The dilated veins surrounding the cord in multiple sclerosis suggest elevated pressure and obstruction of the glymphatic system.

Recently, Clarke et al. published a study using spinal cord susceptibility weighted imaging in multiple sclerosis patients at 7T. They discovered dilated intradural extramedullary veins surrounding the cord. The purpose of this commentary is to point out some recent research by our group, which suggests this dilatation also occurs in the bridging cortical veins surrounding the brain. The dilatation indicates a focal elevation in the venous pressure secondary to impedance mismatching. Due to the shared outflow geometry, dilatation of the outflow veins will obstruct the glymphatic pathway of the spinal cord altering the immune response.

Consensus statement for the management of incidentally found brain white matter hyperintensities in general medical practice.

INTRODUCTION: There is a paradigm shift in our understanding of white matter hyperintensities (WMH) found on brain imaging. They were once thought to be a normal phenomenon of ageing and, therefore, warranted no further investigation. However, evidence now suggests these lesions are markers of poor brain and cardiovascular health, portending an increased risk of stroke, cognitive decline, depression and death. Nevertheless, no specific guidelines exist for the management of incidentally found WMH for general medical practitioners and other clinicians ordering brain magnetic resonance imaging scans for diverse clinical indications. Informed by a literature review and expert opinion gleaned from stroke neurologists, medical and imaging specialists, and general practitioners, we present our consensus statement to guide the management of incidentally found WMH in adults. MAIN RECOMMENDATIONS: When incidental WMH are found on brain imaging: Perform a detailed history and examination to screen for neurological events. Investigate for potential undiagnosed or undertreated cardiovascular risk factors, especially hypertension and diabetes mellitus. Commence intensive and individualised cardiovascular risk management when risk factors are uncovered. Treat underlying risk factors via accepted guidelines but note that antiplatelet and anticoagulant medications should not be prescribed for incidental WMH in the absence of an alternative indication. CHANGES TO MANAGEMENT AS A RESULT OF THIS CONSENSUS STATEMENT: A brain health opportunity. We consider the discovery of incidental WMH on brain imaging to represent an opportunity to investigate for common cardiovascular risk factors and to optimise brain health. This can be commenced and monitored by the general practitioner or physician without delay in waiting for an outpatient neurology review.

Perfusion computed tomography to assist decision making for stroke thrombolysis.

The use of perfusion imaging to guide selection of patients for stroke thrombolysis remains controversial because of lack of supportive phase three clinical trial evidence. We aimed to measure the outcomes for patients treated with intravenous recombinant tissue plasminogen activator (rtPA) at a comprehensive stroke care facility where perfusion computed tomography was routinely used for thrombolysis eligibility decision assistance. Our overall hypothesis was that patients with 'target' mismatch on perfusion computed tomography would have improved outcomes with rtPA. This was a prospective cohort study of consecutive ischaemic stroke patients who fulfilled standard clinical/non-contrast computed tomography eligibility criteria for treatment with intravenous rtPA, but for whom perfusion computed tomography was used to guide the final treatment decision. The 'real-time' perfusion computed tomography assessments were qualitative; a large perfusion computed tomography ischaemic core, or lack of significant perfusion lesion-core mismatch were considered relative exclusion criteria for thrombolysis. Specific volumetric perfusion computed tomography criteria were not used for the treatment decision. The primary analysis compared 3-month modified Rankin Scale in treated versus untreated patients after 'off-line' (post-treatment) quantitative volumetric perfusion computed tomography eligibility assessment based on presence or absence of 'target' perfusion lesion-core mismatch (mismatch ratio >1.8 and volume >15 ml, core <70 ml). In a second analysis, we compared outcomes of the perfusion computed tomography-selected rtPA-treated patients to an Australian historical cohort of non-contrast computed tomography-selected rtPA-treated patients. Of 635 patients with acute ischaemic stroke eligible for rtPA by standard criteria, thrombolysis was given to 366 patients, with 269 excluded based on visual real-time perfusion computed tomography assessment. After off-line quantitative perfusion computed tomography classification: 253 treated patients and 83 untreated patients had 'target' mismatch, 56 treated and 31 untreated patients had a large ischaemic core, and 57 treated and 155 untreated patients had no target mismatch. In the primary analysis, only in the target mismatch subgroup did rtPA-treated patients have significantly better outcomes (odds ratio for 3-month, modified Rankin Scale 0-2 = 13.8, P < 0.001). With respect to the perfusion computed tomography selected rtPA-treated patients (n = 366) versus the clinical/non-contrast computed tomography selected rtPA-treated patients (n = 396), the perfusion computed tomography selected group had higher adjusted odds of excellent outcome (modified Rankin Scale 0-1 odds ratio 1.59, P = 0.009) and lower mortality (odds ratio 0.56, P = 0.021). Although based on observational data sets, our analyses provide support for the hypothesis that perfusion computed tomography improves the identification of patients likely to respond to thrombolysis, and also those in whom natural history may be difficult to modify with treatment.

