions. While glymphatic enrichment appeared only modestly altered after aSDH, it was severely impaired following SAH. In contrast, CSF clearance to blood was markedly reduced in the aSDH case, potentially reflecting compromised dural lymphatic drainage. The limited number of cases prevent broad generalization, but these findings offer novel hypothesis-generating observations that may inform future studies on the effects of surface intracranial hemorrhages on brain clearance pathways.

• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Valnes, Lars Magnus & Mardal, Kent-Andre (2026). The impact of human brain geometry on the transport of an intrathecal tracer. Fluids and Barriers of the CNS. 23. doi: 10.1186/s12987-026-00764-y. Fulltekst i vitenarkiv Vis sammendrag

  Intrathecal contrast-enhanced magnetic resonance imaging (MRI), utilizing the contrast agent gadobutrol as cerebrospinal fluid (CSF) tracer is emerging as a useful method to study glymphatic function in the human brain. A consistent finding with this technique is large inter-individual variability regarding tracer propagation. In this study, we outline an approach which predicts the distribution of tracer in the parenchyma based only on geometric information from brain tissue as captured by MRI, addressing one possible explanation for this variability. Registrations are computed from pre-injection MRI, and used to map images at $$24$$ hours after tracer injection to perform predictions of tracer enrichment in the parenchyma in other patients. We apply the method to a dataset of human brain MRI of $$134$$ patients examined for different tentative diagnoses including idiopathic normal pressure hydrocephalus, spontaneous intracranial hypotension and idiopathic intracranial hypertension, as well as a group of reference patients. Tracer enrichment mapped between patients by image registration correlate strongly with actual observed enrichment. For patients in the reference group, the relative root mean squared error on our predictions is on average $$26\%$$ in the gray matter, and $$15\%$$ or less in other brain regions. Predictions are generally less reliable in the gray matter, and for patients with identified CSF leaks. We show that predictions made from purely geometrical considerations correlate strongly with actual MRI tracer enrichment for patients with similar diagnoses, thus quantifying the role of geometry in tracer enrichment.

• Rieff, Melanie; Lapina, Oksana; Ringstad, Geir; Valnes, Lars; Warsza, Bogna & Eide, Per-Kristian [Vis alle 8 forfattere av denne artikkelen] (2025). U‐Net‐Based Prediction of Cerebrospinal Fluid Distribution and Ventricular Reflux Grading. NMR in Biomedicine. ISSN 0952-3480. Fulltekst i vitenarkiv
• Cengija, Vanja; Eide, Per Kristian & Ringstad, Geir Andre (2025). Do enlarged white matter perivascular spaces reflect brain clearance dysfunction? Insights from intrathecal contrast-enhanced MRI. Neuroradiology. ISSN 0028-3940. doi: 10.1007/s00234-025-03877-7. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Visible perivascular spaces of cerebral white matter at magnetic resonance imaging (MRI) were in several studies proposed to be an integral part of brain-wide perivascular clearance pathways, and their enlargement could therefore serve as markers of perivascular clearance dysfunction. We studied whether MRI-visible perivascular spaces in subcortical white matter communicate with subarachnoid cerebrospinal fluid (CSF). Methods MRI-visible perivascular spaces of the basal ganglia served as controls. Intrathecal 0.5 mmol gadobutrol was utilized as CSF tracer, and T1-weighted MRI was performed before, and at multiple time points after (3, 6, 24 and 48 h) injection. Perivascular spaces with diameter ≥ 2 mm were included in the analysis, and a circular region of interest was placed manually within one perivascular space and in adjacent brain parenchyma of each region. Results The study included 27 symptomatic individuals undergoing clinical work-up of various CSF circulation disorders, but in whom no treatable condition was found. Perivascular spaces of both white matter and basal ganglia enhanced with intrathecal gadobutrol, confirming CSF exchange with perivascular spaces. While perivascular spaces of basal ganglia enhanced most with peak at 6 h (233.2% [34.9 to 431.5%]) (p < 0.01), coinciding with peak enhancement in subarachnoid CSF, perivascular spaces of white matter enhanced less and more slowly with peak at 48 h (159.1% [37.9 to 280.3%]) (p < 0.01). Conclusions The various degrees of CSF exchange with MRI-visible subcortical perivascular spaces suggest these may be dilated for different reasons, therefore questioning their validity as markers of perivascular clearance function.

• Emblem, Kyrre E; Ringstad, Geir; Svensson, Siri Fløgstad; Vatnehol, Svein Are Sirirud; Storås, Tryggve Holck & Vik-Mo, Einar Osland [Vis alle 9 forfattere av denne artikkelen] (2025). Intrathecal contrast-enhanced MRI reveals an alternative route for drug delivery and brain tumor visualization. Cancer Letters. ISSN 0304-3835. 638. doi: 10.1016/j.canlet.2025.218152. Fulltekst i vitenarkiv
• Kipnis, Jonathan; Benveniste, Helene; Eichmann, Anne; Thomas, Jean-Leon; Reich, Daniel S. & Lewis, Laura D. [Vis alle 24 forfattere av denne artikkelen] (2025). Resolving the mysteries of brain clearance and immune surveillance. Neuron. ISSN 0896-6273. 113(23), s. 3908–3923. doi: 10.1016/j.neuron.2025.10.036. Fulltekst i vitenarkiv Vis sammendrag

  Recent advances are transforming our understanding of brain fluid dynamics, highlighting cerebrospinal fluid (CSF) flow as a key process in brain waste clearance. While debates persist regarding its anatomical pathways and regulatory mechanisms, certain core principles have become widely accepted. CSF influx occurs primarily along periarterial spaces, solute clearance follows multiple routes, and glymphatic and meningeal lymphatic systems are functionally connected. Brain clearance is influenced by vascular pulsation, neural activity, and sleep. Immune cells at brain-border niches both monitor solute efflux and modulate flow, linking brain clearance to neuroimmune interactions. A deeper understanding of brain clearance could unlock new therapeutic avenues for autoimmune, neurodegenerative, neoplastic, and psychiatric disorders.

• Pripp, Are Hugo; Ringstad, Geir; Valnes, Lars Magnus & Eide, Per Kristian (2025). A method for measuring first glymphatic influx of a cerebrospinal fluid tracer in the human brain. Frontiers in Neuroscience. ISSN 1662-4548. 19. doi: 10.3389/fnins.2025.1703748. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: The glymphatic system is a brain-wide perivascular transport route for fluids and solutes in which cerebrospinal fluid (CSF) serves as a conduit for solute transport and clearance of brain waste. Intrathecal contrast-enhanced magnetic resonance imaging (MRI), where the intrathecal contrast agent serves as a CSF tracer, has been developed to measure glymphatic function in humans. The normalized MRI T1 signal is a semiquantitative measure of CSF flow and exchange with the brain. Objective: To estimate first-time tracer appearance within brain tissue after intrathecal tracer injection. Methods: This study implemented segmented regression analysis to estimate the first-time tracer appearance of an intrathecal tracer within brain tissues. An increase (breakpoint) in the normalized MRI T1 signal was defined to represent first glymphatic influx of the tracer. The study included 30 reference (REF) subjects with no identified CSF disturbance and 15 patients with a diagnosis of idiopathic intracranial hypertension (IIH). We developed and evaluated the method in REF subjects and further compared it between the two study groups. Results: The time to initial glymphatic tracer enrichment in the REF cohort was approximately 1 h in the frontal, temporal, parietal, and occipital cerebral cortex and ranged from two to 4 h in the corresponding white matter regions. In subcortical limbic structures and basal ganglia structures, it was 0.6 and 2.2 h, respectively. Compared with REF subjects, IIH patients presented a non-significant mean difference in the first appearance of ±0.5 h in the cerebral cortex and white matter regions, with somewhat longer estimated delays in the parietal and insular white matter regions. The results are presented as time series plots and estimates with 95% confidence intervals. Additionally, we provide supplementary R code, which can be adapted for use in future studies, and outline a basic assessment of true versus estimated breakpoints using simulated data. Conclusion: Segmented regression was found feasible to quantify the time to first glymphatic enrichment, i.e., increase in the normalized MRI T1 signal. Moreover, the method seems reasonable to differentiate first glymphatic influx between the cohorts.

• Valnes, Lars Magnus; Storås, Tryggve Holck; Vatnehol, Svein Are Sirirud; Ringstad, Geir Andre; Emblem, Kyrre Eeg & Eide, Per Kristian (2025). Optimized Magnetic Resonance T1 Mapping for Estimation of Intrathecal Contrast Concentrations in Human Brain and Ventricular Cerebrospinal Fluid. Magnetic Resonance in Medicine. ISSN 0740-3194. doi: 10.1002/mrm.70203. Fulltekst i vitenarkiv
• Eide, Paulina; Melin, Erik; Ringstad, Geir; Eide, Per Kristian & Sorteberg, Angelika (2025). Volume of parasagittal dura is associated with blood markers of systemic inflammation | Acta Neurochirurgica. Acta Neurochirurgica. ISSN 0001-6268. 167, s. 1–10. doi: 10.1007/s00701-025-06682-6. Fulltekst i vitenarkiv Vis sammendrag

  The parasagittal dura (PSD) has been hypothesized to act as a neuro-immunological hub, though evidence in favor of the hypothesis is limited. The present study explored whether there is any association between volume and function of PSD and blood markers that may be indicative of systemic inflammation. The patient material included 76 subjects examined with intrathecal contrast-enhanced magnetic resonance imaging (MRI) where the contrast served as a cerebrospinal fluid (CSF) tracer. They were dichotomized into a control- (Ctrl) and a CSF-group. We investigated the correlations between blood markers indicative of systemic inflammation and the volume of PSD, enrichment of tracer in the PSD, and blood-measures of CSF clearance. The blood markers included C-reactive protein (CRP), erythrocyte volume fraction (EVF), hemoglobin (Hb), platelet count, neutrophiles, lymphocytes, and the neutrophil-to-lymphocyte ratio as well as the platelet-to-lymphocyte ratio. Assessment of subjective sleep quality also was included in the analysis. The main finding was that higher CRP indicative of systemic inflammation was correlated with lower volume of PSD. There was an association between lower EVF and Hb levels and lower volume of PSD, but this finding could be explained by confounders such as age, sex and disease. Confounders also explained a correlation between EVF and CSF clearance variables. Impaired subjective sleep quality was associated with markers of systemic inflammation, but not with PSD volume. Higher CRP was correlated with lower volume of PSD suggesting that the size of this anatomical structure associates with systemic inflammation. Further studies are needed to determine whether PSD volume could serve as an imaging marker of systemic inflammation.

• Eide, Per Kristian; Pripp, Are Hugo; Rønning, Pål Andre; Sorteberg, Angelika & Sorteberg, Wilhelm (2025). Comparative analysis of surgical and endovascular aneurysm repair in subarachnoid hemorrhage: a single-center study with 1,171 patients | Acta Neurochirurgica. Acta Neurochirurgica. ISSN 0001-6268. 167, s. 1–15. doi: 10.1007/s00701-025-06670-w. Fulltekst i vitenarkiv Vis sammendrag

  To compare surgical and endovascular therapy (EVT) approaches to aneurysm repair in all aneurysmal subarachnoid hemorrhage (aSAH) patients treated within our institution over a 12-year period from 2011 to 2022. The study comprised a retrospective analysis of prospectively collected data extracted from a hospital quality registry that we established in 2011, containing comprehensive information about all patients treated for aSAH. We included SAH patients within the institution's catchment area who underwent surgical or endovascular aneurysm repair. Exclusion criteria involved patients from external regions, those treated at other institutions, no aneurysm repair performed, or instances undergoing a combination of surgery and EVT. Pretreatment data encompassed the clinical condition at admission, comorbidity, radiological details, aneurysm characteristics, and duration between the bleed and aneurysm repair. Mortality was primary outcome measure; secondary outcome included modified Rankin Score after approximately six months. The study encompassed 1,171 patients (65% women and 35% men) undergoing aneurysm repair from 2011 to 2022. Admission data revealed 31.1% in Hunt-Hess grade 4–5. Surgical repair was performed in 573 (48.9%) patients, and EVT in 598 (51.1%) patients. Pretreatment information was comparable for both groups. Kaplan–Meier survival curves demonstrated lower mortality in the surgical than the EVT group (P = 0.023; Log-rank test) over the 12-year period. The 1-year, 5-year, and 10-year mortality rates were 12.4%, 19.5%, and 27.7% for the surgery group, and 18.7%, 25.2%, and 31.7% for the EVT group, respectively. Modified Rankin Score was worse for EVT. There was lower mortality in surgical than EVT groups in patients treated for anterior communicating artery (ACOM, n = 420) and posterior communicating artery (PCOM, n = 177) aneurysms. Shorter time to aneurysm repair and more extensive cerebrospinal fluid (CSF) drainage characterized the surgery group. Mortality was lower in surgical patients. Plausible explanations are the maintenance of surgical skills and prompt reduction of intracranial pressure.

• Falkenberg-Jensen, Benedicte; Pripp, Are Hugo; Ringstad, Geir & Eide, Per Kristian (2025). Cranial nerves as pathways for human cerebrospinal fluid efflux: In vivo evidence. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. s. 1–11. doi: 10.1177/0271678x251386232. Fulltekst i vitenarkiv Vis sammendrag

  In vivo evidence for cerebrospinal fluid (CSF) efflux along cranial nerves in humans is scarce. This study investigated whether the trigeminal, facial, and vestibulocochlear nerves serve as efflux routes for CSF in humans. A magnetic resonance imaging (MRI) contrast agent, used as a CSF tracer, was administered intrathecally at the lumbar level, and consecutive MRI acquisitions measured tracer enrichment along the trigeminal, facial, and vestibulocochlear nerves. The study included 27 patients undergoing evaluation for potential CSF disturbances, but none of whom exhibited evidence of CSF pathology or other neurological diseases. After intrathecal tracer injection, the tracer enriched the prepontine subarachnoid space. Subsequently tracer enrichment was observed within the trigeminal nerve within the subarachnoid space, Meckel’s cave, within the mandibular branch at the foramen ovale and the inferior alveolar nerve in the mandibular bone. The facial nerve was enriched within the subarachnoid space, as well as within the tympanic segment and mastoid segment nearby the stylomastoid foramen. The vestibulocochlear nerve was enriched with tracer within the subarachnoid space. These findings demonstrate that a CSF tracer penetrates the trigeminal, facial, and vestibulocochlear nerves in a peripheral direction, providing evidence that efflux of CSF occurs along cranial nerves in humans.

• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2025). Geometry Reduced Order Modeling (GROM) with application to modeling of glymphatic function. Brain Research Bulletin. ISSN 0361-9230. 231. doi: 10.1016/j.brainresbull.2025.111558. Fulltekst i vitenarkiv Vis sammendrag

  Computational modeling of the brain has become a key part of understanding how the brain clears metabolic waste, but patient-specific modeling on a significant scale is still out of reach with current methods. We introduce a novel approach for leveraging model order reduction techniques in computational models of brain geometries to alleviate computational costs involved in numerical simulations. Using image registration methods based on magnetic resonance imaging, we compute inter-brain mappings which allow previously computed solutions on other geometries to be mapped on to a new geometry. We investigate this approach on two example problems typical of modeling of glymphatic function, applied to a dataset of 101 MRI of human patients. We discuss the applicability of the method when applied to a patient with no known neurological disease, as well as a patient diagnosed with idiopathic Normal Pressure Hydrocephalus displaying significantly enlarged ventricles. In each of our two example problems, we achieve a speedup of more 750 times compared to the full order problem, while introducing a comparably small additional system assembly overhead. The reduced solutions recover the full order solution with an error of less than 10% in most cases. Statement of significance: In many fields, model order reduction is a key technique in enabling high-throughput numerical simulations, but remains largely unexploited for biomedical modeling of the brain. In this work, we introduce a novel technique for building reduced representations integrating simulations performed on other brain geometries derived from MRI. Using this technique, we may leverage a dataset of previous solutions to accelerate simulations on new geometries, making patient-specific modeling more feasible.

