Current Understanding of the Anatomy, Physiology, and Magnetic Resonance Imaging of Neurofluids: Update From the 2022 "ISMRM Imaging Neurofluids Study group" Workshop in Rome.

Neurofluids is a term introduced to define all fluids in the brain and spine such as blood, cerebrospinal fluid, and interstitial fluid. Neuroscientists in the past millennium have steadily identified the several different fluid environments in the brain and spine that interact in a synchronized harmonious manner to assure a healthy microenvironment required for optimal neuroglial function. Neuroanatomists and biochemists have provided an incredible wealth of evidence revealing the anatomy of perivascular spaces, meninges and glia and their role in drainage of neuronal waste products. Human studies have been limited due to the restricted availability of noninvasive imaging modalities that can provide a high spatiotemporal depiction of the brain neurofluids. Therefore, animal studies have been key in advancing our knowledge of the temporal and spatial dynamics of fluids, for example, by injecting tracers with different molecular weights. Such studies have sparked interest to identify possible disruptions to neurofluids dynamics in human diseases such as small vessel disease, cerebral amyloid angiopathy, and dementia. However, key differences between rodent and human physiology should be considered when extrapolating these findings to understand the human brain. An increasing armamentarium of noninvasive MRI techniques is being built to identify markers of altered drainage pathways. During the three-day workshop organized by the International Society of Magnetic Resonance in Medicine that was held in Rome in September 2022, several of these concepts were discussed by a distinguished international faculty to lay the basis of what is known and where we still lack evidence. We envision that in the next decade, MRI will allow imaging of the physiology of neurofluid dynamics and drainage pathways in the human brain to identify true pathological processes underlying disease and to discover new avenues for early diagnoses and treatments including drug delivery. Evidence level: 1 Technical Efficacy: Stage 3.

Transient acute hydrocephalus after aneurysmal subarachnoid hemorrhage and aneurysm embolization: a single-center experience.

PURPOSE: Acute hydrocephalus is a common complication after aneurysmal subarachnoid hemorrhage (aSAH). It can be self-limiting or require cerebrospinal fluid diversion. We aimed to determine the transient acute hydrocephalus (TAH) rate in patients with aSAH treated endovascularly and evaluate its predictive factors. METHODS: A retrospective review of 357 patients with aSAH who underwent endovascular treatment from March 2013 to December 2019 was performed. Clinical and radiographic data were analyzed and risk factors with potential significance for acute hydrocephalus were identified. We constructed a new risk score, the Drainage Or Transiency of Acute Hydrocephalus after Aneurysmal SAH (DOTAHAS) score, that may differentiate patients who would experience TAH from those needing surgical interventions. RESULTS: Acute hydrocephalus occurred in 129 patients (36%), out of whom in 66 patients (51%) it was self-limiting while 63 patients (49%) required external ventricular drainage placement. As independent risk factors for acute hydrocephalus, we identified older age, poor initial clinical condition, aSAH from posterior circulation, and the extent of cisternal and intraventricular hemorrhage. The following three factors were shown to predict acute hydrocephalus transiency and therefore included in the DOTAHAS score, ranging from 0 to 7 points: Hunt and Hess grade ≥ 3 (1 point), modified Fisher grade 4 (2 points), and Ventricular Hijdra Sum Score (vHSS) ≥ 6 (4 points). Patients scoring ≥ 3 points had significantly higher risk for EVD (P < 0.0001) than other patients. CONCLUSION: The newly developed DOTAHAS score can be useful in identifying patients with transient acute hydrocephalus. Further score evaluation is needed.

The role of mesencephalic aqueduct obstruction in hydrocephalus development: a case report.

We report on three patients with mesencephalic aqueduct obstruction, which completely blocked the cerebrospinal fluid communication between the third and fourth cerebral ventricle, demonstrated by standard and high-resolution magnetic resonance sequences. Only one patient developed radiological and clinical presentation of hydrocephalus, without radiological signs of increased intraventricular pressure. The remaining two patients did not show clinical signs of hydrocephalus and had a normal radiological presentation of the ventricular system. These findings contradict the classical concept of cerebrospinal fluid physiology. This concept assumes a unidirectional circulation of cerebrospinal fluid through the mesencephalic aqueduct from the secretion site, predominantly in the choroid plexuses, to the resorption site, predominantly in the dural venous sinuses. Therefore, the obstruction of the mesencephalic aqueduct would inevitably lead to triventricular hypertensive hydrocephalus in all patients. The current observations, however, accord with the new concept of cerebrospinal fluid physiology, which postulates that cerebrospinal fluid does not circulate unidirectionally because it is both formed and resorbed along the entire capillary network within the central nervous system.

