A new perspective on cerebrospinal fluid dynamics after subarachnoid hemorrhage: From normal physiology to pathophysiological changes

Knowledge about the dynamic metabolism and function of cerebrospinal fluid (CSF) physiology has rapidly progressed in recent decades. It has traditionally been suggested that CSF is produced by the choroid plexus and drains to the arachnoid villi. However, recent findings have revealed that the brain parenchyma produces a large portion of CSF and drains through the perivascular glymphatic system and meningeal lymphatic vessels into the blood. The primary function of CSF is not limited to maintaining physiological CNS homeostasis but also participates in clearing waste products resulting from neurodegenerative diseases and acute brain injury. Aneurysmal subarachnoid hemorrhage (SAH), a disastrous subtype of acute brain injury, is associated with high mortality and morbidity. Post-SAH complications contribute to the poor outcomes associated with SAH. Recently, abnormal CSF flow was suggested to play an essential role in the post-SAH pathophysiological changes, such as increased intracerebral pressure, brain edema formation, hydrocephalus, and delayed blood clearance. An in-depth understanding of CSF dynamics in post-SAH events would shed light on potential development of SAH treatment options. This review summarizes and updates the latest physiological characteristics of CSF dynamics and discusses potential pathophysiological changes and therapeutic targets after SAH.

Effect of position on intracranial pressure and compliance: a cross-sectional study including 101 patients

OBJECTIVE A better understanding of the effect of position on intracranial pressure (ICP) and compliance is important for the development of treatment strategies that can restore normal cerebrospinal fluid (CSF) dynamics. There is limited knowledge on the effect of position on intracranial compliance. In this cross-sectional study the authors tested the association of pulse amplitude (PA) with position and the day/night cycle. Additionally, they describe the postural ICP and PA changes of patients with “normal” ICP dynamics. METHODS This single-center retrospective study included patients with suspected and/or confirmed CSF dynamics abnormalities who had been examined with elective 24-hour ICP monitoring between October 2017 and September 2019. Patients had been enrolled in a short exercise battery including four positions: supine, lumbar puncture position in the left lateral decubitus position, sitting, and standing. Each position was maintained for 2 minutes, and mean ICP and PA were calculated for each position. The 24-hour day and night median ICP and PA data were also collected. Linear regression models were used to test the correlation of PA with position and day/night cycle. All linear regressions were corrected for confounders. The postural ICP monitoring results of patients without obvious ICP dynamics abnormality were summarized. RESULTS One hundred one patients (24 males and 77 females) with a mean age of 39 ± 13years (mean ± standard deviation) were included in the study. The adjusted linear regression models demonstrated a significant association of ICP with position and day/night cycle, with upright (sitting and standing) and day ICP values lower than supine and night ICP values. The adjusted linear regression model was also significant for the association of PA with position and day/night cycle, with upright and day PA values higher than supine and night PA results. These associations were confirmed for patients with and without shunts. Patients without clear ICP dynamics abnormality had tighter control of their postural ICP changes than the other patients; however, the difference among groups was not statistically significant. CONCLUSIONS This is the largest study investigating the effect of postural changes on intracranial compliance. The results of this study suggest that PA, as well as ICP, is significantly associated with posture, increasing in upright positions compared to that while supine. Further studies will be needed to investigate the mechanism behind this association.

Insights of posture dependent pressure characteristics in five rats

Current shunt treatments of hydrocephalus, a condition characterized by excessive accumulation of cerebrospinal fluid (CSF) and intracranial pressure (ICP) fluctuations, suffer malfunctions caused by changes in patient’s posture. Research toward a quantitative model describing posture dependent dynamics of CSF related pressures such as ICP and blood pressure (BP) shall provide relevant information that can lead to a better understanding of CSF dynamics and thus, improved treatment outcomes. In this pilot study, ICP and femoral blood pressure (FBP) were measured concurrently in anaesthetized as well as awake and freely moving rats using radio telemetry. It was shown that despite the inherent challenges of limited space for sensor implants and rapid movements leading to strong artefacts, influences on CSF related pressure fluctuations due to posture changes can be observed in individual rats

Cerebrospinal fluid dynamics in idiopathic intracranial hypertension: a literature review and validation of contemporary findings

Background Idiopathic intracranial hypertension (IIH) is a rare disease of unknown aetiology related possibly to disturbed cerebrospinal fluid (CSF) dynamics and characterised by elevated intracranial pressure (ICP) causing optic nerve atrophy if not timely treated. We studied CSF dynamics of the IIH patients based on the available literature and our well-defined cohort. Method A literature review was performed from PubMed between 1980 and 2020 in compliance with the PRISMA guideline. Our study includes 59 patients with clinical, demographical, neuro-ophthalmological, radiological, outcome data, and lumbar CSF pressure measurements for suspicion of IIH; 39 patients had verified IIH while 20 patients did not according to Friedman’s criteria, hence referred to as symptomatic controls. Results The literature review yielded 19 suitable studies; 452 IIH patients and 264 controls had undergone intraventricular or lumbar CSF pressure measurements. In our study, the mean CSF pressure, pulse amplitudes, power of respiratory waves (RESP), and the pressure constant (P0) were higher in IIH than symptomatic controls (p < 0.01). The mean CSF pressure was higher in IIH patients with psychiatric comorbidity than without (p < 0.05). In IIH patients without acetazolamide treatment, the RAP index and power of slow waves were also higher (p < 0.05). IIH patients with excess CSF around the optic nerves had lower relative pulse pressure coefficient (RPPC) and RESP than those without (p < 0.05). Conclusions Our literature review revealed increased CSF pressure, resistance to CSF outflow and sagittal sinus pressure (SSP) as key findings in IIH. Our study confirmed significantly higher lumbar CSF pressure and increased CSF pressure waves and RAP index in IIH when excluding patients with acetazolamide treatment. In overall, the findings reflect decreased craniospinal compliance and potentially depleted cerebral autoregulation resulting from the increased CSF pressure in IIH. The increased slow waves in patients without acetazolamide may indicate issues in autoregulation, while increased P0 could reflect the increased SSP.