• Dejgaard, Magnhild Skråmestø; Eide, Per Kristian; Tangen, Gro Gujord; Skovlund, Eva; Selbæk, Geir & Wyller, Torgeir Bruun (2025). Cognitive profile and frailty in patients with idiopathic normal pressure. Frontiers in Neurology. 16. doi: 10.3389/fneur.2025.1644507. Fulltekst i vitenarkiv Vis sammendrag

  Background Cognition and frailty are sparsely studied in patients with idiopathic normal pressure hydrocephalus (iNPH). We aimed to describe the preoperative cognitive function compared with normative data and frailty profile in iNPH patients accepted for shunt surgery. Methods All patients were diagnosed according to international guidelines and underwent a standardized cognitive and physical examination and a geriatric assessment prior to surgery. Z -scores for the cognitive tests were calculated based on age and education adjusted population norms. Results The study cohort included 276 iNPH patients accepted for shunt surgery. Mean ± SD age was 73.1 ± 5.7 years, education 12.5 ± 3.8 years, and 61% were male. The median (IQR) score on the Mini-Mental State Evaluation was 27 (24–29), and the median (IQR) Clock Drawing test score was 4 (3–5). Mean (SD) z -score for immediate verbal recall was −1.74 (0.98), for delayed recall −1.66 (1.01), for figure copying −0.85 (1.35) for Trail Making Test A -1.50 (1.09), for Trail Making Test B −1.88 (1.03), for phonemic fluency −1.46 (1.10), and for semantic fluency −1.59 (1.20). Cluster analysis identified three groups, mainly differing regarding visuospatial function. The mean (SD) Frailty Index score was 0.23 (0.13), indicating mild frailty. The frailty domain most affected was physical function. Conclusion iNPH patients showed reduced cognitive function across all domains. The patient group is rather heterogeneous regarding cognitive symptoms, and no specific cognitive profile was identified. Cognitive assessment offers limited utility for diagnosing a typical pattern specific for iNPH but is important due to the complex needs for this patient group. Whether cognitive and frailty profile can be used to identify shunt responders, must be assessed in longitudinal studies.

• Rieff, Melanie; Holzberger, Fabian; Lapina, Oksana; Ringstad, Geir; Valnes, Lars Magnus & Warsza, Bogna [Vis alle 9 forfattere av denne artikkelen] (2025). U-Net-Based Prediction of Cerebrospinal Fluid Distribution and Ventricular Reflux Grading. NMR in Biomedicine. ISSN 0952-3480. 38(5). doi: 10.1002/nbm.70029. Fulltekst i vitenarkiv Vis sammendrag

  Previous work indicates evidence that cerebrospinal fluid (CSF) plays a crucial role in brain waste clearance processes and that altered flow patterns are associated with various diseases of the central nervous system. In this study, we investigate the potential of deep learning to predict the distribution in human brain of a gadolinium-based CSF contrast agent (tracer) administered intrathecal. For this, T1-weighted magnetic resonance imaging (MRI) scans taken at multiple time points before and after injection were utilized. We propose a U-net-based supervised learning model to predict pixel-wise signal increase at its peak after 24 h. Performance is evaluated based on different tracer distribution stages provided during training, including predictions from baseline scans taken before injection. Our findings show that training with imaging data from only the first 2-h postinjection yields tracer flow predictions comparable to models trained with additional later-stage scans. Validation against ventricular reflux gradings from neuroradiologists confirmed alignment with expert evaluations. These results demonstrate that deep learning-based methods for CSF flow prediction deserve more attention, as minimizing MR imaging without compromising clinical analysis could enhance efficiency, improve patient well-being and lower healthcare costs.

• Eide, Per Kristian; Undseth, Ragnhild Marie; Pripp, Are Hugo; Lashkarivand, Aslan; Nedregaard, Bård & Sletteberg, Ruth [Vis alle 10 forfattere av denne artikkelen] (2025). Impact of Subarachnoid Hemorrhage on Human Glymphatic Function: A Time-Evolution Magnetic Resonance Imaging Study. Stroke. ISSN 0039-2499. 56(3), s. 678–691. doi: 10.1161/STROKEAHA.124.047739. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Subarachnoid hemorrhage (SAH) is associated with significant mortality and morbidity. The impact of SAH on human glymphatic function remains unknown. METHODS: This prospective, controlled study investigated whether human glymphatic function is altered after SAH, how it differs over time, and possible underlying mechanisms. Glymphatic enrichment was examined by intrathecal contrastenhanced magnetic resonance imaging (MRI, glymphatic MRI), utilizing the MRI contrast agent gadobutrol (Gadovist, Bayer AG, GE; 0.50 mmol) as a cerebrospinal fluid (CSF) tracer. The distribution of the tracer in the brain and the subarachnoid and ventricular CSF spaces was assessed using standardized multi-phase MRI T1 sequences, and between-group differences in percentage change of standardized T1 signal unit ratios over time were analyzed by linear mixed models. RESULTS: The study comprised 27 patients with SAH (19 female/8 male; 59.3±10.2 years) who were examined <3 months (n=5), 3 to 6 months (n=10), 6 to 12 months (n=5), or >12 months (n=7) after bleed. A sex- and age-matched control group of 22 individuals (15 female/7 male; 55.5±10.5 years) underwent the same glymphatic MRI protocol but had no neurological or CSF disease. The patients with SAH showed a marked impairment of glymphatic enrichment throughout the brain (particularly addressing the cerebral cortex and subcortical white matter), especially after 24 hours. The glymphatic impairment was accompanied by redistribution of CSF tracer from subarachnoid spaces toward ventricles. These alterations were most pronounced after 3 to 6 months and less after 12 months, though with interindividual variation. CSF tracer transport within perivascular subarachnoid spaces was impaired and coincided with impaired glymphatic enrichment. CONCLUSIONS: Human glymphatic function is severely impaired by SAH, particularly shortly after the event. Glymphatic failure is associated with redistribution of CSF from subarachnoid spaces toward ventricles. SAH-related impairment of fluid transport within perivascular subarachnoid spaces may contribute to reduced glymphatic influx. Since patient groups are small, care should be made when concluding about the impact of time on glymphatic function.

• Eide, Per Kristian (2025). Adult Hydrocephalus and the Glymphatic System. Neurosurgery clinics of North America. ISSN 1042-3680. 2, s. 127–140. doi: 10.1016/j.nec.2024.11.002. Fulltekst i vitenarkiv Vis sammendrag

  - Adult hydrocephalus includes various cerebrospinal fluid (CSF) disorders, with idiopathic normal pressure hydrocephalus (iNPH) as the most prevalent type. - Discoveries of the glymphatic-meningeal lymphatic systems have transformed our understanding of CSF dynamics, revealing new pathways for waste clearance and fluid transport, important for hydrocephalus. - The glymphatic system functions as a “brainwashing” pathway, clearing metabolic waste through perivascular spaces. - Impaired glymphatic function is associated with neurodegenerative diseases and may contribute to toxic protein accumulation in hydrocephalus. - The iNPH subtype of adult hydrocephalus may be redefined as a “CSF-proteinopathy,” reflecting both CSF dysfunction and protein buildup, akin to proteinopathies in dementia.

• Ringstad, Geir; Eide, Per Kristian; Naganawa, Shinji & Agarwal, Nivedita (2025). Gadolinium-Based Imaging and the Study of Neurofluid Dynamics. Neuroimaging clinics of North America. ISSN 1052-5149. 35(2), s. 191–209. doi: 10.1016/j.nic.2024.12.008. Fulltekst i vitenarkiv
• Eide, Per Kristian; Hovd, Markus; Pripp, Are Hugo; Gjertsen, Øivind; Løvland, Grethe & Lashkarivand, Aslan [Vis alle 9 forfattere av denne artikkelen] (2025). Altered brain fluid dynamics in spontaneous intracranial hypotension. Fluids and Barriers of the CNS. 22. doi: 10.1186/s12987-025-00679-0. Fulltekst i vitenarkiv Vis sammendrag

  Background This prospective observational study explored alterations in brain fluid dynamics in patients with spontaneous intracranial hypotension (SIH) and confirmed spinal cerebrospinal fluid (CSF) leakage, specifically addressing CSF clearance to blood, glymphatic influx and measures of CSF flow. Methods A cohort of SIH patients with verified spinal CSF leaks was compared with an age- and sex-matched reference group having no CSF disturbance or neurological disorders. Prior to repair of CSF leakage, CSF clearance was quantified using population pharmacokinetics, glymphatic influx was assessed by intrathecal contrast-enhanced magnetic resonance imaging (MRI), and CSF flow patterns were measured using either phase-contrast MRI or multiphase analysis of CSF tracer transport within the subarachnoid spaces. Results The study included eight SIH cases and nine reference subjects. SIH was accompanied with a greater CSF clearance, severely reduced tracer enrichment in the subarachnoid spaces and impaired glymphatic influx throughout the brain, after the patients had been upright. However, with patients in the supine position during MRI scanning, times to first enrichment of tracer in cisterna magna or perivascular subarachnoid spaces were not affected, with no changes in CSF flow through the Sylvian aqueduct, indicating that ventricular CSF production remained unaffected. Conclusions SIH caused by spinal CSF leakage is accompanied with altered brain fluid dynamics, here illustrated by accelerated CSF clearance to blood and reduced glymphatic influx, likely due to reduced CSF volume load to the intracranial compartment in the upright position.

• Aarhus, Mads; Rønning, Pål Andre; Vik-Mo, Einar Osland; Marthinsen, Pål Bache; Ramm-Pettersen, Jon-Terje & Eide, Per Kristian [Vis alle 7 forfattere av denne artikkelen] (2025). Kolloidcyster i tredje hjerneventrikkel. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 145(2). doi: 10.4045/tidsskr.24.0500. Fulltekst i vitenarkiv
• Räsänen, Joel; Helisalmi, Seppo; Heikkinen, Sami; Raivo, Joose; Korhonen, Ville E. & Martiskainen, Henna [Vis alle 33 forfattere av denne artikkelen] (2025). Low prevalence of CWH43 variants among Finnish and Norwegian idiopathic normal pressure hydrocephalus patients: a cohort-based observational study. Fluids and Barriers of the CNS. 22. doi: 10.1186/s12987-025-00625-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Heterozygous CWH43 loss-of-function (LOF) variants have been identified as iNPH risk factors, with 10–15% of iNPH patients carrying these variants in cohorts from the US. Mouse model harboring CWH43 LOF variants display a hydrocephalic phenotype with ventricular cilia alterations. Our aim was to study the effect of CWH43 variants on disease risk and clinical phenotype in Finnish and Norwegian iNPH cohorts. Methods We analyzed CWH43 LOF frameshift deletions (4:49032652 CA/C, Leu533Ter and 4:49061875 CA/C, Lys696AsnfsTer23) in Finnish iNPH patients from the Kuopio NPH registry (n = 630) and FinnGen (iNPH n = 1 131, controls n = 495 400), and Norwegian iNPH patients from EADB (n = 306). The Kuopio and Norwegian cohorts included possible and probable iNPH patients based on the American-European iNPH guidelines. FinnGen cohort included iNPH patients based on ICD-10 G91.2 with the exclusion of secondary etiologies, and controls having no diagnosis of hydrocephalus. Results In the Kuopio cohort of Finnish iNPH patients, 2.9% carried CWH43 variants (Leu533Ter 2.1%, Lys696AsnfsTer23 0.8%), with one homozygous Leu533Ter carrier. In FinnGen, 3.1% of iNPH patients carried heterozygous variants (Leu533Ter 2.6%, Lys696AsnfsTer23 0.5%) compared to 2.5% of controls (p = 0.219, OR = 1.23, 95% CI 0.85–1.72), with no effect on disease risk or onset age. Importantly in the FinnGen cohort, none of the 23 compound heterozygote or 59 homozygote individuals had hydrocephalus diagnosis. In the Norwegian iNPH cohort, 5.2% of patients were heterozygous variant carriers (Leu533Ter 3.3%, Lys696AsnfsTer23 2.0%). No differences in clinical phenotype (age, triad symptoms, shunt response, vascular comorbidities) were found between carriers and noncarriers in any cohort. However, 74% of variant-carrying iNPH patients in FinnGen were female, compared to 47% of noncarriers (p = 0.002). Pedigrees indicated no autosomal dominant co-inheritance of iNPH and the CWH43 variants. Conclusions We studied the iNPH-associated CWH43 LOF variants for the first time on a population-scale. Contrary to previously reported findings in smaller cohorts, our study revealed a low prevalence of these variants in the population-scale Finnish iNPH cohort, with no effect on disease risk of iNPH. The prevalence in the Norwegian iNPH cohort was also low compared to previous studies.

• Therkelsen, Helena Eide; Enger, Rune; Eide, Per Kristian & Ringstad, Geir (2025). Evidence for cellular and solute passage between the brain and skull bone marrow across meninges: A systematic review. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 45(4), s. 581–599. doi: 10.1177/0271678X251316392. Fulltekst i vitenarkiv Vis sammendrag

  A potential two-way passage of cells and substances between the brain and skull bone marrow may open for new insights into neurological disease. The arachnoid membrane was traditionally considered to restrict cells and larger molecules in CSF from entering the dura and bone marrow directly. However, new data on exchange between brain and skull bone marrow have recently emerged. Here, we conducted a systematic literature to answer the question: What is the current evidence regarding the movement of cells and molecules between the brain and skull bone marrow, spanning CSF and meninges? We excluded studies related to head or skull trauma, cranial fractures or defects, cancer invasion, CSF leakage, spontaneous intracranial hypotension, spinal dura mater, and studies solely focusing on meningeal lymphatic vessels or the passage of substances from CSF to meningeal lymphatic vessels. The review identified 16 studies that provide evidence of communication between the brain, meninges and skull bone marrow. Cells (such as B and T cells and neutrophils), bacteria, and substances (tracers, drug compounds) have been reported to pass between the brain and skull bone. However, most studies are performed in rodents, emphasizing the need for translation to humans.

• Eide, Per Kristian & Ringstad, Geir (2024). Glymphatic-stagnated edema induced by traumatic brain injury. TIPS - Trends in Pharmacological Sciences. ISSN 0165-6147. 45(5), s. 390–390. doi: 10.1016/j.tips.2024.01.005. Fulltekst i vitenarkiv Vis sammendrag

  Traumatic brain injury (TBI) outcomes are notably affected by brain edema. A recent report by Hussain et al. unveils a unique form, glymphatic-stagnated brain edema, that stems from impaired glymphatic and lymphatic drainage induced by noradrenergic activation. Consequently, pan-noradrenergic inhibition may emerge as an innovative treatment for TBI-related edema, challenging traditional therapeutic approaches.

