scholarly journals Preclinical update on regulation of intracranial pressure in relation to idiopathic intracranial hypertension

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Sajedeh Eftekhari ◽  
Connar Stanley James Westgate ◽  
Maria Schmidt Uldall ◽  
Rigmor Hoejland Jensen
Keyword(s):  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Special Focus ◽  
Icp Monitoring ◽  
Preclinical Research ◽  
New Drug

Abstract Background Elevated intracranial pressure (ICP) is observed in association with a range of brain disorders. One of these challenging disorders is idiopathic intracranial hypertension (IIH), characterized by raised ICP of unknown cause with significant morbidity and limited therapeutic options. In this review, special focus is put on the preclinical research performed in order to understand the pathophysiology behind ICP regulation and IIH. This includes cerebrospinal fluid dynamics, molecular mechanisms underlying disturbances in brain fluids leading to elevated ICP, role of obesity in IIH, development of an IIH model and ICP measurements in rodents. The review also discusses existing and new drug targets for IIH that have been evaluated in vivo. Conclusions ICP monitoring in rodents is challenging and different methods have been applied. Some of these methods are invasive, depend on use of anesthesia and only allow short-term monitoring. Long-term ICP recordings are needed to study IIH but existing methods are hampered by several limitations. As obesity is one of the most common risk factors for IIH, a rodent obese model has been developed that mimics some key aspects of IIH. The most commonly used drugs for IIH have been evaluated in vivo for their efficacy at lowering ICP in the existing animal models. These studies suggest these drugs, including acetazolamide, might have limited or no reducing effect on ICP. Two drug targets that can impact ICP in healthy rodents are topiramate and a glucagon-like peptide-1 receptor (GLP-1R) agonist. However, it remains to evaluate their effect in an IIH model with more precise and valid ICP monitoring system. Therefore, continued evaluation in the preclinical research with refined tools is of great importance to further understand the pathophysiology behind disorders with raised ICP and to explore new drug targets.

scholarly journals Non-invasive intracranial pressure monitoring in idiopathic intracranial hypertension and lumbar puncture in pediatric patient: Case report

2021 ◽  
Vol 12 ◽  
pp. 493
Author(s):  
Thomas Markus Dhaese ◽  
Leonardo C. Welling ◽  
Alice Magro Kosciasnki ◽  
Gustavo Frigeri ◽  
Judy Auada ◽  
...  
Keyword(s):  
Case Report ◽  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Lumbar Puncture ◽  
Idiopathic Intracranial Hypertension ◽  
Intracranial Pressure Monitoring ◽  
Invasive Technique ◽  
Icp Monitoring ◽  
Pressure Monitoring ◽  
Non Invasive

Background: Intracranial pressure (ICP) monitoring has been variously explored as a diagnostic and therapeutic modality in many pathological conditions leading neurological injury. This monitoring standardly depends on an invasive procedure such as cranial or lumbar catheterization. The gold standard for ICP monitoring is through an intraventricular catheter, but this invasive technique is associated with certain risks such as haemorrhage and infection. (1) Also, it is a high-cost procedure and consequently not available in a variety of underprivileged places and clinical situations in which intracranial hypertension is prevalent (3). An accurate non-invasive and low-priced method to measure elevated ICP would therefore be desirable. Under these circumstances, Brazilian scientists developed a non-invasive method for intracranial pressure monitoring (ICP-NI), which uses an electric resistance extensometer that measures micro deformations of the skull and transforms it into an electrical signal. In this case report, the authors describe a pediatrician patient with the diagnosis of idiopathic intracranial hypertension who was successfully submitted to a lumbar puncture under monitorization with this device. Case description: 7 year old girl with progressive symptoms that lead to the diagnosis of idiopathic intracranial hypertension. The patient was submitted to a lumbar punction with continuous non-invasive ICP monitoring. Conclusion: Estimating ICP (non-invasive) from LP monitoring (invasive) often reflect inaccurate ICP results, and affects negatively on IIH diagnosis and a non-invasive diagnostic method could reduce the requirement for invasive approaches, improving patient health outcomes.

scholarly journals Long-term telemetric intracranial pressure monitoring for diagnosis and therapy optimisation of idiopathic intracranial hypertension

