Assessment of cerebral hemodynamic parameters using pulsatile versus non-pulsatile cerebral blood outflow models.

BACKGROUND: Prior methods evaluating the changes in cerebral arterial blood volume (∆CaBV) assumed that brain blood transport distal to big cerebral arteries can be approximated with a non-pulsatile flow (CFF) model. In this study, a modified ∆CaBV calculation that accounts for pulsatile blood flow forward (PFF) from large cerebral arteries to resistive arterioles was investigated. The aim was to assess cerebral hemodynamic indices estimated by both CFF and PFF models while changing arterial blood carbon dioxide concentration (EtCO2) in healthy volunteers. MATERIALS AND METHODS: Continuous recordings of non-invasive arterial blood pressure (ABP), transcranial Doppler blood flow velocity (CBFVa), and EtCO2 were performed in 53 young volunteers at baseline and during both hypo- and hypercapnia. The time constant of the cerebral arterial bed (τ) and critical closing pressure (CrCP) were estimated using mathematical transformations of the pulse waveforms of ABP and CBFVa, and with both pulsatile and non-pulsatile models of ∆CaBV estimation. Results are presented as median values ± interquartile range. RESULTS: Both CrCP and τ gave significantly lower values with the PFF model when compared with the CFF model (p ≪ 0.001 for both). In comparison to normocapnia, both CrCP and τ determined with the PFF model increased during hypocapnia [CrCPPFF (mm Hg): 5.52 ± 8.78 vs. 14.36 ± 14.47, p = 0.00006; τPFF (ms): 47.4 ± 53.9 vs. 72.8 ± 45.7, p = 0.002] and decreased during hypercapnia [CrCPPFF (mm Hg): 5.52 ± 8.78 vs. 2.36 ± 7.05, p = 0.0001; τPFF (ms): 47.4 ± 53.9 vs. 29.0 ± 31.3, p = 0.0003]. When the CFF model was applied, no changes were found for CrCP during hypercapnia or in τ during hypocapnia. CONCLUSION: Our results suggest that the pulsatile flow forward model better reflects changes in CrCP and in τ induced by controlled alterations in EtCO2.

The BioMonitor 2 insertable cardiac monitor: Clinical experience with a novel implantable cardiac monitor.

INTRODUCTION: Implantable loop recorders (ILR) are leadless subcutaneous devices that allow cardiac monitoring for up to 3 years and are a valuable tool in the diagnosis of arrhythmias, cryptogenic stroke and unexplained syncope. The Biotronik BioMonitor 2 is a novel, insertable ILR allowing long-term continuous monitoring with wireless telemetry options. METHODS: A single-center, prospective, observational study investigating the reliability of sensing quality and detection performance in the BioMonitor 2 ILR, as well as post-implantation patient satisfaction. R-wave amplitude was recorded immediately post implantation and 1 day post implantation, followed by extensive patient instruction. Follow-up was scheduled after 3 months, or after an event. Data from the ILR were retrieved, with documentation of all episodes, R-wave amplitude and noise burden. The anatomical position of the ILR was determined 1 day post implantation and after 3 months. A patient questionnaire was conducted after 3 months. RESULTS: 30 consecutive patients (mean age 71 ±â€¯12 years, 56% male) were analyzed. Indications for ILR implantation were: unexplained syncope (n = 24, 80%), suspected atrial fibrillation (n = 4, 13%), cryptogenic stroke (n = 1, 3%) and palpitations (n = 1, 3%). Median time from skin cut to suture was 8 min. No complications occurred. Mean R-wave amplitude at implantation was 0.84 ±â€¯0.32 mV, at day 1 post implantation 0.96 ±â€¯0.31 mV, and after a mean follow-up of 85 ±â€¯24 days 1.02 ±â€¯0.47 mV (p = 0.01). The mean noise burden was 1.4 ±â€¯2%. CONCLUSION: Implantation of the novel BioMonitor 2 ILR is fast and uncomplicated. Initial sensing values are good and improve over time.

Headache in Caucasian patients with Moyamoya angiopathy - a systematic cohort study.

Background Headache is common in patients with Moyanoya angiopathy (MMA), but usually underestimated in its management and not well characterized. Methods A validated self-administered headache screening questionnaire and a telephone interview were used in order to investigate headache characteristics, frequency and pain intensity in a large cohort of 55 German patients with MMA. Results Thirty-seven patients (67.3%) had suffered from headache in the past year. Headache intensity was rated 3.2 ± 1.3 on a verbal rating scale from 0 to 10. Seventeen patients (47.9%) reported migraine-like headache, 10 patients (27.0%) reported tension type-like headache and 10 patients (27.0%) had a combination of both. The majority of patients with migraine-like headache ( n = 10, 58.8%) described migrainous aura. Headache frequency and intensity improved significantly after revascularization surgery; however, nine patients developed new-onset headache postoperatively. Conclusion Headache is very common in MMA, often with a migraine-like phenotype. Tension type-like headache was also found in 27% of patients, which is a new finding that has not been reported before.

The Interaction Between Heart Systole and Cerebral Circulation During Lower Body Negative Pressure Test.

