Proteomic profile and predictive markers of outcome in patients with subarachnoid hemorrhage.

BACKGROUND: The molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making. METHODS: Ventricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC). RESULTS: CSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale. CONCLUSIONS: We here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.

Elevated systemic venous pressures as a possible pathology in prepubertal pediatric idiopathic intracranial hypertension.

BACKGROUND: Pediatric idiopathic intracranial hypertension (IIH) is a rare and challenging condition. As implied by the nomenclature, the etiologies remain unknown, and multiple etiologies are being investigated. In this study, we explored the potential role of increased systemic or cerebral venous pressure in the pathogenesis. METHOD: An observational cohort study following the STROBE guidelines, including prepubertal children with clinical symptoms and imaging findings consistent with IIH referred to the neurosurgical department, was conducted. The patients underwent a comprehensive diagnostic protocol, including MRI, continuous intracranial pressure (ICP) monitoring, and endovascular venography with venous pressure measurements. RESULTS: The study included 11 consecutive patients (six boys and five girls) with an average age of 2.3 years, and an average BMI of 18.4. Among these, one patient was found to have venous stenosis with a gradient; the other 10 patients presented with normal intracranial anatomy. All patients exhibited elevated venous pressures, with an average superior sagittal sinus pressure of 18.9 mmHg, average internal jugular vein pressure of 17.0 mmHg, and average central venous pressure of 15.9 mmHg. Daytime ICP averaged 12.9 mmHg, whereas nighttime ICP averaged 17.2 mmHg with either A- or B-waves in 10 of the 11 patients. Despite pathological ICP, only three patients had papilledema. CONCLUSIONS: All patients had an increased systemic venous pressure, indicating a possible pathological factor for prepubertal IIH. Additionally, our findings show that young children often only partly meet the Friedman criteria due to a lack of papilledema, emphasizing the need for pediatric-specific diagnostic criteria. Further large-scale studies are needed to confirm these findings and to explore the underlying reasons for this increase in venous pressure and potential new treatment avenues.

Ventricular CSF proteomic profiles and predictors of surgical treatment outcome in chronic hydrocephalus.

BACKGROUND: By applying an unbiased proteomic approach, we aimed to search for cerebrospinal fluid (CSF) protein biomarkers distinguishing between obstructive and communicating hydrocephalus in order to improve appropriate surgical selection for endoscopic third ventriculostomy vs. shunt implants. Our second study purpose was to look for potential CSF biomarkers distinguishing between patients with adult chronic hydrocephalus benefitting from surgery (responders) vs. those who did not (non-responders). METHODS: Ventricular CSF samples were collected from 62 patients with communicating hydrocephalus and 28 patients with obstructive hydrocephalus. CSF was collected in relation to the patients' surgical treatment. As a control group, CSF was collected from ten patients with unruptured aneurysm undergoing preventive surgery (vascular clipping). RESULTS: Mass spectrometry-based proteomic analysis of the samples identified 1251 unique proteins. No proteins differed significantly between the communicating hydrocephalus group and the obstructive hydrocephalus group. Four proteins were found to be significantly less abundant in CSF from communicating hydrocephalus patients compared to control subjects. A PCA plot revealed similar proteomic CSF profiles of obstructive and communicating hydrocephalus and control samples. For obstructive hydrocephalus, ten proteins were found to predict responders from non-responders. CONCLUSION: Here, we show that the proteomic profile of ventricular CSF from patients with hydrocephalus differs slightly from control subjects. Furthermore, we find ten predictors of response to surgical outcome (endoscopic third ventriculostomy or ventriculo-peritoneal shunt) in patients with obstructive hydrocephalus.

The ASPECT Hydrocephalus System: a non-hierarchical descriptive system for clinical use.

