Early diagnosis and treatment of cryptococcosis reduces mortality. Lumbar puncture, also known as spinal tap, and cerebral spinal fluid (CSF) analysis should be performed in patients with suspected CM [3, 6]. For a definitive diagno- sis of CM, Cryptococcus spp. must be identified within CSF from the patients [2, 3, 7]. India ink staining and cul- ture are the traditional important methods for rapid detection of Cryptococcus spp. . The sensitivity of India ink staining of the CSF is up to 70–90%, which tends to be lower in HIV-negative patients, but this value is dependent on both the fungal burden and ope- rator [2–4, 8, 9]. The definitive diagnosis of CM relies on culture on standard Sabouraud dextrose agar (SDA) or using routine and automated culture systems inocu- lated with CSF incubated at 30 °C [4, 10]. However, culture may be negative if exposure to antifungal ther- apy or in non-HIV CM and might need longer incu- bation periods up to several weeks . Serological diagnosis of CM, such as latex agglutination, enzyme- linked immunosorbent assays and lateral flow assay, relies usually on specific monoclonal antibodies to detect cryptococcal antigen polysaccharide (CrAg). Although detection of CrAg has demonstrated good sensitivity and specificity [11–15], extremely high con- centrations of CrAg can yield negative test results in extreme instances, known as high dose hook effect.
In HE, the loss of cortex is massive but seldom complete. In the review by Cecchetto et al. , the remaining cere- bral areas included: 6 cases of remaining fronto-occipital lobe, 2 frontal, 4 occipito-temporal, 1 fronto-temporal, 6 occipital, 2 fronto-occipito-parietal and 1 fronto-temporo- occipital. Remnant parts typically correspond to where in the vast, but somewhat variable, forebrain territory the an- terior cerebral circulatory matrix connects. There is no uniformity of data in the autoptic investigations in the re- ported literature. The average case shows variable rem- nants of cortex supplied by the posterior circulation, notably inferomedial occipital, but also basal portions of the temporal cortex, and midline cortical tissue along the falx, extending into medial frontal cortex may be spared. Most of the cortical area is missing and in its place is a thin-walled, fluid-filled cyst. Brainstem, cerebellum, thal- amus and striatum are usually preserved with a normal histological structure, also demonstrated by the neuro- physiological investigations (evoked potentials) [41-43]. The cerebrospinal fluid circulation is open, but may be athresic. The thin membrane replacing the hemispheric wall is composed of immature nervous tissue elements: glial cells and connective tissue admixture [9,16,44,45] with a notable absence of neurons. The cyst tends to con- tinuously enlarge, due to the increased fluid pressure. In a microscopic examination, such tissue may be found to be gliotic or to exhibit other structural anomalies indicating loss of function [3,4,45]. Olfactory and optic nerves are often spared.
Several animal and human studies have evaluated and described the transit of cefepime from the central distribution (i.e., plasma) to the target areas (i.e., brain and cerebral spinal ﬂuid [CSF]) (13–15). Human studies put cefepime penetration between a median of 8% and mean of 23% (13), and animal models have demonstrated cefepime CSF concentrations between 16.2 and 36% (14, 15). However, there is very little information about the real-time transfer of cefepime from the blood to the CSF from studies with robust samples. Quantitatively deﬁning this relationship will ulti- mately be required to fully understand the exposure drivers of neurotoxicity. Thus, the objective of the proposed research was 2-fold: (i) to explain cefepime transit from the plasma to the CSF and (ii) to estimate the percentage of cefepime crossing from plasma to CSF in a rat model.
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Background: A high dose of anti-infective agents is recommended when treating infectious meningitis. High creatinine clearance (CrCl) may affect the pharmacokinetic / pharmacodynamic relationships of anti-infective drugs eliminated by the kidneys. We recorded the incidence of high CrCl in intensive care unit (ICU) patients admitted with meningitis and assessed the diagnostic accuracy of two common methods used to identify high CrCl. Methods: Observational study performed in consecutive patients admitted with community-acquired acute infectious meningitis (defined by >7 white blood cells/mm 3 in cerebral spinal fluid) between January 2006 and December 2009 to one medical ICU. During the first 7 days following ICU admission, CrCl was measured from 24-hr urine samples (24-hr-UV/P creatinine) and estimated according to Cockcroft-Gault formula and the simplified Modification of Diet in Renal Disease (MDRD) equation. High CrCl was defined as CrCl >140 ml/min/1.73 m 2 by 24-hr-UV/P creatinine. Diagnostic accuracy was performed with ROC curves analysis.