• Eide, Per Kristian; Undseth, Ragnhild Marie; Gjertsen, Øivind; Valnes, Lars Magnus; Ringstad, Geir Andre & Lindstrøm, Erika Kristina (2024). Significant individual variation in cardiac-cycle-linked cerebrospinal fluid production following subarachnoid hemorrhage. Fluids and Barriers of the CNS. 21(1). doi: 10.1186/s12987-024-00587-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Spontaneous subarachnoid hemorrhage (SAH) often results in altered cerebrospinal fluid (CSF) flow and secondary hydrocephalus, yet the mechanisms behind these phenomena remain poorly understood. This study aimed to elucidate the impact of SAH on individual CSF flow patterns and their association with secondary hydrocephalus. Methods In patients who had experienced SAH, changes in CSF flow were assessed using cardiac-gated phasecontrast magnetic resonance imaging (PC-MRI) at the Sylvian aqueduct and cranio-cervical junction (CCJ). Within these regions of interest, volumetric CSF flow was determined for every pixel and net CSF flow volume and direction calculated. The presence of acute or chronic hydrocephalus was deemed from ventriculomegaly and need of CSF diversion. For comparison, we included healthy subjects and patients examined for different CSF diseases. Results Twenty-four SAH patients were enrolled, revealing a heterogeneous array of CSF flow alterations at the Sylvian aqueduct. The cardiac-cycle-linked CSF net flow in Sylvian aqueduct differed from the traditional figures of ventricular CSF production about 0.30–0.40 mL/min. In 15 out of 24 patients (62.5%), net CSF flow was retrograde from the fourth to the third and lateral ventricles, while it was upward at the cranio-cervical junction in 2 out of 2 patients (100%). The diverse CSF flow metrics did not distinguish between individuals with acute or chronic secondary hydrocephalus. In comparison, 4/4 healthy subjects showed antegrade net CSF flow in the Sylvian aqueduct and net upward CSF flow in CCJ. These net CSF flow measures also showed interindividual variability among other patients with CSF diseases. Conclusions There is considerable inter-individual variation in net CSF flow rates following SAH. Net CSF flow in the Sylvian aqueduct differs markedly from the traditional ventricular CSF production rates of 0.30–0.40 mL/min in SAH patients, but less so in healthy subjects. Furthermore, the cardiac-cycle-linked net CSF flow rates in Sylvian aqueduct and CCJ suggest an important role of extra-ventricular CSF production.

• Osch, Matthias J. P. van; Wåhlin, Anders; Scheyhing, Paul; Mossige, Ingrid; Hirschler, Lydiane & Eklund, Anders [Vis alle 16 forfattere av denne artikkelen] (2024). Human brain clearance imaging: Pathways taken by magnetic resonance imaging contrast agents after administration in cerebrospinal fluid and blood. NMR in Biomedicine. ISSN 0952-3480. 37(9). doi: 10.1002/nbm.5159. Fulltekst i vitenarkiv Vis sammendrag

  Over the last decade, it has become evident that cerebrospinal fluid (CSF) plays a pivotal role in brain solute clearance through perivascular pathways and interactions between the brain and meningeal lymphatic vessels. Whereas most of this fundamental knowledge was gained from rodent models, human brain clearance imaging has provided important insights into the human system and highlighted the existence of important interspecies differences. Current gold standard techniques for human brain clearance imaging involve the injection of gadolinium-based contrast agents and monitoring their distribution and clearance over a period from a few hours up to 2 days. With both intrathecal and intravenous injections being used, which each have their own specific routes of distribution and thus clearance of contrast agent, a clear understanding of the kinetics associated with both approaches, and especially the differences between them, is needed to properly interpret the results. Because it is known that intrathecally injected contrast agent reaches the blood, albeit in small concentrations, and that similarly some of the intravenously injected agent can be detected in CSF, both pathways are connected and will, in theory, reach the same compartments. However, because of clear differences in relative enhancement patterns, both injection approaches will result in varying sensitivities for assessment of different subparts of the brain clearance system. In this opinion review article, the “EU Joint Programme – Neurodegenerative Disease Research (JPND)” consortium on human brain clearance imaging provides an overview of contrast agent pharmacokinetics in vivo following intrathecal and intravenous injections and what typical concentrations and concentration–time curves should be expected. This can be the basis for optimizing and interpreting contrast-enhanced MRI for brain clearance imaging. Furthermore, this can shed light on how molecules may exchange between blood, brain, and CSF.

• Räsänen, Joel; Heikkinen, Sami; Mäklin, Kiira; Lipponen, Anssi; Kuulasmaa, Teemu & Mehtonen, Juha [Vis alle 34 forfattere av denne artikkelen] (2024). Risk Variants Associated with Normal Pressure Hydrocephalus: Genome-Wide Association Study in the FinnGen Cohort. Neurology. ISSN 0028-3878. 103(5). doi: 10.1212/WNL.0000000000209694. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH). Methods We used a case-control study design implementing FinnGen data containing 473,691 Finns with genotypes and nationwide health records. Patients with NPH were selected based on ICD-10 G91.2 diagnosis. To select patients with idiopathic NPH (iNPH) for sensitivity analysis, we excluded patients with a potentially known etiology of the condition using an algorithm on their disease history. The controls were the remaining non-hydrocephalic participants. For a replication analysis, the NPH cohort from UK Biobank (UKBB) was used. Results We included 1,522 patients with NPH (mean age 72.2 years, 53% women) and 451,091 controls (mean age 60.5 years, 44% women). In the GWAS comparing patients with NPH with the controls, we identified 6 gene regions significantly (p < 5.0e-8) associated with NPH that replicated in a meta-analysis with UKBB (NPH n = 173). The top loci near the following genes were rs7962263, SLCO1A2 (odds ratio [OR] 0.71, 95% CI 0.65–0.78, p = 1.0e-14); rs798495, AMZ1/GNA12 (OR 1.29, 95% CI 1.20–1.39, p = 2.9e-12); rs10828247, MLLT10 (OR 0.77, 95% CI 0.71–0.83, p = 1.5e-11); rs561699566 and rs371919113, CDCA2 (OR 0.76, 95% CI 0.70–0.82, p = 1.5e-11); rs56023709, C16orf95 (OR 1.24, 95% CI 1.16–1.33, p = 3.0e-9); and rs62434144, PLEKHG1 (OR 1.23, 95% CI 1.14–1.32, p = 1.4e-8). In the sensitivity analysis comparing only patients with iNPH (n = 1,055) with the controls (n = 451,091), 4 top loci near the following genes remained significant: rs7962263, SLCO1A2 (OR 0.70, 95% CI 0.63–0.78, p = 2.1e-11); rs10828247, MLLT10 (OR 0.74, 95% CI 0.62–0.82, p = 4.6e-10); rs798511, AMZ1/GNA12 (OR 1.28, 95% CI 1.17–1.39, p = 1.7e-8); and rs56023709, C16orf95 (OR 1.28, 95% CI 1.17–1.39, p = 1.7e-8). Discussion We identified 6 loci significantly associated with NPH in the thus far largest GWAS in chronic hydrocephalus. The genes near the top loci have previously been associated with blood-brain barrier and blood-CSF barrier function and with increased lateral brain ventricle volume. The effect sizes and allele frequencies remained similar in NPH and iNPH cohorts, indicating the identified loci are risk determinants for iNPH and likely not explained by associations with other etiologies. However, the exact role of these loci is still unknown, warranting further studies.

• Ringstad, Geir & Eide, Per Kristian (2024). Glymphatic-lymphatic coupling: assessment of the evidence from magnetic resonance imaging of humans. Cellular and Molecular Life Sciences (CMLS). ISSN 1420-682X. 81(1). doi: 10.1007/s00018-024-05141-2. Fulltekst i vitenarkiv Vis sammendrag

  solutes to meningeal lymphatic vessels have sparked a tremendous interest in translating these seminal findings from animals to humans. A potential two-way coupling between the brain extra-vascular compartment and the peripheral immune system has implications that exceed those concerning neurodegenerative diseases, but also imply that the central nervous system has pushed its immunological borders toward the periphery, where cross-talk mediated by cerebrospinal fluid may play a role in a range of neoplastic and immunological diseases. Due to its non-invasive approach, magnetic resonance imaging has typically been the preferred methodology in attempts to image the glymphatic system and meningeal lymphatics in humans. Even if flourishing, the research field is still in its cradle, and interpretations of imaging findings that topographically associate with reports from animals have yet seemed to downplay the presence of previously described anatomical constituents, particularly in the dura. In this brief review, we illuminate these challenges and assess the evidence for a glymphatic-lymphatic coupling. Finally, we provide a new perspective on how human brain and meningeal clearance function may possibly be measured in future.

• Eide, Per Kristian (2024). Neurosurgery and the glymphatic system. Acta Neurochirurgica. ISSN 0001-6268. 166(1). doi: 10.1007/s00701-024-06161-4. Fulltekst i vitenarkiv Vis sammendrag

  The discovery of the glymphatic system has fundamentally altered our comprehension of cerebrospinal fluid transport and the removal of waste from brain metabolism. In the past decade, since its initial characterization, research on the glymphatic system has surged exponentially. Its potential implications for central nervous system disorders have sparked significant interest in the field of neurosurgery. Nonetheless, ongoing discussions and debates persist regarding the concept of the glymphatic system, and our current understanding largely relies on findings from experimental animal studies. This review aims to address several key inquiries: What methodologies exist for evaluating glymphatic function in humans today? What is the current evidence supporting the existence of a human glymphatic system? Can the glymphatic system be considered distinct from the meningeal-lymphatic system? What is the human evidence for glymphatic-meningeal lymphatic system failure in neurosurgical diseases? Existing literature indicates a paucity of techniques available for assessing glymphatic function in humans. Thus far, intrathecal contrast-enhanced magnetic resonance imaging (MRI) has shown the most promising results and have provided evidence for the presence of a glymphatic system in humans, albeit with limitations. It is, however, essential to recognize the interconnection between the glymphatic and meningeal lymphatic systems, as they operate in tandem. There are some human studies demonstrating deteriorations in glymphatic function associated with neurosurgical disorders, enriching our understanding of their pathophysiology. However, the translation of this knowledge into clinical practice is hindered by the constraints of current glymphatic imaging modalities.

• Quesada, Cesar Luis Vera; Shreyas, Rao; Torp, Reidun; Niehusmann, Pitt & Eide, Per Kristian (2024). Lack of inflammation or immune response in cyst tissue of patients with symptomatic non-hydrocephalic pineal cysts. Journal of the Neurological Sciences. ISSN 0022-510X. 462. doi: 10.1016/j.jns.2024.123111. Fulltekst i vitenarkiv Vis sammendrag

  Pineal cysts are frequently encountered as incidental findings in magnetic resonance imaging, usually devoid of symptoms, yet some patients exhibit symptomatic manifestations possibly associated with the cyst, even in the absence of hydrocephalus. The etiology of these symptoms remains contentious. This study aims to investigate the presence of lymphatic endothelial cell (LEC) markers and indications of inflammation or immune response within the pineal cysts of patients experiencing symptomatic non-hydrocephalic presentations. Eight patients who underwent surgical excision of their cysts were included in the study. Immunohistochemistry was utilized to assess the expression of LYVE-1, PDPN, and VEGFR3 as LEC markers, alongside IL-6 and CD3 for indications of inflammation or immune activity. Our analysis revealed an absence of inflammatory markers or immune response. However, a distinct expression of VEGFR3 was observed, likely localized to neurons within the pineal cyst tissue. We propose that these VEGFR3+ neurons within the pineal cyst may contribute to the headache symptoms reported by these patients. Further investigations are warranted to substantiate this hypothesis.

• Eide, Per Kristian & Ringstad, Geir (2024). Functional analysis of the human perivascular subarachnoid space. Nature Communications. 15, s. 1–14. doi: 10.1038/s41467-024-46329-1. Fulltekst i vitenarkiv Vis sammendrag

  The human subarachnoid space harbors the cerebrospinal fluid, which flows within a landscape of blood vessels and trabeculae. Functional implications of subarachnoid space anatomy remain far less understood. This study of 75 patients utilizes a cerebrospinal fluid tracer (gadobutrol) and consecutive magnetic resonance imaging to investigate features of early (i.e. within 2-3 h after injection) tracer propagation within the subarachnoid space. There is a time-dependent perivascular pattern of enrichment antegrade along the major cerebral artery trunks; the anterior-, middle-, and posterior cerebral arteries. The correlation between time of first enrichment around arteries and early enrichment in nearby cerebral cortex is significant. These observations suggest the existence of a compartmentalized subarachnoid space, where perivascular ensheathment of arteries facilitates antegrade tracer passage towards brain tissue. Periarterial transport is impaired in subjects with reduced intracranial pressure-volume reserve capacity and in idiopathic normal pressure hydrocephalus patients who also show increased perivascular space size.

• Frič, Radek; Bryne, Eline; Warsza, Bogna; Due-Tønnessen, Bernt Johan & Eide, Per Kristian (2024). Preoperative estimation of intracranial compliance in symptomatic children with Chiari malformation type 1: impact on outcome and risk of complications. Acta Neurochirurgica. ISSN 0001-6268. 166(1), s. 1–11. doi: 10.1007/s00701-024-05897-3. Fulltekst i vitenarkiv Vis sammendrag

  Background The role of reduced intracranial compliance (ICC) in the outcome after foramen magnum decompression (FMD) was demonstrated in adults with Chiari malformation Type 1 (CMI). However, similar observations from children treated for CMI are missing. Methods We reviewed pediatric cases of CMI referred to FMD between 2006 and 2022. Children with clinical and/or radiological signs suggesting reduced ICC (Group A) underwent overnight measurements of the pulsatile intracranial pressure (ICP): mean ICP wave amplitude (MWA) served as a surrogate marker of ICC. Children with more typical symptoms of CMI (Group B) underwent FMD without preoperative ICC estimation. This study presents the clinical, radiological, and outcome differences between these groups. Results Sixty-four children (mean age 11.1 ± 4.3 years) underwent FMD: In Group A (n = 30), the finding of reduced ICC as estimated from preoperative ICP measurement resulted in CSF diversion (ventriculoperitoneal shunt) before FMD in 11 children. Two patients required shunt due to complications after FMD (total shunt rate 43%). In Group B (n = 34) treated with FMD without preoperative ICC estimation, five children (15%) required shunting due to complications. In Group A, we found a significantly higher frequency of headache, nausea, fatigue, and dizziness. The outcome assessed by the modified Chicago Chiari Outcome Scale (mean follow-up 83 ± 57 months) was comparable between the groups, but the complication rate after FMD was significantly lower in Group A (7% vs. 32%; p = 0.011). The number of procedures (ICP measurement, FMD, shunt, re-do FMD, shunt revisions) was significantly higher in Group A (2.6 ± 0.9 vs. 1.5 ± 1.1 per patient; p < 0.001). Conclusion In symptomatic children with CMI, the preoperative estimation of ICC from the overnight measurement of pulsatile ICP was more reliable for identifying those with reduced ICC than clinical and radiological assessment alone. When children with abnormally reduced ICC were identified and treated with CSF diversion before FMD, the complication rate was significantly reduced.

• Frič, Radek; Bryne, Eline; Warsza, Bogna & Eide, Per Kristian (2024). Intracranial pulse pressure amplitude as an indicator of intracranial compliance: observations in symptomatic children with Chiari malformation type I. Journal of Neurosurgery: Pediatrics. ISSN 1933-0707. 34(3), s. 293–300. doi: 10.3171/2024.4.PEDS24168. Fulltekst i vitenarkiv
• Melin, Erik; Ringstad, Geir; Valnes, Lars Magnus & Eide, Per Kristian (2023). Human parasagittal dura is a potential neuroimmune interface. Communications Biology. 6(1). doi: 10.1038/s42003-023-04634-3. Fulltekst i vitenarkiv Vis sammendrag

  Parasagittal dura (PSD) is located on both sides of the superior sagittal sinus and harbours arachnoid granulations and lymphatic vessels. Efflux of cerebrospinal fluid (CSF) to human PSD has recently been shown in vivo. Here we obtain PSD volumes from magnetic resonance images in 76 patients under evaluation for CSF disorders and correlate them to age, sex, intracranial volumes, disease category, sleep quality, and intracranial pressure. In two subgroups, we also analyze tracer dynamics and time to peak tracer level in PSD and blood. PSD volume is not explained by any single assessed variable, but tracer level in PSD is strongly associated with tracer in CSF and brain. Furthermore, peak tracer in PSD occurs far later than peak tracer in blood, implying that PSD is no major efflux route for CSF. These observations may indicate that PSD is more relevant as a neuroimmune interface than as a CSF efflux route.