In patients with hydrocephalus, prognosis and intervention are based on multiple factors. This includes, but is not limited to, time of onset, patient age, treatment history, and obstruction of cerebrospinal fluid flow. Consequently, several distinct hydrocephalus classification systems exist. The International Classification of Diseases (ICD) is universally applied, but in ICD-10 and the upcoming ICD-11, hydrocephalus diagnoses incorporate only a few factors, and the hydrocephalus diagnoses of the ICD systems are based on different clinical measures. As a consequence, multiple diagnoses can be applied to individual cases. Therefore, similar patients may be described with different diagnoses, while clinically different patients may be diagnosed identically. This causes unnecessary dispersion in hydrocephalus diagnostics, rendering the ICD classification of little use for research and clinical decision-making. This paper critically reviews the ICD systems for scientific and functional limitations in the classification of hydrocephalus and presents a new descriptive system. We propose describing hydrocephalus by a system consisting of six clinical key factors of hydrocephalus: A (anatomy); S (symptomatology); P (previous interventions); E (etiology); C (complications); T (time-onset and current age). The "ASPECT Hydrocephalus System" is a systematic, nuanced, and applicable description of patients with hydrocephalus, with a potential to resolve the major issues of previous classifications, thus providing new opportunities for standardized treatment and research.

Posthemorrhagic Hydrocephalus in Patients with Subarachnoid Hemorrhage Occurs Independently of CSF Osmolality.

The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.

B-waves are present in patients without intracranial pressure disturbances.

Intracranial pressure (ICP) B-waves are defined as short, repeating elevations of ICP of up to 50 mmHg with a frequency of 0.5-2 waves/min. The presence of B-waves in overnight recordings is regarded as a pathological phenomenon. However, the physiology of B-waves is still not fully understood and studies with transcranial Doppler, as a surrogate marker for ICP, have suggested that B-waves could be a normal physiological phenomenon. We present four patients without known structural neurological disease other than a coincidentally found unruptured intracranial aneurysm. One of the patients had experienced well-controlled epilepsy for several years, but was included because ICP under these conditions is unlikely to be abnormal. Following informed consent, all four patients had a telemetric ICP probe implanted during a prophylactic operation with closure of the aneurysm. They underwent overnight ICP monitoring with simultaneous polysomnography (PSG) sleep studies at 8 weeks after the operation. These patients exhibited nocturnal B-waves, but did not have major structural brain lesions. Their ICP values were within the normal range. Nocturnal B-waves occurred in close association with sleep-disordered breathing (SDB) in rapid eye movement (REM) and non-REM sleep stages. SDB during REM sleep was associated with ramp-type B-waves; SDB during non-REM sleep was associated with the sinusoidal type of B-wave. We propose that B-waves are a physiological phenomenon associated with SDB and that the mechanical changes during respiration could have an essential and previously unrecognised role in the generation of B-waves.

Telemetric intracranial pressure monitoring in children.

PURPOSE: Repeated intracranial pressure (ICP) measurements are essential in treatment of patients with complex cerebrospinal fluid (CSF) disorders. These patients often have a long surgical history with numerous invasive lumbar or intracranial pressure monitoring sessions and/or ventriculoperitoneal (VP) shunt revisions. Telemetric ICP monitoring might be an advantageous tool in treatment of these patients. In this paper, we evaluate our experience with this technology in paediatric patients. METHODS: During a 4-year period, we implanted telemetric ICP sensors (Raumedic NEUROVENT-P-tel) in 20 paediatric patients to minimise the number of future invasive procedures. Patients were diagnosed with hydrocephalus, idiopathic intracranial hypertension (IIH) or an arachnoid cyst. Most patients (85%) had a VP shunt at the time of sensor implantation. RESULTS: In total, 32 sensors were inserted in the 20 patients; the cause of re-implantation was technical malfunction of the implant. One sensor was explanted due to wound infection and one due to skin erosion. We experienced no complications directly related to the implantation/explantation procedures. A total of 149 recording sessions were conducted, including 68 home monitoring sessions. The median implantation period was 523 days with a median duration of clinical use at 202 days. The most likely consequence of a recording session was non-surgical treatment alteration (shunt valve adjustment or acetazolamide dose adjustment). CONCLUSION: Telemetric ICP monitoring in children is safe and potentially decreases the number of invasive procedures. We find that telemetric ICP monitoring aids the clinical management of patients with complex CSF disorders and improves everyday life for both patient and parents. It allows continuous ICP measurement in the patient's home and thereby potentially reducing hospitalisations, leading to significant cost savings.