Immediate Impact of Yogic Breathing on Pulsatile Cerebrospinal Fluid Dynamics

Cerebrospinal fluid (CSF), a clear fluid bathing the central nervous system (CNS), undergoes pulsatile movements, and plays a critical role for the removal of waste products from the brain including amyloid beta, a protein associated with Alzheimer's disease. Regulation of CSF dynamics is critical for maintaining CNS health, and increased pulsatile CSF dynamics may alter brain's waste clearance due to increased mixing and diffusion. As such, understanding the mechanisms driving CSF movement, and interventions that influence its resultant removal of wastes from the brain is of high scientific and clinical impact. Since pulsatile CSF dynamics is sensitive and synchronous to respiratory movements, we are interested in identifying potential integrative therapies such as yogic breathing to regulate and enhance CSF dynamics, which has not been reported before. Here, we investigated the pre-intervention baseline data from our ongoing randomized controlled trial, and examined whether yogic breathing immediately impacts pulsatile CSF dynamics compared to spontaneous breathing. We utilized our previously established non-invasive real-time phase contrast magnetic resonance imaging (RT-PCMRI) approach using a 3T MRI instrument, and computed and rigorously tested differences in CSF velocities (instantaneous, respiratory, cardiac 1st and 2nd harmonics) at the level of foramen magnum during spontaneous versus four yogic breathing patterns. In examinations of 18 healthy participants (eight females, ten males; mean age 34.9 ± 14 (SD) years; age range: 18-61 years), we discovered immediate increase in cranially-directed velocities of instantaneous-CSF 16% - 28% and respiratory-CSF 60% - 118% during yogic versus spontaneous breathing, with most statistically significant changes during deep abdominal breathing (28%, p=0.0008, and 118%, p=0.0001, respectively). Further, cardiac pulsation was the primary source of pulsatile CSF during all breathing conditions except during deep abdominal breathing, when there was a comparable contribution of respiratory and cardiac 1st harmonic power [0.59 ± 0.78], demonstrating respiration can be the primary regulator of CSF depending on individual differences in breath depth and location. Further work is needed to investigate the impact of sustained training yogic breathing on increased pulsatile CSF dynamics and brain waste clearance for CNS health.

Cumulative Damage: Cell Death in Posthemorrhagic Hydrocephalus of Prematurity

Globally, approximately 11% of all infants are born preterm, prior to 37 weeks’ gestation. In these high-risk neonates, encephalopathy of prematurity (EoP) is a major cause of both morbidity and mortality, especially for neonates who are born very preterm (<32 weeks gestation). EoP encompasses numerous types of preterm birth-related brain abnormalities and injuries, and can culminate in a diverse array of neurodevelopmental impairments. Of note, posthemorrhagic hydrocephalus of prematurity (PHHP) can be conceptualized as a severe manifestation of EoP. PHHP impacts the immature neonatal brain at a crucial timepoint during neurodevelopment, and can result in permanent, detrimental consequences to not only cerebrospinal fluid (CSF) dynamics, but also to white and gray matter development. In this review, the relevant literature related to the diverse mechanisms of cell death in the setting of PHHP will be thoroughly discussed. Loss of the epithelial cells of the choroid plexus, ependymal cells and their motile cilia, and cellular structures within the glymphatic system are of particular interest. Greater insights into the injuries, initiating targets, and downstream signaling pathways involved in excess cell death shed light on promising areas for therapeutic intervention. This will bolster current efforts to prevent, mitigate, and reverse the consequential brain remodeling that occurs as a result of hydrocephalus and other components of EoP.

From head micro-motions towards CSF dynamics and non-invasive intracranial pressure monitoring

Continuous monitoring of the intracranial pressure (ICP) is essential in neurocritical care. There are a variety of ICP monitoring systems currently available, with the intraventricular fluid filled catheter transducer currently representing the “gold standard”. As the placement of catheters is associated with the attendant risk of infection, hematoma formation, and seizures, there is a need for a reliable, non-invasive alternative. In the present study we suggest a unique theoretical framework based on differential geometry invariants of cranial micro-motions with the potential for continuous non-invasive ICP monitoring in conservative traumatic brain injury (TBI) treatment. As a proof of this concept, we have developed a pillow with embedded mechanical sensors and collected an extensive dataset (> 550 h on 24 TBI coma patients) of cranial micro-motions and the reference intraparenchymal ICP. From the multidimensional pulsatile curve we calculated the first Cartan curvature and constructed a ”fingerprint” image (Cartan map) associated with the cerebrospinal fluid (CSF) dynamics. The Cartan map features maxima bands corresponding to a pressure wave reflection corresponding to a detectable skull tremble. We give evidence for a statistically significant and patient-independent correlation between skull micro-motions and ICP time derivative. Our unique differential geometry-based method yields a broader and global perspective on intracranial CSF dynamics compared to rather local catheter-based measurement and has the potential for wider applications.

Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug’s physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.