• Vinje, Vegard; Zapf, Bastian; Ringstad, Geir; Eide, Per Kristian; Rognes, Marie Elisabeth & Mardal, Kent-Andre (2023). Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation. Fluids and Barriers of the CNS. 20. doi: 10.1186/s12987-023-00459-8. Fulltekst i vitenarkiv Vis sammendrag

  Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5 $$\times $$ × that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1–9 $$\mu $$ μ m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

• Warsza, Bogna; Due-Tønnessen, Pernille; Due-Tønnessen, Paulina; Pripp, Are Hugo; Ringstad, Geir & Eide, Per Kristian (2023). Prevalence of pineal cysts in healthy individuals: Emphasis on size, morphology and pineal recess crowding. Journal of the Neurological Sciences. ISSN 0022-510X. 453. doi: 10.1016/j.jns.2023.120801. Fulltekst i vitenarkiv Vis sammendrag

  The present study aimed to determine prevalence of non-hydrocephalic pineal cysts of different size and morphology in healthy individuals. In a cohort of healthy individuals who as part of research volunteered to undergo magnetic resonance imaging (MRI) of the brain, we performed a systematic search for occurrence of pineal cysts of different sizes, morphology and evidence of crowding of the pineal recess. Degree of crowding in the pineal recess was estimated by the imaging biomarkers anterior-posterior diameter and cyst-tectum-splenium (CTS) ratio at midsagittal MRI. The study included a cohort of 994 healthy individuals, aged 47.0 ±21.1 years in whom a pineal cyst was demonstrated in 337/994 (37.5%) individuals. A small cyst within a mainly solid gland was observed in 252/994 (25.4%) subjects and a mainly cystic gland in121/994 (12.2%). The pineal cysts were more frequent in women than men, and were associated with age, though not with reduced prevalence in aged individuals, as previously reported. Cysts with maximum anterior-posterior diameter ≥10 mm were seen in 51/ 994 (5.1%) individuals, and with CTS ratio ≥0.9 in 16/994 (1.6%) individuals. The occurrence of pineal cysts is frequent and is seen more frequently in women. It usually presents as a small cyst in a predominantly solid gland; however, pineal cysts causing crowding of the pineal recess with a CTS ratio ≥0.9 was seen in merely 1.6% of participants.

• Eide, Per Kristian; Lindstrøm, Erika Kristina; Pripp, Are Hugo; Valnes, Lars Magnus & Ringstad, Geir (2023). Physiological alterations of pineal recess crowding in symptomatic non-hydrocephalic pineal cysts. Brain Communications. 5(2). doi: 10.1093/braincomms/fcad078. Fulltekst i vitenarkiv Vis sammendrag

  Pineal cysts are prevalent in the population. Due to more widespread use of magnetic resonance imaging, an increasing number of symptomatic patients with non-hydrocephalic pineal cysts are referred to neurologists and neurosurgeons. Currently, there is no gen- erally accepted theoretical framework for linking symptoms to a pineal cyst. We have previously suggested that cyst-induced crowding of the pineal recess may affect venous runoff from the deep cerebral veins crossing the cyst. However, evidence underpinning this hy- pothesis is sparse. In the present study, we asked whether crowding of the pineal recess without imaging signs of hydrocephalus may be accompanied with alterations in blood flow of the internal cerebral veins, cerebrospinal fluid flow in the Sylvian aqueduct and cere- brospinal fluid-mediated tracer clearance from the brain along extravascular pathways (referred to as glymphatic function). This pro- spective, observational study included symptomatic individuals with non-hydrocephalic pineal cysts who underwent a standardized magnetic resonance imaging protocol (n = 25): Eleven patients were treated surgically with craniotomy and cyst extirpation and 14 individuals were managed conservatively without surgery. Our findings suggest that cyst-induced crowding of the pineal recess may have brain-wide effects: (i) There was a significant negative correlation between degree of crowding within the pineal recess and change in maximum venous flow velocity at the cyst, and a significant positive correlation between maximum venous flow velocity change at the cyst and net cerebrospinal fluid flow in the Sylvian aqueduct; (ii) increased degree of crowding in the pineal recess was accompanied by significantly impaired glymphatic enrichment in the cerebral cortex and subcortical white matter, indicative of a brain-wide effect in this cohort who also reported markedly impaired subjective sleep quality; (iii) there was a significant negative correlation between the apparent diffusion coefficient (suggestive of interstitial water content) within the thalamus and glymphatic enrichment of tracer and (iv) pineal recess crowding associated with symptoms. Comparison of the surgical cases [in whom 10/11 (91%) reported marked clinical improvement at follow-up] and the conservatively managed cases [in whom 1/14 (7%) reported marked clinical improvement at follow-up] showed differences in pre-treatment glymphatic tracer enrichment as well as differences in tracer enrichment in subarachnoid cerebrospinal fluid spaces. Taken together, we interpret these observations to support the hy- pothesis that cyst-induced crowding of the pineal recess without hydrocephalus may alter blood flow of the internal cerebral veins and cerebrospinal fluid flow and even cause brain-wide impairment of glymphatic transport with possible implications for cerebro- spinal fluid transport of trophic factors such as melatonin.

• Melin, Erik; Pripp, Are Hugo; Eide, Per Kristian & Ringstad, Geir (2023). In vivo distribution of cerebrospinal fluid tracer in human upper spinal cord and brain stem. JCI Insight. 8(23). doi: 10.1172/jci.insight.173276. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND. Intrathecal injection is an attractive route through which drugs can be administered and directed to the spinal cord, restricted by the blood-spinal cord barrier. However, in vivo data on the distribution of cerebrospinal fluid (CSF) substances in the human spinal cord are lacking. We conducted this study to assess the enrichment of a CSF tracer in the upper cervical spinal cord and the brain stem. METHODS. After lumbar intrathecal injection of a magnetic resonance imaging (MRI) contrast agent, gadobutrol, repeated blood samples and MRI of the upper cervical spinal cord, brain stem, and adjacent subarachnoid spaces (SAS) were obtained through 48 hours. The MRI scans were then analyzed for tracer distribution in the different regions and correlated to age, disease, and amounts of tracer in the blood to determine CSF-to-blood clearance. RESULTS. The study included 26 reference individuals and 35 patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH). The tracer enriched all analyzed regions. Moreover, tracer enrichment in parenchyma was associated with tracer enrichment in the adjacent SAS and with CSF-to-blood clearance. Clearance from the CSF was delayed in patients with iNPH compared with younger reference patients. CONCLUSION. A CSF tracer substance administered to the lumbar thecal sac can access the parenchyma of the upper cervical spinal cord and brain stem. Since CSF-to-blood clearance is highly individual and is associated with tracer level in CSF, clearance assessment may be used to tailor intrathecal treatment regimes.

• Frič, Radek; Ringstad, Geir & Eide, Per Kristian (2023). Low versus High Intracranial Compliance in Adult Patients with Chiari Malformation Type 1–Comparison of Long-Term Outcome After Tailored Treatment. World Neurosurgery. ISSN 1878-8750. 173, s. e699–e707. doi: 10.1016/j.wneu.2023.02.134. Fulltekst i vitenarkiv Vis sammendrag

  Background In patients with Chiari malformation type 1 (CMI) presenting with low intracranial compliance (ICC), foramen magnum decompression (FMD) often fails and the complication rate may be higher. We therefore routinely perform a preoperative assessment of ICC from intracranial pressure measurement. Patients with low ICC are treated with ventriculoperitoneal shunt (VPS) before FMD. In this study, we assess the outcome of patients with low ICC, compared with patients with high ICC treated with FMD alone. Methods We reviewed the clinical and radiologic data of all consecutive patients with CMI treated between April 2008 and June 2021. ICC was assessed by overnight measurement of the pulsatile intracranial pressure: mean wave amplitude (MWA) above a previously defined threshold for abnormality was considered a surrogate marker for low ICC. The outcome was scored by Chicago Chiari Outcome Scale. Results Of 73 patients, 23 with low ICC (average MWA 6.8 ± 1.2 mm Hg) received VPS before FMD, whereas 50 with high ICC (average MWA 4.4 ± 1.0 mm Hg) received only FMD. After a mean follow-up of 78.7 ± 41.4 months, 96% of all patients subjectively improved. The mean Chicago Chiari Outcome Scale score was 13.1 ± 2.2. Enlargement of cerebrospinal fluid space in the foramen magnum was achieved in 95% and regression of syringomyelia in 74% of cases. We found no significant difference in outcome between the patients with low and high ICC. Conclusions By identifying patients with CMI associated with low ICC and tailoring their treatment by VPS before FMD, we achieved favorable clinical and radiologic outcomes comparable to those with high ICC.

• Eide, Per Kristian; Lashkarivand, Aslan; Pripp, Are Hugo; Valnes, Lars Magnus; Hovd, Markus Herberg & Ringstad, Geir [Vis alle 8 forfattere av denne artikkelen] (2023). Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders. Nature Communications. 14, s. 1–14. doi: 10.1038/s41467-023-37685-5. Fulltekst i vitenarkiv Vis sammendrag

  Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegen- eration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to- blood clearance variables from pharmacokinetic modeling (proxy of menin- geal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neuro- degeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function.

• Quesada, Cesar Luis Vera; Shreyas, Rao; Torp, Reidun & Eide, Per Kristian (2023). Widespread distribution of lymphatic vessels in human dura mater remote from sinus veins. Frontiers in Cell and Developmental Biology. 11. doi: 10.3389/fcell.2023.1228344. Fulltekst i vitenarkiv Vis sammendrag

  Background and purpose: Previous experimental studies have shown that meningeal lymphatic vessels are located primarily along the walls of the dural sinus veins. Whether they are more widespread throughout human dura mater has presently not been characterized. The present study explored in humans whether meningeal lymphatic vessels may be identified remote from the sinus veins and whether they differ in the various location of dura mater. Methods: We included 15 patients who underwent neurosurgery, in whom dura mater was removed as part of the planned procedure. Tissue was prepared for immunohistochemistry using the lymphatic endothelial cell markers lymphatic vessel endothelial hyaluronan receptor 1 protein (LYVE-1), podoplanin and vascular endothelial growth factor receptor 3 (VEGFR3). Results: Lymphatic endothelial cell positive cells were found in dura mater at the posterior fossa (n = 8), temporal skull base (n = 5), frontal convexity (n = 1), and cranio-cervical junction (n = 1). They were most commonly seen remote from blood vessels, but also occurred along blood vessels, and seemed to be most abundant at the skull base. Conclusion: The present observations show that human lymphatic vessels are widespread in dura mater, not solely lining the dural sinuses.

• Thavarajasingam, Santhosh G.; El-Khatib, Mahmoud; Vemulapalli, Kalyan; Iradukunda, Hector A. Sinzinkayo; K, Sajeenth Vishnu & Borchert, Robin [Vis alle 8 forfattere av denne artikkelen] (2023). Radiological predictors of shunt response in the diagnosis and treatment of idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis. Acta Neurochirurgica. ISSN 0001-6268. 165, s. 369–419. doi: 10.1007/s00701-022-05402-8. Fulltekst i vitenarkiv Vis sammendrag

  Background Patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) may improve clinically following cerebrospinal fluid (CSF) diversion (shunt) surgery, though the predictors of shunt response remain debated. Currently, radiological features play an important role in the diagnosis of iNPH, but it is not well established which radiological markers most precisely predict shunt responsive iNPH. Objective To conduct a systematic review and meta-analysis to identify radiological predictors of shunt responsiveness, evaluate their diagnostic effectiveness, and recommend the most predictive radiological features. Methods Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR were searched for original studies investigating radiological predictors of shunt response in iNPH patients. Included studies were assessed using the ROBINS-1 tool, and eligible studies were evaluated using a univariate meta-analysis. Results Overall, 301 full-text papers were screened, of which 28 studies were included, and 26 different radiological features were identified, 5 of these met the inclusion criteria for the meta-analysis: disproportionately enlarged subarachnoid space (DESH), callosal angle, periventricular white matter changes, cerebral blood flow (CBF), and computerized tomography cisternography. The meta-analysis showed that only callosal angle and periventricular white matter changes significantly differentiated iNPH shunt responders from non-responders, though both markers had a low diagnostic odds ratio (DOR) of 1.88 and 1.01 respectively. None of the other radiological markers differentiated shunt responsive from shunt non-responsive iNPH. Conclusion Callosal angle and periventricular changes are the only diagnostically effective radiological predictors of shunt responsive iNPH patients. However, due to the DORs approximating 1, they are insufficient as sole predictors and are advised to be used only in combination with other diagnostic tests of shunt response. Future research must evaluate the combined use of multiple radiological predictors, as it may yield beneficial additive effects that may allow for more robust radiological shunt response prediction.

• Sperre, Anette; Karsrud, Ina; Rodum, Anja; Lashkarivand, Aslan; Valnes, Lars Magnus & Ringstad, Geir [Vis alle 7 forfattere av denne artikkelen] (2023). Prospective Safety Study of Intrathecal Gadobutrol in Different Doses. American Journal of Neuroradiology. ISSN 0195-6108. 44(5), s. 511–516. doi: 10.3174/ajnr.A7841. Fulltekst i vitenarkiv
• Eide, Per Kristian; Lashkarivand, Aslan; Pripp, Are Hugo; Valnes, Lars Magnus; Hovd, Markus & Ringstad, Geir [Vis alle 8 forfattere av denne artikkelen] (2023). Mechanisms behind changes of neurodegeneration biomarkers in plasma induced by sleep deprivation. Brain Communications. 5(6). doi: 10.1093/braincomms/fcad343. Fulltekst i vitenarkiv Vis sammendrag

  Acute sleep deprivation has been shown to affect cerebrospinal fluid and plasma concentrations of biomarkers associated with neurodegeneration, though the mechanistic underpinnings remain unknown. This study compared individuals who, for one night, were either subject to total sleep deprivation or free sleep, (i) examining plasma concentrations of neurodegeneration biomarkers the morning after sleep deprivation or free sleep and (ii) determining how overnight changes in biomarkers plasma concentrations correlate with indices of meningeal lymphatic and glymphatic clearance functions. Plasma concentrations of amyloid-β 40 and 42, phosphorylated tau peptide 181, glial fibrillary acid protein and neurofilament light were measured longitudinally in subjects who from Day 1 to Day 2 either underwent total sleep deprivation (n = 7) or were allowed free sleep (n = 21). The magnetic resonance imaging contrast agent gadobutrol was injected intrathecally, serving as a cerebrospinal fluid tracer. Population pharmacokinetic model parameters of gadobutrol cerebrospinal fluid-to-blood clearance were utilized as a proxy of meningeal lymphatic clearance capacity and intrathecal contrast-enhanced magnetic resonance imaging as a proxy of glymphatic function. After one night of acute sleep deprivation, the plasma concentrations of amyloid-β 40 and 42 were reduced, but not the ratio, and concentrations of the other biomarkers were unchanged. The overnight change in amyloid-β 40 and 42 plasma concentrations in the sleep group correlated significantly with indices of meningeal lymphatic clearance capacity, while this was not seen for the other neurodegeneration biomarkers. However, overnight change in plasma concentrations of amyloid-β 40 and 42 did not correlate with the glymphatic marker. On the other hand, the overnight change in plasma concentration of phosphorylated tau peptide 181 correlated significantly with the marker of glymphatic function in the sleep deprivation group but not in the sleep group. The present data add to the evidence of the role of sleep and sleep deprivation on plasma neurodegeneration concentrations; however, the various neurodegeneration biomarkers respond differently with different mechanisms behind sleep-induced alterations in amyloid-β and tau plasma concentrations. Clearance capacity of meningeal lymphatics seems more important for sleep-induced changes in amyloid-β 40 and 42 plasma concentrations, while glymphatic function seems most important for change in plasma concentration of phosphorylated tau peptide 181 during sleep deprivation. Altogether, the present data highlight diverse mechanisms behind sleep-induced effects on concentrations of plasma neurodegeneration biomarkers.