New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus.

The goal of this review is the presentation of the new (Bulat-Klarica-Oreskovic) hypothesis of cerebrospinal fluid (CSF) physiology and the ensuing new concept of hydrocephalus development in light of this hypothesis. The widely accepted classic hypothesis of CSF physiology and the traditional concept of hydrocephalus are contradicted by numerous experimental and clinical data, which consequently results in unsatisfying clinical treatment and patient recovery. Therefore, the newly presented concept of hydrocephalus development and possible future treatments are discussed. A new definition suggests that hydrocephalus is a pathological state in which CSF is excessively accumulated inside the cranial part of the CSF system, predominantly in one or more brain ventricles as a consequence of impaired hydrodynamics of intracranial fluids between CSF, brain, and blood compartments.

Monoamine Neurotransmitter Metabolite Concentration as a Marker of Cerebrospinal Fluid Volume Changes.

OBJECTIVE: In our previous papers we demonstrated that changes in blood and cerebrospinal fluid (CSF) osmolarity have a strong influence on CSF pressure and volume, which is in accordance with a new proposed hypothesis of CSF physiology. Thus, acute changes in CSF volume should be reflected in the CSF concentration of different central nervous system (CNS) metabolites. METHODS: In anesthetized cats (n = 4) we measured the outflow volume of CSF by cisternal free drainage at a negative CSF pressure (-10 cmH2O) before and after the intraperitoneal (i.p.) application of a hypo-osmolar substance (distilled water). In samples of CSF collected at different time intervals (30 min) we measured the concentration of homovanillic acid (HVA). RESULTS: In spite of fact that constant CSF outflow volume was obtained after a 30-min period in our model, the concentration of HVA gradually increased over time and became stable after 90 min. After the i.p. application of distilled water the outflow CSF volume increased significantly, whereas the concentration of HVA significantly decreased over 30 min. CONCLUSIONS: The results observed suggest that alterations in serum osmolarity change the CSF volume and concentrations of neurotransmitter metabolites because of the osmotic arrival of water from CNS blood capillaries in all CSF compartments.

The Effect of Body Position on Intraocular and Intracranial Pressure in Rabbits.

BACKGROUND: The correlation between cerebrospinal fluid (CSF) and intraocular pressure (IOP) is still unclear. We compared CSF and IOP measured by the same invasive technique using a new experimental model in rabbits during changes of body position. METHODS: Pressure changes were recorded in the lateral ventricle (LV), the cortical subarachnoid space (CSS), and the anterior ocular chamber of anesthetized rabbits (n = 12). Animals and measuring instruments were both fixed on a board at an adequate hydrostatic level. RESULTS: In a horizontal position, control IOP (15.1 ± 1.6 cmH2O) and CSF pressure in the LV (12.4 ± 0.6 cmH2O) and CSS (12.2 ± 0.9 cmH2O) were similar during the 60-min period. When changing the body position from horizontal to vertical (upright), CSF pressures decreased drastically (LV = -5.5 ± 2.6 cmH2O and CSS = -7.7 ± 2.3 cmH2O), while the IOP decreased moderately (IOP = 13.3 ± 0.5 cmH2O). CONCLUSION: Change in body position from horizontal to vertical causes drastic changes in CSF pressure and moderate changes in IOP. Thus, IOP is not reflected by the CSF pressure. In an upright position, the values of CSF pressure were equal to the hydrostatic distance between measuring points and the foramen magnum, which suggests that CSF pressure inside the cranium depends on its anatomical and biophysical features, and not on CSF secretion and absorption.

The effects of lumboperitoneal and ventriculoperitoneal shunts on the cranial and spinal cerebrospinal fluid volume in a patient with idiopathic intracranial hypertension.

