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.

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 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.

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.

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.

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.

The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke.

It is unknown whether collateral vessel status, as seen on computed tomography angiography, can predict the fate of penumbral tissue identified on perfusion computed tomography and thereby influence clinical outcome. We tested this hypothesis in consecutive patients who underwent perfusion computed tomography/computed tomography angiography within 6 h of anterior circulation stroke, who also had repeat perfusion/infarct volume imaging at 24 h, and modified Rankin Scale at 3 months. Collateral status was graded as good or reduced depending on the extent of contrast visualized distal to the occlusion on computed tomography angiography. 'Perfusion computed tomography mismatch' ratio was calculated from the ratio of the mean transit time lesion/cerebral blood volume lesion. Of 92 patients with proximal intracranial vessel occlusion, good collateral status (51/92) was significantly associated with reduced infarct expansion and more favourable functional outcomes (modified Rankin Scale 0-2). Significant univariate predictors of favourable outcome were good collateral status, major reperfusion at 24 h, presence of perfusion computed tomography mismatch (for a range of ratios: > or = 1.2, > or = 2, > or = 3, > or = 3.5) and baseline National Institutes of Health Stroke Scale score. Notably, none of the 37 patients with a perfusion computed tomography mismatch ratio < 3.0 had a favourable outcome. In patients with perfusion computed tomography mismatch, significant independent predictors of favourable outcome were good collateral status, major reperfusion and baseline National Institutes of Health Stroke Scale score. There was also a strong interaction between major reperfusion and good collateral status in the regression models. In patients with proximal vessel occlusion, perfusion computed tomography mismatch is a prerequisite for a favourable clinical response, but good collateral status appears a critical determinant of ultimate outcome, particularly if major reperfusion occurs.

A mathematical model of idiopathic intracranial hypertension incorporating increased arterial inflow and variable venous outflow collapsibility.

OBJECT: A collapsible segment in the venous outflow has been noted in many patients with idiopathic intracranial hypertension (IIH). Mathematical modeling has shown that these collapsible segments can account for the elevated cerebrospinal fluid (CSF) pressures associated with IIH. However, the model required an elevated outflow resistance of up to 10 times normal to predict the CSF pressures actually found clinically. Measurement of blood flow in patients with IIH has shown that inflow rates vary, with higher rates noted in patients with lesser outflow stenoses. The aim of this work was to extend a simple model of cerebral hydrodynamics to accommodate a collapsible sinus and elevations in cerebral blood flow in accordance with in vivo measurements. METHODS: Forty patients with IIH underwent MR imaging in which the degree of stenosis on MR venography was compared with the total blood inflow by using MR flow quantification. The relative outflow resistance in IIH was estimated using the CSF opening pressure. The patients were compared with 14 age-matched control individuals. RESULTS: Patients were divided into 3 groups based on MR venography appearances (minimal stenosis, stenosis of 40-70% and > 70% stenosis). In vivo measurements suggested a relative resistance elevation of 2.5 times normal, 4.2 times normal, and 4.8 times normal in the 3 groups, respectively. There was an increased inflow of 1.56 times normal, 1.28 times normal, and 1.19 times normal in these groups. CONCLUSIONS: The model correctly predicted the CSF pressures noted in vivo, suggesting that high arterial inflow is required for patients with low-grade stenoses to be symptomatic.

Arterial inflow and venous outflow in idiopathic intracranial hypertension associated with venous outflow stenoses.

A reduction in the proportion of the arterial inflow drained by the superior sagittal sinus in idiopathic intracranial hypertension (IIH) patients without stenoses has been noted and this has suggested elevated collateral flow. This study defines the interaction between arterial inflow and venous outflow in patients with outflow stenoses and IIH. Forty patients with clinical IIH underwent standard MRI, MR venography and MR flow quantification studies of the cerebral arteries and veins. There were 21/40 patients with venous stenoses. The arterial inflow was 21% higher than normal (p=0.01); however, the superior sagittal sinus outflow was normal, giving a reduced percentage of venous outflow compared to inflow. Seven patients were followed up after remission of their symptoms and the arterial inflows and percentage outflow returned to normal. There is a spectrum of findings in IIH; patients with stenoses have lower inflows than those with patent sinuses but still have evidence of collateral flow.

Magnetic resonance imaging quantification of compliance and collateral flow in late-onset idiopathic aqueductal stenosis: venous pathophysiology revisited.

OBJECT: Findings in animal models of noncommunicating hydrocephalus have suggested that a reduction in compliance of the superior sagittal sinus, an elevation in venous outflow pressure, and the development of venous collateral flow may be associated with this condition. Although elevated venous pressure is known to cause hydrocephalus in children, this mechanism has fallen out of favor as a theory in adults. METHODS: Twenty-one patients with late-onset idiopathic aqueductal stenosis (LIAS) underwent magnetic resonance imaging with flow quantification measuring the degree of ventricular enlargement, sulcal compression, total blood inflow, superior sagittal/straight sinus outflow, aqueduct flow, arteriovenous delay (AVD), and the extent of collateral venous flow. Data obtained in these patients were compared with those obtained in 21 age-matched control individuals. RESULTS: There was a reduction in compliance in the patients with LIAS in whom the AVD decreased by 50% (p = 0.01). The arterial inflow and the straight sinus outflow were normal, but the sagittal sinus outflow was reduced by 23% (p = 0.001). This indicated that significant collateral venous outflow pathways were draining blood away from the superficial but not the deep drainage system. CONCLUSIONS: Similar to the animal models, patients with LIAS exhibit a reduced venous compliance and an elevation in venous collateral flow. Together, these findings suggest that an elevation in venous pressure may be associated with this disease process. A review of the literature has indicated that only subtle differences may exist in the pathophysiology among patients with LIAS, normal-pressure hydrocephalus, and idiopathic intracranial hypertension.

Idiopathic hydrocephalus in children and idiopathic intracranial hypertension in adults: two manifestations of the same pathophysiological process?

OBJECT: Both idiopathic intracranial hypertension (IIH) in adults and idiopathic hydrocephalus in children have been shown to involve elevations in venous pressure that resolve once the cerebrospinal fluid pressure is reduced. It has been assumed that the venous pressure elevations in both conditions are not hemodynamically significant, but measurement of venous collateral flow in IIH has shown these pressure elevations to be of consequence. The authors used the same methodology to see if the venous pressure elevations noted in childhood hydrocephalus are important. METHODS: Fourteen patients with idiopathic childhood hydrocephalus underwent magnetic resonance imaging with flow quantification. The degree of ventricular enlargement, total blood inflow, and superior sagittal/straight sinus outflow was measured. The degree of collateral venous flow was calculated for each venous territory. The findings were compared with findings in 14 age-matched controls. RESULTS: In children with hydrocephalus the cerebral blood inflow was normal, but the superior sagittal sinus (SSS) and straight sinus outflows were reduced by 27% and 38%, respectively, compared with measurements in controls (p = 0.03 and 0.002). These findings suggest that approximately 150 ml of blood per minute was returning via collateral channels from that portion of the brain drained by the SSS, and 60 ml/minute was returning from collaterals in the deep venous territory. CONCLUSIONS: Similarly to patients with IIH, children with hydrocephalus show a significant elevation in collateral venous flow, indicating that the same venous pathophysiological process may be operating in both conditions. Whether or not the ventricles dilate may depend on the differences in brain compliance between adults and children.

Comparison of the sagittal sinus cross-sectional area between patients with multiple sclerosis, hydrocephalus, intracranial hypertension and spontaneous intracranial hypotension: a surrogate marker of venous transmural pressure?

There is evidence that patients with multiple sclerosis (MS) and hydrocephalus share some common pathophysiological mechanisms. Alterations in CSF pressure are known to affect cerebral venous sinus geometry. To further explore these mechanisms, we measured the superior sagittal sinus (SSS) cross-sectional area 3 cm above the torcular using T2 images in 20 MS, 10 spontaneous intracranial hypotension (SIH), 21 hydrocephalus and 20 idiopathic intracranial hypertension (IIH) patients and compared with 20 matched controls. The SSS area was reduced by 25% in hydrocephalus (p = 0.0008), increased by 22% (p = 0.037) in SIH and unchanged in IIH compared to matched controls. In MS there was a 16% increase in SSS area (p = 0.01).The findings suggest that changes in SSS cross-sectional are common between MS and SIH patients, while in hydrocephalus and IIH these are different.

Association between arterial inflow and venous outflow in idiopathic and secondary intracranial hypertension.

Twenty-four patients with a clinical diagnosis of idiopathic intracranial hypertension underwent standard magnetic resonance (MR) imaging. On the basis of MR venography, two groups of patients could be identified: (i) one group with an intrinsic venous outflow obstruction (intrinsic); and (ii) a non-intrinsically obstructed (extrinsic) group. MRI flow quantification studies of the cerebral arteries and veins, measuring arterial blood inflow as well as superior sagittal sinus (SSS) and straight sinus (ST) outflow, were performed. The MR venography confirmed that there were 12 intrinsic patients and 12 extrinsic patients. In the intrinsic group, total arterial inflow was normal; however, the SSS outflow was reduced by 35% (p=0.0001). Arterial inflow in extrinsic patients was 55% higher than normal (p=0.0001); however, the SSS flow was normal. In intrinsic venous outflow obstruction, total cerebral inflow is maintained despite a reduction in outflow. In the idiopathic cases, there was cerebral hyperaemia suggesting a derangement of autoregulation.

CT perfusion source images improve identification of early ischaemic change in hyperacute stroke.

CT perfusion scanning produces dynamic contrast-enhanced brain images, but to generate and interpret the colour maps of cerebral perfusion from these source images requires specialist neuroimaging knowledge. We hypothesized that physicians without such training might still utilise the CT perfusion source images (CTPSI) to diagnose early ischaemic change. Fifteen patients had cerebral non-contrast CT (NCCT) and perfusion CT within 6 hours of hemispheric stroke onset. We tested 15 non-stroke clinicians and radiology trainees, plus three experts, in assessing the presence and extent of early ischaemic change on NCCT versus CTPSI. Day 5-7 CT or MRI was used as the gold standard. Agreement with follow-up imaging was poor for both detection, and extent of early ischaemic change on NCCT (kappa = 0.01-0.11). There was a marked improvement in agreement for both the presence and extent of early ischaemic change on CTPSI (kappa = 0.67-0.83). CTPSI were much more accurate than NCCT in identifying acute ischaemic change. 'Less expert' users accurately identified major early ischaemic change on acute CTPSI. These findings suggest that such physicians might utilise CTPSI to screen potential thrombolysis candidates.