Idiopathic normal pressure hydrocephalus (iNPH) is a condition characterized by ventricular enlargement and normal intracranial pressure (ICP) caused by disturbed cerebral spinal fluid (CSF) dynamics . The cause is still unknown. The iNPH signs are typically subcortical, characterized by slow progressive impairment of gait and balance, cognitive deterioration and urinary inconti- nence . Treatment of iNPH patients with ventricular- peritoneal or ventricular-atrial shunts is successful, with an improvement rate of more than 80% in recent short- term studies, and an acceptable complication rate [3–7]. At present, clinicians have two invasive predictive tests to select patient candidates for surgery: a test measur- ing compliance of craniospinal space or resistance to CSF outflow (Rout), and a test measuring the effect on symp- toms of temporary drainage of CSF (CSF tap test) [8–10]. These tests are, however, not totally specific or sensitive and can be used for selecting patients for shunt surgery but not for excluding patients from treatment [11, 12]. Better methods for the identification of responders and non-responders are required. Cerebral blood flow (CBF) is reduced in iNPH patients, mainly in the frontal cortex and in accordance with the subcortical symptomatology, in the basal ganglia, in the thalami and also in the perive- ntricular white matter (PVWM) [13–19]. As the subcor- tical and periventricular regions seem to be of special interest in iNPH, magnetic resonance (MR) perfusion imaging with its relatively high resolution and sensitivity for deep structures might be of value as a diagnostic and predictive tool . Some authors have also investigated the role of diffusion MRI in determining brain parenchy- mal damage in PVWM and basal ganglia (BG) areas and the role of apparent diffusion coefficient (ADC) in pre- dicting surgical outcome [21–26].
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Ultimately, these newly developed measures will need to be simple, cost-effective, and capable of capturing the subtle changes that can differentiate healthy aging from preclinical AD. These tests also need to be useful across all ethnicities and educational strata as well as proving sensitive to change over the short timeframe of a clinical trial. Given the significant advances made toward the in vivo detection of biomarkers in preclinical AD (that is, amyloid imaging, cerebral spinal fluid (CSF) amyloid/ tau, magnetic resonance imaging (MRI) volume loss) [6,18,19], a recent meta-analysis indicated that early amyloid pathology, a biomarker of preclinical AD, ap- pears to have a greater influence on memory-related sys- tems  in clinically normal older adults than other cognitive domains. The authors therefore selected the
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CNS: Central Nervous System; CSF: Cerebral Spinal Fluid; CSFL: Cerebral Spinal Fluid Leak; CT: Computed Tomography (no contrast); CTA: Computed Tomography Angiography (contrast); DMF: Dimethyl formamide; Fc: Fluorescein; FBS: Fetal Bovine Serum; FL: Fluorescence; IF: Intrathecal Fluorescein; MR or MRI: Magnetic Resonance Imaging (no contrast); MRA: Magnetic Resonance Angiography (contrast); NMR: Nuclear Magnetic Resonance spectroscopy; PBS: Phosphate Buffered Saline; PET: Positron Emission Tomography; SPECT: Single Photon Emission Computed Tomography; TBI: Traumatic Brain Injury; TLC: Thin Layer Chromatography; TOS: Time Of Synthesis; US: Ultrasound; UPLC-MS: Ultrahigh Pressure Liquid Chromatography- Mass Spectrometry; VP: ventriculoperitoneal
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He had a medium pressure VPS (P.S. Medical, Medtro- nic, Minneapolis, USA,) inserted. The procedure was car- ried out in the routine fashion and a ventricular catheter was introduced through a right parieto-occipital burr hole. Adequate placement was confirmed by the drainage of clear cerebral spinal fluid (CSF) under pressure, with care taken to drain less than 5cm 3 to send for a cell count, chemistry and culture. The peritoneal catheter was inserted into the peritoneal cavity using a percutan- eous technique. The procedure was uneventful, and our patient was extubated after surgery and started oral feed- ing after four hours. Eighteen hours later, he became lethargic with difficulty feeding and vomiting, despite a soft anterior fontanel. An emergency cranial computed tomography (CT) scan demonstrated a bilateral hyper- density signal in his cerebellar hemispheres, representing hemorrhages (Figures 3, 4 and 5). There was no change in the size of the ventricles, and the ventricular catheter was in good position with no associated intraventricular hemorrhage (Figure 6).