Changes in intracranial pressure and pulse wave amplitude during postural shifts.

BACKGROUND: Monitoring of intracranial pressure (ICP) and ICP pulse wave amplitude (PWA) is an integrated part of neurosurgery. An increase in ICP usually leads to an increase in PWA. These findings have yet to be replicated during the positional shift from supine to upright, where we only know that ICP decreases. Our main aim is to clarify whether the positional shift also results in a change in pulse wave amplitude. METHOD: Our database was retrospectively reviewed for subjects having had a standardized investigation of positional ICP. In all subjects, mean ICP and PWA were determined with both an automatic and a manual method and compared using Student's t test. Finally, ICP and PWA were tested for correlation in both in supine and upright position. RESULTS: The study included 29 subjects. A significant change in ICP (Δ14.1 mmHg, p < 0.01) and no significant change in PWA (Δ0.4 mmHg, p = 0.06) were found. Furthermore, a linear correlation between ICP and PWA was found in both supine and upright positions (p < 0.01). CONCLUSIONS: We found that during the positional shift from supine to upright, ICP is reduced while PWA remains unaffected. This indicates that the pressure-volume curve is shifted downward according to a hydrostatic pressure offset, while the slope of the curve does not change. In addition, the correlation between ICP and PWA in both supine and upright position validates the previous research on the matter.

Telemetry in intracranial pressure monitoring: sensor survival and drift.

BACKGROUND: Telemetric intracranial pressure (ICP) monitoring enable long-term ICP monitoring on patients during normal day activities and may accordingly be of use during evaluation and treatment of complicated ICP disorders. However, the benefits of such equipment depend strongly on the validity of the recordings and how often the telemetric sensor needs to be re-implanted. This study investigates the clinical and technical sensor survival time and drift of the telemetric ICP sensor: Raumedic Neurovent-P-tel. METHODS: Implanted telemetric ICP sensors in the period from January 2011 to December 2017 were identified, and medical records reviewed for complications, explantation reasons, and parameters relevant for determining clinical and technical sensor survival time. Explanted sensors were tested in an experimental setup to study baseline drift. RESULTS: In total, implantation of 119 sensors were identified. Five sensors (4.2%) were explanted due to skin damage, three (2.5%) due to wound infection, and two (1.7%) due to ethylene oxide allergy. No other complications were observed. The median clinical sensor survival time was 208 days (95% CI 150-382). The median technical sensor survival time was 556 days (95% CI 382-605). Explanted sensors had a median baseline drift of 2.5 mmHg (IQR 2.0-5.5). CONCLUSION: In most cases, the ICP sensor provides reliable measurements beyond the approved implantation time of 90 days. Thus, the sensor should not be routinely removed after this period, if ICP monitoring is still indicated. However, some sensors showed technical malfunction prior to the CE-approval, underlining that caution should always be taken when analyzing telemetric ICP curves.

Intracranial pressure following surgery of an unruptured intracranial aneurysm-a model for normal intracranial pressure in humans.

OBJECTIVE: Optimizing the treatment of several neurosurgical and neurological disorders relies on knowledge of the intracranial pressure (ICP). However, exploration of normal ICP and intracranial pressure pulse wave amplitude (PWA) values in healthy individuals poses ethical challenges, and thus the current documentation remains scarce. This study explores ICP and PWA values for healthy adults without intracranial pathology expected to influence ICP. METHODS: Adult patients (age > 18 years) undergoing surgery for an unruptured intracranial aneurysm without any other neurological co-morbidities were included. Patients had a telemetric ICP sensor inserted, and ICP was measured in four different positions: supine, lateral recumbent, standing upright, and 45-degree sitting, at day 1, 14, 30, and 90 following the surgery. RESULTS: ICP in each position did not change with time after surgery. Median ICP was 6.7 mmHg and median PWA 2.1 mmHg in the supine position, while in the upright standing position median ICP was - 3.4 mmHg and median PWA was 1.9 mmHg. After standardization of the measurements from the transducer site to the external acoustic meatus, the median ICPmidbrain was 8.3 mmHg in the supine position and 1.2 mmHg in the upright standing position. CONCLUSION: Our study provides insights into normal ICP dynamics in healthy adults following a uncomplicated surgery for an unruptured aneurysm. These results suggest a slightly wider normal reference range for invasive intracranial pressure than previously suggested, and present the first normal values for PWA in different positions. Further studies are, however, essential to enhance our understanding of normal ICP. Trial registration The study was preregistered at www. CLINICALTRIALS: gov (NCT03594136) (11 July 2018).