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Victor F. Velazquez Sanchez ◽  
Giath Al Dayri ◽  
Christoph A. Tschan
Keyword(s):  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Complex Disease ◽  
Home Monitoring ◽  
Third Ventriculostomy ◽  
Icp Monitoring ◽  
Home Telemonitoring ◽  
Valve Opening

Abstract Background Idiopathic intracranial hypertension (IIH) is a disease which is difficult to diagnose and moreover difficult to treat. We developed a strategy for long-term telemonitoring of intracranial pressure (ICP), by incorporation of the NEUROVENT®-P-tel System, with the goal of improved diagnosis and consequent therapy of this disease. We highlight the results obtained through this approach. Methods Twenty patients with suspected IIH who were treated in our hospital from August 2014 to October 2020 (16 females, 4 males, median age 36,6 years), were assigned to one of two ICP monitoring settings, “Home-Telemonitoring” (n = 12) and “Home-Monitoring” (n = 8). The ICP data were analysed and used conjointly with the accompanying clinical picture for establishment of IIH diagnosis, and telemonitoring was resumed for therapy optimisation of confirmed cases. Results The diagnosis of IIH was confirmed in 18 of the 20 patients. Various surgical/interventional treatments were applied to the confirmed cases, including ventriculoperitoneal (VP) shunting (n = 15), stenting of the transvers venous sinus (n = 1), endoscopic third ventriculostomy (ETV) (n = 1), and ETV in combination with endoscopic laser-based coagulation of the choroid Plexus (n = 1). Optimal adjustment of the implanted shunt valves was achieved with an average valve opening pressure of 6,3 ± 2,17 cm H2O for differential valves, and of 29,8 ± 3,94 cm H2O for gravitational valves. The Home-Telemonitoring setting reduced consequent outpatient visits, compared to the Home-Monitoring setting, with an average of 3,1 visits and 4,3 visits, respectively. No complications were associated with the surgical implantation of the P-tel catheter. Conclusion This study offers insight into the use of long-term ICP monitoring for management of IIH patients in combination with dual-valve VP shunts. The use of NEUROVENT® P-tel system and potentially other similar fully implantable ICP-monitoring devices, albeit invasive, may be justified in this complex disease. The data suggest recommending an initial adjustment of dual-valve VP-shunts of 30 and 6 cm H2O, for gravitational and differential valves, respectively. Further research is warranted to explore potential integration of this concept in IIH management guidelines.

scholarly journals Topiramate is more effective than acetazolamide at lowering intracranial pressure

Cephalalgia ◽  
2018 ◽  
Vol 39 (2) ◽  
pp. 209-218 ◽  
Author(s):  
William J Scotton ◽  
Hannah F Botfield ◽  
Connar SJ Westgate ◽  
James L Mitchell ◽  
Andreas Yiangou ◽  
...  
Keyword(s):  
Intracranial Pressure ◽  
Oral Administration ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Subcutaneous Administration ◽  
Female Rats ◽  
In Vivo Studies ◽  
Human Dose ◽  
High Doses

Background The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. Methods We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. Results At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% ( p = 0.0009) and 21% ( p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% ( p = 0.018), compared to 5% reduction with acetazolamide ( p = >0.999). Conclusion Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

scholarly journals Understanding the link between obesity and headache- with focus on migraine and idiopathic intracranial hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Connar Stanley James Westgate ◽  
Ida Marchen Egerod Israelsen ◽  
Rigmor Højland Jensen ◽  
Sajedeh Eftekhari
Keyword(s):  
Weight Loss ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Molecular Mechanisms ◽  
The Body ◽  
Preclinical Research ◽  
Trigeminovascular System ◽  
Novel Treatments ◽  
Headache Severity ◽  
Inflammatory Stimuli

Abstract Background Obesity confers adverse effects to every system in the body including the central nervous system. Obesity is associated with both migraine and idiopathic intracranial hypertension (IIH). The mechanisms underlying the association between obesity and these headache diseases remain unclear. Methods We conducted a narrative review of the evidence in both humans and rodents, for the putative mechanisms underlying the link between obesity, migraine and IIH. Results Truncal adiposity, a key feature of obesity, is associated with increased migraine morbidity and disability through increased headache severity, frequency and more severe cutaneous allodynia. Obesity may also increase intracranial pressure and could contribute to headache morbidity in migraine and be causative in IIH headache. Weight loss can improve both migraine and IIH headache. Preclinical research highlights that obesity increases the sensitivity of the trigeminovascular system to noxious stimuli including inflammatory stimuli, but the underlying molecular mechanisms remain unelucidated. Conclusions This review highlights that at the epidemiological and clinical level, obesity increases morbidity in migraine and IIH headache, where weight loss can improve headache morbidity. However, further research is required to understand the molecular underpinnings of obesity related headache in order to generate novel treatments.

