Barrier Disruption In Patients Research Articles

Angiopoietin II in Critically Ill Septic Patients: A Post Hoc Analysis of the DRAK Study.

Angiopoietin II (Ang-II) plays a pivotal role in the development of microcirculatory dysfunction as it provokes endothelial barrier disruption in patients with sepsis or septic shock. In particular, those with acute kidney injury show high Ang-II concentrations. So far, it is unclear which covariates influence Ang-II concentration in the early phase of sepsis, especially if extracorporeal therapies also do. Ang-II concentrations were measured in 171 patients with sepsis after the first day of antibiotic treatment between 03/2013 and 01/2015. Ang-II was correlated with potential influencing factors (Spearman correlation). A multivariate model was established including the significant correlating parameters. The Mann-Whitney U test and the Kruskal-Wallis test were used to detect significant differences in Ang-II concentration. The median Ang-II concentration was 8015 pg/mL (interquartile range (IQR): 5024-14,185). A total of forty patients were treated with kidney replacement therapy (KRT) and 20 were supported by venovenous extracorporeal membrane oxygenation (vv-ECMO). Sequential organ failure assessment (SOFA) score (r = 0.541), creatinine clearance (r = -0.467), urinary output (r = -0.289), interleukin (IL)-6 (r = 0.529), C-reactive protein (CRP) (r = 0.241), platelet count (r = -0.419), bilirubin (r = 0.565), lactate (r = 0.322), KRT (r = 0.451), and fluid balance (r = 0.373) significantly correlated with Ang-II concentration and were included in the multivariate model. There, creatinine clearance (p < 0.01, b = -26.3, 95% confidence interval (CI) -41.8--10.8), fluid balance (p = 0.002, b = 0.92, 95% CI 0.33-1.51), and CRP (p = 0.004, b = 127.6, 95% CI 41.6-213.7) were associated with Ang-II concentration. Furthermore, patients with KRT (median: 15,219 pg/mL, IQR: 10,548-20,270) had significantly (p < 0.01) higher Ang-II concentrations than those with vv-ECMO support (median: 6412 pg/mL, IQR: 5246-10,257) or those without extracorporeal therapy (median: 7156 pg/mL, IQR: 4409-12,741). Increased CRP, positive fluid balance, and impaired kidney function were associated with higher Ang-II concentrations in critically ill patients in the early stage of sepsis in this post hoc analysis. In particular, patients with KRT had very high Ang-II concentrations, whereas the use of vv-ECMO was not related to higher Ang-II concentrations. The significance for clinical practice should be clarified by a prospective study with standardized measurements.

Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma

PurposeWe report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors. MethodsMonthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI. ResultsOur treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose – the metric used to control the procedure – came from bursts with wideband emissions. ConclusionUsing a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage.

Possible role for blood‐brain barrier disruption in patients with Alzheimer’s disease spectrum and non‐Alzheimer’s disease pathological changes

AbstractBackgroundThe blood‐brain barrier (BBB) breakdown has been suggested as an early marker for Alzheimer’s disease (AD); yet the relationship between BBB breakdown and AD‐specific biomarkers based on the amyloid/tau/neurodegeneration (ATN) framework, is not clear. This study aimed to investigate the relationship between BBB permeability, AD‐specific biomarkers, and cognition in patients with cognitive decline.MethodIn this prospective observational study, we enrolled 62 participants with mild cognitive impairment or dementia between January 2019 and October 2020. All participants were assessed cognitive tests, amyloid PET, dynamic contrast enhanced MRI for BBB permeability (Ktrans), CSF studies for Aβ42/40 ratio, CSF phosphorylated tau Thr181 protein (p‐tau), CSF total tau protein (t‐tau), and structural MRI for neurodegeneration.ResultCompared with the Aβ‐G, the Aβ+G had a higher median Ktrans in the frontal cortices (P = 0.049). In Aβ‐G, Ktrans was positively correlated with CSF p‐tau level in the cerebral cortex (all p &lt; 0.05 except for the occipital cortex). In Aβ+G, Ktrans of occipital cortices was related with CSF Aβ42/40 (rho = 0.403, p = 0.027), and CSF t‐tau level (rho = ‐0.404, p = 0.027), whereas, Ktrans of frontal (rho = ‐0.610, p&lt;0.001), insular (r = ‐0.400, p = 0.028), parietal (rho = ‐0.446, p = 0.013) and temporal cortices (rho = ‐ 0.435, p = 0.016) was negatively related with hippocampal volume. When adjusting age and education, neither BBB permeability nor CSF biomarkers predict cognition.ConclusionOur results suggest that the relationship between BBB permeability and ATN biomarkers is evident, more interestingly, this relationship varies with the presence of Aβ plaque accumulation.