A randomized trial of tenecteplase versus alteplase for acute ischemic stroke.

BACKGROUND: Intravenous alteplase is the only approved treatment for acute ischemic stroke. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, is an alternative thrombolytic agent. METHODS: In this phase 2B trial, we randomly assigned 75 patients to receive alteplase (0.9 mg per kilogram of body weight) or tenecteplase (0.1 mg per kilogram or 0.25 mg per kilogram) less than 6 hours after the onset of ischemic stroke. To favor the selection of patients most likely to benefit from thrombolytic therapy, the eligibility criteria were a perfusion lesion at least 20% greater than the infarct core on computed tomographic (CT) perfusion imaging at baseline and an associated vessel occlusion on CT angiography. The coprimary end points were the proportion of the perfusion lesion that was reperfused at 24 hours on perfusion-weighted magnetic resonance imaging and the extent of clinical improvement at 24 hours as assessed on the National Institutes of Health Stroke Scale (NIHSS, a 42-point scale on which higher scores indicate more severe neurologic deficits). RESULTS: The three treatment groups each comprised 25 patients. The mean (±SD) NIHSS score at baseline for all patients was 14.4±2.6, and the time to treatment was 2.9±0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P=0.004) and clinical improvement (P<0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P=0.02). CONCLUSIONS: Tenecteplase was associated with significantly better reperfusion and clinical outcomes than alteplase in patients with stroke who were selected on the basis of CT perfusion imaging. (Funded by the Australian National Health and Medical Research Council; Australia New Zealand Clinical Trials Registry number, ACTRN12608000466347.).

An association between external hydrocephalus in infants and reversible collapse of the venous sinuses.

The etiology of external hydrocephalus is usually ascribed to either a delay in maturation or obstruction of the arachnoid granulations, but the arachnoid granulations are absent in neonates. Venous outflow stenoses, similar to those seen in idiopathic intracranial hypertension (IIH), have been described in external hydrocephalus. A reversible collapse of the sinuses is known to operate in IIH, but collapsible sinuses have not been previously described in infants with external hydrocephalus. Three infants with external hydrocephalus had magnetic resonance venography at differing time points during their illness. The venous sinuses varied in size depending on the cerebrospinal fluid pressure similar to IIH in adults. External hydrocephalus may be analogous to IIH in adults.

A perspective on the evidence for glymphatic obstruction in spaceflight associated neuro-ocular syndrome and fatigue.

Spaceflight associated neuro-ocular syndrome (SANS) alters the vision of astronauts during long-duration spaceflights. Previously, the current authors have discussed the similarities and differences between SANS and idiopathic intracranial hypertension to try to elucidate a possible pathophysiology. Recently, a theory has been advanced that SANS may occur secondary to failure of the glymphatic system caused by venous dilatation within the brain and optic nerves. There is recent evidence to suggest glymphatic obstruction occurs in childhood hydrocephalus, multiple sclerosis and syringomyelia due to venous outflow dilatation similar to that proposed in SANS. The purpose of the current paper is to discuss the similarities and differences between the known CSF and venous pathophysiology in SANS with these other terrestrial diseases, to see if they can shed any further light on the underlying cause of this microgravity-induced disease.

A scoping review of the discrepancies in the measurement of cerebral blood flow in idiopathic intracranial hypertension: oligemia, euvolemia or hyperemia?

BACKGROUND: The literature regarding the global cerebral blood flow (CBF) in idiopathic intracranial hypertension (IIH) is divergent leading to skepticism about the significance of blood flow to the disease's underlying pathophysiology. METHODS: The purpose of the current paper is to perform a PRISMA scoping review of the literature describing the CBF in IIH. The review investigated the PUBMED and Scopus data bases looking at case mix, technique and the methodologies employed by the studies selected. DISCUSSION: Many studies indicate that the flow in IIH is normal but others show the flow to be altered. These later studies show a range of flows from a reduction of 20% to an increase of 50% compared to control values. Obesity is a common finding in IIH and is known to reduce CBF, anemia occurs in approximately 20% of IIH patients and is a potent cause of an increased CBF. Thus, variations in case mix may have a significant effect on the final outcome in those studies which are underpowered. The varying techniques which have been used to estimate CBF have differing strengths and weaknesses which may also have a bearing on the outcome. Some papers have significant confounding methodological issues. CONCLUSIONS: This review suggests each of the variables investigated are responsible for the divergent CBF findings in IIH.

