Influence of cerebrospinal fluid drainage in the first days after aneurysm rupture on the severity of early brain injury following aneurysmal subarachnoid hemorrhage.

PURPOSE: Progressive cerebral edema with refractory intracranial hypertension (ICP) requiring decompressive hemicraniectomy (DHC) is a severe manifestation of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH). The purpose of the study was to investigate whether a more pronounced cerebrospinal fluid (CSF) drainage has an influence on cerebral perfusion pressure (CPP) and the extent of EBI after aSAH. METHODS: Patients with aSAH and indication for ICP-monitoring admitted to our center between 2012 and 2020 were retrospectively included. EBI was categorized based on intracranial blood burden, persistent loss of consciousness, and SEBES (Subarachnoid Hemorrhage Early Brain Edema Score) score on the third day after ictus. The draining CSF and vital signs such as ICP and CPP were documented daily. RESULTS: 90 out of 324 eligible aSAH patients (28%) were included. The mean age was 54.2 ± 11.9 years. DHC was performed in 24% (22/90) of patients. Mean CSF drainage within 72 h after ictus was 168.5 ± 78.5 ml. A higher CSF drainage within 72 h after ictus correlated with a less severe EBI and a less frequent need for DHC (r=-0.33, p = 0.001) and with a higher mean CPP on day 3 after ictus (r = 0.2351, p = 0.02). CONCLUSION: A more pronounced CSF drainage in the first 3 days of aSAH was associated with higher CPP and a less severe course of EBI and required less frequently a DHC. These results support the hypothesis that an early and pronounced CSF drainage may facilitate blood clearance and positively influence the course of EBI.

Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks.

BACKGROUND: Malignant cerebral edema is a devastating complication of stroke, resulting in deterioration and death if hemicraniectomy is not performed prior to herniation. Current approaches for predicting this relatively rare complication often require advanced imaging and still suffer from suboptimal performance. We performed a pilot study to evaluate whether neural networks incorporating data extracted from routine computed tomography (CT) imaging could enhance prediction of edema in a large diverse stroke cohort. METHODS: An automated imaging pipeline retrospectively extracted volumetric data, including cerebrospinal fluid (CSF) volumes and the hemispheric CSF volume ratio, from baseline and 24 h CT scans performed in participants of an international stroke cohort study. Fully connected and long short-term memory (LSTM) neural networks were trained using serial clinical and imaging data to predict those who would require hemicraniectomy or die with midline shift. The performance of these models was tested, in comparison with regression models and the Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score, using cross-validation to construct precision-recall curves. RESULTS: Twenty of 598 patients developed malignant edema (12 required surgery, 8 died). The regression model provided 95% recall but only 32% precision (area under the precision-recall curve [AUPRC] 0.74), similar to the EDEMA score (precision 28%, AUPRC 0.66). The fully connected network did not perform better (precision 33%, AUPRC 0.71), but the LSTM model provided 100% recall and 87% precision (AUPRC 0.97) in the overall cohort and the subgroup with a National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 (p = 0.0001 vs. regression and fully connected models). Features providing the most predictive importance were the hemispheric CSF ratio and NIHSS score measured at 24 h. CONCLUSIONS: An LSTM neural network incorporating volumetric data extracted from routine CT scans identified all cases of malignant cerebral edema by 24 h after stroke, with significantly fewer false positives than a fully connected neural network, regression model, and the validated EDEMA score. This preliminary work requires prospective validation but provides proof of principle that a deep learning framework could assist in selecting patients for surgery prior to deterioration.

Perivascular abnormalities in pediatric encephalopathy with fulminant brain edema.