Distinct Cerebrospinal Fluid Lipid Signature in Patients with Subarachnoid Hemorrhage-Induced Hydrocephalus.

Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic's landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.

Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters.

INTRODUCTION: Posthemorrhagic hydrocephalus (PHH) often develops following hemorrhagic events such as intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Treatment is limited to surgical diversion of the cerebrospinal fluid (CSF) since no efficient pharmacological therapies are available. This limitation follows from our incomplete knowledge of the molecular mechanisms underlying the ventriculomegaly characteristic of PHH. Here, we aimed to elucidate the molecular coupling between a hemorrhagic event and the subsequent PHH development, and reveal the inflammatory profile of the PHH pathogenesis. METHODS: CSF obtained from patients with SAH was analyzed for inflammatory markers using the proximity extension assay (PEA) technique. We employed an in vivo rat model of IVH to determine ventricular size, brain water content, intracranial pressure, and CSF secretion rate, as well as for transcriptomic analysis. Ex vivo radio-isotope assays of choroid plexus transport were employed to determine the direct effect of choroidal exposure to blood and inflammatory markers, both with acutely isolated choroid plexus and after prolonged exposure obtained with viable choroid plexus kept in tissue culture conditions. RESULTS: The rat model of IVH demonstrated PHH and associated CSF hypersecretion. The Na+/K+-ATPase activity was enhanced in choroid plexus isolated from IVH rats, but not directly stimulated by blood components. Inflammatory markers that were elevated in SAH patient CSF acted on immune receptors upregulated in IVH rat choroid plexus and caused Na+/K+/2Cl- cotransporter 1 (NKCC1) hyperactivity in ex vivo experimental conditions. CONCLUSIONS: CSF hypersecretion may contribute to PHH development, likely due to hyperactivity of choroid plexus transporters. The hemorrhage-induced inflammation detected in CSF and in the choroid plexus tissue may represent the underlying pathology. Therapeutic targeting of such pathways may be employed in future treatment strategies towards PHH patients.

Lysophosphatidic acid as a CSF lipid in posthemorrhagic hydrocephalus that drives CSF accumulation via TRPV4-induced hyperactivation of NKCC1.

BACKGROUND: A range of neurological pathologies may lead to secondary hydrocephalus. Treatment has largely been limited to surgical cerebrospinal fluid (CSF) diversion, as specific and efficient pharmacological options are lacking, partly due to the elusive molecular nature of the CSF secretion apparatus and its regulatory properties in physiology and pathophysiology. METHODS: CSF obtained from patients with subarachnoid hemorrhage (SAH) and rats with experimentally inflicted intraventricular hemorrhage (IVH) was analyzed for lysophosphatidic acid (LPA) by alpha-LISA. We employed the in vivo rat model to determine the effect of LPA on ventricular size and brain water content, and to reveal the effect of activation and inhibition of the transient receptor potential vanilloid 4 (TRPV4) ion channel on intracranial pressure and CSF secretion rate. LPA-mediated modulation of TRPV4 was determined with electrophysiology and an ex vivo radio-isotope assay was employed to determine the effect of these modulators on choroid plexus transport. RESULTS: Elevated levels of LPA were observed in CSF obtained from patients with subarachnoid hemorrhage (SAH) and from rats with experimentally-inflicted intraventricular hemorrhage (IVH). Intraventricular administration of LPA caused elevated brain water content and ventriculomegaly in experimental rats, via its action as an agonist of the choroidal transient receptor potential vanilloid 4 (TRPV4) channel. TRPV4 was revealed as a novel regulator of ICP in experimental rats via its ability to modulate the CSF secretion rate through its direct activation of the Na+/K+/2Cl- cotransporter (NKCC1) implicated in CSF secretion. CONCLUSIONS: Together, our data reveal that a serum lipid present in brain pathologies with hemorrhagic events promotes CSF hypersecretion and ensuing brain water accumulation via its direct action on TRPV4 and its downstream regulation of NKCC1. TRPV4 may therefore be a promising future pharmacological target for pathologies involving brain water accumulation.

