An axisymmetric and fully 3D poroelastic model for the evolution of hydrocephalus.

We formulate in general terms the equations for axisymmetric and fully 3D models of a hydrocephalic brain. The model is developed using small strain poroelasticity that includes non-linear permeability. The axisymmetric model is solved for four ventricle shapes, an ellipsoid, a 'peanut' shape, a 'cross' shape and a 'bone' shape. The distribution of fluid pressure, velocity and content in the deformed parenchyma for a blocked aqueduct provides new qualitative insight into hydrocepahlus. Some observations are offered for two forms of cerebrospinal fluid flow abnormality, normal pressure hydrocephalus and idiopathic intracranial hypertension. The model is extended to include a gravitational term in the governing equations and the effect of hydrostatic pressure variation is considered. Results of a fully 3D simulations are described for two horn-like lateral ventricles and one case with two lateral ventricles and a third ventricle.     

特发性正常压力脑积水的外科治疗进展

特发性正常颅压脑积水(i NPH)是一组原因不明的,以步态不稳、认知障碍、尿失禁三联征为主要临床表现,而脑脊液腰穿压力正常的进行性发展的临床综合征。合适的分流手术后i NPH患者可有良好的预后。手术方式以脑室腹腔分流术最为常见。早期诊断,早期治疗可明显改善患者的病情。经充分评估后诊断为i NPH的患者尽早进行手术治疗,预后较好。     

In vivo viscoelastic properties of the brain in normal pressure hydrocephalus

Nearly half a century after the first report of normal pressure hydrocephalus (NPH), the pathophysiological cause of the disease still remains unclear. Several theories about the cause and development of NPH emphasize disease-related alterations of the mechanical properties of the brain. MR elastography (MRE) uniquely allows the measurement of viscoelastic constants of the living brain without intervention. In this study, 20 patients (mean age, 69.1 years; nine men, 11 women) with idiopathic (n = 15) and secondary (n = 5) NPH were examined by cerebral multifrequency MRE and compared with 25 healthy volunteers (mean age, 62.1 years; 10 men, 15 women). Viscoelastic constants related to the stiffness (μ) and micromechanical connectivity (α) of brain tissue were derived from the dynamics of storage and loss moduli within the experimentally achieved frequency range of 25-62.5 Hz. In patients with NPH, both storage and loss moduli decreased, corresponding to a softening of brain tissue of about 20% compared with healthy volunteers (p < 0.001). This loss of rigidity was accompanied by a decreasing α parameter (9%, p < 0.001), indicating an alteration in the microstructural connectivity of brain tissue during NPH. This disease-related decrease in viscoelastic constants was even more pronounced in the periventricular region of the brain. The results demonstrate distinct tissue degradation associated with NPH. Further studies are required to investigate the source of mechanical tissue damage as a potential cause of NPH-related ventricular expansions and clinical symptoms.     

Idiopathic intracranial hypertension and transverse sinus stenosis: a modelling study

^** Email: sas56{at}psu.edu Idiopathic intracranial hypertension (IIH) is a syndrome ofunknown etiology characterized by elevated intracranial pressure(ICP). Although a stenosis of the transverse sinus has beenobserved in many IIH patients, the role this feature plays inIIH is in dispute. In this paper, a lumped-parameter model isdeveloped for the purpose of analytically investigating theelevated pressures associated with IIH and a collapsible transversesinus. This analysis yields practical predictions regardingthe degree of elevated ICPs and the effectiveness of varioustreatment methods. Results suggest that IIH may be caused bya sufficiently collapsible transverse sinus, but it is alsopossible that a stenosed sinus may persist following resolutionof significant intracranial hypertension.     