BACKGROUND: Acute encephalopathy with acute brain swelling (ABS) is a recently proposed disease of unknown etiology, characterized by rapid progression to whole-brain swelling. To our knowledge, we reported the first case of a patient with acute encephalopathy with ABS wherein brain magnetic resonance imaging (MRI) abnormalities were noted prior to the diffuse brain swelling onset. CASE PRESENTATION: An 11-year-old boy was admitted to our unit owing to prolonged disturbance of consciousness following febrile status epilepticus. At the initial visit, the vital signs were within the normal range, except for the body temperature and consciousness level (Glasgow Coma Scale 6; E1V1M4). The initial laboratory results showed elevated inflammatory marker levels and mild hyponatremia. Cerebrospinal fluid analysis revealed albuminocytologic dissociation, whereas the myelin basic protein level was not elevated. Electroencephalography showed diffuse, high-amplitude slow waves. No abnormalities were detected on the initial brain computed tomography (CT) scan. However, at 11 h after the seizure onset, diffuse hyperintense lesions were observed throughout the cerebrum on T2-weighted brain MRI. The patient was diagnosed with acute encephalopathy and received methylprednisolone-pulse therapy (1 g) with high-dose gamma globulin (1 g/kg) administration. At 14 h after the seizure onset, the patient was declared brain-dead; the brain CT findings revealed whole-brain swelling and herniation. CONCLUSION: Our findings were suggestive of a perivascular pathophysiology and may be used for subtyping acute encephalopathy. In cases where such findings are observed, subsequent development of severe diffuse brain swelling should be considered.

Putting 'CSF-Shift Edema' Hypothesis to Test: Comparing Cisternal and Parenchymal Pressures After Basal Cisternostomy for Head Injury.

BACKGROUND: Increased brain edema in head injury is due to shift of cerebrospinal fluid (CSF) from cisterns at high pressure to brain parenchyma at low pressure. By opening basal cisterns and decreasing the increased cisternal pressure, basal cisternostomy (BC) results in reversal of CSF shift from parenchyma to cisterns, leading to decreased brain edema. Though the CSF-shift edema hypothesis is based on pressure difference between cisterns and brain parenchyma, the relationship of these pressures has not been studied. METHODS: A prospective clinical study was conducted from November 2018 to March 2020 including adult patients with head injury who were candidates for standard decompressive hemicraniectomy (DHC). All patients had neurological assessment and head computed tomography preoperatively and postoperatively. All patients underwent BC with DHC. Postoperatively, parenchymal and cisternal pressures and neurological condition were monitored hourly for 72 hours. RESULTS: Nine (5 men, 4 women) patients with head injury (mean age, 45.7 years; range, 25-72 years) underwent DHC-BC. Median Glasgow Coma Scale score of patients at admission was 8 (range, 4-14), and median midline shift on computed tomography was 8 mm (range, 7-12 mm). There was a significant difference between opening (25.70 ± 10.48 mm Hg) and closing (11.30 ± 5.95 mm Hg) parenchymal pressures (t9 = 3.963, P = 0.003). Immediate postoperative cisternal pressure was 1-11 mm Hg and was lower than immediate postoperative parenchymal pressure in all except 1 patient. Postoperatively, if cisternal pressure remained low, parenchymal pressure also decreased, and patients showed clinical improvement. Patients showing increased cisternal pressure showed increased parenchymal pressure and clinical worsening. CONCLUSIONS: Our study supports the CSF-shift edema hypothesis. Following DHC-BC, cisternal pressure is lowered to near-atmospheric pressure, and its relationship to parenchymal pressure predicts the future course of patients by reversal or re-reversal of CSF shift.

Amount of Brain Edema Correlates With Neurologic Recovery in Pediatric Cerebral Malaria.