Reference values for intracranial pressure and lumbar cerebrospinal fluid pressure: a systematic review.

BACKGROUND: Although widely used in the evaluation of the diseased, normal intracranial pressure and lumbar cerebrospinal fluid pressure remain sparsely documented. Intracranial pressure is different from lumbar cerebrospinal fluid pressure. In addition, intracranial pressure differs considerably according to the body position of the patient. Despite this, the current reference values do not distinguish between intracranial and lumbar cerebrospinal fluid pressures, and body position-dependent reference values do not exist. In this study, we aim to establish these reference values. METHOD: A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and Web of Sciences. Methodological quality was assessed using an amended version of the Joanna Briggs Quality Appraisal Checklist. Intracranial pressure and lumbar cerebrospinal fluid pressure were independently evaluated and subdivided into body positions. Quantitative data were presented with mean ± SD, and 90% reference intervals. RESULTS: Thirty-six studies were included. Nine studies reported values for intracranial pressure, while 27 reported values for the lumbar cerebrospinal fluid pressure. Reference values for intracranial pressure were - 5.9 to 8.3 mmHg in the upright position and 0.9 to 16.3 mmHg in the supine position. Reference values for lumbar cerebrospinal fluid pressure were 7.2 to 16.8 mmHg and 5.7 to 15.5 mmHg in the lateral recumbent position and supine position, respectively. CONCLUSIONS: This systematic review is the first to provide position-dependent reference values for intracranial pressure and lumbar cerebrospinal fluid pressure. Clinically applicable reference values for normal lumbar cerebrospinal fluid pressure were established, and are in accordance with previously used reference values. For intracranial pressure, this study strongly emphasizes the scarcity of normal pressure measures, and highlights the need for further research on the matter.

Deciding on Appropriate Telemetric Intracranial Pressure Monitoring System.

BACKGROUND: The clinical advantage of telemetric intracranial pressure (ICP) monitoring has previously been limited by issues with inaccuracy and zero-drift. Today, 2 comparable telemetric ICP monitoring systems are available performing adequately in these parameters. The objective of this study is to identify appropriate uses of each system. METHODS: The 2 telemetric ICP monitoring systems from Raumedic (implant: Neurovent-P-tel) and Miethke (implant: Sensor Reservoir) are compared in terms of fundamental differences, sensor survival, monitoring possibilities, complications, and cost/benefit. Two illustrative cases are presented highlighting clinical advantages and disadvantages of each system. RESULTS: Both systems provide transdermal (telemetric) ICP measurements through external application of a reader unit cabled to a portable data sampler. Thereby, they allow several ICP monitoring sessions without multiple surgical insertions of a cabled ICP sensor. The Miethke implant has a high sampling frequency (40 Hz) and a long CE (Conformité Européenne) approval (3 years) but cannot be used for long-duration monitoring sessions. In comparison, the Raumedic implant has a lower sampling frequency (5 Hz) and shorter CE approval (90 days) but can be used for long-duration monitoring sessions. The standard 3-year cost for a patient with a Neurovent-P-tel is 17,380 €, and for the Sensor Reservoir it is 15,790 €. CONCLUSIONS: The Miethke system is useful in outpatient clinics where patients have sequential point measurements of ICP performed, whereas the Raumedic system is ideal for long-duration ICP monitoring outside the hospital. When choosing between the 2 systems, it must primarily be decided if the clinical situation requires long-duration monitoring sessions or continuous repeated ambulatory follow-up sessions.