Is there progression of endolymphatic hydrops in Ménière's disease? Longitudinal magnetic resonance study.

Endolymphatic hydrops (EH) is universal in Ménière´s disease (MD). Given its chronic course, with variable interval before complete clinical picture is installed, it seems relevant to understand the progression of vestibular EH and hemato-perilymphatic barrier disruption in patients with MD and monosymptomatic presentations. 239 consecutive patients were referred to us with suspected hydropic ear disease. 50 individuals accepted to participate in this study-final longitudinal sample included 24 patients (7 D1, 7 D2, 10 D3). Control group included ten patients. At recruitment, a clinical and MRI re-evaluation was done (3T, intravenous technique) (MR2) and 2years after MRI was repeated (MR3). Previous MRI (MRI1) were retrospectively evaluated. Patients were classified as definite (D1), possible (D2) and atypical (D3-monosymptomatic) MD. Control group included non-typical symptoms (C2/C3) and 6 asymptomatic (C1). Vestibular endolymphatic ratio (vER) and grading, presence/absence of cochlear EH, asymmetry of cochlear perilymphatic enhancement, and rate of progression of vER were assessed by two independent neuroradiologists and compared between patient and control groups (index ear). EH was universal and pronounced in D1 and remained stable. vER progression was more variable and higher in some D3 patients (index ear worse) and in D2 (non-index), although this observation was not statistically significant. Considering that many probable and monosymptomatic presentations progress years later into definite MD and given the bilateral tendency of the disease, these findings may indicate that there is an initial accelerated worsening of EH in initial stages of the disease. These data should be confirmed with controlled and larger sample studies.

CSF Biomarkers in COVID-19 Associated Encephalopathy and Encephalitis Predict Long-Term Outcome.

Patients with coronavirus disease 2019 (COVID-19) frequently develop acute encephalopathy and encephalitis, but whether these complications are the result from viral-induced cytokine storm syndrome or anti-neural autoimmunity is still unclear. In this study, we aimed to evaluate the diagnostic and prognostic role of CSF and serum biomarkers of inflammation (a wide array of cytokines, antibodies against neural antigens, and IgG oligoclonal bands), and neuroaxonal damage (14-3-3 protein and neurofilament light [NfL]) in patients with acute COVID-19 and associated neurologic manifestations (neuro-COVID). We prospectively included 60 hospitalized neuro-COVID patients, 25 (42%) of them with encephalopathy and 14 (23%) with encephalitis, and followed them for 18 months. We found that, compared to healthy controls (HC), neuro-COVID patients presented elevated levels of IL-18, IL-6, and IL-8 in both serum and CSF. MCP1 was elevated only in CSF, while IL-10, IL-1RA, IP-10, MIG and NfL were increased only in serum. Patients with COVID-associated encephalitis or encephalopathy had distinct serum and CSF cytokine profiles compared with HC, but no differences were found when both clinical groups were compared to each other. Antibodies against neural antigens were negative in both groups. While the levels of neuroaxonal damage markers, 14-3-3 and NfL, and the proinflammatory cytokines IL-18, IL-1RA and IL-8 significantly associated with acute COVID-19 severity, only the levels of 14-3-3 and NfL in CSF significantly correlated with the degree of neurologic disability in the daily activities at 18 months follow-up. Thus, the inflammatory process promoted by SARS-CoV-2 infection might include blood-brain barrier disruption in patients with neurological involvement. In conclusion, the fact that the levels of pro-inflammatory cytokines do not predict the long-term functional outcome suggests that the prognosis is more related to neuronal damage than to the acute neuroinflammatory process.

Pilot study of repeated blood-brain barrier disruption in patients with mild Alzheimer\u2019s disease with an implantable ultrasound device