BACKGROUND: Cerebral malaria (CM) remains a leading cause of mortality and morbidity in children in sub-Saharan Africa. Recent studies using brain magnetic resonance imaging have revealed increased brain volume as a major predictor of death. Similar morphometric predictors of morbidity at discharge are lacking. The aim of this study was to investigate the utility of serial cranial cisternal cerebrospinal fluid (CSF) volume measurements in predicting morbidity at discharge in pediatric CM survivors. METHODS: In this case-control study, 54 Malawian pediatric CM survivors with neurologic sequelae evident at discharge who underwent serial magnetic resonance imaging scans while comatose were matched to concurrently admitted children with serial imaging who made full recoveries. Serial cranial cisternal CSF volume quantified by radiologists blinded to outcome was evaluated as a predictor of neurologic deficits at discharge. The probability of neurologic sequelae was determined using a model that included coma duration and changes in cisternal CSF volume over time. RESULTS: Coma duration before admission was similar between cases and controls (16.1 vs. 15.3; P = 0.81), but overall coma was longer among children with sequelae (60 vs. 38 hours; P < 0.01). Lower initial CSF volumes and decreased volumes over time were both associated with a higher probability of neurologic sequelae at discharge. CONCLUSIONS: Among pediatric CM survivors with prolonged coma, lower initial CSF volume and decreasing volume during coma is associated with neurologic sequelae at discharge. These findings suggest that cerebral edema is an underlying contributor to both morbidity and mortality in pediatric CM.

Cerebrospinal fluid influx drives acute ischemic tissue swelling.

Stroke affects millions each year. Poststroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here, we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of poststroke edema needs to be revised, and these findings could provide a conceptual basis for development of alternative treatment strategies.

Selective mGluR1 Negative Allosteric Modulator Reduces Blood-Brain Barrier Permeability and Cerebral Edema After Experimental Subarachnoid Hemorrhage.

The blood-brain barrier (BBB) disruption leads to the vasogenic brain edema and contributes to the early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the mechanisms underlying the BBB damage following SAH are poorly understood. Here we reported that the neurotransmitter glutamate of cerebrospinal fluid (CSF) was dramatically increased in SAH patients with symptoms of cerebral edema. Using the rat SAH model, we found that SAH caused the increase of CSF glutamate level and BBB permeability in EBI, intracerebroventricular injection of exogenous glutamate deteriorated BBB damage and cerebral edema, while intraperitoneally injection of metabotropic glutamate receptor 1(mGluR1) negative allosteric modulator JNJ16259685 significantly attenuated SAH-induced BBB damage and cerebral edema. In an in vitro BBB model, we showed that glutamate increased monolayer permeability of human brain microvascular endothelial cells (HBMEC), whereas JNJ16259685 preserved glutamate-damaged BBB integrity in HBMEC. Mechanically, glutamate downregulated the level and phosphorylation of vasodilator-stimulated phosphoprotein (VASP), decreased the tight junction protein occludin, and increased AQP4 expression at 72 h after SAH. However, JNJ16259685 significantly increased VASP, p-VASP, and occludin, and reduced AQP level at 72 h after SAH. Altogether, our results suggest an important role of glutamate in disruption of BBB function and inhibition of mGluR1 with JNJ16259685 reduced BBB damage and cerebral edema after SAH.

Sanctuary site central nervous system relapse-refractory DLBCL responding to nivolumab and lenalidomide.

Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. In diffuse large B-cell lymphoma (DLBCL), the incidence of CNS relapse is only ∼5% in unselected cohorts. Immunotherapy is the treatment that either boosts the patient's own immune system or uses man-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth. We are presenting a thirty-eight year old man who, presented with neck nodes, axillary nodes, altered sensorium, abnormal body movements, unconsciousness, weight loss and, fever, with a past history of DLBCL in May 2008, treated with 6 cycles of CHOP and completed in November 2008. After 9 years in April 2018, the patient developed similar symptoms and treated with salvage chemotherapy with R-DHAP which was completed in September 2018. Post-treatment PET-CT showed partial metabolic response and we started external beam radiotherapy to initial bulky disease. After completion of radiotherapy, the patient was very reluctant for any type of therapy and went home. After one month he presented to us with persistent vomiting, abnormal body movements and, altered sensorium. On examination, his Glasgow Coma Scale (GCS) was E2V3M2 and he was admitted in Intensive Care Unit. The patient was managed with mannitol, dexamethasone, antiepileptics, antibiotics and other supportive care medicines. His brain magnetic resonance imaging (MRI) was showing multiple heterogeneously enhancing lesions with surrounding vasogenic oedema and his cerebrospinal fluid analysis was positive for malignant cells. He was managed with triple intrathecal chemotherapy with methotrexate 12 mg, Cytarabine 50 mg, and Hydrocortisone 50 mg along with other supportive care medicines, and after 4-5 days he regained consciousness and he was able to talk and understand verbal commands. In view of improvement in general condition and performance status, we started biweekly triple intra-thecal therapy, and Inj. Nivolumab 3 mg per kg q 2 weekly. From the second cycle, we started Lenalidomide 10 mg once a day for 21 days with 7 days gap along with 2 weekly nivolumab and biweekly triple IT chemotherapy. After one month his CSF analysis was negative for malignant cells. Now he is on regular treatment with weekly IT chemotherapy, 2 weekly nivolumab and 3 weeks on and one week off lenalidomide. After 2 months of treatment, his MRI Brain was showing. At the time of submission of this article, he has completed the fifth cycle of immunotherapy and two cycles of lenalidomide. He was able to manage his daily ADL and able to walk with a stick. The patient tolerated immunotherapy, triple IT therapy and lenalidomide very well without much intolerable side effects. Therefore, we concluded that nivolumab and lenalidomide was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory sanctuary site CNS B- cell lymphomas. Additional studies of Nivolumab and lenalidomide in these diseases are ongoing.

Usefulness of a quantitative analysis of the cerebrospinal fluid volume proportion in brain computed tomography for predicting neurological prognosis in cardiac arrest survivors who undergo target temperature management.

PURPOSE: Brain swelling post-cardiac arrest may affect cerebrospinal fluid volume. We aimed to investigate the prognostic performance of the proportion of cerebrospinal fluid volume (pCSFV) using brain computed tomography (CT) in cardiac arrest survivors. MATERIALS AND METHODS: This retrospective multicentre study included adult comatose cardiac arrest survivors who underwent brain CT scan prior to target temperature management (TTM) from 2015 to 2016. Grey-to-white matter ratio (GWR) and pCSFV values were calculated. pCSFV analysis was performed using automated quantitative analysis programming. The primary outcome was a 6-month neurological outcome. RESULTS: Of 251 patients (median age, 57 years), 173 (68.9%) were male, 87 (34.7%) had a shockable rhythm, and 160 (63.7%) had unfavourable neurological outcomes. GWR but not pCSFV was significantly higher in terms of favourable neurological outcomes (p = .015). pCSFV prognostic performances were similar to GWR, and were poor overall, (0.521; 95% confidence interval [CI], 0.446-0.694 vs. 0.515; 95% CI, 0.441-0.589). After adjusting for covariates, pCSFV but not GWR was independently associated with neurological outcome 6 months following cardiac arrest (p = .049). CONCLUSION: pCSFV was independently associated with neurological outcome 6 months following cardiac arrest, however prognostic performance was not good.

Atypical presentation of fulminant primary central nervous system angiitis.

BACKGROUND: Primary Angiitis of the Central Nervous System (PACNS) is a rare cause of CNS vasculitis that should be included as part complete differential diagnosis, especially in cases with suggestive imaging findings and an absence of secondary causes for CNS vasculitis. CASE PRESENTATION: We describe a case of a 47-year-old previously healthy Caucasian male presenting with rapid progression of encephalopathy and fevers. Extensive infectious, autoimmune, and imaging workups were unrevealing. A diagnosis of PACNS was made posthumously on histopathology. CONCLUSIONS: PACNS is a challenging diagnosis owing to frequent discrepancies between radiologic and histopathologic findings. Tissue biopsy is key to diagnosing PACNS.

Cerebrospinal Fluid, Brain Electrolytes Balance, and the Unsuspected Intrinsic Property of Melanin to Dissociate the Water Molecule.

BACKGROUND & OBJECTIVE: Regulation of composition, volume and turnover of fluids surrounding the brain and damp cells is vital. These fluids transport all substances required for cells and remove the unwanted materials. This regulation tends to act as barrier to prevent free exchange of materials between the brain and blood. There are specific mechanisms concerned with fluid secretion of the controlled composition of the brain, and others responsible for reabsorption eventually to blood and the extracellular fluid whatever their composition is. The current view assumes that choroidal plexuses secrete the major part of Cerebrospinal Fluid (CSF), while the Blood-Brain Barrier (BBB) has a much less contribution to fluid production, generating Interstitial Fluid (ISF) that drains to CSF. The skull is a rigid box; thereby the sum of volumes occupied by the parenchyma with its ISF, related connective tissue, the vasculature, the meninges and the CSF must be relatively constant according to the Monroe-Kellie dogma. This constitutes a formidable challenge that normal organisms surpass daily. The ISF and CSF provide water and solutes influx and efflux from cells to these targeted fluids in a quite precise way. Microvessels within the parenchyma are sufficiently close to every cell where diffusion areas for solutes are tiny. Despite this, CSF and ISF exhibit very similar compositions, but differ significantly from blood plasma. Many hydrophilic substances are effectively prevented from the entry into the brain via blood, while others like neurotransmitters are extremely hindered from getting out of the brain. Anatomical principle of the barrier and routes of fluid transfer cannot explain the extraordinary accuracy of fluids and substances needed to enter or leave the brain firmly. There is one aspect that has not been deeply analyzed, despite being prevalent in all the above processes, it is considered a part of the CSF and ISF dynamics. This aspect is the energy necessary to propel them properly in time, form, space, quantity and temporality. CONCLUSION: The recent hypothesis based on glucose and ATP as sources of energy presents numerous contradictions and controversies. The discovery of the unsuspected intrinsic ability of melanin to dissociate and reform water molecules, similar to the role of chlorophyll in plants, was confirmed in the study of ISF and CSF biology.

Introducing the concept of "CSF-shift edema" in traumatic brain injury.

Brain edema after severe traumatic brain injury (TBI) plays an important role in the outcome and survival of injured patients. It is also one of the main targets in the therapeutic approach in the current clinical practice. To date, the pathophysiology of traumatic brain swelling is complex and, being that it is thought to be mainly cytotoxic and vasogenic in origin, not yet entirely understood. However, based on new understandings of the hydrodynamic aspects of cerebrospinal fluid (CSF), an additional mechanism of brain swelling can be considered. An increase in pressure into the subarachnoid space, secondary to traumatic subarachnoid hemorrhage, would result in a rapid shift of CSF from the cisterns, through the paravascular spaces, into the brain, resulting in an increase of brain water content. This mechanism of brain swelling would be termed as "CSF-shift edema." This "CSF-shift," promoted by a pressure gradient, leads to increased pressure inside the paravascular spaces and the interstitium of the brain, disturbing the functions of the paravascular system, with implications of secondary brain injury. Cisternostomy, an emerging surgical treatment, would reverse the direction of the CSF-shift, allowing for a decrease in brain swelling. In addition, this technique would reduce the pressure in the paravascular spaces and interstitium, leading to a recovery of the functionality of the paravascular system.

Levels of Interleukin-1ß, Interleukin-18, and Tumor Necrosis Factor-α in Cerebrospinal Fluid of Aneurysmal Subarachnoid Hemorrhage Patients May Be Predictors of Early Brain Injury and Clinical Prognosis.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe cerebrovascular accident with high morbidity and mortality. The aim of this study is to investigate the relationship between level of inflammatory cytokines in cerebrospinal fluid (CSF) of aSAH patients, the severity of aSAH, and the outcome of aSAH patients. METHODS: aSAH patients were prospectively included and followed-up for 6 months. CSF samples were collected at 1-3, 4-6, and 7-9 days after aSAH onset. Levels of interleukin (IL)-1ß, IL-18, and tumor necrosis factor-α (TNF-α) in the CSF of aSAH patients were measured by enzyme-linked immunosorbent assay. RESULTS: Eighty-one aSAH patients were enrolled. The levels of IL-1ß, IL-18 and TNF-α in the CSF were especially higher in the group of aSAH patients with cerebral edema, cerebral vasospasm, and a high grade on Hunt-Hess scale, the high World Federation of Neurological Surgeons grades, and Fisher grade (P < 0.01). Higher levels of plasma C-reactive protein in the blood were correlated with poor outcome. The areas under the receiver operating characteristic curves for the levels of inflammatory cytokines in CSF were 0.85, 0.84, and 0.95, respectively. Clinical features (age, Hunt-Hess grade, etc.) were positively correlated with poor outcomes (P < 0.05). CONCLUSIONS: The levels of IL-1ß, IL-18, and TNF-α in CSF were elevated in aSAH patients and were positively associated with cerebral edema and acute hydrocephalus. Our findings suggest that CSF inflammatory cytokines might be biomarkers to assess severity and predict outcomes.

Real-time Noninvasive Monitoring of Intracranial Fluid Shifts During Dialysis Using Volumetric Integral Phase-Shift Spectroscopy (VIPS): A Proof-of-Concept Study.

BACKGROUND: Cerebral edema, which is associated with increased intracranial fluid, is often a complication of many acute neurological conditions. There is currently no accepted method for real-time monitoring of intracranial fluid volume at the bedside. We evaluated a novel noninvasive technique called "Volumetric Integral Phase-shift Spectroscopy (VIPS)" for detecting intracranial fluid shifts during hemodialysis. METHODS: Subjects receiving scheduled hemodialysis for end-stage renal disease and without a history of major neurological conditions were enrolled. VIPS monitoring was performed during hemodialysis. Serum osmolarity, electrolytes, and cognitive function with mini-mental state examination (MMSE) were assessed. RESULTS: Twenty-one monitoring sessions from 14 subjects (4 women), mean group age 50 (SD 12.6), were analyzed. The serum osmolarity decreased by a mean of 6.4 mOsm/L (SD 6.6) from pre- to post-dialysis and correlated with an increase in the VIPS edema index (E-Dex) of 9.7% (SD 12.9) (Pearson's correlation r = 0.46, p = 0.037). Of the individual determinants of serum osmolarity, changes in serum sodium level correlated best with the VIPS edema index (Pearson's correlation, r = 0.46, p = 0.034). MMSE scores did not change from pre- to post-dialysis. CONCLUSIONS: We detected an increase in the VIPS edema index during hemodialysis that correlated with decreased serum osmolarity, mainly reflected by changes in serum sodium suggesting shifts in intracranial fluids.

Sulfonylurea Receptor-1: A Novel Biomarker for Cerebral Edema in Severe Traumatic Brain Injury.

OBJECTIVES: Cerebral edema is a key poor prognosticator in traumatic brain injury. There are no biomarkers identifying patients at-risk, or guiding mechanistically-precise therapies. Sulfonylurea receptor-1-transient receptor potential cation channel M4 is upregulated only after brain injury, causing edema in animal studies. We hypothesized that sulfonylurea receptor-1 is measurable in human cerebrospinal fluid after severe traumatic brain injury and is an informative biomarker of edema and outcome. DESIGN: A total of 119 cerebrospinal fluid samples were collected from 28 severe traumatic brain injury patients. Samples were retrieved at 12, 24, 48, 72 hours and before external ventricular drain removal. Fifteen control samples were obtained from patients with normal pressure hydrocephalus. Sulfonylurea receptor- 1 was quantified by enzyme-linked immunosorbent assay. Outcomes included CT edema, intracranial pressure measurements, therapies targeting edema, and 3-month Glasgow Outcome Scale score. MAIN RESULTS: Sulfonylurea receptor-1 was present in all severe traumatic brain injury patients (mean = 3.54 ± 3.39 ng/mL, peak = 7.13 ± 6.09 ng/mL) but undetectable in all controls (p < 0.001). Mean and peak sulfonylurea receptor-1 was higher in patients with CT edema (4.96 ± 1.13 ng/mL vs 2.10 ± 0.34 ng/mL; p = 0.023). There was a temporal delay between peak sulfonylurea receptor-1 and peak intracranial pressure in 91.7% of patients with intracranial hypertension. There was no association between mean/peak sulfonylurea receptor-1 and mean/peak intracranial pressure, proportion of intracranial pressure greater than 20 mm Hg, use of edema-directed therapies, decompressive craniotomy, or 3-month Glasgow Outcome Scale. However, decreasing sulfonylurea receptor-1 trajectories between 48 and 72 hours were significantly associated with improved cerebral edema and clinical outcome. Area under the multivariate model receiver operating characteristic curve was 0.881. CONCLUSIONS: This is the first report quantifying human cerebrospinal fluid sulfonylurea receptor-1. Sulfonylurea receptor-1 was detected in severe traumatic brain injury, absent in controls, correlated with CT-edema and preceded peak intracranial pressure. Sulfonylurea receptor-1 trajectories between 48 and 72 hours were associated with outcome. Because a therapy inhibiting sulfonylurea receptor-1 is available, assessing cerebrospinal fluid sulfonylurea receptor-1 in larger studies is warranted to evaluate our exploratory findings regarding its diagnostic, and monitoring utility, as well as its potential to guide targeted therapies in traumatic brain injury and other diseases involving cerebral edema.

Automated quantification of cerebral edema following hemispheric infarction: Application of a machine-learning algorithm to evaluate CSF shifts on serial head CTs.

Although cerebral edema is a major cause of death and deterioration following hemispheric stroke, there remains no validated biomarker that captures the full spectrum of this critical complication. We recently demonstrated that reduction in intracranial cerebrospinal fluid (CSF) volume (∆ CSF) on serial computed tomography (CT) scans provides an accurate measure of cerebral edema severity, which may aid in early triaging of stroke patients for craniectomy. However, application of such a volumetric approach would be too cumbersome to perform manually on serial scans in a real-world setting. We developed and validated an automated technique for CSF segmentation via integration of random forest (RF) based machine learning with geodesic active contour (GAC) segmentation. The proposed RF + GAC approach was compared to conventional Hounsfield Unit (HU) thresholding and RF segmentation methods using Dice similarity coefficient (DSC) and the correlation of volumetric measurements, with manual delineation serving as the ground truth. CSF spaces were outlined on scans performed at baseline (< 6 h after stroke onset) and early follow-up (FU) (closest to 24 h) in 38 acute ischemic stroke patients. RF performed significantly better than optimized HU thresholding (p < 10- 4 in baseline and p < 10- 5 in FU) and RF + GAC performed significantly better than RF (p < 10- 3 in baseline and p < 10- 5 in FU). Pearson correlation coefficients between the automatically detected ∆ CSF and the ground truth were r = 0.178 (p = 0.285), r = 0.876 (p < 10- 6) and r = 0.879 (p < 10- 6) for thresholding, RF and RF + GAC, respectively, with a slope closer to the line of identity in RF + GAC. When we applied the algorithm trained from images of one stroke center to segment CTs from another center, similar findings held. In conclusion, we have developed and validated an accurate automated approach to segment CSF and calculate its shifts on serial CT scans. This algorithm will allow us to efficiently and accurately measure the evolution of cerebral edema in future studies including large multi-site patient populations.