Lumboperitoneal (LP) and ventriculoperitoneal (VP) shunts are a frequent treatment modality for idiopathic intracranial hypertension (IIH). Although these shunts have been used for a long time, it is still not clear how they change the total craniospinal CSF volume and what portions of cranial and spinal CSF are affected. This report for the first time presents the results of a volumetric analysis of the total cranial and spinal CSF space in a patient with IIH. We performed an automated segmentation of the cranial and a manual segmentation of the spinal CSF space first with an LP shunt installed and again after the LP shunt was replaced by a VP shunt. When the LP shunt was in place, the total CSF volume was smaller than when the VP shunt was in place (222.4 cm(3) vs 279.2 cm(3)). The difference was almost completely the result of the spinal CSF volume reduction (49.3 cm(3) and 104.9 cm(3) for LP and VP, respectively), while the cranial CSF volume was not considerably altered (173.2 cm(3) and 174.2 cm(3) for LP and VP, respectively). This report indicates that LP and VP shunts in IIH do not considerably change the cranial CSF volume, while the reduction of CSF volume after LP shunt placement affects almost exclusively the spinal part of the CSF system. Our results suggest that an analysis of both the cranial and the spinal part of the CSF space is necessary for therapeutic procedures planning and for an early recognition of numerous side effects that often arise after shunts placement in IIH patients.

Fluid filtration and reabsorption across microvascular walls: control by oncotic or osmotic pressure? (secondary publication).

AIM: Relationships between hydrostatic and oncotic (colloid osmotic) pressures in both capillaries and interstitium are used to explain fluid filtration and reabsorption across microvascular walls. These pressures are incorporated in the Starling oncotic hypothesis of capillaries which fails, however, to explain fluid homeostasis when hydrostatic capillary pressure is high (in feet during orthostasis) and low (in lungs), or when oncotic plasma pressure is significantly decreased in experiments and some clinical states such as genetic analbuminaemia. METHODS: To explain fluid homeostasis we propose osmotic counterpressure hypothesis of capillaries which claims: 1) during water filtration across microvascular wall in arterial capillary, the plasma osmolytes are sieved (retained) so that plasma osmotic counterpressure is generated, 2) this osmotic counterpressure rises along the length of capillary and when it reaches capillary hydrostatic pressure the water filtration is halted, and 3) in venous capillaries and postcapillary venules where hydrostatic pressure is low, the osmotic counterpressure is instrumental in water reabsorption from interstitium what leads to dissipation of osmotic counterpressure. According to modified van't Hoff's equation the generation of osmotic counterpressure depends on plasma concentration of osmolytes and their restricted passage (reflection coefficient) across microvascular wall in comparison to water. RESULTS: Plasma NaCl makes 83% of plasma osmolarity and shows restricted passage across the walls of cerebral and peripheral continuous capillaries, so that Na and Cl are the most important osmolytes for generation of osmotic counterpressure. Our calculation indicates that at various rates of water filtration the osmotic counterpressure of NaCl acts as negative feedback control: higher hydrostatic pressure and water filtration rate create higher osmotic counterpressure which opposes filtration and leads to higher water reabsorption rate. Furthermore, our analysis indicates that fluid volume changes in arterial capillaries are proportionally 100 times larger than in interstial fluid. CONCLUSION: The osmotic counterpressure hypothesis explains fluid homeostasis at high, mean and low capillary hydrostatic pressures. Plasma proteins and inorganic electrolytes contribute 0.4% and 94% to plasma osmolarity, respectively, so that plasma proteins have low osmotic (oncotic) pressure and despite high restriction of their passage across microvascular wall they contribute little to build up of osmotic counterpressure in comparison to electrolytes. However, absence or very low concentration of plasma proteins increases microvascular wall permeability to water and osmolytes compromising build up of osmotic counterpressure leading to development of interstial oedema.

Measurement of cerebrospinal fluid formation and absorption by ventriculo-cisternal perfusion: what is really measured?

The generally accepted hypothesis on cerebrospinal fluid (CSF) hydrodynamics suggests that CSF is actively formed mainly by the choroid plexuses, circulates unidirectionally along the brain ventricles and subarachnoid space, and is passively absorbed mainly into the dural venous sinuses. CSF formation rate (Vf) has been extensively studied using the ventriculo-cisternal perfusion technique and the results have been used as the key evidence confirming the mentioned hypothesis. This technique and the equation for Vf calculation are based on the assumption that the dilution of the indicator substance is a consequence of the newly formed CSF, ie, that a higher CSF formation rate will result in a higher degree of dilution. However, it has been experimentally shown that the indicator substance dilution inside the CSF system does not occur because of a "newly formed" CSF, but as consequence of a number of other factors (departure of substances into the surrounding tissue, flowing around the collecting cannula into the cortical and spinal subarachnoid space, departure into the contralateral ventricle, etc). This technique allows "calculation" of the CSF formation even in dead animals, in an in vitro model, and in any other part of the CSF system outside the ventricles that is being perfused. Therefore, this method is indirect and any dilution of the indicator substance in the perfusate caused by other reasons would result in questionable and often contradictory conclusions regarding CSF formation rates.

Long lasting near-obstruction stenosis of mesencephalic aqueduct without development of hydrocephalus--case report.

The aim of this study is to present the five-year longitudinal magnetic resonance imaging (MRI) follow up of a patient with incidental finding of near-obstruction stenosis of the aqueduct of Sylvius due to a large pineal cyst. The patient was scanned 3 times on a 3T MR device using a set of standard structural sequences supplemented with high-resolution constructive interference of steady state (CISS) T2 sequence for precise delineation of the aqueduct of Sylvius and cardiac-gated phase-contrast sequences for the analysis of cerebrospinal fluid (CSF) movement. On all MR scans, the size of the pineal cyst and severity of near-obstruction aqueductal stenosis did not show any morphological changes. There was no significant ventricular enlargement although structural CISS sequence showed a near-obstruction stenosis and cardiac-gated phase-contrast sequences did not detect CSF movement through the aqueduct of Sylvius. Our findings are contradictory to the classic hypothesis of CSF physiology based on secretion, circulation, and absorption of CSF, which states that the impairment of CSF circulation through the aqueduct of Sylvius inevitably leads to a hypertensive hydrocephalus development involving the third and the lateral ventricle. Our research group previously proposed a new hypothesis of CSF physiology, which offers more suitable explanation for such clinical cases.

Volumetric analysis of cerebrospinal fluid and brain parenchyma in a patient with hydranencephaly and macrocephaly--case report.

The aim of this study was to perform for the first time the intracranial volumetric analysis of cerebrospinal fluid (CSF) and brain parenchyma in the supratentorial and infratentorial space in a 30-year-old female patient with hydranencephaly and macrocephaly. A head scan performed using a 3T magnetic resonance was followed by manual segmentation of the brain parenchyma and CSF on T2 coronal brain sections. The volume of CSF and brain parenchyma was measured separately for the supratentorial and infratentorial space. The total volume of the intracranial space was 3645.5 cm3. In the supratentorial space, the volume of CSF was 3375.2 cm3 and the volume of brain parenchyma was 80.3 cm3. In the infratentorial space, the volume of CSF was 101.3 cm3 and the volume of the brain parenchyma was 88.7 cm3. In the supratentorial space, there was severe malacia of almost all brain parenchyma with no visible remnants of the choroid plexuses. Infratentorial structures of the brainstem and cerebellum were hypoplastic but completely developed. Since our patient had no choroid plexuses in the supratentorial space and no obstruction between dural sinuses and CSF, development of hydrocephalus and macrocephaly cannot be explained by the classic hypothesis of CSF physiology with secretion, unidirectional circulation, and absorption as its basic postulates. However, the origin and turnover of the enormous amount of intracranial CSF volume, at least 10-fold larger than normal, and the mechanisms of macroencephaly development could be elucidated by the new hypothesis of CSF physiology recently published by our research team.

Changes of cerebrospinal fluid pressure gradient in different body positions under experimental impairment of cerebrospinal fluid pathway: new insight into hydrocephalus development.