持续腰大池置管脑脊液压力检测对Tap试验阴性iNPH患者的诊疗价值

目的探讨腰大池置管持续测定脑脊液压力对腰椎穿刺脑脊液放液试验(Tap试验)阴性的特发性正常压力脑积水(iNPH)患者的诊疗价值。方法选择82例Tap试验阴性的iNPH患者作为研究对象,持续12 h行腰大池置管脑脊液压力测定后行脑室—腹腔分流术。根据颅内压波幅与颅内压相关系数(RAP)值分为2组,RAP≥0.6的34例患者为高RAP组,RAP<0.6的48例患者为低RAP组。比较2组手术前后无障碍直线折返计时行走测试(TUGT)时间、简易精神评价测量表(MMSR)评分和排尿评分,评估2组患者步态不稳、认知障碍、排尿障碍改善率及治疗效果。结果术后1个月,高RAP组TUGT时间较术前及低RAP组明显缩短,MMSR评分较术前及低RAP组明显提高,排尿评分较术前及低RAP组明显降低,差异有统计学意义(P<0.05)。高RAP组术后1个月步态不稳、认知障碍、排尿障碍改善率高于低RAP组,差异有统计学意义(P<0.05)。高RAP组患者脑室—腹腔分流术后疗效总有效率高于低RAP组,差异有统计学意义(P<0.05)。结论Tap试验阴性的iNPH患者经持续12 h腰大池置管脑脊液压力测定再筛查,以RAP≥0.6作为行脑室—腹腔分流术的指标具有较高的诊疗价值。     

Prevalence of papilloedema in patients with sleep apnoea syndrome: a prospective study

The association of papilloedema (PO) with respiratory diseases and especially obstructive sleep apnoea (OSA) syndrome has been emphasised in many reports. The pathophysiology could rely on the episodic increase of intracranial pressure related to apnoeic episodes during night sleep. Nevertheless, prevalence of papilloedema in patient with OSA syndrome remains unknown. As this information could improve diagnosis and therapeutic strategies, the aim of the present study was to investigate the prevalence of PO in an OSA syndrome population. From 95 successive, recently diagnosed OSA patients, 35 answered a questionnaire about visual symptoms and underwent fundoscopic examination. Visual symptoms suggestive of PO were present in 40% of the patients, but none had PO. As a conclusion, PO does not seem to be frequently associated with OSA syndrome and systematic screening of PO in these patients does not seem to be warranted. Nevertheless, patients with visual complaints evocative of papilloedema should have their eye fundus checked since the association between OSA and PO exists. Further studies, including more patients, might be useful to establish which patients are at particular risk for this complication.     

Expression of TGF-βs and TGF-β type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus

We investigated cerebrospinal fluid (CSF) samples from 21 patients with idiopathic normal pressure hydrocephalus (INPH) and 14 controls without neurological disease. The concentrations of leucine-rich α-2-glycoprotein (LRG), transforming growth factor (TGF)-β1, 2, 3 and TGF-β type II receptor (TβR-II) in CSF were measured using ELISA. TGF-β1, TβR-II and LRG CSF levels of patients with INPH were significantly higher than controls, whereas no significant differences in TGF-β2 levels were found between INPH patients and controls. The present study suggests that TGF-βs expressions may be modulated differently in patients with INPH. These results also indicate that the CSF level assay of TGF-β1, TβR-II and LRG is useful for the diagnosis of patients with INPH, and TGF-β1, TβR-II and LRG may be involved in the pathogenesis of the disease.     

Benign external hydrocephalus in a boy with autosomal dominant microcephaly

In a 3-month-old boy with microcephaly, magnetic resonance imaging (MRI) revealed accumulation of bifrontal extracerebral fluid. Because of the typical MRI findings and the disappearance of these findings later on, he was diagnosed as a case of benign external hydrocephalus. Both his mother and maternal grandmother had microcephaly, without neurological or dysmorphic manifestations. The pedigree is most consistent with an autosomal dominantly inherited microcephaly. This seems to be the first report of benign external hydrocephalus found in a patient with an autosomal dominant microcephaly.     

The production of cerebrospinal fluid in experimental communicating hydrocephalus

Summary Utilizing an atraumatic model to produce chronic hydrocephalus, CSF production was measured during and after development of communicating hydrocephalus. CSF volume production was significantly lower in animals with increased pressure. Animals with chronic hydrocephalus and normal pressures had abnormal CSF production. Diminished CSF production appears to offer a potential compensatory mechanism when CSF absorption is altered.     

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.     

Analytic solution during an infusion test of the linear unsteady poroelastic equations in a spherically symmetric model of the brain

Ian Sobey Computing Laboratory, University of Oxford, Wolfson Building, Parks Road, Oxford OX1 3QD, UK Email: ian.sobey{at}comlab.ox.ac.uk Received on July 9, 2007. Revised on May 14, 2008. Accepted on September 11, 2008. This work determines the spatial and temporal distribution ofcerebrospinal fluid (CSF) pressure and brain displacement duringan infusion test in a spherically symmetric model of the brain.The response of CSF pressure and parenchymal displacement toblood pressure pulsations is determined in the solution. Weuse a spherically symmetric, three-component poroelastic modelof the brain, differentiating between the solid elastic matrix,the CSF and the arterial blood compartments. The governing equationsare linearized with quasi-constant poroelastic parameters. Thesolution does reproduce the average intracranial pressure increaseduring the test as well as the rise in CSF pressure pulsationamplitude due to transmission of blood pressure oscillations.In addition, the CSF flux into and out of the parenchyma isshown over time.     

A model of in-vivo hydrocephalus shunt dynamics for blockage and performance diagnostics.

The accumulation of excess cerebrospinal fluid in the ventricles of the brain results in hydrocephalus, a condition that is fatal if left untreated. The usual remedy is to insert a shunt into the ventricles of the brain, which drains excess fluid away, moderated by a pressure dependent valve. It is important that the system functions properly so that a reasonable intracranial pressure is maintained. Unfortunately, pressure measurements in the ventricles are highly invasive, while pressure measurements in the shunt outside the skull may not detect any blockage in the catheter inside. Here we develop a model primarily aimed at detecting in vivo a blockage and other shunt malfunction using non-invasive measurements, so that shunt valves can be adjusted accordingly. The system offers a clear insight into how currently available clinical measurements may be utilized. We then extend this to investigate the phenomenon of 'chatter' (rapid opening and closing) and other mechanisms including intracranial pressure pulsatility. Although simple, the model offers a clear indication of what is required for successful regulation of both intracranial pressure and shunt flow.     

Infusion technique can be used to distinguish between dysfunction of a hydrocephalus shunt system and a progressive dementia

In a deteriorating shunted patient with hydrocephalus, an investigation of shunt function is often performed to distinguish a dysfunctioning shunt from an aggravated condition of the disease. The paper illustrates how a lumbar cerebrospinal fluid (CSF) infusion method can be used to evaluate post-operative deterioration in a shunted patient in order to give the physician valuable support in the shunt revision decision. A 77-year-old man with hydrocephalus was treated operatively by the insertion of a CSF shunt. Owing to shunt failure, the shunt was revised twice during a 5 year period. Using a computerised infusion technique method, with two needles placed in the lumbar subarachnoid space, the CSF dynamic system was determined pre- and post-operatively with the functioning as well as the dysfunctioning shunts. The data were verified with a bench-test of the extirpated CSF shunt. There was a significant difference in conductance G between CSF systems with an open shunt and CSF systems with no shunt or an occluded shunt (ΔG=38mm³ s⁻¹ kPa⁻¹, p=0.014, n=7, ANOVA). CSF dynamics investigations, with and without a shunt, can give valuable clinical support in the management of a deteriorating hydrocephalus patient. With further development of the lumbar infusion method moving towards easy-to-use equipment, there is potential for widespread clinical use.     

Development of hydrocephalus and classical hypothesis of cerebrospinal fluid hydrodynamics: facts and illusions