Spectrum of cerebral spinal fluid findings in patients with posterior reversible encephalopathy syndrome.

The purpose of this study is to characterize the spectrum of cerebrospinal fluid (CSF) findings in patients with posterior reversible encephalopathy syndrome (PRES)and determine its associations with severity of edema. In this retrospective cross-sectional study electronic medical reports were screened for patients with PRES. Clinical and laboratory data closest to onset of clinical symptoms were collected. Neuroimaging reports from all patients were categorized according to the presence of vasogenic edema,cytotoxic edema and contrast enhancement. From Jan 1999to Feb 2015, 87 patients with PRES and CSF findings were included. Mean total protein levels were 793 ± 929 mg/l. Median cell counts were 2/µl (IQR 1-4). Eight patients had cell counts[6/µl with a maximum of 41/µl. In 31 patients with extended CSF analysis, mean CSF/serum albuminquotient (QAlb) was 10.1 (IQR 6-17.3). An elevated QAlb (age-adjusted) was found in 74 % of these 31 patients. PRES patients with severe edema had higher mean total protein levels in CSF (mean difference = 407 mg/l; 95 %CI 187-628). Significant correlations were found for edema severity with levels of CSF protein (r = 0.48, p<0.001) as well with QAlb (r = 0.44, p = 0.013). This study shows that total protein in CSF and QAlb are elevated and correlate with severity of edema in PRES patients, whereas pleocytosis was rare in our cohort. This supports the theory that PRES is caused by a dysfunctional blood brain barrier.

CSF Volumetric Analysis for Quantification of Cerebral Edema After Hemispheric Infarction.

BACKGROUND: Malignant cerebral edema (CED) complicates at least 20 % of large hemispheric infarcts (LHI) and may result in neurological deterioration or death. Midline shift (MLS) is a standard but crude measure of edema severity. We propose that volumetric analysis of shifts in cerebrospinal fluid (CSF) over time provides a reliable means of quantifying the spectrum of edema severity after LHI. METHODS: We identified 38 patients from 2008 to 2014 with NIHSS ≥8, baseline CT <6 h after stroke onset, at least 1 follow-up (FU) CT, and no parenchymal hematoma. The volumes of CSF (sulci, ventricles, and cisterns) ipsilateral (IL) and contralateral (CL) to infarct on baseline and FU CTs were quantified by manually assisted outlining with MIPAV image analysis software, as was infarct volume and MLS on FU CTs. Percentage change in CSF volumes (∆CSF) from baseline to FU scans was correlated with MLS and compared in those with vs. without malignant edema (defined as hemicraniectomy, osmotic therapy, or death/neurological deterioration with MLS ≥5 mm). RESULTS: 11 of 38 subjects (29 %) developed malignant edema. Neither baseline NIHSS nor CSF volume differed between those with and without edema (median NIHSS 18 vs. 13, p = 0.12, CSF volume 102 vs. 124 ml, p = 0.16). Inter-rater reliability for CSF measurements was excellent (intraclass correlation coefficient 0.97). ∆CSF correlated strongly with MLS at peak edema (r = -0.75), even adjusting for infarct volume (p = 0.009). ∆CSF was also greater in those with malignant edema [-55 % (IQR -49 to -62) vs. -36 % (-27 to -45), p = 0.004]. ∆CSF was the greatest within IL sulci [-97 % (-86 to -99) vs. -71 % (-41 to -79), p = 0.002] but also significantly greater within CL sulci in those with malignant edema [-50 % (-29 to -65) vs. -25 % (0 to -31), p = 0.014]. More than half this CSF volume reduction occurred by the time of first FU CT around 24 h after stroke, while MLS rose later. CONCLUSIONS: Volumetric CSF analysis reliably quantifies CED and distinguishes those with malignant edema and MLS from those with a more benign course after LHI. ∆CSF may provide an earlier and more sensitive indicator of edema severity across a broader dynamic range than MLS.