scholarly journals Comparative observational study on the clinical presentation, intracranial volume measurements, and intracranial pressure scores in patients with either Chiari malformation Type I or idiopathic intracranial hypertension

2017 ◽  
Vol 126 (4) ◽  
pp. 1312-1322 ◽  
Author(s):  
Radek Frič ◽  
Per Kristian Eide
Keyword(s):  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Chiari Malformation ◽  
Normal Pressure ◽  
Type I ◽  
Icp Monitoring ◽  
Chiari Malformation Type I ◽  
Intracranial Compliance ◽  
Volume Measurements

OBJECTIVE Several lines of evidence suggest common pathophysiological mechanisms in Chiari malformation Type I (CMI) and idiopathic intracranial hypertension (IIH). It has been hypothesized that tonsillar ectopy, a typical finding in CMI, is the result of elevated intracranial pressure (ICP) combined with a developmentally small posterior cranial fossa (PCF). To explore this hypothesis, the authors specifically investigated whether ICP is comparable in CMI and IIH and whether intracranial volumes (ICVs) are different in patients with CMI and IIH, which could explain the tonsillar ectopy in CMI. The authors also examined whether the symptom profile is comparable in these 2 patient groups. METHODS The authors identified all CMI and IIH patients who had undergone overnight diagnostic ICP monitoring during the period from 2002 to 2014 and reviewed their clinical records and radiological examinations. Ventricular CSF volume (VV), PCF volume (PCFV), and total ICV were calculated from initial MRI studies by using volumetric software. The static and pulsatile ICP scores during overnight monitoring were analyzed. Furthermore, the authors included a reference (REF) group consisting of patients who had undergone ICP monitoring due to suspected idiopathic normal-pressure hydrocephalus or chronic daily headache and showed normal pressure values. RESULTS Sixty-six patients with CMI and 41 with IIH were identified, with comparable demographics noted in both groups. The occurrence of some symptoms (headache, nausea, and/or vomiting) was comparable between the cohorts. Dizziness and gait ataxia were significantly more common in patients with CMI, whereas visual symptoms, diplopia, and tinnitus were significantly more frequent in patients with IIH. The cranial volume measurements (VV, PCFV, and ICV) of the CMI and IIH patients were similar. Notably, 7.3% of the IIH patients had tonsillar descent qualifying for diagnosis of CMI (that is, > 5 mm). The extent of tonsillar ectopy was significantly different between the CMI and IIH cohorts (p < 0.001) but also between these 2 cohorts and the REF group. Pulsatile ICP was elevated in both cohorts without any significant between-group differences; however, static ICP was significantly higher (p < 0.001) in the IIH group. CONCLUSIONS This study showed comparable and elevated pulsatile ICP, indicative of impaired intracranial compliance, in both CMI and IIH cohorts, while static ICP was higher in the IIH cohort. The data did not support the hypothesis that reduced PCFV combined with increased ICP causes tonsillar ectopy in CMI. Even though impaired intracranial compliance seems to be a common pathophysiological mechanism behind both conditions, the mechanisms explaining the different clinical and radiological presentations of CMI and IIH remain undefined.

scholarly journals Evaluation of cerebrovascular hemodynamics in patients with idiopathic intracranial hypertension using transcranial Doppler

2020 ◽  
Vol 56 (1) ◽  
Author(s):  
Mahmoud M. Allam ◽  
Hatem A. Almasry ◽  
Sandra M. Ahmed ◽  
Youssuf G. Taha ◽  
Mohammed I. Oraby
Keyword(s):  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Lumbar Puncture ◽  
Transcranial Doppler ◽  
Idiopathic Intracranial Hypertension ◽  
Pulsatility Index ◽  
Research Work ◽  
Increased Intracranial Pressure ◽  
Significant Relation ◽  
Before And After

