Treatment of huge hypertensive putaminal hemorrhage by surgery and cerebrospinal fluid drainage

Objective

There is limited information available regarding the treatment of huge hypertensive putaminal hemorrhage (HPH). This study aimed to evaluate our experience of 33 patients with huge HPH who were treated by open surgery (decompressive craniectomy and hematoma evacuation) and external cerebrospinal fluid (CSF) drainage.

Methods

We reviewed the records of 33 consecutive patients admitted to our hospital with huge HPH (≥60 cm³). All patients were treated by decompressive craniectomy, hematoma evacuation, and CSF drainage. Data collected included age, gender, blood pressure at admission, Glasgow Coma Scale (GCS) score, intracranial hemorrhage (ICH) location, ICH volume, degree of midline shift, presence/absence of basal cistern obliteration at admission and before surgery, and presence/absence of intraventricular hemorrhage (IVH). Outcome was assessed by the Glasgow Outcome Scale score at 30 days after surgery.

Results

The median GCS score was 5.0 at admission, and improved to 8.0 at 1 week after surgery. The median ICH volume was 95 cm³ before surgery and 4 cm³ after surgery. IVH was observed in 93.9% of patients. The overall survival rate to discharge was 75.6% (25/33), including 15.1% (4/33) with good function, 36.4% (12/33) with disability, and 24.3% (8/33) in a vegetative state. The mortality rate was 24.3% (8/33). Patients with right-sided ICH had better outcomes than those with left-sided ICH. No patients with GCS score ≤6 and ICH volume ≥90 cm³ at admission achieved good postoperative function. Operative time was significantly shorter with hematoma evacuation via the transcortical approach than via the transsylvian approach (3.41 ± 0.75 h vs. 4.14 ± 0.59 h, P < 0.001). There were no significant differences in the rates of mortality or survival with good function between the two groups.

Conclusions

Treatment of huge HPH by decompressive craniectomy, hematoma evacuation, and CSF drainage is life-saving. Patients with GCS score 7–8, ICH volume 60–90 cm³, and right-sided ICH may achieve good recovery. The transcortical approach appears to be more effective than the transsylvian approach for rapid decompression of the edematous brain.     

Vascular endothelial growth factor in the CSF of elderly patients with ventriculomegaly: Variability,periodicity and levels in drainage responders and non-responders

Objectives

The aim of this study was to examine lumbar CSF-VEGF levels from elderly patients with ventriculomegaly to evaluate the possible circadian or periodic concentration profile and relevance to the prediction of drainage response.

Methods

Lumbar CSF samples were collected in 1-h interval over 35 h from 22 patients with ventriculomegaly. CSF-VEGF levels were measured to elucidate the possible circadian or periodic concentration profiles. These VEGF levels were evaluated for correlations with clinical response to CSF drainage, ventricle size and other clinical information.

Results

The 35-h CSF-VEGF levels demonstrated a periodic concentration pattern with significant episodic fluctuation with 3–5 h intervals. CSF-VEGF levels in non-responder group in which patients did not show clinical improvement with CSF drainage were significantly higher than these in responder group.

Conclusion

VEGF variation in hydrocephalus patients suggests its possible pathophysiological role in hydrocephalus. The periodic concentration pattern of CSF-VEGF must be considered when choosing the most appropriate time for sample collection or clinical manipulation. Increased VEGF level in patients who showed no improvement with CSF drainage suggests that a possible greater ischemic or vascular injury may play a role in these patients. Pending further studies, these results suggest that high VEGF levels have a potential application in predicting non-responder patients with CSF drainage and so reducing the morbidity and cost of drainage and shunting in these patients.     

Granulocyte macrophage colony‐stimulating factor promotes regeneration of retinal ganglion cells in vitro through a mammalian target of rapamycin‐dependent mechanism

Lack of regeneration in the adult central nervous system (CNS) is a major hurdle that limits recovery from neurological ailments. Although accumulating research suggests the possibility of axon regeneration by targeting intrinsic signaling mechanisms, it remains a matter of controversy whether functional recovery can be achieved by manipulating aspects of molecular signaling. Recent studies have shown that granulocyte macrophage colony‐stimulating factor (GM‐CSF) may be an effective means of targeting repair following CNS injury; how this molecule is able to produce this effect is not known. Indeed, GM‐CSF has been shown to promote neuronal survival, potentially through activation of as yet unknown cytokine‐dependent signals and potentially through regulation of antiapoptotic mechanisms. It is well established that the loss of intrinsic regenerative ability is highly correlated with development of CNS neurons. We therefore designed experiments, using a well‐established in vitro retinal ganglion cell (RGC) culture system, to evaluate the effect of GM‐CSF on axon growth and cell survival and define possible mechanisms involved in GM‐CSF‐mediated effects in vitro. Several developmental stages were evaluated, with particular focus placed on stages at which axon growth is known to be significantly diminished. Our results reveal that GM‐CSF not only promotes axon growth in postnatal RGCs but also enhances cell survival through a mammalian target of rapamycin (mTOR)‐dependent mechanism. © 2013 Wiley Periodicals, Inc.     