BackgroundTemporary disruption of the blood-brain barrier (BBB) using pulsed ultrasound leads to the clearance of both amyloid and tau from the brain, increased neurogenesis, and mitigation of cognitive decline in pre-clinical models of Alzheimer’s disease (AD) while also increasing BBB penetration of therapeutic antibodies. The goal of this pilot clinical trial was to investigate the safety and efficacy of this approach in patients with mild AD using an implantable ultrasound device.MethodsAn implantable, 1-MHz ultrasound device (SonoCloud-1) was implanted under local anesthesia in the skull (extradural) of 10 mild AD patients to target the left supra-marginal gyrus. Over 3.5 months, seven ultrasound sessions in combination with intravenous infusion of microbubbles were performed twice per month to temporarily disrupt the BBB. 18F-florbetapir and 18F-fluorodeoxyglucose positron emission tomography (PET) imaging were performed on a combined PET/MRI scanner at inclusion and at 4 and 8 months after the initiation of sonications to monitor the brain metabolism and amyloid levels along with cognitive evaluations. The evolution of cognitive and neuroimaging features was compared to that of a matched sample of control participants taken from the Alzheimer’s Disease Neuroimaging Initiative (ADNI).ResultsA total of 63 BBB opening procedures were performed in nine subjects. The procedure was well-tolerated. A non-significant decrease in amyloid accumulation at 4 months of − 6.6% (SD = 7.2%) on 18F-florbetapir PET imaging in the sonicated gray matter targeted by the ultrasound transducer was observed compared to baseline in six subjects that completed treatments and who had evaluable imaging scans. No differences in the longitudinal change in the glucose metabolism were observed compared to the neighboring or contralateral regions or to the change observed in the same region in ADNI participants. No significant effect on cognition evolution was observed in comparison with the ADNI participants as expected due to the small sample size and duration of the trial.ConclusionsThese results demonstrate the safety of ultrasound-based BBB disruption and the potential of this technology to be used as a therapy for AD patients. Research of this technique in a larger clinical trial with a device designed to sonicate larger volumes of tissue and in combination with disease-modifying drugs may further enhance the effects observed.Trial registrationClinicalTrials.gov, NCT03119961

Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human β-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.

Blood-ocular barrier disruption in patients with acute stroke

Prompted by the unexpected finding of gadolinium leakage into ocular structures (GLOS) in acute stroke patients, we studied the frequency and nature of this finding in 167 patients. Patients were selected who had an MRI with gadolinium at baseline and another MRI with fluid-attenuated inversion recovery (FLAIR) imaging at 2 and/or 24 hours later. GLOS was detected as lack of vitreous and/or aqueous fluid suppression on postcontrast FLAIR images. GLOS, evident on postcontrast FLAIR MRI, occurred in 127/167 (76%) patients: 86/109 (79%) patients treated with tissue plasminogen activator and 41/58 (71%) who were untreated. At 2 hours after administration of the contrast, GLOS was more common in the aqueous chamber alone, occurring in 67% of patients, compared to the vitreous chamber alone, seen in 6% of patients; it occurred in both chambers in 27% of patients. At 24 hours, GLOS was present in 121/162 (75%) patients, always involving the vitreous chamber, but also affecting the aqueous chamber in 6% of cases. Vitreous GLOS at 24 hours was associated with increasing age (p = 0.002) and a higher burden of cerebral white matter hyperintensities (p = 0.017). Patients with rapid diffuse GLOS, defined as GLOS involving both chambers at 2 hours, had larger infarcts (p = 0.022) and a higher degree of blood-brain barrier permeability (p = 0.025). We found GLOS to be common in patients with acute stroke; delayed GLOS was a marker for chronic vascular disease. The mechanism for acute GLOS remains uncertain but may be a remote effect of acute cerebral injury on the blood-ocular barrier.

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

BackgroundFilaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations.ObjectiveWe hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.

Risk Factors for Blood-Brain Barrier Disruption in Patients with Chronic Cerebrovascular Disease Presenting with Acute Stroke (P2.245)

Risk Factors for Blood-Brain Barrier Disruption in Patients with Chronic Cerebrovascular Disease Presenting with Acute Stroke (P2.245)

Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy.

The authors assessed the risk factors and outcomes associated with blood-brain barrier (BBB) disruption in patients with severe, nonpenetrating, traumatic brain injury (TBI) requiring decompressive craniectomy. At 2 major neurotrauma centers in Western Australia, a retrospective cohort study was conducted among 97 adult neurotrauma patients who required an external ventricular drain (EVD) and decompressive craniectomy during 2004-2012. Glasgow Outcome Scale scores were used to assess neurological outcomes. Logistic regression was used to identify factors associated with BBB disruption, defined by a ratio of total CSF protein concentrations to total plasma protein concentration > 0.007 in the earliest CSF specimen collected after TBI. Of the 252 patients who required decompressive craniectomy, 97 (39%) required an EVD to control intracranial pressure, and biochemical evidence of BBB disruption was observed in 43 (44%). Presence of disruption was associated with more severe TBI (median predicted risk for unfavorable outcome 75% vs 63%, respectively; p = 0.001) and with worse outcomes at 6, 12, and 18 months than was absence of BBB disruption (72% vs 37% unfavorable outcomes, respectively; p = 0.015). The only risk factor significantly associated with increased risk for BBB disruption was presence of nonevacuated intracerebral hematoma (> 1 cm diameter) (OR 3.03, 95% CI 1.23-7.50; p = 0.016). Although BBB disruption was associated with more severe TBI and worse long-term outcomes, when combined with the prognostic information contained in the Corticosteroid Randomization after Significant Head Injury (CRASH) prognostic model, it did not seem to add significant prognostic value (area under the receiver operating characteristic curve 0.855 vs 0.864, respectively; p = 0.453). Biochemical evidence of BBB disruption after severe nonpenetrating TBI was common, especially among patients with large intracerebral hematomas. Disruption of the BBB was associated with more severe TBI and worse long-term outcomes, but when combined with the prognostic information contained in the CRASH prognostic model, this information did not add significant prognostic value.