In a similar study, Kimura and colleagues  used a combination two-dimensional electrophoresis and LC- MS/MS with an ESI-LCQ instrument to obtain higher sensitivity for low abundance proteins. Patient sera from a NPSLE patient with white matter hyperintensities on T2-weighted MRI scan was reacted to a two-dimensional electrophoresis rat cerebral lysate blot. In total, nine reactive spots were seen and ﬁ ve were analyzed by LC- MS/MS. Th e two spots of greatest intensity corresponded to 60 kDa heat shock protein (Hsp60) , which func- tions to refold proteins that are misfolded and/or facili- tate degradation of proteins that cannot be recovered . Enhanced expression of Hsp60 can induce endo- thelial cell apoptosis and Hsp60 expression on the surface of endothelial cells has been reported to be directly related to coronary artery disease , opening the possi- bility of a similar relationship in the cerebral vasculature. In a follow-up study of 180 patients with neurological diseases (including 15 with SLE) and 23 healthy controls, Kimura and colleagues showed that the titer levels of anti-Hsp60 antibodies were directly correlated to severity of white matter hyperintensities in the brain, suggesting the presence of anti-Hsp60 antibodies as both a
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In the current study, we derived an ODE model that in- corporates information about cerebrospinal fluid (CSF) biomarkers and their role in regulating both microglial behavior and subsequent secondary tissue damage. We present model fits to clinical CSF cytokine data, and quali- tative projections of microglial and tissue damage states. From these results, we derived ensembles of model param- eters associated with distinct patient clusters with favorable and unfavorable scores on the Glasgow Outcome Scale (GOS) at 6 months post-injury. We propose this modeling framework as a tool to suggest differences in underlying mechanisms that potentially contribute to the temporal di- versification of acute neuroinflammatory patterns after in- jury. We demonstrate these mechanistic computational modeling results as proof-of-concept data that can provide key qualitative insights, to be complemented by subse- quent experimental testing of model predictions, toward the design of personalized intervention strategies for TBI.
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The predominant mechanism in most cases of trau- matic brain injury (TBI) is diffuse axonal injury . While axonal injury is common in all TBI regardless of severity, a shearing of the axons occurs in human diffuse axonal injury (DAI) leading to progressive changes that ultimately may result in the loss of connections between nerve cells. The slow progression of events in DAI con- tinues for up to several weeks after injury creating a window of opportunity for therapeutic intervention. There are approximately 500,000 new cases of TBI in the U.S. each year , and the incidence requiring hospitali- zation is estimated to be approximately 200-225/100,000 population. Currently, it is estimated that brain injuries account for 12% of all hospital admissions in the United States . When compared to spinal cord injury, which accounts for less than 1% of hospital admissions, it is clear that TBI is a medical care problem which has a sig- nificant impact financially within the United States. Ap- proximately 30,000 - 44,000 people will survive a severe TBI with GCS score TBI (GCS#10). Yet with new med- ical management techniques, less than 10% will remain in a persistent vegetative state. A GCS score of eight or less generally reflects a state of unconsciousness in which the patient demonstrates no eye opening, does not follow simple commands to move muscles, and has vo- calizations which are limited to sounds. Such signs are indicative of severe brain injury . Approximately 52,000 to 56,000 people die each year from TBI , re- sulting in direct costs approximated at more than $50 billion annually . The costs of severe TBI to the indi- vidual and family are extremely high . Acute medical and rehabilitation bills are often around $100,000 with
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AAV: adeno-associated virus; AD: Alzheimer’s disease; ARF6: ADP-ribosylation factor 6; ART : antiretroviral therapy; BBB: blood–brain barrier; BCSFB: blood– cerebral-spinal-fluid barrier; BLMB: blood–leptomeningeal barrier; BMEC: brain microvascular endothelial cell; BRB: blood–retinal barrier; CLN-5: claudin-5; CM: cerebral malaria; CP: choroid plexus; CNS: central nervous system; CSI: clinically isolated syndrome; EAE: experimental autoimmune encephalomyelitis; EC: endothelial cell; EMPs: endothelial microparticles; EV: extracellular vesicles; FRα: folate receptor; HAND: HIV-1-associated neurocognitive disorders; hiPSC- MSCs: human induced pluripotent cell-derived mesenchymal stem cells; MP: microparticle; MS: multiple sclerosis; MRI: magnetic resonance imaging; MSC: mesenchymal stem cell; MV: microvesicle; MVB: multi-vesicular bodies; NPC: neural progenitor cells; NRP1: Neuropilin 1; NVU: neurovascular unit; OPC: oli- godendrocyte precursor cells; Pgp: p-glycoprotein; PPP: platelet poor plasma; PRBC: parasitized red blood cells; ROS: reactive oxygen species; RPE: retinal pigmented epithelium; RRMS: relapsing/remitting MS; SAS: subarachnoid space; TEM: transendothelial migration; TJ: tight junctions; TBI: traumatic brain injury; vWF: von Willibrand factor.