SYSMEX XN-1000血球仪在脑脊液和胸腹水白细胞计数中的可行性探讨

目的：探讨SYSMEX XN-1000血液分析仪(简称SYSMEX XN-1000)的体液模式在脑脊液和胸腹水白细胞计数中应用的可行性。方法分别采用手工显微镜镜检法和SYSMEX XN-1000对183例脑脊液和胸腹水标本进行白细胞计数,将所测结果按A：(0~1000)×106/L,B：(1001~5000)×106/L,C：>5000×106/L分为三组,分别进行统计学分析。结果与手工显微镜镜检法相比,SYSMEX XN-1000所测结果差异无统计学意义(P>0.05)。A、B、C三组的相关系数分别为0.993、0.984、0.996,A组回归方程为y=1.007x-1.072,B组回归方程为y=1.003x+19.776,C组回归方程为y=1.241x-1419.365。结论 SYSMEX XN-1000血液分析仪可用于临床脑脊液和胸腹水中白细胞计数,其操作简单易行,结果稳定可靠,但如果仪器进行样品检测时报警,应当手工镜检复核,以提高结果的准确性和可靠性。     

Influence of delayed CSF storage on concentrations of phospho-tau protein (181), total tau protein and beta-amyloid (1-42)

It is generally accepted that cerebrospinal fluid (CSF) biomarkers such as tau protein, phosphorylated tau protein (threonine 181) and beta-amyloid (1-42) can facilitate early and differential diagnosis of Alzheimer's disease (AD). Since the respective concentrations can only be measured in a number of specialized centers, time to CSF specimen work-up has been considered as crucial for the stability of the respective biomarkers. When shipping of CSF samples is needed for biomarker measurement and immediate freezing of samples is not available, an overnight delay of up to 24h frequently occurs. Therefore, we investigated the potential impact of a 24h delayed freezing on CSF biomarker concentrations and compared it to 2h storage (room temperature, 20 degrees C) and an immediate freezing. First, storage at room temperature for 2h had only marginal, non-significant effects on the concentrations of CSF total tau protein and phospho-tau protein (181) compared to immediate freezing. Second, storage at room temperature for 24h did not significantly affect total tau protein or phospho-tau protein but beta-amyloid (1-42) concentrations which increased significantly compared to the samples frozen immediately. These results indicate that CSF samples for the evaluation of total tau and phospho-tau protein may be kept at room temperature for up to 24h whereas CSF samples for beta-amyloid (1-42) need to be frozen immediately.     

Role of spinal metabotropic glutamate receptors in regulation of lower urinary tract function in the decerebrate unanesthetized rat

Biomarker levels in cerebrospinal fluid (CSF) may serve as surrogate markers for treatment efficacy in clinical trials of disease-modifying drugs against Alzheimer's disease (AD). A prerequisite, however, is that the marker is sufficiently stable over time in individual patients. Here, we tested the stability of the three established CSF biomarkers for AD, total tau (T-tau), tau phosphorylated at threonine 181 (P-tau(181)) and the 42 amino acid isoform of beta-amyloid (Abeta42), over 6 months in a cohort of AD patients on stable treatment with acetylcholinesterase (AChE) inhibitors. Fifty-three patients completed the study, 29 men and 24 women, mean age (+/-S.D.) 76.1+/-7.9 years. Mean levels of CSF biomarkers were very stable between baseline and endpoint, with coefficients of variation (CVs) of 4.4-6.1%. Intra-individual biomarker levels at baseline and endpoint were also highly correlated with Pearson r-values above 0.95 (p<0.0001), for all three markers. We conclude that T-tau, P-tau and Abeta42 concentrations in CSF are remarkably stable over a 6-month period in individual AD patients. This suggest that these biomarkers may have a potential to identify and monitor very minor biochemical changes induced by treatment, and thus support their possible usefulness as surrogate markers in clinical trials with drug candidates with disease-modifying potential, such as secretase inhibitors, Abeta immunotherapy and tau phosphorylation inhibitors.     

Critical role of microvasculature basal lamina in ischemic brain injury

Cerebral vascular system can be divided into two categories: the macrovessels and microvessels. The microvessels consist of arterioles, capillaries and venules. There are three basic components in the microvasculature: endothelial cells, basal lamina and end-feet of astrocytes. The basal lamina is situated between the endothelial cells and the end-feet of astrocytes, and connects these two layers together. Damage to the basal lamina causes the dismantlement of microvascular wall structures, which in turn results in increase of microvascular permeability, hemorrhagic transformation, brain edema and compromise of the microcirculation. The present article reviews microvascular changes during ischemic brain injury, with emphasis on basal lamina damage.     

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of l-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A)receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.     

Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models

Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro–in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (C_b,u), unbound plasma (C_p,u), and CSF compound concentrations (C_CSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (C_b,u/C_p,u and C_CSF/C_p,u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although C_CSF does not quantitatively correspond to C_b,u for efflux transporter substrates, it is mostly within 3-fold higher of C_b,u in rat and NHP, suggesting that C_CSF can be used as a surrogate for C_b,u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates.     

Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination

New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5–9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2–27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7–157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4–90.3), and Enders’Edmonston (IRR: 8.5; 95% CI: 1.9–38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3–87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs.