Electrical modulation of the sympathetic nervous system in order to augment cerebral blood flow: a protocol for an experimental study

Introduction: Cerebral blood flow (CBF) is regulated by several mechanisms. Neurogenic control has been a matter of debate, even though several publications reported the effects of changes in sympathetic tone on CBF. Transcutaneous electrical nerve stimulation and spinal-cord stimulation have been shown to influence peripheral and cerebral blood flow through a sympathetic pathway. The authors hypothesise that certain pathological conditions result in a relative increase in the neurogenic regulation of CBF and that this regulation can be modulated electrically. Methods and analysis: Patients with cerebral vasospasm after subarachnoid haemorrhage will be included. The experimental set-up measures several parameters that are involved in cerebral blood flow regulation in patients with cerebral vasospasm after subarachnoid haemorrhage. Measurements are taken at baseline and with stimulation in several frequencies. An ad hoc statistical analysis is used to evaluate different settings of the electrical stimulation. Autoregulation is evaluated with transfer function analysis and autoregulatory index calculations. Ethics and dissemination: Ethical registration was granted by Medical Review Ethics Committee Groningen (ID METc 2010.123). All participants provide written informed consent on participation. Upon finishing a pilot study to investigate feasibility and effect, either future prospective (randomised) studies will be designed, or other modalities of electrical stimulation will be explored using the same set-up

Bilateral multiple coronary artery fistulae with angina pectoris and syncope

AbstractCoronary artery fistulae (CAF) are rare cardiac anomalies. They frequently arise from the right coronary artery (RCA) with fistulae originating from the left anterior descending artery (LAD) or from multiple arteries being less common. They do not usually cause symptoms and are incidentally diagnosed on routine cardiac imaging. We report a 70years old male patient presenting with chest pain and syncope during physical activity. Diagnostic coronary angiography revealed bilateral multiple CAF originating from both the LAD and RCA. As high blood flow output was recognized in these large vascular anomalies contributing to ‘steal phenomenon’ surgical intervention was planned. This manuscript aimed to present the case and review the current literature for the management and treatment of these coronary anomalies

The influence of transcutaneous electrical neurostimulation (TENS) on human cerebral blood flow velocities

It has been shown that transcutaneous electrical neurostimulation (TENS) reduces sympathetic tone. Spinal cord stimulation (SCS) has proven qualities to improve coronary, peripheral, and cerebral blood circulation. Therefore, we postulate that TENS and SCS affect the autonomic nervous system in analogous ways. In this line of thought, cervical application of TENS might be a useful and simple adjunct in the treatment of cerebrovascular disease by improving cerebral blood flow. Experiments were performed in order to assess whether cervical TENS is safe and whether an effect on cerebral blood flow velocity (CBFV) can be shown in healthy subjects. A controlled, non-randomized, phase 1 study was performed with 20 healthy volunteers. Cervical TENS was applied in several frequencies, with and without hyperventilation. Continuous registration of blood pressure, pulse, CBFV (estimated by transcranial Doppler sonography) and end-tidal carbon dioxide concentration was performed. Cervical TENS was well-tolerated by all subjects. Despite small effects on heart rate (HR) and mean arterial blood pressure (MAP), a significant effect on middle cerebral artery (MCA) blood flow velocity was not demonstrated. No effect of age, gender, current or session order on MCA, HR, or MAP was found. TENS did not influence the effect of hyperventilation. In these experiments, application of cervical TENS is proven to be a safe procedure. However, no effects on cerebral blood flow velocity could be detected, perhaps due to the intact cerebral autoregulation in the healthy volunteers

Surgical clipping as the preferred treatment for aneurysms of the middle cerebral artery

In recent years the endovascular treatment of intracranial aneurysms (coiling) has progressively gained recognition, particularly after the publication of the International Subarachnoid Aneurysm Trial (ISAT) in 2002. Despite the fact that in ISAT middle cerebral artery (MCA) aneurysms were clearly underrepresented, the study is often used as an argument to favor coiling above surgery in MCA aneurysms. Taken into account that MCA aneurysms are very well accessible for surgery, a contemporary assessment of the benefits of a preferred surgical strategy for MCA aneurysms was performed in a tertiary neurovascular referral center. A prospectively kept single-center database of 151 consecutive patients with an MCA aneurysm was reviewed over a 6-year period (2001-2006). Long-term follow-up after surgical treatment of a ruptured MCA aneurysm was obtained in 74 out of 77 (96%) patients. The outcome was compared with relevant series in the literature. After a mean follow-up of 4.7 years, 59 out of 74 surgically treated patients (80%) with a ruptured MCA aneurysm had a good outcome (mRankin 0-2). All patients with an unruptured MCA aneurysm also had a good outcome after clipping. This is well-matched with the findings of the literature search, and competitive with the endovascular results. Surgical clipping is recommended as the principal treatment strategy for MCA aneurysms. This is not only ethically defendable in view of the surgical results but also in line with a strategy to maintain surgical experience within centralized neurovascular centers

Petrology, diagenesis amd reservoir potential of Narrabeen group sandstones, Sydney Basin, N.S.W.

ObjectivesTranscutaneous electrical neurostimulation (TENS) and spinal cord stimulation have been shown to increase peripheral and cerebral blood flow. We postulate that certain pathological conditions attenuate cerebral autoregulation, which may result in a relative increase of the importance of neurogenic regulation of cerebral blood flow, which could be decreased by electrical modulation. We therefore assess the effects of TENS on cerebral blood flow velocities (CBFVs) and cerebral saturation in patients with cerebral vasospasm after subarachnoid hemorrhage (SAH). Materials and MethodsCervical TENS was applied in 10 SAH patients with transcranial Doppler (TCD)-proven cerebral vasospasm. Measurements included plethysmography, near-infrared spectroscopy, capnography, and CBFVs by TCD. After determining the optimal frequency and current, patients were treated with cervical TENS for two periods of three days, with a pause of one day in between. ResultsThe TENS electrodes were not always tolerated by the patients. Higher frequencies demonstrated the most prominent combined effects. ETCO2 was 0.19% lower with TENS off than with TENS on (p = 0.05). Mean arterial blood pressure and pulse were not significantly different over time. CBFV in MCA was decreased (p = 0.07) while cerebral oxygen saturation was increased (p = 0.01) after the use of TENS. ConclusionsOur data suggest improved cerebral blood flow when using cervical TENS in patients with cerebral vasospasm. Several factors could have attenuated the effects: the electrodes were poorly tolerated, ETCO2 increased during TENS, few vessels showed prolonged vasospasm, and overall flow velocities were low. Still, an on-off effect of TENS over time was detected

Clinical applicability of signal heterogeneity and tumor border assessment on T2-weighted MR images to distinguish astrocytic from oligodendroglial origin of gliomas

Background and purpose: Radiological features on magnetic resonance imaging (MRI) were attributed to oligodendroglioma, although the diagnostic accuracy in a real-world clinical setting remains partially elusive. This study investigated the accuracy and robustness of tumor heterogeneity and tumor border delineation on T2-weighted MRI to distinguish oligodendroglioma from astrocytoma. Materials and methods: Eight readers from three different specialties (radiology, neurology, neurosurgery) with varying levels of experience blindly rated 79 T2-weighted MR images of patients with either oligodendroglioma or astrocytoma. After the first reading session, all readers were re-invited for a second reading session within three weeks. Diagnostic accuracy, including area under the receiver operator characteristics curve (AUC), and intra-observer variability and inter-observer variability were used as outcome measures. Results: Pooled sensitivity and specificity to distinguish oligodendroglioma from astrocytoma for the use of tumor heterogeneity were 59.9 % respectively 74.5 %, and 85.7 % respectively 40.1 % for tumor border. A second reading session did not result in a significant change in sensitivity or specificity for tumor heterogeneity (P = 0.752 and P = 0.733, respectively) or tumor border (P = 0.309 and P = 0.271, respectively). An AUC of 0.825 was achieved with regard to predicting oligodendroglial origin of gliomas. Intra-observer agreement ranged from moderate to very good for tumor heterogeneity (kappa-value 0.43–0.87) and tumor border (0.40–0.84). A moderate inter-oberserver agreement was achieved for tumor heterogeneity and tumor border (kappa-value of 0.50 and 0.45, respectively). Conclusion: This study demonstrates that tumor heterogeneity and tumor borders on T2-weighted MRI could be used with moderate Finter-observer agreement to non-invasively distinguish oligodendroglioma from astrocytoma.</p

Concordant Symptomatic Intracranial Aneurysm in a Monozygotic Twin:A Case Report and Review of the Literature