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The inclusion criteria for entry into this trial were that patients had to be in good health, determined on the basis of routine clinical laboratory test screening results, physical examinations, vital signs and 12-lead electrocar- diograms (ECGs). Exclusion criteria included a history or evidence of any other CNS disorder that could be interpreted as a cause of dementia; Hachinski Ischemic Scale score >4; a magnetic resonance imaging (MRI) scan not consistent with AD or evidence of any other CNS condition; minimal vascular changes or more than three microhaemorrhagic lesions; and a history of psy- chiatric illness, cerebral haemorrhage, seizures or strokes during the 3 years preceding the study; and cardiovascu- lar disease or diabetes.
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The optic nerve sheath diameter (ONSD) is often taken as a proxy of intracranial hypertension in brain injury patients [1–3]. The space surrounding the optic nerve is a continuation of the intracranial subarachnoid space. With the compensatory redistri- bution of cerebrospinal fluid (CSF) seen in cases of intracranial hypertension, the raised intracranial pressure (ICP) instantaneously distends the ONSD . In traumatic brain injury (TBI) and post-cardiac arrest patients, the ONSD calculated based on ultra- sound or computed tomography (CT) image is cor- related with the invasive ICP [5, 6]. An increase in ONSD from the baseline CT was associated with an unfavorable neurological outcome [7–9]. Although measurement of ONSD by portable ultrasound is feasible and convenient, there are still obstacles to its widespread clinical application [5, 10]. Moreover, some studies found no correlation between ONSD and ICP [11, 12]. Primary brain injury or decom- pression craniectomy (DC) may alter CSF hydro- dynamics or destroy the optic nerve sheath [13, 14]. Therefore, it remains unclear whether ONSD can be applied in patients with skull defects after DC. This study explored the value of the ONSD calculated based on ultrasound images in patients with skull defects following hemicraniectomy.
Walter E. Dandy, the noted neurosurgeon, published the first description of pneumoencephalography and its use in diag- nosing intracranial tumors and hydrocephalus in 1919. 11 In this article, he noted that the normal spinal cord could be seen outlined by the air injected into the spinal canal. He postulated that the same technique could be used to localize spinal cord tumors with the air column extending up to the level of the lesion. However, he did not publish any more on this topic until 1925. 12 In 1921, the injection of air into the subarachnoid space followed by x-ray examination was described indepen- dently by 2 Scandinavian physicians. Hans Christian Jaco- baeus, a Swedish internist, reported on the use of pneumomy- elography to diagnose spinal cord tumors. 13 This development evolved from his earlier unsuccessful attempts to treat tuber- culous meningitis by replacing 100 mL of CSF with air. 13,14 Sofus Widero¨e, a Norwegian surgeon, described a similar pro- cedure to diagnose a spinal cord tumor. 15
outermost duramater. Between the pia and arachnoid mater is the subarachnoid space. In this space, cerebrospinal fluid, spinal nerves, blood vessels that supply the spinal cord and dentate ligaments are present. Although the spinal cord ends at the level of L1 in adults, the subarachnoid space continues till S2 level. The outermost membrane in the spinal cord is the longitudinally organized fibroelastic membrane, the duramater. This layer is the direct extension of the cranial duramater and extends as the spinal dura from the foramen magnum to S2, where the filum terminale blends with the periosteum of the subdural space which contains only small amounts of serous fluid to allow the dura and arachnoid move over each other. Surrounding the duramater is the epidural space which extends from foramen magnum to the sacral hiatus. Posterior to the epidural space is the ligamentum flavum. Immediately posterior to the ligamentum flavum is the interspinous ligament extending from the external occipital protuberance to the coccyx. Posterior to this structure is the supraspinous ligament.