According to the classical hypothesis of the cerebrospinal fluid (CSF) hydrodynamics, CSF is produced inside the brain ventricles, than it circulates like a slow river toward the cortical subarachnoid space, and finally it is absorbed into the venous sinuses. Some pathological conditions, primarily hydrocephalus, have also been interpreted based on this hypothesis. The development of hydrocephalus is explained as an imbalance between CSF formation and absorption, where more CSF is formed than is absorbed, which results in an abnormal increase in the CSF volume inside the cranial CSF spaces. It is believed that the reason for the imbalance is the obstruction of the CSF pathways between the site of CSF formation and the site of its absorption, which diminishes or prevents CSF outflow from the cranium. In spite of the general acceptance of the classical hypothesis, there are a considerable number of experimental results that do not support such a hypothesis and the generally accepted pathophysiology of hydrocephalus. A recently proposed new working hypothesis suggests that osmotic and hydrostatic forces at the central nervous system microvessels are crucial for the regulation of interstial fluid and CSF volume which constitute a functional unit. Based on that hypothesis, the generally accepted mechanisms of hydrocephalus development are not plausible. Therefore, the recent understanding of the correlation between CSF physiology and the development of hydrocephalus has been thoroughly presented, analyzed and evaluated, and new insights into hydrocephalus etiopathology have been proposed, which are in accordance with the experimental data and the new working hypothesis.     

The use of injectable spherically symmetric cell aggregates self-assembled in a thermo-responsive hydrogel for enhanced cell transplantation

Typical cell transplantation techniques involve the administration of dissociated cells directly injected into muscular tissues; however, retention of the transplanted cells at the sites of the cell graft is frequently limited. An approach, using spherically symmetric aggregates of cells with a relatively uniform size self-assembled in a thermo-responsive methylcellulose hydrogel system, is reported in the study. The obtained cell aggregates preserved their endogenous extracellular matrices (ECM) and intercellular junctions because no proteolytic enzyme was used when harvesting the cell aggregates. Most of the cells within aggregates (with a radius of approximately 100 μm) were viable as indicated by the live/dead staining assay. After injection through a needle, the cell aggregates remained intact and the cells retained their activity upon transferring to another growth surface. The cell aggregates obtained under sterile conditions were transplanted into the skeletal muscle of rats via local injection. The dissociated cells were used as a control. It was found that the cell aggregates can provide an adequate physical size to entrap into the muscular interstices and offer a favorable ECM environment to enhance retention of the transplanted cells at the sites of the cell graft. These results indicated that the spherically symmetric cell aggregates developed in the study may serve as a cell delivery vehicle for therapeutic applications.     

A unique N-glycan on human transferrin in CSF: a possible biomarker for iNPH

Idiopathic normal pressure hydrocephalus (iNPH) is an elderly dementia caused by abnormal metabolism in the cerebrospinal fluid (CSF). The tap test is the current basis for confirming iNPH, but it shows very low sensitivity, indicating that many patients who might be cured by a shunt operation will be missed. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we found two transferrin isoforms: one had a unique N-glycan (Tf-1) whereas the other had N-glycan similar to that of serum transferrin (Tf-2). Glycan analyses revealed that Tf-1 had branching (biantennary) asialo- and agalacto-complex type N-glycans (N-acetylglucosamine [GlcNAc]-terminated glycans), which carried bisecting β1,4-N-acetylglucosamine and core α1,6-fucose. To examine glycoform whether changes in iNPH, we introduced the Tf-2/Tf-1 ratio as a diagnostic index, which minimized blot-to-blot variations in measurement. The Tf-2/Tf-1 ratios of iNPH patients are significantly higher than those of controls (p = 0.0019) and Alzheimer's patients (p = 0.0010). This suggests that the Tf-2/Tf-1 ratio could distinguish iNPH from Alzheimer's disease, and possibly other dementias. In conclusion, glycoform analysis has diagnostic potential in neurological diseases.     

Effect of repeated measurements of blood pressure on blood pressure in essential hypertension: Role of anxiety

Over the past years, we repeatedly observed that of the hypertensive population entered into our behavioral treatment programs, more than half were actually false hypertensives. With repeated measurements of blood pressure (BP), only one-third remained hypertensive, while two-thirds showed a significant decrease in BP. The purpose of this study was to determine which factors correlate with the decrease in BP and could be useful in distinguishing the true and the false hypertensives. Of the 24 patients in this study, 15 decreased their mean arterial pressure by at least 5 mm Hg during a 6-week period of home and clinic BP measurement, while 9 did not. The 9 patients with BPs that did not change had lower State Anxiety, Trait Anxiety scores, lower diastolic BP, and lower heart rates compared to the group whose BPs decreased. These results suggest that under certain conditions a relationship exists between anxiety and elevated blood pressure. In a segment of the hypertensive population, anxious patients may be placed on inappropriate anti-hypertensive medication if a BP measurement period is not conducted before intervention.     