The development of an intracranial aneurysm (IA) is a multifactorial process, involving genetic and environmental factors. The presence of IA or aneurysmal subarachnoid hemorrhage (aSAH) in twins is particularly interesting, since both genetic and environmental factors can be studied. It also raises the question of whether, when one twin is affected, the other asymptomatic twin should be examined for an IA. We report on a monozygotic (MZ) twin-pair with aSAH in both twins and we review all reported cases of IA in MZ twins. Including our case, we found only 14 MZ twin-pairs in which both twins harbored an IA, suggesting a heavy underreporting in the medical literature. In this small group, a high concordance was noted in the sites of IAs. In MZ twins, the preferred sites for IAs are the branching arteries, while aneurysms arising from fusion arteries are rare. These sites differ from the preferential sites seen in series of familial IAs and series of sporadic IAs. We therefore hypothesize that the twinning process might play a significant role in the development of IAs in MZ twins. To further explore and substantiate this, the large twin registries should be studied. Although IAs in MZ twins with a negative family history for IAs should not be regarded as familial IAs, screening of the asymptomatic twin should be seriously considered if one MZ twin presents with an aSAH or an IA, because of the high fatality rates reported in asymptomatic (and not screened) MZ twin-halves

Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial)

Background: Glioblastoma (GBM) is the most common primary, malignant brain tumour with a 5-year survival of 5%. If possible, a glioblastoma is resected and further treated with chemoradiation therapy (CRT), but resection is not feasible in about 30% of cases. Current standard of care in these cases is a biopsy followed by CRT. Magnetic resonance (MR) imaging-guided laser interstitial thermal therapy (LITT) has been suggested as a minimally invasive alternative when surgery is not feasible. However, high-quality evidence directly comparing LITT with standard of care is lacking, precluding any conclusions on (cost-)effectiveness. We therefore propose a multicenter randomized controlled study to assess the (cost-)effectiveness of MR-guided LITT as compared to current standard of care (EMITT trial). Methods and analysis: The EMITT trial will be a multicenter pragmatic randomized controlled trial in the Netherlands. Seven Dutch hospitals will participate in this study. In total 238 patients will be randomized with 1:1 allocation to receive either biopsy combined with same-session MR-guided LITT therapy followed by CRT or the current standard of care being biopsy followed by CRT. The primary outcomes will be health-related quality of life (HR-QoL) (non-inferiority) using EORTC QLQ-C30 + BN20 scores at 5 months after randomization and overall survival (superiority). Secondary outcomes comprise cost-effectiveness (healthcare and societal perspective) and HR-QoL of life over an 18-month time horizon, progression free survival, tumour response, disease specific survival, longitudinal effects, effects on adjuvant treatment, ablation percentage and complication rates. Discussion: The EMITT trial will be the first RCT on the effectiveness of LITT in patients with glioblastoma as compared with current standard of care. Together with the Dutch Brain Tumour Patient association, we hypothesize that LITT may improve overall survival without substantially affecting patients’ quality of life. Trial registration: This trial is registered at ClinicalTrials.gov (NCT05318612)

Head-To-Head Comparison of PET and Perfusion Weighted MRI Techniques to Distinguish Treatment Related Abnormalities from Tumor Progression in Glioma

The post-treatment imaging surveillance of gliomas is challenged by distinguishing tumor progression (TP) from treatment-related abnormalities (TRA). Sophisticated imaging techniques, such as perfusion-weighted magnetic resonance imaging (MRI PWI) and positron-emission tomography (PET) with a variety of radiotracers, have been suggested as being more reliable than standard imaging for distinguishing TP from TRA. However, it remains unclear if any technique holds diagnostic superiority. This meta-analysis provides a head-to-head comparison of the diagnostic accuracy of the aforementioned imaging techniques. Systematic literature searches on the use of PWI and PET imaging techniques were carried out in PubMed, Embase, the Cochrane Library, ClinicalTrials.gov and the reference lists of relevant papers. After the extraction of data on imaging technique specifications and diagnostic accuracy, a meta-analysis was carried out. The quality of the included papers was assessed using the QUADAS-2 checklist. Nineteen articles, totaling 697 treated patients with glioma (431 males; mean age ± standard deviation 50.5 ± 5.1 years) were included. The investigated PWI techniques included dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labeling (ASL). The PET-tracers studied concerned [S-methyl- 11C]methionine, 2-deoxy-2-[ 18F]fluoro-D-glucose ([ 18F]FDG), O-(2-[ 18F]fluoroethyl)-L-tyrosine ([ 18F]FET) and 6-[ 18F]-fluoro-3,4-dihydroxy-L-phenylalanine ([ 18F]FDOPA). The meta-analysis of all data showed no diagnostic superior imaging technique. The included literature showed a low risk of bias. As no technique was found to be diagnostically superior, the local level of expertise is hypothesized to be the most important factor for diagnostically accurate results in post-treatment glioma patients regarding the distinction of TRA from TP

Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation

Background Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells. Methods We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders. Results We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC. Conclusions This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation