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.

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.

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.

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.

A comparison between the pathophysiology of multiple sclerosis and normal pressure hydrocephalus: is pulse wave encephalopathy a component of MS?

BACKGROUND: It has been suggested there is a chronic neurodegenerative disorder, underlying the pathophysiology of multiple sclerosis (MS), which is distinct from the more obvious immune-mediated attack on the white matter. Limited data exists indicating there is an alteration in pulse wave propagation within the craniospinal cavity in MS, similar to the findings in normal pressure hydrocephalus (NPH). It is hypothesized MS may harbor pulse wave encephalopathy. The purpose of this study is to compare blood flow and pulse wave measurements in MS patients with a cohort of NPH patients and control subjects, to test this hypothesis. METHODS: Twenty patients with MS underwent magnetic resonance (MR) flow quantification techniques. Mean blood flow and stroke volume were measured in the arterial inflow and venous out flow from the sagittal (SSS) and straight sinus (ST). The arteriovenous delay (AVD) was defined. The results were compared with both age-matched controls and NPH patients. RESULTS: In MS there was a 35 % reduction in arteriovenous delay and a 5 % reduction in the percentage of the arterial inflow returning via the sagittal sinus compared to age matched controls. There was an alteration in pulse wave propagation, with a 26 % increase in arterial stroke volume but 30 % reduction in SSS and ST stroke volume. The AVD and blood flow changes were in the same direction to those of NPH patients. CONCLUSIONS: There are blood flow and pulsation propagation changes in MS patients which are similar to those of NPH patients. The findings would be consistent with an underlying pulse wave encephalopathy component in MS.

Childhood hydrocephalus secondary to posterior fossa tumor is both an intra- and extraaxial process.

OBJECTIVE Ventricular dilation secondary to tumor obstruction of the posterior fossa CSF outflow in childhood is an intraaxial process. However, third ventriculostomy or complete tumor removal often fails to reduce the pressure in some children, and in others there is a delayed reduction in intracranial pressure; this is termed the adaptation period. The cause of this adaptation period has not been studied. Venous sinus compression is highly correlated with other forms of childhood hydrocephalus, and this study seeks to follow the changes that occur in sinus cross-sectional area after surgery. METHODS Twelve children with posterior fossa tumors underwent MRI examination that included standard T2-weighted and 3D contrast-enhanced images obtained preoperatively, in the immediate postoperative period, and after several months. The volumes of the lateral and third ventricles and the minimum cross-sectional area of the transverse and sigmoid sinuses were measured. Patients were categorized by 1) shunt status (those who required a shunt vs those who did not) and 2) by age (those younger than 3 years vs those older than 3 years at diagnosis). RESULTS There was a significant reduction in ventricular volume in both the immediate and secondary follow-up periods for all patients. There was preoperative venous sinus compression in all groups, which did not change significantly in the immediate postoperative period but did improve in the secondary follow-up period. The younger children had larger ventricles and smaller sinuses before surgery compared with the older children. CONCLUSIONS In children with obstructed hydrocephalus caused by tumor, there is secondary compression of venous outflow, indicating both an intra- and extraaxial process. The expansion of the sinuses following decompression of the posterior fossa is delayed and may correlate with the adaptation period. Younger children have greater sinus compression than older ones.

Pulse wave myelopathy: An update of an hypothesis highlighting the similarities between syringomyelia and normal pressure hydrocephalus.

Most hypotheses trying to explain the pathophysiology of idiopathic syringomyelia involve mechanisms whereby CSF is pumped against a pressure gradient, from the subarachnoid space into the cord parenchyma. On review, these theories have universally failed to explain the disease process. A few papers have suggested that the syrinx fluid may originate from the cord capillary bed itself. However, in these papers, the fluid is said to accumulate due to impaired fluid drainage out of the cord. Again, there is little evidence to substantiate this. This proffered hypothesis looks at the problem from the perspective that syringomyelia and normal pressure hydrocephalus are almost identical in their manifestations but only differ in their site of effect within the neuraxis. It is suggested that the primary trigger for syringomyelia is a reduction in the compliance of the veins draining the spinal cord. This reduces the efficiency of the pulse wave dampening, occurring within the cord parenchyma, increasing arteriolar and capillary pulse pressure. The increased capillary pulse pressure opens the blood-spinal cord barrier due to a direct effect upon the wall integrity and interstitial fluid accumulates due to an increased secretion rate. An increase in arteriolar pulse pressure increases the kinetic energy within the cord parenchyma and this disrupts the cytoarchitecture allowing the fluid to accumulate into small cystic regions in the cord. With time the cystic regions coalesce to form one large cavity which continues to increase in size due to the ongoing interstitial fluid secretion and the hyperdynamic cord vasculature.

Cerebrospinal fluid absorption block at the vertex in chronic hydrocephalus: obstructed arachnoid granulations or elevated venous pressure?