TH2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis

Here we report that Th2 cytokines increase kallikrein 7 expression and function in keratinocytes. Our finding describes a link between the Th2 environment and epidermal barrier dysfunction in atopic dermatitis.

Heme oxygenase-1 overexpression in patients with malignant obstructive jaundice

To investigate the role of heme oxygenase-1 (HO-1) in the oxidative stress damage of intestinal mucosa barrier disruption in patients with malignant obstructive jaundice (MOJ). Fifteen jaundiced patients with malignant biliary obstruction undergoing endoscopic retrograde cholangiopancreatography (ERCP) examination or treatment were enrolled. The control group was comprised of 10 healthy subjects with gastroscopy and 10 patients with non-jaundiced biliary obstruction. Patients were subjected to duodenal biopsy to assess the intestinal oxidative stress as estimated by lipid peroxidation (malondialdehyde) and activity of superoxide dismutase (SOD). Apoptosis of epithelial cell was examined by TdT-mediated dUTP-biotin nick end labeling. Immunohistochemistry and Western blotting were employed to examine the distribution and expression of HO-1 proteins in intestinal mucosa. MOJ jaundiced patients presented high levels of intestinal oxidative stress with a significantly increased level of lipid peroxidation [(1.79 +/- 0.24) vs (1.09 +/- 0.28) vs (1.18 +/- 0.32) nmol x mg(-1) x prot(-1), P = 0.041] and a decreased SOD activity [(303 +/- 10) vs (398 +/- 11) vs (406 +/- 11) nmol x mg(-1) x prot(-1), P = 0.017]. The apoptotic rate of intestinal epithelial cells was significantly higher in jaundiced group than in non-jaundiced control group. Apoptotic index was (69.1 +/- 5.9)%, (28.6 +/- 3.5)% and (10.2 +/- 2.5)% respectively (P < 0.01). The staining of HO-1 was predominantly localized in cytoplasm. In jaundiced patients, HO-1 was obviously elevated than those in the control group (HO-1 optical density 0.28 +/- 0.04 vs 0.20 +/- 0.04 vs 0.13 +/- 0.05) (P < 0.01). Similar outcomes were obtained by quantitative analysis of Western blotting images [HO-1/GAPDH (10.7 +/- 0.7)% vs (7.6 +/- 0.5)% vs (3.9 +/- 0.4)%, P < 0.01]. MOJ induces intestinal oxidative stress and it may be a key contributing factor to intestinal barrier failure in the patient population. HO-1 protein level is rising with the progression of obstruction. Perhaps HO-1 has a protective effect upon MOJ through anti-oxidative damage.

Maculopathy as a Complication of Blood–Brain Barrier Disruption in Patients with Central Nervous System Lymphoma

To report on the development of visually significant maculopathy associated with blood-brain barrier disruption (BBBD) therapy for the treatment of central nervous system (CNS) lymphoma. Retrospective case series. Chart review of 20 patients undergoing BBBD therapy for treatment of CNS lymphoma at the Cleveland Clinic. Patients with documented maculopathy were included in analysis. Seven (54%) of 13 patients were identified with new macular retinal pigment epithelium (RPE) changes after BBBD treatment. The RPE changes consisted of fine clumps of hyperpigmentation in the foveal region associated with variable degrees of RPE loss. These changes were bilateral but often asymmetric. Two patients had decreased visual acuity resulting from maculopathy. One patient had documented progression of maculopathy after completion of treatment. Maculopathy is a frequent finding after BBBD therapy for CNS lymphoma.