• Quesada, Cesar Luis Vera; Shreyas, Rao; Torp, Reidun & Eide, Per Kristian (2023). Immunohistochemical visualization of lymphatic vessels in human dura mater: methodological perspectives. Fluids and Barriers of the CNS. 20. doi: 10.1186/s12987-023-00426-3. Fulltekst i vitenarkiv Vis sammendrag

  Background Despite greatly renewed interest concerning meningeal lymphatic function over recent years, the lymphatic structures of human dura mater have been less characterized. The available information derives exclusively from autopsy specimens. This study addressed methodological aspects of immunohistochemistry for visualization and characterization of lymphatic vessels in the dura of patients. Methods Dura biopsies were obtained from the right frontal region of the patients with idiopathic normal pressure hydrocephalus (iNPH) who underwent shunt surgery as part of treatment. The dura specimens were prepared using three different methods: Paraformaldehyde (PFA) 4% (Method #1), paraformaldehyde (PFA) 0.5% (Method #2), and freeze-fixation (Method #3). They were further examined with immunohistochemistry using the lymphatic cell marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and as validation marker we used podoplanin (PDPN). Results The study included 30 iNPH patients who underwent shunt surgery. The dura specimens were obtained average 16.1 ± 4.5 mm lateral to the superior sagittal sinus in the right frontal region (about 12 cm posterior to glabella). While lymphatic structures were seen in 0/7 patients using Method #1, it was found in 4/6 subjects (67%) with Method #2, while in 16/17 subjects (94%) using Method #3. To this end, we characterized three types of meningeal lymphatic vessels: (1) Lymphatic vessels in intimate contact with blood vessels. (2) Lymphatic vessels without nearby blood vessels. (3) Clusters of LYVE-1-expressing cells interspersed with blood vessels. In general, highest density of lymphatic vessels were observed towards the arachnoid membrane rather than towards the skull. Conclusions The visualization of meningeal lymphatic vessels in humans seems to be highly sensitive to the tissue processing method. Our observations disclosed most abundant lymphatic vessels towards the arachnoid membrane, and were seen either in close association with blood vessels or remote from blood vessels.

• Lashkarivand, Aslan & Eide, Per Kristian (2023). Brain Sagging Dementia. Current Neurology and Neuroscience Reports. ISSN 1528-4042. 23(10), s. 593–605. doi: 10.1007/s11910-023-01297-9. Fulltekst i vitenarkiv Vis sammendrag

  Purpose of Review Brain sagging dementia (BSD) is a rare but devastating form of early-onset dementia characterized by intracranial hypotension and behavioral changes resembling behavioral variant frontotemporal dementia. This review aims to provide a comprehensive overview of BSD, highlighting its pathomechanism, diagnostic tools, and available treatment options. Recent Findings BSD exhibits a complex clinical manifestation with insidious onset and gradual progression of behavioral disinhibition, apathy, inertia, and speech alterations. Additionally, patients may exhibit brainstem and cerebellar signs such as hypersomnolence and gait disturbance. Although headaches are common, they may not always demonstrate typical orthostatic features. Recent radiological advances have improved the detection of CSF leaks, enabling targeted treatment and favorable outcomes. Summary Understanding the pathomechanism and available diagnostic tools for BSD is crucial for a systematic approach to timely diagnosis and treatment of this reversible form of early-onset dementia, as patients often endure a complex and lengthy clinical course.

• Ringstad, Geir; Valnes, Lars Magnus; Vatnehol, Svein Are Sirirud; Pripp, Are Hugo & Eide, Per Kristian (2023). Prospective T1 mapping to assess gadolinium retention in brain after intrathecal gadobutrol. Neuroradiology. ISSN 0028-3940. 65(9), s. 1321–1331. doi: 10.1007/s00234-023-03198-7. Fulltekst i vitenarkiv Vis sammendrag

  Purpose A possible pathway behind gadolinium retention in brain is leakage of contrast agents from blood to cerebrospi- nal fluid and entry into brain along perivascular (glymphatic) pathways. The object of this study was to assess for signs of gadolinium retention in brain 4 weeks after intrathecal contrast enhanced MRI. Methods We prospectively applied standardized T1 mapping of the brain before and 4 weeks after intrathecal administration of 0.5 mmol gadobutrol in patients under work-up of cerebrospinal fluid circulation disorders. Due to methodological limita- tions, a safety margin for percentage change in T1 time was set to 3%. Region-wise differences were assessed by pairwise comparison using t-tests and forest plots, and statistical significance was accepted at .05 level (two-tailed). Results In a cohort of 76 participants (mean age 47.2 years ± 17.9 [standard deviation], 47 women), T1 relaxation times remained unchanged in cerebral cortex and basal ganglia 4 weeks after intrathecal gadobutrol. T1 was reduced from 1082 ± 46.7 ms to 1070.6 ± 36.5 ms (0.98 ±2.9%) (mean [standard deviation]) (p=0.001) in white matter, thus within the pre- defined 3% safety margin. The brain stem and cerebellum could not be assessed due to poor alignment of posterior fossa structures at scans from different time points. Conclusion Gadolinium retention was not detected in the cerebral hemispheres 4 weeks after an intrathecal dose of 0.5 mmol gadobutrol, implying that presence of contrast agents in cerebrospinal fluid is of minor importance for gadolinium retention in brain.

• Jacobsen, Henrik Holvin; Jørstad, Øystein Kalsnes; Moe, Morten Carsten; Petrovski, Goran; Pripp, Are Hugo & Sandell, Tiril [Vis alle 7 forfattere av denne artikkelen] (2022). Noninvasive Estimation of Pulsatile and Static Intracranial Pressure by Optical Coherence Tomography. Translational Vision Science & Technology. 11. doi: 10.1167/tvst.11.1.31. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: To explore the ability of optical coherence tomography (OCT) to noninvasively estimate pulsatile and static intracranial pressure (ICP). Methods: An OCT examination was performed in patients who underwent continuous overnight monitoring of the pulsatile and static ICP for diagnostic purpose. We included two patient groups, patients with idiopathic intracranial hypertension (IIH; n = 20) and patients with no verified cerebrospinal fluid disturbances (reference; n = 12). Several OCT parameters were acquired using spectral-domain OCT (RS-3000 Advance; NIDEK, Singapore). The ICP measurements were obtained using a parenchymal sensor (Codman ICP MicroSensor; Johnson & Johnson, Raynham, MA, USA). The pulsatile ICP was determined as the mean ICP wave amplitude (MWA), and the static ICP was determined as the mean ICP. Results: The peripapillary Bruch's membrane angle (pBA) and the optic nerve head height (ONHH) differed between the IIH and reference groups and correlated with both MWA and mean ICP. Both OCT parameters predicted elevated MWA. Area under the curve and cutoffs were 0.82 (95% confidence interval [CI], 0.66–0.98) and -0.65° (sensitivity/specificity; 0.75/0.92) for pBA and 0.84 (95% CI, 0.70–0.99) and 405 µm (0.88/0.67) for ONHH. Adjusting for age and body mass index resulted in nonsignificant predictive values for mean ICP, whereas the predictive value for MWA remained significant. Conclusions: This study provides evidence that the OCT parameters pBA and ONHH noninvasively can predict elevated pulsatile ICP, represented by the MWA. Translational Relevance: OCT shows promise as a method for noninvasive estimation of ICP.

• Aukrust, Camilla Grøver; Paulsen, Anne Henriette; Uche, Enoch Ogbonnaya; Kamalo, Patrick Dongosolo; Sandven, Irene & Fjeld, Heidi E [Vis alle 8 forfattere av denne artikkelen] (2022). Aetiology and diagnostics of paediatric hydrocephalus across Africa: a systematic review and meta-analysis. The Lancet Global Health. ISSN 2572-116X. 10(12), s. e1793–e1806. doi: 10.1016/S2214-109X(22)00430-2. Fulltekst i vitenarkiv Vis sammendrag

  Background We aimed to identify the aetiological distribution and the diagnostic methods for paediatric hydrocephalus across Africa, for which there is currently scarce evidence. Methods In this systematic review and meta-analysis, we searched MEDLINE (Ovid), the Cochrane Database of Systematic Reviews (Wiley), Embase (Ovid), Global Health (Ovid), Maternity & Infant Care (Ovid), Scopus, African Index Medicus (Global Index Medicus, WHO) and Africa-Wide Information (EBSCO) from inception to Nov 29, 2021. We included studies from any African country reporting on the distribution of hydrocephalus aetiology in children aged 18 years and younger, with no language restrictions. Hydrocephalus was defined as radiological evidence of ventriculomegaly or associated clinical symptoms and signs of the disorder, or surgical treatment for hydrocephalus. Exclusion criteria were studies only reporting on one specific subgroup or one specific cause of hydrocephalus. We also excluded conference and meetings abstracts, grey literature, editorials, commentaries, historical reviews, systematic reviews, case reports and clinical guidelines, as well as studies on non-humans, fetuses, or post-mortem reports. The proportions of postinfectious hydrocephalus, non-postinfectious hydrocephalus, and hydrocephalus related to spinal dysraphism were calculated using a random-effects model. Additionally, we included a category for unclear cases. Diagnostic methods were described qualitatively. To assess methodological study quality, we applied critical appraisal checklists provided by the Joanna Briggs Institute. The study was registered in Prospero (CRD42020219038). Findings Our search yielded 3783 results, of which 1880 (49·7%) were duplicates and were removed. The remaining 1903 abstracts were screened and 122 (6·4%) full articles were sought for retrieval; of these, we included 38 studies from 18 African countries that studied a total of 6565 children. The pooled proportion of postinfectious hydrocephalus was 28% (95% CI 22–36), non-postinfectious hydrocephalus was 21% (95% CI 13–30), and of spinal dysraphism was 16% (95% CI 12–20), with substantial heterogeneity. The pooled proportion of hydrocephalus of unclear aetiology was 20% (95% CI 13–28). Interpretation Our findings suggest that postinfectious hydrocephalus is the single most common cause of paediatric hydrocephalus in Africa. For targeted investments to be optimal, there is a need for consensus regarding the aetiological classification of hydrocephalus and improved access to diagnostic services.

• Thavarajasingam, Santhosh G.; El-Khatib, Mahmoud; Vemulapalli, Kalyan V.; Iradukunda, Hector A. Sinzinkayo; Laleye, Joshua & Russo, Salvatore [Vis alle 8 forfattere av denne artikkelen] (2022). Cerebrospinal fluid and venous biomarkers of shunt-responsive idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis. Acta Neurochirurgica. ISSN 0001-6268. 164, s. 1719–1746. doi: 10.1007/s00701-022-05154-5. Fulltekst i vitenarkiv Vis sammendrag

  Background Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH. Objective To conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately. Methods Original studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses. Results The study included 13 studies; seven addressed lumbar CSF levels of amyloid-β 1–42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-β 1–42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (− 0.55 SMD, p = 0.04) and Total-Tau (− 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-β 1–42 (− 0.26 SMD, p = 0.55) or the other included biomarkers. Conclusion This meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-β 1–42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.

• Lashkarivand, Aslan & Eide, Per Kristian (2022). Brain Sagging Dementia-Diagnosis, Treatment, and Outcome: A Review. Neurology. ISSN 0028-3878. 98(19), s. 798–805. doi: 10.1212/WNL.0000000000200511. Fulltekst i vitenarkiv
• Eide, Per Kristian (2022). Cellular changes at the glia-neuro-vascular interface in definite idiopathic normal pressure hydrocephalus. Frontiers in Cellular Neuroscience. 16. doi: 10.3389/fncel.2022.981399. Fulltekst i vitenarkiv Vis sammendrag

  Idiopathic normal pressure hydrocephalus (iNPH) is a subtype of dementia with overlap toward Alzheimer's disease. Both diseases show deposition of the toxic metabolites amyloid-β and tau in brain. A unique feature with iNPH is that a subset of patients may improve clinically following cerebrospinal fluid (CSF) diversion (shunt) surgery. The patients responding clinically to shunting are denoted Definite iNPH, otherwise iNPH is diagnosed as Possible iNPH or Probable iNPH, high-lightening that the clinical phenotype and underlying pathophysiology remain debated. Given the role of CSF disturbance in iNPH, the water channel aquaporin-4 (AQP4) has been suggested a crucial role in iNPH. Altered expression of AQP4 at the astrocytic endfeet facing the capillaries could affect glymphatic function, i.e., the perivascular transport of fluids and solutes, including soluble amyloid-β and tau. This present study asked how altered perivascular expression of AQP4 in subjects with definite iNPH is accompanied with cellular changes at the glia-neuro-vascular interface. For this purpose, information was retrieved from a database established by the author, including prospectively collected management data, physiological data and information from brain biopsy specimens examined with light and electron microscopy. Individuals with definite iNPH were included together with control subjects who matched the definite iNPH cohort closest in gender and age. Patients with definite iNPH presented with abnormally elevated pulsatile intracranial pressure measured overnight. Cortical brain biopsies showed reduced expression of AQP4 at astrocytic endfeet both perivascular and toward neuropil. This was accompanied with reduced expression of the anchor molecule dystrophin (Dp71) at astrocytic perivascular endfeet, evidence of altered cellular metabolic activity in astrocytic endfoot processes (reduced number of normal and increased number of pathological mitochondria), and evidence of reactive changes in astrocytes (astrogliosis). Moreover, the definite iNPH subjects demonstrated in cerebral cortex changes in capillaries (reduced thickness of the basement membrane between astrocytic endfeet and endothelial cells and pericytes, and evidence of impaired blood-brain-barrier integrity). Abnormal changes in neurons were indicated by reduced post-synaptic density length, and reduced number of normal mitochondria in pre-synaptic terminals. In summary, definite iNPH is characterized by profound cellular changes at the glia-neurovascular interface, which probably reflect the underlying pathophysiology.

• Eide, Per Kristian; Lashkarivand, Aslan; Hagen-Kersten, Åsmund Aleksander; Gjertsen, Øivind; Nedregaard, Bård & Sletteberg, Ruth [Vis alle 11 forfattere av denne artikkelen] (2022). Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus. Frontiers in Neurology. 13, s. 1–21. doi: 10.3389/fneur.2022.857328. Fulltekst i vitenarkiv Vis sammendrag

  Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.

• Hornkjøl, Martin; Valnes, Lars Magnus; Ringstad, Geir; Rognes, Marie Elisabeth; Eide, Per Kristian & Mardal, Kent-Andre [Vis alle 7 forfattere av denne artikkelen] (2022). CSF circulation and dispersion yield rapid clearance from intracranial compartments. Frontiers in Bioengineering and Biotechnology. 10, s. 1–14. doi: 10.3389/fbioe.2022.932469. Fulltekst i vitenarkiv Vis sammendrag

  In this paper, we used a computational model to estimate the clearance of a tracer driven by the circulation of cerebrospinal fluid (CSF) produced in the choroid plexus (CP) located within the lateral ventricles. CSF was assumed to exit the subarachnoid space (SAS) via different outflow routes such as the parasagittal dura, cribriform plate, and/or meningeal lymphatics. We also modelled a reverse case where fluid was produced within the spinal canal and absorbed in the choroid plexus in line with observations on certain iNPH patients. No directional interstitial fluid flow was assumed within the brain parenchyma. Tracers were injected into the foramen magnum. The models demonstrate that convection in the subarachnoid space yields rapid clearance from both the SAS and the brain interstitial fluid and can speed up intracranial clearance from years, as would be the case for purely diffusive transport, to days.

• Zapf, Bastian; Haubner, Johannes; Kuchta, Miroslav; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2022). Investigating molecular transport in the human brain from MRI with physics-informed neural networks. Scientific Reports. 12. doi: 10.1038/s41598-022-19157-w. Fulltekst i vitenarkiv Vis sammendrag

  In recent years, a plethora of methods combining neural networks and partial differential equations have been developed. A widely known example are physics-informed neural networks, which solve problems involving partial differential equations by training a neural network. We apply physics-informed neural networks and the finite element method to estimate the diffusion coefficient governing the long term spread of molecules in the human brain from magnetic resonance images. Synthetic testcases are created to demonstrate that the standard formulation of the physics-informed neural network faces challenges with noisy measurements in our application. Our numerical results demonstrate that the residual of the partial differential equation after training needs to be small for accurate parameter recovery. To achieve this, we tune the weights and the norms used in the loss function and use residual based adaptive refinement of training points. We find that the diffusion coefficient estimated from magnetic resonance images with physics-informed neural networks becomes consistent with results from a finite element based approach when the residuum after training becomes small. The observations presented here are an important first step towards solving inverse problems on cohorts of patients in a semi-automated fashion with physics-informed neural networks.

• Eide, Per Kristian; Sorteberg, Angelika; Nome, Terje; Rønning, Pål Andre & Sorteberg, Wilhelm (2022). Early surgical versus endovascular repair of ruptured blood-blister aneurysm of the internal carotid artery: a single-center 20-year experience. Journal of Neurosurgery. ISSN 0022-3085. 137(6), s. 1766–1775. doi: 10.3171/2022.3.JNS2216. Fulltekst i vitenarkiv Vis sammendrag

  OBJECTIVE Early repair of ruptured blood-blister aneurysms (BBAs) of the internal carotid artery (ICA) remains challenging. Although both surgical and endovascular therapies have been established, their relative superiority remains debated. The authors assessed their single-center experience and compared early deconstructive versus reconstructive repair and early reconstructive surgical versus endovascular repair of ruptured BBAs of the ICA. METHODS The study included patients who underwent repair of ruptured BBAs of the ICA within 1 week after the ictus during a 20-year period. Multiple variables were recorded, including clinical state, severity of subarachnoid hemorrhage (SAH), characteristics of the BBA, treatment details, complication profile, need for secondary treatment, and clinical outcome. RESULTS In total, 27 patients underwent early surgical (n = 16) or endovascular (n = 11) repair of BBAs at a median of 24 hours (range 9–120 hours) after the ictus during the period from September 2000 to June 2021 (20.4 years). Primary deconstructive repair (n = 6) without bypass was accompanied by middle cerebral artery (MCA) territory infarction in 5 of 6 (83%) patients and a high mortality rate (4/6 [67%]). Among the 21 patients who underwent early reconstructive repair, surgery was performed in 11 patients (clipping in 6 and clip-wrapping in 5 patients) and endovascular repair in 10 patients (flow diversion in 7 and stent/stent-assisted coiling in 3 patients). No differences were found in complication profiles or clinical outcomes between the surgical and endovascular groups. The mortality rate was low (2/21 [9.5%]), with 1 fatality in each group. CONCLUSIONS From the authors’ experience, both surgical and endovascular approaches permitted reconstructive repair of ruptured BBAs of the ICA, with no modality proving superior. Reconstructive treatment is preferable to ICA sacrifice, and if sacrifice is chosen, it should be accompanied with bypass surgery or delayed to the phase when cerebral vasospasm has resumed. The rare occurrence of this disease calls for prospective multicenter studies to improve treatment and delineate which modality is preferable in individual cases.

• Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege & Ringstad, Geir [Vis alle 7 forfattere av denne artikkelen] (2022). Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders. Fluids and Barriers of the CNS. 19(1). doi: 10.1186/s12987-022-00352-w. Fulltekst i vitenarkiv Vis sammendrag

  Background Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. Methods Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. Results Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. Conclusions The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.

• Eide, Per Kristian; Pripp, Are Hugo; Berge, Benedikte; Hrubos-Strøm, Harald; Ringstad, Geir & Valnes, Lars Magnus (2022). Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 42(9), s. 1676–1692. doi: 10.1177/0271678X221090747. Fulltekst i vitenarkiv Vis sammendrag

  Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.

• Eide, Per Kristian & Hansson, Hans-Arne (2022). A New Perspective on the Pathophysiology of Idiopathic Intracranial Hypertension: Role of the Glia-Neuro-Vascular Interface. Frontiers in Molecular Neuroscience. 15. doi: 10.3389/fnmol.2022.900057. Fulltekst i vitenarkiv Vis sammendrag

  Idiopathic intracranial hypertension (IIH) is a neurological disease characterized by symptoms and signs of increased intracranial pressure (ICP) of unknown cause. Most attention has been given to the role of cerebrospinal fluid (CSF) disturbance and intracranial venous hypertension caused by sinus vein stenosis. We previously proposed that key pathophysiological processes take place within the brain at the glia-neuro-vascular interface. However, the relative importance of the proposed mechanisms in IIH disease remains unknown. Modern treatment regimens aim to reduce intracranial CSF and venous pressures, but a substantial proportion of patients experience lasting complaints. In 2010, the first author established a database for the prospective collection of information from individuals being assessed for IIH. The database incorporates clinical, imaging, physiological, and biological data, and information about treatment/outcome. This study retrieved information from the database, asking the following research questions: In IIH subjects responding to shunt surgery, what is the occurrence of signs of CSF disturbance, sinus vein stenosis, intracranial hypertension, and microscopic evidence of structural abnormalities at the glia-neuro-vascular interface? Secondarily, do semi-quantitative measures of abnormal ultrastructure at the glia-neurovascular differ between subjects with definite IIH and non-IIH (reference) subjects? The study included 13 patients with IIH who fulfilled the diagnostic criteria and who improved following shunt surgery, i.e., patients with definite IIH. Comparisons were done regarding magnetic resonance imaging (MRI) findings, pulsatile and static ICP scores, and immune-histochemistry microscopy. Among these 13 IIH subjects, 6/13 (46%) of patients presented with magnetic resonance imaging (MRI) signs of CSF disturbance (empty sella and/or distended perioptic subarachnoid spaces), 0/13 (0%) of patients with IIH had MRI signs of sinus vein stenosis, 13/13 (100%) of patients with IIH presented with abnormal preoperative pulsatile ICP [overnight mean ICP wave amplitude (MWA) above thresholds], 3/13 (23%) patients showed abnormal static ICP (overnight mean ICP above threshold), and 12/13 (92%) of patients with IIH showed abnormal structural changes at the glia-neuro-vascular interface. Comparisons of semi-quantitative structural variables between IIH and aged- and gender-matched reference (REF) subjects showed IIH abnormalities in glial cells, neurons, and capillaries. The present data suggest a key role of disease processes affecting the glia-neuro-vascular interface.

• Frič, Radek; Langvatn, Erlend Aambø; Due-Tønnessen, Bernt Johan & Eide, Per Kristian (2021). The role of pulsatile and static intracranial pressure measurements in the management of children with craniosynostosis–an institutional experience from 49 patients. Acta Neurochirurgica. ISSN 0001-6268. 163(7), s. 2015–2023. doi: 10.1007/s00701-020-04680-4. Fulltekst i vitenarkiv
• Rostalski, Hannah; Korhonen, Ville; Kuulasmaa, Teemu; Solje, Eino; Krüger, Johanna & Kaivola, Karri [Vis alle 14 forfattere av denne artikkelen] (2021). A Novel Genetic Marker for the C9orf72 Repeat Expansion in the Finnish Population. Journal of Alzheimer's Disease. ISSN 1387-2877. 83(3), s. 1325–1332. doi: 10.3233/JAD-210599. Fulltekst i vitenarkiv Vis sammendrag

  Background: C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exp requires elaborative methods. Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp. Methods: We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15–30) and full-length (&gt; 60 repeats) C9exp carriers (n = 41) to C9exp negative patients (&lt; 15 repeats, n = 801). Results: In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p &lt; 2×10–15), while the strongest association was found with rs139185008 (OR 39.4, p &lt; 5×10–18). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3×10–15) and motor neuron disease ALS (OR 5.19, 3×10–21). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p = 9.0×10–8). Conclusion: Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland.

• Eide, Per Kristian; Pripp, Are Hugo; Ringstad, Geir & Valnes, Lars Magnus (2021). Impaired glymphatic function in idiopathic intracranial hypertension. Brain Communications. 3:fcab043(2), s. 1–14. doi: 10.1093/braincomms/fcab043. Fulltekst i vitenarkiv Vis sammendrag

  Idiopathic intracranial hypertension is a brain disease incorporating cerebrospinal fluid disturbance, increased intracranial pressure and visual failure, but with unknown cause. This study examined a hypothesis that glymphatic function is impaired in idiopathic intracranial hypertension patients. The MRI contrast agent gadobutrol was utilized as a cerebrospinal fluid tracer following intrathecal administration. Consecutive standardized T1 MRI acquisitions over 48 h were done to assess tracer distribution within brain of 15 idiopathic intracranial hypertension patients and 15 reference individuals who were comparable in age and gender distribution. Using FreeSurfer software, we semi-quantified tracer level in multiple brain regions as T1 MRI signal change. The tracer enriched the entire brain of idiopathic intracranial hypertension and reference subjects. In idiopathic intracranial hypertension, tracer enrichment was increased and clearance of tracer delayed from a wide range of brain regions, including both grey and white matter. Differences were most evident in frontal and temporal regions. The pulsatile intracranial pressure was measured overnight and tracer propagation in brain compared between individuals with pathological and normal pulsatile intracranial pressure. In individuals with pathological pulsatile intracranial pressure, tracer enrichment was stronger and clearance from brain delayed, particularly in regions nearby large artery trunks at the brain surface. The present in vivo observations provide evidence for impaired glymphatic function in several brain regions of idiopathic intracranial hypertension patients. Glymphatic failure may imply altered clearance of metabolic byproducts, which may precede neurodegeneration. Further studies are needed to characterize glymphatic failure in idiopathic intracranial hypertension.

• Mannerak, Mari Aaroe; Lashkarivand, Aslan & Eide, Per Kristian (2021). Trigeminal neuralgia and genetics: A systematic review. Molecular Pain. 17. doi: 10.1177/17448069211016139. Fulltekst i vitenarkiv Vis sammendrag

  Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1–2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.

• Sorteberg, Wilhelm; Sorteberg, Angelika; Jacobsen, Eva Astrid; RØNNING, PÅL ANDRE; Nome, Terje & Eide, Per Kristian (2021). Endovascular versus surgical treatment of cranial dural arteriovenous fistulas: a single-center 8-year experience. Acta Neurochirurgica. ISSN 0001-6268. 164(1), s. 151–161. doi: 10.1007/s00701-021-04950-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Cranial dural arteriovenous fistulas (dAVFs) are rare lesions managed mainly with endovascular treatment (EVT) and/or surgery. We hypothesize that there may be subtypes of dAVFs responding better to a specific treatment modality in terms of successful obliteration and cessation of symptoms and/or risks. Methods All dAVFs treated during 2011–2018 at our hospital were analyzed retrospectively. Presenting symptoms, radiological variables, treatment modality, complications, and residual symptoms were related to dAVF type using the original Djindjian classification. Results We treated 112 dAVFs in 107 patients (71, 66% males). They presented with hemorrhage (n = 23; 21%), non-hemorrhagic symptoms (n = 75; 70%), or were discovered incidentally (n = 9; 8%). There were 25 (22%) type I, 29 (26%) type II, 26 (23%) type III, and 32 (29%) type IV fistulas. EVT was the primary treatment modality in 72/112 (64%) dAVFs whereas 40/112 (36%) underwent primary surgery with angiographic obliteration rates of 60% and 90%, respectively. Using a secondary treatment modality in 23 dAVFs, we obtained a final obliteration rate of 93%, including all type III/IV and 26/27 (96%) type II dAVFs. Except for headache, residual symptoms were rare and minor. Permanent neurological complications consisted of five cranial nerve deficits. Conclusions We recommend EVT as first treatment modality in types I, II, and in non-hemorrhagic type III/IV dAVFs. We recommend surgery as first treatment choice in acute hemorrhagic dAVFs and as secondary choice in type III/IV dAVFs not successfully occluded by EVT. Combining the two modalities provides obliteration in 9/10 dAVF cases at a low procedural risk.

• Masina, Riccardo; Ansaripour, Ali; Beneš, Vladimír; Berhouma, Moncef; Choque-Velasquez, Joham & Eide, Per Kristian [Vis alle 18 forfattere av denne artikkelen] (2021). Surgical treatment of symptomatic pineal cysts without hydrocephalus—meta-analysis of the published literature. Acta Neurochirurgica. ISSN 0001-6268. 164(1), s. 61–77. doi: 10.1007/s00701-021-05054-0. Fulltekst i vitenarkiv Vis sammendrag

  Background To examine published data and assess evidence relating to safety and efficacy of surgical management of symptomatic pineal cysts without hydrocephalus (nhSPC), we performed a systematic review of the literature and meta-analysis. Methods Following the PRISMA guidelines, we searched Pubmed and SCOPUS for all reports with the query ‘Pineal Cyst’ AND ‘Surgery’ as of March 2021, without constraints on study design, publication year or status (PROSPERO_CRD:42,021,242,517). Assessment of 1537 hits identified 26 reports that met inclusion and exclusion criteria. Results All 26 input studies were either case reports or single-centre retrospective cohorts. The majority of outcome data were derived from routine physician-recorded notes. A total of 294 patients with surgically managed nhSPC were identified. Demographics: Mean age was 29 (range: 4–63) with 77% females. Mean cyst size was 15 mm (5–35). Supracerebellar-infratentorial approach was adopted in 90% of cases, occipital-transtentorial in 9%, and was not reported in 1%. Most patients were managed by cyst resection (96%), and the remainder by fenestration. Mean post-operative follow-up was 35 months (0–228). Presentation: Headache was the commonest symptom (87%), followed by visual (54%), nausea/vomit (34%) and vertigo/dizziness (31%). Other symptoms included focal neurology (25%), sleep disturbance (17%), cognitive impairment (16%), loss of consciousness (11%), gait disturbance (11%), fatigue (10%), ‘psychiatric’ (2%) and seizures (1%). Mean number of symptoms reported at presentation was 3 (0–9). Outcomes: Improvement rate was 93% (to minimise reporting bias only consecutive cases from cohort studies were considered, N = 280) and was independent of presentation. Predictors of better outcomes were large cyst size (OR = 5.76; 95% CI: 1.74–19.02) and resection over fenestration (OR = 12.64; 3.07–52.01). Age predicted worse outcomes (OR = 0.95; 0.91–0.99). Overall complication rate was 17% and this was independent of any patient characteristics. Complications with long-term consequences occurred in 10 cases (3.6%): visual disturbance (3), chronic incisional pain (2), sensory disturbance (1), fatigue (1), cervicalgia (1), cerebellar stroke (1) and mortality due to myocardial infarction (1). Conclusions Although the results support the role of surgery in the management of nhSPCs, they have to be interpreted with a great deal of caution as the current evidence is limited, consisting only of case reports and retrospective surgical series. Inherent to such studies are inhomogeneity and incompleteness of data, selection bias and bias related to assessment of outcome carried out by the treating surgeon in the majority of cases. Prospective studies with patient-reported and objective outcome assessment are needed to provide higher level of evidence.

• Eide, Per Kristian & Ringstad, Geir (2021). Cerebrospinal fluid egress to human parasagittal dura and the impact of sleep deprivation. Brain Research. ISSN 0006-8993. 1772. doi: 10.1016/j.brainres.2021.147669. Fulltekst i vitenarkiv Vis sammendrag

  Emerging evidence suggests that the glymphatic system and meningeal lymphatic vessels are instrumental for clearance of toxic metabolites from the brain. Animal and human studies suggest that glymphatic circulation is up-regulated during sleep. Meningeal lymphatic clearance may be more efficient in the wake state, as shown in rodents. We have previously shown clearance of cerebrospinal fluid directly from the subarachnoid space to the parasagittal dura, which harbors meningeal lymphatic vessels. Hence, assessing molecular clearance from parasagittal dura provides an opportunity to decipher the role of sleep/sleep deprivation in human lymphatic clearance function. In this study, we applied magnetic resonance imaging to explore whether sleep deprivation modifies molecular clearance from human parasagittal dura, utilizing an intrathecal magnetic resonance imaging contrast agent as tracer. We hypothesized that tracer enhancement in parasagittal dura would differ after sleep deprivation. One group of individuals (n = 7) underwent one night’s total sleep deprivation while a control group (n = 9) was allowed unrestricted sleep. There were no sleep restrictions after the 24-hour time point. After one night of sleep deprivation (at 24 h), we found neither evidence for altered tracer enrichment in the parasagittal dura, nor after a day of unrestricted sleep (at 48 h). The hypothesis of altered molecular egress to parasagittal dura after sleep deprivation was not supported by our data. Further studies are required to determine the role of sleep for molecular clearance from cerebrospinal fluid to meningeal lymphatic vessels in humans.

• Eide, Per Kristian (2021). Abnormal intracranial pulse pressure amplitude despite normalized static intracranial pressure in idiopathic intracranial hypertension refractory to conservative medical therapy. Life. 11(6). doi: 10.3390/life11060537. Fulltekst i vitenarkiv Vis sammendrag

  Idiopathic intracranial hypertension (IIH) incorporates symptoms and signs of increased intracranial pressure (ICP) and is diagnosed by increased lumbar cerebrospinal fluid pressure. However, our knowledge about the characteristics of ICP abnormality, e.g., changes in pulsatile versus static ICP, remains scarce. This study questioned how overnight pulsatile ICP (mean ICP wave amplitude, MWA) associates with static ICP (mean ICP) in IIH patients who were refractory to conservative medical treatment. The material included 80 consecutive IIH patients undergoing ICP monitoring prior to shunt, as part of work-up for failed conservative medical therapy. In this group, the overnight mean ICP was normalized in 52/80 patients, but with abnormal overnight MWA in 45 of the 52 patients. Even though there was a positive correlation between MWA and mean ICP at group level and within individual ICP recordings, the levels of MWA were abnormal in a high proportion of patients despite normalized mean ICP. Taken together, the present results disclosed lasting abnormal pulsatile ICP despite normalized static ICP in IIH patients refractory to conservative medical therapy, which may reflect the underlying pathophysiology. It is tentatively suggested that abnormal pulsatile ICP in IIH may reflect alterations at the glia–neurovascular interface, resulting in impaired astrocytic pulsation absorber mechanisms.

• Eide, Per Kristian; Mariussen, Espen; Uggerud, Hilde Thelle; Pripp, Are Hugo; Lashkarivand, Aslan & Hassel, Bjørnar [Vis alle 9 forfattere av denne artikkelen] (2021). Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood. JCI Insight. 6(9), s. 1–13. doi: 10.1172/jci.insight.147063. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND. Methodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances. METHODS. The MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours. RESULTS. In a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4). CONCLUSION. Assessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity. FUNDING. The work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

• Eide, Per Kristian; Vinje, Vegard; Pripp, Are Hugo; Mardal, Kent-Andre & Ringstad, Geir (2021). Sleep deprivation impairs molecular clearance from the human brain. Brain. ISSN 0006-8950. 144(3), s. 863–874. doi: 10.1093/brain/awaa443. Fulltekst i vitenarkiv
• Eide, Per Kristian; Valnes, Lars Magnus; Lindstrøm, Erika Kristina; Mardal, Kent-Andre & Ringstad, Geir (2021). Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases. Fluids and Barriers of the CNS. 18(1). doi: 10.1186/s12987-021-00251-6. Fulltekst i vitenarkiv Vis sammendrag

  Background Several central nervous system diseases are associated with disturbed cerebrospinal fluid (CSF) flow patterns and have typically been characterized in vivo by phase-contrast magnetic resonance imaging (MRI). This technique is, however, limited by its applicability in space and time. Phase-contrast MRI has yet to be compared directly with CSF tracer enhanced imaging, which can be considered gold standard for assessing long-term CSF flow dynamics within the intracranial compartment. Methods Here, we studied patients with various CSF disorders and compared MRI biomarkers of CSF space anatomy and phase-contrast MRI at level of the aqueduct and cranio-cervical junction with dynamic intrathecal contrast-enhanced MRI using the contrast agent gadobutrol as CSF tracer. Tracer enrichment of cerebral ventricles was graded 0–4 by visual assessment. An intracranial pressure (ICP) score was used as surrogate marker of intracranial compliance. Results The study included 94 patients and disclosed marked variation of CSF flow measures across disease categories. The grade of supra-aqueductal reflux of tracer varied, with strong reflux (grades 3–4) in half of patients. Ventricular tracer reflux correlated with stroke volume and aqueductal CSF pressure gradient. CSF flow in the cerebral aqueduct was retrograde (from 4th to 3rd ventricle) in one third of patients, with estimated CSF net flow volume about 1.0 L/24 h. In the cranio-cervical junction, net flow was cranially directed in 78% patients, with estimated CSF net flow volume about 4.7 L/24 h. Conclusions The present observations provide in vivo quantitative evidence for substantial variation in direction and magnitude of CSF flow, with re-direction of aqueductal flow in communicating hydrocephalus, and significant extra-cranial CSF production. The grading of ventricular reflux of tracer shows promise as a clinical useful method to assess CSF flow pattern disturbances in patients.

• Ringstad, Geir & Eide, Per Kristian (2021). Molecular trans-dural efflux to skull bone marrow in humans with CSF disorders. Brain. ISSN 0006-8950. 145(4), s. 1464–1472. doi: 10.1093/brain/awab388. Fulltekst i vitenarkiv Vis sammendrag

  Dural sinuses were recently identified as a hub for peripheral immune surveillance of brain-derived antigens cleared through CSF. However, animal studies have also indicated that substances and cells may enter the intracranial compartment directly from bone marrow. We used MRI and a CSF tracer to investigate in vivo whether intracranial molecules can move via dura to skull bone marrow in patients with suspicion of CSF disorders. Tracer enrichment in CSF, dural regions and within skull bone marrow was assessed up to 48 h after intrathecal administration of gadobutrol (0.5 ml, 1 mmol/ml) in 53 patients. In participants diagnosed with disease, tracer enrichment within diploe of skull bone marrow was demonstrated nearby the parasagittal dura, nearby extensions of parasagittal dura into diploe, and in diploe of skull bone remote from the dura extensions. This crossing of meningeal and skull barriers suggests that bone marrow may contribute in brain immune surveillance also in humans.

• Eide, Per Kristian (2021). Familial occurrence of classical and idiopathic trigeminal neuralgia. Journal of the Neurological Sciences. ISSN 0022-510X. 434. doi: 10.1016/j.jns.2021.120101. Fulltekst i vitenarkiv Vis sammendrag

  Trigeminal neuralgia (TN) is a severe facial pain disease with unknown pathogenesis. It has been thought that the familial form of TN is rare with a prevalence of about 1–2% among affected individuals, but emerging evidence suggests a role of genetic factors. This study examined the occurrence of familial TN among patients with classical or idiopathic TN. Patients with TN recruited from a hospital registry received an informed consent form with a questionnaire, and individuals reporting other family members with TN underwent a structured phone-interview. For affected family members, type of TN, available clinical, imaging, management results and available hospital patient records were studied. Pedigrees for all affected families were established. This study included 268 patients with either classical or idiopathic TN. The familial form of TN was present in 41/268 (15.3%) patients, that is, 37/244 (15.2%) patients with classical TN and in 4/24 (16.7%) with idiopathic TN. Total 38 families were identified, with two affected members in 32/38 families (84.2%), three affected family members in 5/38 (13.2%) and four family members in 1/38 (2.6%) families. Comparing the 41 familial TN cases with the 227 sporadic TN patients showed significantly earlier onset of TN and a significantly higher occurrence of right-sided pain in familial cases, while there was no difference in gender distribution, occurrence of arterial hypertension or trigeminal branch involved. Among patients with classical or idiopathic TN, the occurrence of the familial form of the disease is more frequent than traditionally assume

• Khan, Haroon; Naseer, Noman; Yazidi, Anis; Eide, Per Kristian; Hassan, Wajahat & Mirtaheri, Peyman (2021). Analysis of Human Gait Using Hybrid EEG-fNIRS-Based BCI System: A Review. Frontiers in Human Neuroscience. 14, s. 1–29. doi: 10.3389/fnhum.2020.613254. Fulltekst i vitenarkiv Vis sammendrag

  Human gait is a complex activity that requires high coordination between the central nervous system, the limb, and the musculoskeletal system. More research is needed to understand the latter coordination's complexity in designing better and more effective rehabilitation strategies for gait disorders. Electroencephalogram (EEG) and functional near-infrared spectroscopy (fNIRS) are among the most used technologies for monitoring brain activities due to portability, non-invasiveness, and relatively low cost compared to others. Fusing EEG and fNIRS is a well-known and established methodology proven to enhance brain–computer interface (BCI) performance in terms of classification accuracy, number of control commands, and response time. Although there has been significant research exploring hybrid BCI (hBCI) involving both EEG and fNIRS for different types of tasks and human activities, human gait remains still underinvestigated. In this article, we aim to shed light on the recent development in the analysis of human gait using a hybrid EEG-fNIRS-based BCI system. The current review has followed guidelines of preferred reporting items for systematic reviews and meta-Analyses (PRISMA) during the data collection and selection phase. In this review, we put a particular focus on the commonly used signal processing and machine learning algorithms, as well as survey the potential applications of gait analysis. We distill some of the critical findings of this survey as follows. First, hardware specifications and experimental paradigms should be carefully considered because of their direct impact on the quality of gait assessment. Second, since both modalities, EEG and fNIRS, are sensitive to motion artifacts, instrumental, and physiological noises, there is a quest for more robust and sophisticated signal processing algorithms. Third, hybrid temporal and spatial features, obtained by virtue of fusing EEG and fNIRS and associated with cortical activation, can help better identify the correlation between brain activation and gait. In conclusion, hBCI (EEG + fNIRS) system is not yet much explored for the lower limb due to its complexity compared to the higher limb. Existing BCI systems for gait monitoring tend to only focus on one modality. We foresee a vast potential in adopting hBCI in gait analysis. Imminent technical breakthroughs are expected using hybrid EEG-fNIRS-based BCI for gait to control assistive devices and Monitor neuro-plasticity in neuro-rehabilitation. However, although those hybrid systems perform well in a controlled experimental environment when it comes to adopting them as a certified medical device in real-life clinical applications, there is still a long way to go.

• Eide, Per Kristian; Pripp, Are Hugo & Ringstad, Geir (2020). Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamicsâin idiopathic normal pressure hydrocephalus. Brain Communications. 2(2). doi: 10.1093/braincomms/fcaa187. Fulltekst i vitenarkiv Vis sammendrag

  Disturbed clearance of toxic metabolites from the brain via cerebrospinal fluid is emerging as an important mechanism behind dementia and neurodegeneration. To this end, magnetic resonance imaging work-up of dementia diseases is largely focused on anatomical derangements of the brain. This study explores magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in patients with the dementia subtype idiopathic normal pressure hydrocephalus and a cohort of reference subjects. All study participants underwent multi-phase magnetic resonance imaging up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml, 1 mmol/ml), serving as cerebrospinal fluid tracer. Imaging biomarkers of cerebrospinal fluid tracer dynamics (i.e. ventricular reflux grades 0–4 and clearance) were compared with anatomical magnetic resonance imaging biomarkers of cerebrospinal fluid space anatomy (Evans’ index, callosal angle and disproportional enlargement of subarachnoid spaces hydrocephalus) and neurodegeneration (Schelten’s medial temporal atrophy scores, Fazeka’s scores and entorhinal cortex thickness). The imaging scores were also related to a pulsatile intracranial pressure score indicative of intracranial compliance. In shunt-responsive idiopathic normal pressure hydrocephalus, the imaging biomarkers demonstrated significantly altered cerebrospinal fluid tracer dynamics (ventricular reflux grades 3–4 and reduced clearance of tracer), deranged cerebrospinal fluid space anatomy and pronounced neurodegeneration. The altered MRI biomarkers were accompanied by pressure indices of impaired intracranial compliance. In conclusion, we present novel magnetic resonance imaging biomarkers characterizing idiopathic normal pressure hydrocephalus pathophysiology, namely measures of cerebrospinal fluid molecular redistribution and clearance, which add information to traditional imaging scores of cerebrospinal fluid space anatomy and neurodegeneration.

• Melin, Erik; Eide, Per Kristian & Ringstad, Geir (2020). In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans. Scientific Reports. 10(1). doi: 10.1038/s41598-020-72031-5. Fulltekst i vitenarkiv Vis sammendrag

  Extra-vascular molecular clearance routes from the brain and cerebrospinal fluid (CSF) remain insufficiently characterized in humans. Animal studies consistently suggest that the cribriform plate and nasal lymphatic vessels are crucial for molecular clearance from CSF. In this study, we aimed to examine human in vivo transport of a CSF tracer from CSF to nasal mucosa. We hypothesised a CSF tracer would enrich in nasal mucosa provided that nasal lymphatic drainage has a significant role in CSF molecular clearance. Consecutive magnetic resonance imaging during 48 h after intrathecal administration of a tracer (gadobutrol) was performed in 24 patients. Despite a strong enrichment of CSF tracer in CSF spaces nearby the cribriform plate, there was no significant enrichment of CSF tracer in nasal mucosa, as measured in superior, medial and inferior turbinates, or in the nasal septum. Therefore, this in vivo study questions the importance of CSF drainage to the human nasal mucosa and emphasizes the need of further human studies.