It is generally accepted that hydrocephalus is a consequence of the disbalance between cerebrospinal fluid (CSF) secretion and absorption which should in turn lead to CSF pressure gradient development and ventricular enlargement. To test CSF pressure gradient role in hydrocephalus development, we experimentally caused CSF system impairment at two sites in cats. In the first group of animals, we caused Sylvian aqueduct obstruction and recorded CSF pressure changes pre and post obstruction at three measuring sites (lateral ventricle -LV, cortical-CSS and lumbar subarachnoid space -LSS) during 15 min periods and in different body positions over 360 degrees. In the second group of experiments, we caused cervical stenosis by epidural plastic semiring implantation and monitored CSF pressure changes pre and post stenosis implantation at two measuring sites (lateral ventricle and lumbar subarachnoid space) during 15 min periods in different body positions over 360 degrees. Both groups of experimental animals had similar CSF pressures before stenosis or obstruction at all measuring points in the horizontal position. During head-up verticalization, CSF pressures inside the cranium gradually became more subatmospheric with no significant difference between LV and CSS, as they are measured at the same hydrostatic level, while CSF pressure inside LSS became more positive, causing the development of a large hydrostatic gradient between the cranial and the spinal space. With cervical stenosis, CSF pressure inside the cranium is positive during head-up verticalization, while in cats with aqueductal obstruction CSF pressure inside the CSS remains negative, as it was during control period. Concomitantly, CSF pressure inside LV becomes less negative, thus creating a small hydrostatic gradient between LV and CSS. Since CSF pressure and gradient changes occur only by shifting body position from the horizontal plane, our results indicate that cervical stenosis in a head-up vertical position reduces blood perfusion of the whole brain, while aqueductal obstruction impairs only the perfusion of the local periventricular brain tissue. It seems that, for evolutionary important bipedal activity, free craniospinal communication and good spinal space compliance represent crucial biophysical parameters for adequate cerebral blood perfusion and prevention of pathophysiological changes leading to the development of hydrocephalus.

Predictive value of spinal CSF volume in the preoperative assessment of patients with idiopathic normal-pressure hydrocephalus.

Introduction: The pathophysiology, diagnosis, and management of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. Although some prognostic tests recommended in iNPH guidelines should have high sensitivity and high predictive value, there is often no positive clinical response to surgical treatment. Materials and methods: In our study, 19 patients with clinical and neuroradiological signs of iNPH were selected for preoperative evaluation and possible further surgical treatment according to the guidelines. MR volumetry of the intracranial and spinal space was performed. Patients were exposed to prolonged external lumbar drainage in excess of 10 ml per hour during 3 days. Clinical response to lumbar drainage was assessed by a walk test and a mini-mental test. Results: Twelve of 19 patients showed a positive clinical response and underwent a shunting procedure. Volumetric values of intracranial space content in responders and non-responders showed no statistically significant difference. Total CSF volume (sum of cranial and spinal CSF volumes) was higher than previously published. No correlation was found between spinal canal length, CSF pressure, and CSF spinal volume. The results show that there is a significantly higher CSF volume in the spinal space in the responder group (n = 12) (120.5 ± 14.9 ml) compared with the non-responder group (103.1 ± 27.4 ml; n = 7). Discussion: This study demonstrates for the first time that CSF volume in the spinal space may have predictive value in the preoperative assessment of iNPH patients. The results suggest that patients with increased spinal CSF volume have decreased compliance. Additional prospective randomized clinical trials are needed to confirm our results.

Dependence of cerebrospinal fluid pressure and volume on the changes in serum osmolarity in cats.

OBJECTIVES: To study the effect of blood osmolarity on cerebrospinal fluid (CSF) volume and CSF pressure in cats. METHODS: Three types of methods were used on anesthetized cats. The first, ventriculo-cisternal perfusion (12.96 µL/min) before and after i.v. application of 20% mannitol; the second, measuring the outflow of CSF by cisternal free drainage; and the third, measuring CSF pressure in the ventricles of an intact CSF system, with the second and third method being performed before and after the i.p. application of a hypo-osmolar substance (distilled water). RESULTS: In the first group, the application of 20% mannitol led to a significantly reduced (p < 0.005) outflow volume (from 12.60 ± 0.29 to 0.94 ± 0.09 µL/min). In the second group, the outflow CSF volume significantly increased (p < 0.001) after the application of distilled water (from 18.8 ± 0.3 to 28.2 ± 0.7 µL/min). In the third group, after the application of distilled water, the CSF pressure also significantly increased (p < 0.05; from 8.3 ± 0.8 to 16.1 ± 0.14 cm H(2)O). CONCLUSION: We conclude that changes in serum osmolarity change the CSF volume because of the osmotic gradient between the blood and all of the CSF compartments, and also that the change in CSF pressure is closely associated with changes in CSF volume.