VASCULAR ENDOTHELIAL GROWTH FACTOR IS ASSOCIATED WITH BLOOD BRAIN BARRIER DYSFUNCTION IN EOSINOPHILIC MENINGITIS CAUSED BY ANGIOSTRONGYLUS CANTONENSIS INFECTION

Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor and a mediator of brain edema. To assess the role of vascular endothelial growth factor in eosinophilic meningitis, vascular endothelial growth factor was measured in the cerebrospinal fluid (CSF) and blood of 9 patients with eosinophilic meningitis in a cohort study. VEGFCSF was detected in 8 (90%) of 9 eosinophilic meningitis patients (range, 45-2190 pg/mL) at presentation. The mean VEGFCSF at presentation, 1 week, and 2 weeks after admission was 568 pg/mL, 751 pg/mL, and 1031 pg/mL, respectively. There was an association between VEGFCSF, CSF protein, white cell count, and eosinophil counts. The VEGFSERUM fluctuated during the 6-month follow-up period. These results indicate that vascular endothelial growth factor may be associated with blood-brain barrier disruption in patients with eosinophilic meningitis.

Focal Cortical Dysfunction and Blood???Brain Barrier Disruption in Patients With Postconcussion Syndrome

Postconcussion syndrome (PCS) refers to symptoms and signs commonly occurring after mild head injury. The pathogenesis of PCS is unknown. The authors quantitatively analyzed EEG recordings, localized brain sources for abnormal activity, and correlated it with imaging studies. Data from 17 patients with neurologic symptomatology consistent with ICD-10 criteria for PCS was analyzed. Normalized quantitative EEG (QEEG) revealed significantly higher power in the delta band and lower power in the alpha band compared with matched controls. The generators for the abnormal rhythms were focally localized in neocortical regions. Brain computerized tomography and/or MRI did not reveal focal abnormality at the time of diagnosis. Single photon emission computed tomography (SPECT) after 99mTc-ethylcysteinate dimer administration showed a focal reduction in perfusion in 85% (n = 11) of the patients, and abnormal blood-brain barrier (BBB) after 99mTc-diethylenetriaminepentaacetic acid administration in 73% (n = 8). In 75% of these patients, low-resolution brain electromagnetic tomography analysis showed that the generators for abnormal rhythms were closely related to the anatomic location of the BBB lesion. These data point to focal cortical dysfunction in conjunction with BBB disruption and hypoperfusion as a possible mechanism of pathogenesis in at least some PCS patients, and offer QEEG and SPECT as important tools in evaluating these patients.

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma. Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion. Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration. Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.

Visualization of blood-brain barrier disruption on MR images of cats with acute cerebral infarction: value of administering a high dose of contrast material.

The detection of blood-brain barrier disruption in patients with cerebral infarction by means of contrast-enhanced MR images improves the specificity of diagnosis, enables lesion dating, and on occasion improves lesion detection. Accordingly, we performed a study to determine the extent of visualization of disruption of the blood-brain barrier on contrast-enhanced MR images, with specific attention to contrast dose, in a cat model of acute cerebral infarction. We used doses of 0.1 and 0.3 mmol/kg of a gadolinium chelate, gadoteridol, which is characterized by extracellular distribution and renal excretion, and was approved by the Food and Drug Administration for clinical use at these doses. Blood flow in the middle cerebral artery was occluded unilaterally in seven cats for 1 hr, followed by 4 hr of reperfusion. T2- and T1-weighted MR images were obtained before the injection of contrast material. After injection, the time course of enhancement was observed for 1 hr by repeated sequential acquisition of T1-weighted images. Five cats received an initial injection of 0.1 mmol/kg of contrast material, supplemented 33 min later by 0.2 mmol/kg (cumulative dose, 0.3 mmol/kg). Two cats received a single injection of contrast material, either 0.1 or 0.3 mmol/kg. The images were reviewed in a prospective fashion by a single observer, who was blinded to the dose of contrast material and the timing of image acquisition, in order to detect abnormal contrast enhancement. Changes in single intensity were quantified by region-of-interest measurements. Enhancement at 4 and 13 min, respectively, after injection of contrast material was 25 +/- 10% and 38 +/- 7% with 0.1 mmol/kg, vs 80 +/- 12% and 100 +/- 15% with 0.3 mmol/kg (n = 5). The difference between doses was statistically significant (p < .002) for all time points. Abnormal contrast enhancement was visible in three of six cats that received 0.1 mmol/kg and in all cats that received 0.3 mmol/kg. By 13 min after injection, enhancement had peaked with a dose of 0.1 mmol/kg and was within 20% of maximum with a dose of 0.3 mmol/kg. Detection of disruption of the blood-brain barrier in acute cerebral infarction in cats is improved when high doses (0.3 mmol/kg) of contrast material are used. Disruption may not be visualized when 0.1 mmol/kg, the currently accepted standard dose, is used.

Cerebral blood flow and cerebral oxygen consumption during hypothermia.

Cerebral blood flow and cerebral oxygen consumption during hypothermia.