Hypertensive urgencies during the first wave of the COVID-19 pandemic in a tertiary hospital setting: a U-shaped alarming curve

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic provoked unprecedented disturbance in hypertension care, while alarming concerns arose about its long-term consequences. We investigated the trends of emergency visits and admissions regarding uncontrolled hypertension in order to assess the impact of COVID-19 spread on population behavior towards hypertension urgencies during its first wave.Material and methodsData from daily unscheduled visits and admission counts in the Cardiology sector were collected from the Emergency Department database of a tertiary General Hospital in Athens, Greece for the period January 15^th to July 15^th 2020. These data were compared with those from the previous year. Cases of patients who presented with hypertensive urgency or who were admitted due to uncontrolled hypertension were separately analyzed.ResultsA total of 7,373 patient records were analyzed. Hypertension urgency cases demonstrated a U-shaped distribution in 2020, showing a declining trend during the rapid virus spread, an image that was reversed after the transmission rate’s decline. COVID-19 incidence in Greece was inversely associated with uncontrolled hypertension admissions during its declining phase (r = –0.64, p = 0.009), whereas total attendance exhibited a similar correlation during the first and the following months of the pandemic (r = 0.677, p = 0.031, r = –0.789, p = 0.001). Uncontrolled hypertension rate on admission was positively related to the national incidence of COVID-19 cases during the first months of 2020 (r = 0.82, p = 0.045).ConclusionsHypertensive urgency-related visits followed a U-shape distribution during the pandemic’s first wave with the attendance nadir coinciding with the virus spread peak. This is a complex phenomenon, closely related to increased levels of public stress, disruptions in health care services and to a lesser extent to the imposed restrictions in transportation. The initial relative increase in uncontrolled hypertension-related admissions rate, combined with the later increase of hypertensive urgencies may be indicative of blood pressure deregulation among the studied population, which is multifactorial and potentially detrimental.     

咪唑克生对体外血脑屏障炎症模型通透性的影响

目的:观察咪唑克生(idazoxan,IDA)对体外血脑屏障(blood-brain barrier,BBB)炎症模型的通透性、紧密连接蛋白ZO-1表达和分布及基质金属蛋白酶-9(matrix metalloproteinases-9,MMP-9)和MMP-9抑制物——金属蛋白酶组织抑制物-1(tissue inhibitor of metalloproteinase-1,TIMP-1)表达的影响。方法:采用培养7 d的小鼠脑微血管内皮细胞株b.End3建立体外BBB模型,采用TNF-α(10 nmol/L)处理24 h诱导BBB炎症模型,并对BBB炎症模型分别采用IDA 50、100、200μmol/L预处理6 h以观察IDA对BBB炎症模型的作用。通过检测异硫氰酸荧光标记的葡聚糖通过率来确立模型的通透性,采用Western blot法检测紧密连接蛋白ZO-1的表达,通过免疫荧光法观察ZO-1的分布情况,并通过RT-PCR法检测MMP-9/TIMP-1的表达。结果:培养7 d的b.End3细胞汇合成稳定的单层连接,有较好的屏障功能,而采用TNF-α处理24 h后诱导的BBB炎症模型的通透性明显升高,紧密连接蛋白ZO-1在膜上的表达明显减少、不连续,Western blot法显示ZO-1蛋白表达水平明显下降,MMP-9的表达明显升高;而采用IDA 50、100、200μmol/L预处理6 h能明显降低其通透性,增加ZO-1蛋白的表达和改善ZO-1的分布异常,降低MMP-9的表达,其中200μmol/L IDA作用最明显,差异有统计学意义(P0.01)。结论:IDA能够直接作用于脑血管内皮细胞,降低TNF-α诱导的体外BBB炎症模型MMP-9的表达,增加紧密连接蛋白ZO-1的表达、修复紧密连接ZO-1的异常分布,从而改善其异常增高的通透性。