• Halvorsen, Merete; Edeklev, Camilla; Fraser-Green, Jorunn; Løvland, Grethe; Vatnehol, Svein Are Sirirud & Gjertsen, Øivind [Vis alle 10 forfattere av denne artikkelen] (2020). Off-label intrathecal use of gadobutrol: safety study and comparison of administration protocols. Neuroradiology. ISSN 0028-3940. 63(1), s. 51–61. doi: 10.1007/s00234-020-02519-4. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Magnetic resonance imaging (MRI) contrast agents have been used off-label for diagnosis of cerebrospinal fluid (CSF) leaks and lately also for assessment of the glymphatic system and meningeal lymphatic drainage. The purpose of this study was to further evaluate the short- and long-term safety profile of intrathecal MRI contrast agents. Methods In this prospective study, we compared the safety profile of different administration protocols of intrathecal gadobutrol (GadovistTM; 1.0 mmol/ml). Gadobutrol was administered intrathecal in a dose of 0.5 mmol, with or without iodixanol (VisipaqueTM 270 mg I/ml; 3 ml). In addition, a subgroup was given intrathecal gadobutrol in a dose of 0.25 mmol. Adverse events were assessed at 1 to 3 days, 4 weeks, and after 12 months. Results Among the 149 patients, no serious adverse events were seen in patients without history of prior adverse events. The combination of gadobutrol with iodixanol did not increase the occurrence of non-serious adverse events after days 1–3. Intrathecal gadobutrol in a dose of 0.25 mmol caused less severity of nausea, as compared with the dose of 0.5 mmol. The clinical diagnosis was the major determinant for occurrence of non-serious adverse events after intrathecal gadobutrol. Conclusion This prospective study showed that intrathecal administration of gadobutrol in a dose of 0.5 mmol is safe. Non-serious adverse events were to a lesser degree affected by the administration protocols, though preliminary data are given that side effects of intrathecal gadobutrol are dose-dependent.

• Ringstad, Geir & Eide, Per Kristian (2020). Glymfatisk MR. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(1), s. 1–2. doi: 10.4045/tidsskr.19.0651. Fulltekst i vitenarkiv
• Carare, Roxana O.; Aldea, Roxana; Agarwal, Nivedita; Bacskai, Brian J.; Bechman, Ingo & Boche, Delphine [Vis alle 45 forfattere av denne artikkelen] (2020). Clearance of interstitial fluid (ISF) and CSF (CLIC) group—part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. 12(1), s. 1–7. doi: 10.1002/dad2.12053. Fulltekst i vitenarkiv Vis sammendrag

  Two of the key functions of arteries in the brain are (1) the well‐recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri‐arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

• Evensen, Karen Brastad & Eide, Per Kristian (2020). Mechanisms behind altered pulsatile intracranial pressure in idiopathic normal pressure hydrocephalus: role of vascular pulsatility and systemic hemodynamic variables. Acta Neurochirurgica. ISSN 0001-6268. 162(8), s. 1803–1813. doi: 10.1007/s00701-020-04423-5. Fulltekst i vitenarkiv Vis sammendrag

  Background The dementia subtype idiopathic normal pressure hydrocephalus (iNPH) has unknown etiology, but one characteristic is elevated intracranial pressure (ICP) wave amplitudes in those individuals who respond with clinical improvement following cerebrospinal fluid (CSF) diversion. To explore the mechanisms behind altered ICP wave amplitudes, we correlated central aortic blood pressure (BP) and ICP waveform amplitudes (intracranial aortic amplitude correlation) and examined how this correlation relates to ICP wave amplitude levels and systemic hemodynamic parameters. Methods The study included 29 patients with probable iNPH who underwent continuous multi-hour measurement of ICP, radial artery BP, and systemic hemodynamic parameters. The radial artery BP waveforms were used to estimate central aortic BP waveforms, and the intracranial aortic amplitude correlation was determined over consecutive 4-min periods. Results The average intracranial aortic amplitude correlation was 0.28 ± 0.16 at the group level. In the majority of iNPH patients, the intracranial aortic amplitude correlation was low, while in about 1/5 patients, the correlation was rather high (average Pearson correlation coefficient > 0.4). The degree of correlation was hardly influenced by systemic hemodynamic parameters. Conclusions In about 1/5 iNPH patients of this study, the intracranial aortic amplitude correlation (IAACAORTIC) was rather high (average Pearson correlation coefficient > 0.4), suggesting that cerebrovascular factors to some extent may affect the ICP wave amplitudes in a subset of patients. However, in 14/19 (74%) iNPH patients with elevated ICP wave amplitudes, the intracranial aortic amplitude correlation was low, indicating that the ICP pulse amplitude in most iNPH patients is independent of central vascular excitation, ergo it is modulated by local cerebrospinal physiology. In support of this assumption, the intracranial aortic amplitude correlation was not related to most systemic hemodynamic variables. An exception was found for a subgroup of the patients with high systemic vascular resistance, where there was a correlation.

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• Laubo, Sami; Eide, Per Kristian & Rognes, Marie Elisabeth (2026). Predicting individual contrast enrichment and clearance by learning glymphatic magnetic resonance imaging. Fulltekst i vitenarkiv
• Laubo, Sami; Eide, Per Kristian & Rognes, Marie Elisabeth (2026). Predicting molecular transport in brain fluids using longitudinal MRI. Fulltekst i vitenarkiv Vis sammendrag

  Cerebrospinal fluid (CSF) plays a critical role in the clearance of metabolic waste products from the brain and serves as a delivery route for some neuropharmaceuticals. However, the high inter-patient variability in CSF dynamics observed in various nervous system diseases indicates a need for personalized approaches to understand and predict transport in CSF. A method to observe CSF transport in the brain is via injection of a CSF contrast agent followed by longitudinal magnetic resonance imaging (MRI) sequences. This provides sequential snapshots of the tracer distribution in the brain at different time points. We propose a supervised convolutional neural network (CNN) model to predict the pixel-wise signal increase at peak parenchymal enrichment, 24 hours post-injection, utilizing the longitudinal MRI scans. To incorporate the temporal information inherent in longitudinal scans, we combine a U-Net architecture with a convolutional long short-term memory (ConvLSTM) module modified to integrate the varying time intervals between MRI scans. While models with single-input pre-injection or post-injection MRI scan showed potential, they are often not fully able to capture the temporal evolution of tracer transport. The time-aware ConvLSTM U-Net demonstrates a significant increase in predictive quality compared with the single-input models. The longitudinal model also exhibit improved robustness on patients with varying CSF dynamics which is crucial for trustworthy applications in medicine. Lastly, we discuss the need to incorporate direct physical components to improve patient predictions.

• Laubo, Sami; Eide, Per Kristian & Rognes, Marie Elisabeth (2026). Predicting individual brain contrast enrichment and clearance by learning glymphatic MR. Fulltekst i vitenarkiv Vis sammendrag

  Cerebrospinal fluid (CSF) plays a critical role in the clearance of metabolic waste products from the brain and serves as a delivery route for some neuropharmaceuticals. However, the high inter-patient variability in CSF dynamics observed in various nervous system diseases indicates a need for personalized approaches to understand and predict transport in CSF. A method to observe CSF transport is via intrathecal lumbar injection of the CSF contrast agent gadobutrol followed by longitudinal T1-weighted magnetic resonance imaging (MRI) sequences. This provides sequential snapshots of the tracer distribution in the brain at different time points. We propose a supervised convolutional neural network (CNN) model to predict the pixel-wise signal increase at peak parenchymal enrichment — 24 hours post-injection — utilizing the longitudinal MRI scans. To incorporate the temporal information inherent in longitudinal scans, we combine a U-Net architecture with a convolutional long short-term memory (ConvLSTM) module modified to integrate the varying time intervals between MRI scans. This module recurrently updates feature states extracted from each MRI scan into a combined representation. While baseline models using a single pre-injection or post-injection MRI scan showed potential, they are often not fully able to capture the temporal evolution of tracer transport. The time-aware ConvLSTM U-Net demonstrates a significant increase in predictive quality compared with the baseline models. The model also exhibit improved robustness on patients with varying CSF dynamics, crucial for trustworthy application. Finally, we analyse different image metrics to determine the most clinically relevant quantitative measures, and employ explainable artificial intelligence techniques to better understand the current limitations of CNNs in glymphatic MRI.

• Laubo, Sami; Eide, Per Kristian & Rognes, Marie Elisabeth (2026). Predicting individual contrast enrichment and clearance by learning glymphatic MRI. Fulltekst i vitenarkiv Vis sammendrag

  In and around the brain flows a clear liquid, essential for a healthy and functioning brain. This fluid is called the cerebrospinal fluid (CSF) and plays a critical role in the clearance of metabolic waste products from the brain and serves as a delivery route for nutrients and some neuropharmaceuticals and chemotherapy drugs. Altered CSF dynamics are observed in various nervous system diseases. Alzheimer’s and Parkinson’s disease are two examples where one observes the accumulation of proteins normally cleared by CSF. The variability and altered CSF dynamics seen in both health and disease calls for patient specific planning and dosing of CSF transported drugs. Our goal is to investigate how we can utilize image-based machine learning to predict the distribution of a CSF tracer post-injection. Using longitudinal MRI scans after injecting a CSF tracer allows for snapshots of the tracer distribution in the brain over time, from which we can utilize deep learning to predict the 24 hour post-injection MRI scan. We apply a standard U-Net architecture on the pre-injection MRI scan, as well as a U-Net modified with a proposed Convolutional Time-aware Long Short-term Memory (ConvTLSTM) to utilize the full sequence of MRI scans. The ConvTLSTM U-Net outperforms the pre-injection U-Net, where around half of the predictions have a sufficient clinically relevant quality.

• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Acar, Evrim & Mardal, Kent-Andre (2026). Data-driven insights from glymphatic MRI​. Fulltekst i vitenarkiv
• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian; Nordengen, Kaja & Mardal, Kent-Andre (2026). Image registration as a tool for modeling and analysis of brain solute transport​. Fulltekst i vitenarkiv
• Solheim, Andreas; Ringstad, Geir; Valnes, Lars Magnus; Eide, Per Kristian & Mardal, Kent-Andre (2025). The role of brain geometry in glymphatic modeling. Fulltekst i vitenarkiv
• Solheim, Andreas; Ringstad, Geir; Eide, Per Kristian & Mardal, Kent-Andre (2025). An image registration-based approach for model order reduction in brain geometries. Fulltekst i vitenarkiv
• Gundersen, Julia Kristine; Holmøy, Anne Katrin; Eide, Per Kristian & Winther, Jacob Andreas (2025). Arginine vasopressin deficiency after surgical ligation of an unruptured anterior communicating artery aneurysm – a case report and literature review. doi: 10.3389/fendo.2025.1662205. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Plasma osmolality is maintained within a narrow range by secretion of arginine vasopressin (AVP). AVP deficiency (formerly known as central diabetes insipidus) is a rare complication of surgery in the hypothalamic and pituitary region. Case description: A 50-year-old male patient developed postoperative dehydration, polyuria and cognitive impairment following surgical clip ligation of an unruptured anterior communicating artery (ACOM) aneurysm. Endocrine tests revealed moderate hypernatremia, plasma hyperosmolality and urine hypoosmolality. Magnetic resonance imaging of the brain uncovered delayed cerebral infarctions in genu rostrum of corpus callosum and bilateral oedema of fornix anterior columns. All clinical findings supported the diagnosis of central AVP deficiency, likely involving the anterior hypothalamic nuclei. Follow-up 2 months postoperatively confirmed persisting AVP deficiency and cognitive impairment. Conclusion: AVP deficiency without associated haemorrhage is exceedingly rare, with only seven cases identified in our literature review. This case highlights that postoperative AVP deficiency may present with mild or unspecific symptoms. Importantly, concurrent cognitive impairment may occur, further complicating compliance to treatment. Therefore, close postoperative monitoring is crucial for correct diagnosis and bed-side management.

• Døving, Mats; Stray, August; Anandan, Steven; Eide, Per Kristian; Skogen, Karoline & Koht, Jeanette (2024). En kvinne i 40-årene med smerter i øret. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(1), s. 1–8. doi: 10.4045/tidsskr.23.0543. Fulltekst i vitenarkiv
• Lashkarivand, Aslan & Eide, Per Kristian (2024). Dementia in spontaneous intracranial hypotension: a call for accurate terminology. Neuroradiology. ISSN 0028-3940. doi: 10.1007/s00234-024-03530-9. Fulltekst i vitenarkiv
• Hovd, Markus Herberg; Mariussen, Espen; Uggerud, Hilde Thelle; Lashkarivand, Aslan; Christensen, Hege & Ringstad, Geir [Vis alle 7 forfattere av denne artikkelen] (2023). CSF to blood clearance differs substantially across individuals and patients with CSF disorders. Fluids and Barriers of the CNS. 19. doi: 10.1186/s12987-022-00397-x. Fulltekst i vitenarkiv
• Melin, Erik; Eide, Per Kristian & Ringstad, Geir (2023). Author Correction: In vivo assessment of cerebrospinal fluid efflux to nasal mucosa in humans (Scientific Reports, (2020), 10, 1, (14974), 10.1038/s41598-020-72031-5). Scientific Reports. 13(1). doi: 10.1038/s41598-023-43372-8. Fulltekst i vitenarkiv
• Ringstad, Geir & Eide, Per Kristian (2023). The pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain. Nature Communications. 14. doi: 10.1038/s41467-023-40508-2. Fulltekst i vitenarkiv
• Thavarajasingam, Santhosh G.; El-Khatib, Mahmoud; Vemulapalli, Kalyan V.; Ramsay, Daniele S. C.; Ponniah, Hariharan Subbiah & Fernandes, Rafael T. [Vis alle 8 forfattere av denne artikkelen] (2023). Inadequacies in iNPH diagnosis: envisioning a paradigm shift towards integrated, multi-modal testing, and consensus-driven research for improved patient outcomes. Acta Neurochirurgica. ISSN 0001-6268. doi: 10.1007/s00701-023-05754-9. Fulltekst i vitenarkiv
• Lashkarivand, Aslan & Eide, Per Kristian (2022). The first report on brain sagging dementia caused by a cranial leak: A case report. Frontiers in Neurology. 13, s. 1–6. doi: 10.3389/fneur.2022.1006060. Fulltekst i vitenarkiv Vis sammendrag

  Objective Brain Sagging Dementia (BSD) is an increasingly recognized syndrome for which diagnostic criteria recently were proposed. There have been no reports on BSD caused by a cranial leak. Here we present the first report on a patient with BSD caused by a cranial leak. Case description A 60-year old male patient was admitted with a 2-year history of orthostatic headache and gradually progressive cognitive and behavioral changes. Traditional treatments for spontaneous intracranial hypotension, including repeated epidural blood patches, failed. Brain imaging showed severe brain sagging, and intracranial pressure monitoring demonstrated intracranial hypotension. No leakage site was found. His past medical history revealed an accident where a ski pole struck his head at age ten. Due to progressive clinical decline, surgery was pursued. A cranial defect with an accompanying cerebrospinal fluid leak site representing the trauma from his childhood was found and repaired. He also was in need of a ventriculoperitoneal shunt. Following surgery, he improved and recovered completely. Discussion This case report illustrates that a cranial leak may cause BSD, even with a “lucid interval” between trauma and symptom debut spanning many years. Moreover, this report validates well the recently proposed BSD diagnostic criteria.

• Sorteberg, Wilhelm; Sorteberg, Angelika; Jacobsen, Eva Astrid; Rønning, Pål Andre; Nome, Terje & Eide, Per Kristian (2022). Microsurgery as first-line treatment in acute hemorrhagic cranial dural arteriovenous fistulas (dAVFs) and ruptured intracranial aneurysms—anachronism or duty? Acta Neurochirurgica. ISSN 0001-6268. 164, s. 1303–1305. doi: 10.1007/s00701-022-05197-8. Fulltekst i vitenarkiv
• Ringstad, Geir & Eide, Per Kristian (2021). Safety of Intrathecal Gadolinium-based Contrast Agents and Benefit versus Risk. Radiology. ISSN 0033-8419. 229(1), s. E223–E224. doi: 10.1148/radiol.2021203351. Fulltekst i vitenarkiv
• Eide, Per Kristian & Sorteberg, Wilhelm (2021). Invasive tests for predicting shunt response in idiopathic normal pressure hydrocephalus: the risk aspect. Acta Neurochirurgica. ISSN 0001-6268. 164, s. 481–482. doi: 10.1007/s00701-021-05050-4. Fulltekst i vitenarkiv

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