Syringomyelia Is Associated with a Reduction in Spinal Canal Compliance, Venous Outflow Dilatation and Glymphatic Fluid Obstruction.

The cause of the cystic dilatation of the cord found in syringomyelia has been a source of conjecture for a considerable time. Recent studies have shown that there is a reduction in craniospinal compliance in both childhood hydrocephalus and multiple sclerosis which leads to venous outflow dilatation. Both diseases are associated with glymphatic outflow obstruction. Venous dilatation will narrow the perivenous glymphatic outflow pathway and lead to an increase in glymphatic outflow resistance. Syringomyelia has been shown to be associated with reduced spinal canal compliance. This paper discusses the possibility that venous dilatation and obstructed glymphatic outflow within the cord may be behind the cystic dilatation found within syringomyelia.

Investigating the hemodynamic implications of triangular cross-sectioned superior sagittal sinus vessels and the errors associated with idealised modelling.

The superior sagittal sinus (SSS) is a blood vessel that is often observed to be approximately triangular in cross-section, due to how the venous wall attaches to the surrounding tissue. Despite this, the vessel has been assumed to be circular, when models are generated without patient-specific data. In this study, the differences between the cerebral hemodynamics of one circular, three triangular and five patient-specific cross-sectional models of a SSS were conducted. The errors associated with using circular cross-sectioned flow extensions were also determined. Computational fluid dynamics (CFD) models were generated from these geometries, with a population mean transient blood flow profile incorporated. The maximal helicity of the fluid flow was found to be elevated in the triangular cross-section, compared to the circular, with a higher wall shear stress (WSS) observed over a smaller, more concentrated region on the posterior sinus wall. The errors associated with using a circular cross-section were detailed, with the cross-sectional area appearing to have a greater influence on the hemodynamic parameters than the triangularity or circularity of the cross-section. This highlighted the importance of exhibiting caution when incorporating idealised modelling, especially when commenting on the true hemodynamics of these models. Errors were also found to be induced when using a circular cross-sectioned flow extension, for a geometry which was non-circular. This study highlights the importance of understanding the human anatomy when modelling blood vessels.

Dilatation of the bridging cerebral veins in multiple sclerosis correlates with fatigue and suggests an increase in pressure.

BACKGROUND: There is a significant increase in the parenchymal microvessel blood volume in the earliest forms of multiple sclerosis (MS) which may be due to venular dilatation. Increased cortical venous pressure could account for this finding. Venous pressure is also implicated in the physiology of fatigue. The purpose of this study is to discover if there is dilatation of the veins within the subarachnoid space in multiple sclerosis and to estimate the pressures required to maintain any enlargement found. These findings will be correlated with the fatigue symptoms found in MS. METHODS: 103 patients with MS were compared with a control group of 50 patients. Post contrast 3DT1 images were used. The cross-sectional area of the bridging cortical veins and the vein of Galen were measured. RESULTS: In MS, the superficial territory cortical veins were 29% larger and the veins of Galen were 25% larger than the controls. CONCLUSION: There is evidence of a significant increase in the bridging vein transmural pressure in MS, estimated to be approximately 6.5 mmHg in the superficial cortical veins. MS patients with significant fatigue have larger cortical veins than those who are not significantly fatigued.

An olfactory 'stress test' may detect preclinical Alzheimer's disease.

BACKGROUND: The olfactory bulb (OB) receives extensive cholinergic input from the basal forebrain and is affected very early in Alzheimer's disease (AD). We speculated that an olfactory 'stress test' (OST), targeting the OB, might be used to unmask incipient AD. We investigated if change in olfactory performance following intranasal atropine was associated with several known antecedents or biomarkers of AD. METHODS: We measured change in performance on the University of Pennsylvania Smell Identification Test (UPSIT) in the left nostril before (20-items) and after (remaining 20-items) intranasal administration of 1 mg of atropine. We administered cognitive tests, measured hippocampal volume from MRI scans and recorded Apolipoprotein E genotype as indices relevant to underlying AD. RESULTS: In a convenience sample of 56 elderly individuals (14 probable AD, 13 cognitive impairment no dementia, 29 cognitively intact) the change in UPSIT score after atropine ('atropine effect' = AE) correlated significantly with demographically scaled episodic memory score (r = 0.57, p < 0.001) and left hippocampal volume (LHCV) (r = 0.53, p < 0.001). Among non-demented individuals (n = 42), AE correlated with episodic memory (r = 0.52, p < 0.001) and LHCV (r = 0.49, p < 0.001) and hierarchical linear regression models adjusted for age, gender, education, and baseline UPSIT showed that the AE explained more variance in memory performance (24%) than did LHCV (15%). The presence of any APOE ϵ4 allele was associated with a more negative AE (p = 0.014). CONCLUSIONS: The OST using atropine as an olfactory probe holds promise as a simple, inexpensive screen for early and preclinical AD and further work, including longitudinal studies, is needed to explore this possibility.

The measurement of CSF flow through the aqueduct in normal and hydrocephalic children: from where does it come, to where does it go?

PURPOSE: Despite 100 years of study, the theories of cerebrospinal fluid (CSF) formation and absorption remain controversial. Measuring CSF flow through the aqueduct using magnetic resonance imaging (MRI) provides a unique insight into the physiology of CSF hydrodynamics. The published data in adults tend to refute rather than support the prevailing theories of CSF flow. There are limited data regarding this metric in children. This paper seeks to measure the aqueduct flow in normal and hydrocephalic children to help formulate a more complete theory of CSF flow. METHODS: Twenty-four children with communicating hydrocephalus aged from 4 months to 16 years underwent MRI flow quantification of the aqueduct measuring the net flow. The patients were compared to 19 controls. RESULTS: The controls revealed two different flow patterns: (1) an infantile pattern characterized by flow directed into the ventricular system and (2) a mature pattern with flow directed out of the ventricles, similar to the published findings in adults. In infants with communicating hydrocephalus, the aqueduct flow changed direction but was of similar magnitude compared with the controls (p = 0.001). In the older hydrocephalic children, the flow was elevated 7-fold, but the direction was unchanged compared to the controls (p = 0.002). CONCLUSIONS: There is an abrupt change in the aqueduct CSF flow pattern at the age of 2 years from an infantile pattern to a mature pattern. These findings together with the findings in hydrocephalic children do not support the current theories of CSF hydrodynamics. A new theory of CSF circulation based on capillary absorption is presented.

A perspective on spaceflight associated neuro-ocular syndrome causation secondary to elevated venous sinus pressure.

Spaceflight associated neuro-ocular syndrome (SANS) alters the vision of astronauts during long-duration spaceflights. There is controversy regarding SANS being similar to patients with idiopathic intracranial hypertension (IIH). IIH has been shown to be due to an elevation in venous sinus pressure. The literature suggests an increase in jugular vein pressure secondary to a headward shift of fluid occurs in SANS but this may not be enough to significantly alter the intracranial pressure (ICP). The literature regarding cardiac output and cerebral blood flow (CBF) in long-duration spaceflight is contradictory, however, more recent data suggests increased flow. Recent modelling has shown that an increase in CBF can significantly increase sinus pressure. The purpose of the present paper is to review the SANS vascular dynamics literature and through mathematical modelling suggest the possible underlying cause of SANS as an elevation in venous sinus pressure, secondary to the redistribution of fluids towards the head, together with a significant increase in pressure drop across the venous system related to the CBF.

Dilatation of the bridging cerebral cortical veins in childhood hydrocephalus suggests a malfunction of venous impedance pumping.

Dogs with a naturally occurring form of hydrocephalus have an elevated transmural venous pressure leading to cortical vein dilatation. The purpose of this study is to discover if there is vein dilatation in childhood hydrocephalus and to estimate the pressure required to maintain any enlargement found. Children with hydrocephalus between the ages of 4 and 15 years were compared with a control group. Magnetic resonance venography (MRV) and flow quantification were performed. The arterial inflow, sagittal sinus and straight sinus venous outflow were measured and the outflow percentages compared to the inflow were calculated. The cross-sectional area of the veins were measured. There were a total of 18 children with hydrocephalus, compared to 72 age and sex matched control MRV's and 22 control flow quantification studies. In hydrocephalus, the sagittal sinus venous return was reduced by 12.9%, but the straight sinus flow was not significantly different. The superficial territory veins were 22% larger than the controls but the vein of Galen was unchanged. There is evidence of a significant increase in the superficial vein transmural pressure in childhood hydrocephalus estimated to be approximately 4 mmHg. An impedance pump model is suggested to explain these findings.