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Magnetic Resonance Imaging (MRI) of the brain and whole spine demonstrated multiple enhancing lesions involving the cerebellum, left midbrain, left pons. A right medullary lesion was also visualized in addition to mul- tiple foci of enhancement involving the cerebral hemi- spheres. There were multiple enhancing lesions in the thoracic spine with associated swelling (Fig. 1). Nerve conduction studies were within normal limits. However, needle studies of the bilateral lower extremities and lum- bar paraspinal muscles demonstrated acute denervation suggestive of radicular and or lower motor neuron dys- function. Computed Tomography (CT) of the chest and abdomen scans revealed left axillary adenopathy, numer- able small hypodensitities in the spleen and multiple lesions in the kidneys (Fig. 2). A PET scan was not per- formed as it would have been unlikely to yield additional insight into the patient’s condition beyond that provided by the MRI.
In this study, the paths of received photons from each layer were recorded. Figure 10 shows the ratios of the backscattered intensities from different layer versus the source- detector separation with multi-wavelength. Obviously, the signal from the surface (scalp and skull) layer and cerebral cortex layer were crossed at about 3.3 cm of source-detector separation. In this result of this individualised model, the backscattered light from the cerebral cortex layer is greater than 50%, while the source-detector separation exceeds the cross-point. Compare this result with Figure 9, the total received intensity was decreases strongly with the source-detector separation increas- ing. Hence, the source-detector separation in this individualised case was optimally set as 3.3 cm for NIRS measurement.
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Results: 47 years old (IQ 26–53), with 73.2 % were female, having a SAPS II 41 (32–45), GCS 7 (5–8), and at least one episode of mydriasis in 48.8 %. Thrombosis location was 80.5 % in lateral sinus and 53.7 % in superior sagittal sinus; intracranial hematoma was present in 78.0 %, signs of intracranial hypertension in 60.9 %, cerebral edema in 58.5 % and venous ischemia in 43.9 %. All patients received heparin therapy, and 9 cases had endovascular treatment (21.9 %); osmotherapy (53.7 %) and decompressive craniectomy (16 cases, 39 %) necessary to control intracranial hypertension. Ten patients/41 (24.4 %) died in ICU and 18/31 (58.1 %) were discharged from ICU with outcome 0–3 of mRS. After 12 months, 92 % of survivors (23/25) had a mRS between 0 and 3. The proportion of death was 31.7 % at 1 year.
The Monro-Kellie doctrine states that inside the adult skull there is blood, cerebrospinal fluid (CSF), and brain tissue in a state of volume equilibrium; an increase in volume of one component is compensated by an equiva- lent decrease in volume of another. A small increase in brain volume does not lead to increases in ICP because CSF and venous blood are displaced into the spinal canal. Once the ICP is ~25 mmHg, small increases in brain volume cause marked elevations in ICP. This is the basis of an exponential relationship between ICP and intracranial volume and the concept of RAP, which is a running correlation coefficient (R) between mean ICP amplitude (A) and ICP pulse amplitude (P). RAP ~0 indicates good compensatory reserve, whereas RAP ~1 indicates that ICP rises greatly with a small increase in volume . Here, we argue that the Monro-Kellie doc- trine may also apply to the injured cord. After severe TSCI, the pia is damaged, evidenced by the observations that the injured cord appears swollen on MRI  and, at the injury site, subdural ISP equals intraparenchymal ISP . Spinal cord swelling may generate forces radi- ally and rostro-caudally. Since most neuronal fibers run rostro-caudally, cord edema will produce radial rather than rostro-caudal cord expansion. The denticulate liga- ments and nerve roots may also restrict rostro-caudal cord expansion. If rostro-caudal spinal cord expansion were possible, then the spinal cord above the injury would be displaced upward whereas the spinal cord below the injury would be displaced downward. Such displacements are not seen on MRI scans; instead, there is radial swelling of the injured cord against the dura. The observations that, after a laminectomy, the dural sac diameter at the injury site appears the same as above or below, and that ISP at the injury site remains high, suggest that the spinal dura is non-distensible. Thus, as the injured cord swells, the compensatory mechanisms of displacing CSF and venous blood become exhausted