BACKGROUND: The lack of absorption of CSF at the vertex in chronic hydrocephalus has been ascribed to an elevation in the arachnoid granulation outflow resistance (Rout). The CSF infusion studies measuring Rout are dependent on venous sinus pressure but little is known about the changes in pressure which occur throughout life or with the development of hydrocephalus. METHODS: Twenty patients with chronic hydrocephalus underwent MR venography and MR flow quantification techniques. The venous outflow pressure was estimated from the sinus blood flow and the cross-sectional area of the transverse sinuses. Adult controls as well as a normal young cohort were selected to estimate the change in sinus pressure which occurs throughout life and following the development of hydrocephalus. Significance was tested with a Student's t-test. RESULTS: The size of the transverse sinuses was unchanged from the 1(st) to the 5(th) decade of life, indicating a stable outflow resistance. However, the blood flow was reduced by 42%, indicating a likely similar reduction in pressure gradient across the sinuses. The sinuses of hydrocephalus patients were 38% smaller than matched controls, indicating a 2.5 times increase in resistance. Despite the 24% reduction in blood flow, a significant increase in sinus pressure is suggested. CONCLUSIONS: The size of the venous sinuses normally does not change over the age range investigated but sinus pressure is reduced proportional to an age-related blood flow reduction. Hydrocephalus is associated with much smaller sinuses than normal and an elevation in venous pressure may explain the lack of CSF absorption into the arachnoid granulations in chronic hydrocephalus.

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.

Hemodynamically significant venous collapse underlying neonatal hydrocephalus.

OBJECT: It is known that CSF diversion in neonatal hydrocephalus can significantly increase cerebral blood flow, suggesting that a rapidly reversible elevation in vascular resistance underlies this disorder. Various sites of vascular compression have been described in the literature, from the arterioles to the capillary bed to the venules and sinuses. The purpose of this study was to define the site of the hemodynamically significant vascular compression seen in neonatal hydrocephalus. METHODS: The author performed a retrospective review of all patients who, in the first 28 days of life, had undergone 3-T MRI examination, including MR venography and susceptibility weighted scanning, at a tertiary care referral hospital in the period from April 2010 to April 2013. The maximum size of the subependymal veins over the thalamus and transverse sinuses was measured. RESULTS: Three children with hydrocephalus were identified, and 10 children with a normal ventricular size served as controls. The subependymal veins were twice as prominent and the transverse sinuses were half as large in the patients with hydrocephalus compared with those in controls. CONCLUSIONS: The hemodynamically significant elevation in vascular resistance, which occurs in neonatal hydrocephalus, appears to be located in the venous sinuses.

Early detection of microstructural white matter changes associated with arterial pulsatility.

Increased cerebral blood flow pulsatility is common in vascular dementia and is associated with macrostructural damage to cerebral white matter or leukoaraiosis (LA). In this study, we examine whether cerebral blood flow pulsatility is associated with macrostructural and microstructural changes in cerebral white matter in older adults with no or mild LA and no evidence of dementia. Diffusion Tensor Imaging was used to measure fractional anisotropy (FA), an index of the microstructural integrity of white matter, and radial diffusivity (RaD), a measure sensitive to the integrity of myelin. When controlling for age, increased arterial pulsation was associated with deterioration in both measures of white matter microstructure but not LA severity. A stepwise multiple linear regression model revealed that arterial pulsatility index was the strongest predictor of FA (R = 0.483, adjusted R (2) = 0.220), followed by LA severity, but not age. These findings suggest that arterial pulsatility may provide insight into age-related reduction in white matter FA. Specifically, increased arterial pulsatility may increase perivascular shear stress and lead to accumulation of damage to perivascular oligodendrocytes, resulting in microstructural changes in white matter and contributing to proliferation of LA over time. Changes in cerebral blood flow pulsatility may therefore provide a sensitive index of white matter health that could facilitate the early detection of risk for perivascular white matter damage and the assessment of the effectiveness of preventative treatment targeted at reducing pulsatility.

Hypertensive slit ventricle syndrome: pseudotumor cerebri with a malfunctioning shunt?

Symptomatic shunt malfunction without ventricular enlargement is known as slit ventricle syndrome (SVS). Patients presenting with this syndrome are not a homogeneous group. Of the 5 different types classified by Rekate, Type 1 is caused by CSF overdrainage and is associated with low pressures; Types 2 and 3 are associated with shunt blockage and elevated CSF pressures; Type 4 is cephalocranial disproportion that increases brain parenchymal pressure but not CSF pressure; and Type 5 is headache unrelated to shunt function. The low and normal CSF pressure types are relatively well understood, but the high-pressure forms are more problematic. In the high-pressure forms of SVS it is said that the lack of ventricular dilation is related to a reduction in brain compliance analogous to idiopathic intracranial hypertension or pseudotumor cerebri. Despite this, there is little evidence in the literature to support this conjecture. With this in mind, 3 cases of SVS associated with elevated CSF pressure are presented. The MR venogram findings and hemodynamics of these 3 cases are shown to be identical to those of pseudotumor cerebri. A literature review indicates that an underlying venous impairment may be functioning in the patients who re-present with small ventricles following shunt malfunction.

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.