Modelling of the dilated sagittal sinuses found in multiple sclerosis suggests increased wall stiffness may be a contributing factor.

The cross-sectional area of the superior sagittal sinus (SSS) is larger in multiple sclerosis than normal and correlates with disease severity and progression. The sinus could be enlarged due to a decrease in the pressure difference between the lumen and the subarachnoid space, an increase in wall thickness or increased wall stiffness. The cross-sectional area of the SSS and straight sinus (ST) were measured in 103 patients with multiple sclerosis and compared to 50 controls. The cross-sectional area of the SSS and ST were increased by 20% and 13% compared to the controls (p = 0.005 and 0.02 respectively). The deflection of the wall of the sinus was estimated. The change in pressure gradient, wall thickness or elastic modulus between groups was calculated by modelling the walls as simply supported beams. To account for these findings, the modelling suggests either a 70% reduction in transmural venous pressure or a 2.4 fold increase in SSS wall stiffness plus an 11% increase in wall thickness or a combination of changes. An increase in sinus pressure, although the most straight forward possibility to account for the change in sinus size may exist in only a minority of patients. An increase in sinus wall stiffness and thickness may need further investigation.

Quantified hemodynamic parameters of the venous system in multiple sclerosis: A systematic review.

BACKGROUND: Multiple Sclerosis (MS) is a complex neurodegenerative condition that is influenced by a combination of genetic and environmental factors. Included in these factors is the venous system, however, the extent to which it influences the etiology of MS has yet to be fully characterised. The aim of this review is to critically summarize the literature available concerning the venous system in MS, primarily concerning specific data on the venous pressure and blood flow in this system. METHODS: A systematic review was conducted with the application of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The advanced search functions of both the Scopus and PubMed databases were used to conduct the literature search, resulting in 136 unique articles initially identified. Applying relevant exclusion criteria, 22 of the studies were chosen for this review. RESULTS: The selected studies were analysed for venous pressure and blood flow related findings, with 14 studies contributing data on the internal jugular vein (IJV) flow rate, 5 on blood flows of the intracranial venous sinuses, 2 on blood flow pulsatility and 6 supplying information relevant to the venous pressure (3 studies contributed to multiple areas). The general findings of the review included that the IJV flow was not significantly different between MS patients and controls, however, there were variances between stenotic (S) and non-stenotic (NS) MS patients. Due to the limited data in the other two areas defined in this review, further research is required to establish if any variances in MS are present. CONCLUSION: It remains unclear if there are significant differences in many flow variables between MS patients and controls considered in this review. It would be advantageous if future work in this area focused on understanding the hemodynamics of this system, primarily concerning how the flow rate, venous pressure and vascular resistance are related, and any impact that these factors have on the etiology of MS.

External hydrocephalus in infants: six cases with MR venogram and flow quantification correlation.

PURPOSE: The cause of external hydrocephalus in infants is largely unknown. However, familial macrocephaly and delayed maturation of the arachnoid granulations are thought to play a part in the idiopathic cases. Secondary cases of external hydrocephalus are associated with hemorrhage, meningitis, and elevated venous pressure. Recently, elevated venous pressure has been shown to be a much more common cause of communicating hydrocephalus in children than previously thought. The purpose of this study is to investigate venous pressure as a cause of external hydrocephalus. METHODS: Six children with external hydrocephalus underwent an MRI examination including MR venography and MR flow quantification techniques. A chart review was performed to correlate the clinical findings with the MR findings. Six children with normal head circumferences and growth profile served as controls. RESULTS: The net aqueduct flow in both normal and hydrocephalic children was into the ventricles. There was a spectrum of blood flow findings in the infants with hydrocephalus. (1) Those with normal arterial inflow showed venous outflow stenoses or anomalies. (2) Those with normal MR venograms tended to have elevated cerebral blood inflow. CONCLUSIONS: The absorption of CSF in infants is into the capillary bed of the deep white matter rather than the arachnoid granulations. Absorption into a capillary bed depends on hydrostatic pressure. Similar to older children with communicating hydrocephalus, the infants in this cohort with external hydrocephalus showed evidence of an elevation in venous pressure. Elevated venous pressure may be a much more common cause of external hydrocephalus than previously recognized.