Abstract Background Idiopathic intracranial hypertension (IIH) is a disorder of increased intracranial pressure without a clear cause and can have serious visual effects. Previous research work suggests that transcranial Doppler measurements of pulsatility index correlate accurately with elevated intracranial pressure. Objective To assess the cerebrovascular hemodynamic changes in patients with IIH using transcranial Doppler before and after lumbar puncture and CSF withdrawal. Methods An interventional study conducted on 40 patients (31 females and 9 males) fulfilling the modified Dandy criteria for diagnosis of idiopathic intracranial hypertension, MRI brain, and MRV was done to the patients. Lumbar puncture was done for all included patients to measure intracranial pressure and CSF withdrawal. Transcranial Doppler was performed for all included before and after lumbar puncture and CSF withdrawal and the following parameters were measured: peak systolic velocity (PSV), end diastolic velocity (EDV), resistivity index (RI), and pulsatility index (PI). Results Significant relation was found between grades of papilledema and PSV, RI, and PI (p value 0.012, 0.025, 0.016) but no significant relation was found between grades of papilledema and EDV (0.102). Significant changes occurred in parameters of TCD pre- and post-CSF withdrawal including PSV, EDV, and PI (p value 0.001, 0.015, 0.019) denoting a significant change in cerebral hemodynamics after CSF withdrawal which denotes a decrease in intracranial pressure. Conclusion Increased intracranial pressure significantly affects cerebral blood flow. A normalization of transcranial Doppler parameters occurs following lowering of intracranial pressure through lumbar puncture and CSF withdrawal.

scholarly journals 11β-Hydroxysteroid dehydrogenase type 1 inhibition in idiopathic intracranial hypertension: a double-blind randomized controlled trial

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Keira Markey ◽  
James Mitchell ◽  
Hannah Botfield ◽  
Ryan S Ottridge ◽  
Tim Matthews ◽  
...  
Keyword(s):  
Intracranial Hypertension ◽  
Lumbar Puncture ◽  
Idiopathic Intracranial Hypertension ◽  
Controlled Trial ◽  
Hydroxysteroid Dehydrogenase ◽  
Opening Pressure ◽  
Double Blind ◽  
Randomized Controlled

Abstract Treatment options for idiopathic intracranial hypertension are limited. The enzyme 11β-hydroxysteroid dehydrogenase type 1 has been implicated in regulating cerebrospinal fluid secretion, and its activity is associated with alterations in intracranial pressure in idiopathic intracranial hypertension. We assessed therapeutic efficacy, safety and tolerability and investigated indicators of in vivo efficacy of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo in idiopathic intracranial hypertension. A multicenter, UK, 16-week phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017 or placebo was conducted. Women aged 18–55 years with active idiopathic intracranial hypertension (&gt;25 cmH2O lumbar puncture opening pressure and active papilledema) were included. Participants received 400 mg of oral AZD4017 twice daily compared with matching placebo over 12 weeks. The outcome measures were initial efficacy, safety and tolerability. The primary clinical outcome was lumbar puncture opening pressure at 12 weeks analysed by intention-to-treat. Secondary clinical outcomes were symptoms, visual function, papilledema, headache and anthropometric measures. In vivo efficacy was evaluated in the central nervous system and systemically. A total of 31 subjects [mean age 31.2 (SD = 6.9) years and body mass index 39.2 (SD = 12.6) kg/m2] were randomized to AZD4017 (n = 17) or placebo (n = 14). At 12 weeks, lumbar puncture pressure was lower in the AZD4017 group (29.7 cmH2O) compared with placebo (31.3 cmH2O), but the difference between groups was not statistically significant (mean difference: −2.8, 95% confidence interval: −7.1 to 1.5; P = 0.2). An exploratory analysis assessing mean change in lumbar puncture pressure within each group found a significant decrease in the AZD4017 group [mean change: −4.3 cmH2O (SD = 5.7); P = 0.009] but not in the placebo group [mean change: −0.3 cmH2O (SD = 5.9); P = 0.8]. AZD4017 was safe, with no withdrawals related to adverse effects. Nine transient drug-related adverse events were reported. One serious adverse event occurred in the placebo group (deterioration requiring shunt surgery). In vivo biomarkers of 11β-hydroxysteroid dehydrogenase type 1 activity (urinary glucocorticoid metabolites, hepatic prednisolone generation, serum and cerebrospinal fluid cortisol:cortisone ratios) demonstrated significant enzyme inhibition with the reduction in serum cortisol:cortisone ratio correlating significantly with reduction in lumbar puncture pressure (P = 0.005, R = 0.70). This is the first phase II randomized controlled trial in idiopathic intracranial hypertension evaluating a novel therapeutic target. AZD4017 was safe and well tolerated and inhibited 11β-hydroxysteroid dehydrogenase type 1 activity in vivo. Reduction in serum cortisol:cortisone correlated with decreased intracranial pressure. Possible clinical benefits were noted in this small cohort. A longer, larger study would now be of interest.

TMOD-02. GENERATION OF A NOVEL MOUSE MODEL FOR BRAIN TUMORS OF THE DNA METHYLATION CLASS “GBM MYCN”

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi215-vi216
Author(s):  
Melanie Schoof ◽  
Carolin Göbel ◽  
Dörthe Holdhof ◽  
Sina Al-Kershi ◽  
Ulrich Schüller
Keyword(s):  
Dna Methylation ◽  
Brain Tumors ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Tumor Development ◽  
Model Systems ◽  
Preclinical Research ◽  
Human Gbm

Abstract DNA methylation based classification of brain tumors has revealed a high heterogeneity between tumors and led to the description of multiple distinct subclasses. The increasing subdivision of tumors can help to understand molecular mechanisms of tumor development and to improve therapy if appropriate model systems for preclinical research are available. Multiple recent publications have described a subgroup of pediatric glioblastoma which is clearly separable from other pediatric and adult glioblastoma in its DNA methylation profile (GBM MYCN). Many cases in this group are driven by MYCN amplifications and harbor TP53 mutations. These tumors almost exclusively occur in children and were further described as highly aggressive with a median overall survival of only 14 months. In order to further investigate the biology and treatment options of these tumors, we generated hGFAP-cre::TP53 Fl/Fl ::lsl-MYCN mice. These mice carry a loss of TP53 and show aberrant MYCN expression in neural precursors of the central nervous system. The animals develop large forebrain tumors within the first 80 days of life with 100 % penetrance. These tumors resemble human GBM MYCN tumors histologically and are sensitive to AURKA and ATR inhibitors in vitro. We believe that further characterization of the model and in vivo treatment studies will pave the way to improve treatment of patients with these highly aggressive tumors.

Intracranial hypertension and papilloedema as a complication to low antiretroviral therapy adherence in a man living with chronic HIV

2021 ◽  
Vol 14 (3) ◽  
pp. e237504
Author(s):  
Rosa Maja Møhring Gynthersen ◽  
Helene Mens ◽  
Marianne Wegener ◽  
Neval Ete Wareham
Keyword(s):  
Antiretroviral Therapy ◽  
Intracranial Pressure ◽  
Intracranial Hypertension ◽  
Idiopathic Intracranial Hypertension ◽  
Ventricular Volume ◽  
Art Adherence ◽  
Hiv Viral Load ◽  
Blurred Vision ◽  
Antiretroviral Therapy Adherence ◽  
Acute Retroviral Syndrome

We describe a 61-year-old man living with HIV on antiretroviral therapy (ART), who presented with headache, dizziness and blurred vision. Latest CD4+ cell count 3 months prior to admission was 570×106 cells/mL and HIV viral load <20 copies/mL. The patient was diagnosed with cerebrospinal fluid (CSF) lymphocytic pleocytosis, raised intracranial pressure and papilloedema. Neuroimaging showed normal ventricular volume and no mass lesions, suggesting (1) neuroinfection (2) idiopathic intracranial hypertension or (3) retroviral rebound syndrome (RRS) as possible causes. Neuroinfection was ruled out and idiopathic intracranial hypertension seemed unlikely. Elevated plasma HIV RNA level was detected consistent with reduced ART adherence prior to admission. RRS is a virological rebound after ART interruption, which can mimic the acute retroviral syndrome of acute primary infection. To the best of our knowledge, we describe the second case of RRS presenting as CSF lymphocytic pleocytosis and elevated intracranial pressure after low ART adherence.

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