The time constant (τ[s]) estimates how fast the arterial part of the cerebrovascular bed fills with blood volume during the cardiac cycle, whereas a product of τ and heart rate (HR) (τ*HR[%]) assesses how this period of arterial filling is related to an entire heart cycle. In this study we aimed to investigate cerebral hemodynamics using τ and τ*HR during a progressive lower body negative pressure (LBNP) test.Transcranial Doppler cerebral blood flow velocity (CBFV), Finapres arterial blood pressure (ABP), and HR, along with end-tidal CO2, were simultaneously recorded in 38 healthy volunteers during an LBNP test. The τ was estimated using mathematical transformation of ABP and CBFV pulse waveforms. After a gradual shortening of τ from baseline (0.20 ± 0.06 s) to maximal LBNP before the onset of presyncope (0.15 ± 0.05 s), we observed a significant increase in τ at presyncope (0.24 ± 0.15 s; p = 0.0001). In the course of LBNP, the τ*HR did not significantly change from baseline (25.6 ± 5.7 % vs 26.6 ± 8.9 %, p = n.s.) except for presyncope, when it increased to 40.4 ± 21.1 % (p < 0.000001). Because the time needed to fill the arterial part of the cerebrovascular bed with blood is prolonged during presyncope, an increased part of the heart cycle seems to be spent on the cerebral blood supply.

Increasing Intracranial Pressure After Head Injury: Impact on Respiratory Oscillations in Cerebral Blood Flow Velocity.

Experiments have shown that closed-box conditions alter the transmission of respiratory oscillations (R waves) to organ blood flow already at a marginal pressure increase. How does the increasing intracranial pressure (ICP) interact with R waves in cerebral blood flow after head injury (HI)?Twenty-two head-injured patients requiring sedation and mechanical ventilation were monitored for ICP, Doppler flow velocity (FV) in the middle cerebral arteries, and arterial blood pressure (ABP). The analysis included transfer function gains of R waves (9-20 cpm) from ABP to FV, and indices of pressure-volume reserve (RAP) and autoregulation (Mx). Increasing ICP has dampened R-wave gains from day 1 to day 4 after HI in all patients. A large impact (ΔGain /ΔICP right: 0.14 ± 0.06; left: 0.18 ± 0.08) was associated with exhausted reserves (RAP ≥0.85). When RAP was <0.85, rising ICP had a lower impact on R-wave gains (ΔGain /ΔICP right: 0.05 ± 0.02; left: 0.06 ± 0.04; p < 0.05), but increased the pulsatility indices (right: 1.35 ± 0.55; left: 1.25 ± 0.52) and Mx indices (right: 0.30 ± 0.12; left: 0.28 ± 0.08, p < 0.05). Monitoring of R waves in blood pressure and cerebral blood flow velocity has suggested that rising ICP after HI might have an impact on cerebral blood flow directly, even before autoregulation is impaired.

Moyamoya disease in Southeast Asians: genetic and autopsy data, new cases, systematic review, and meta-analysis of all patients from the literature.

BACKGROUND: Moyamoya disease (MMD) is a rare disorder causing ischemic and hemorrhagic juvenile stroke. It is associated with the founder susceptibility variant p.R4810K in the RNF213 gene in East Asia. Our aim was to enhance understanding of MMD in so far poorly characterized Southeast Asians and exploring differences with Caucasian Europeans. METHODS: By retrospective analysis of medical records and systematic database search on PubMed for all published cases, we identified Southeast Asian patients with MMD. We extracted and pooled proportions using fixed-effects models. Our own cohort was tested for the East Asian RNF213 founder variant p.R4810K. One of our Southeast Asian patients underwent post-mortem histopathological examination. RESULTS: The study cohort comprised 32 Southeast Asians. Mean age at onset in the entire cohort was 32.5 ± 20.3 years (n = 24), 43.4 ± 8.7 years in patients admitted to our center (n = 11), and 23.4 ± 22.4 years in patients from the international literature (n = 13). Female-to-male ratio was 1.6:1. MMD predominantly affected bilateral anterior intracranial vessels. Cerebral ischemia outnumbered transient ischemic attacks (TIAs) and intracranial hemorrhage. TIAs, arterial hypertension and obesity were significantly less frequent in Southeast Asian patients compared to Caucasian Europeans. p.R4810K was absent in all examined Southeast Asians despite of typical histopathological signs of MMD in one autopsy case. CONCLUSION: Clinical and histopathological manifestations of MMD in Southeast Asians are similar to those in Caucasian Europeans. The genotype of MMD in Southeast Asians differs from that of most East Asian patients.

Progression of initially unilateral Moyamoya angiopathy in Caucasian Europeans.

BACKGROUND: Moyamoya angiopathy (MMA) is a rare cause of stroke in Caucasians, but it is much more frequent in East Asia. Since 2021, diagnostic criteria not only comprise bilateral, but also unilateral MMA. Hitherto, progression of unilateral MMA has predominantly been described in East Asians. Our study aimed to analyze the occurrence and characteristics of progression of initially unilateral MMA in Caucasian Europeans. METHODS: By retrospective analysis of medical records of 200 European Caucasians with MMA, admitted to our German center between 2010 and 2022, cases of unilateral MMA and its progression, i.e. progressive ipsi- or novel contralateral arterial stenosis, during follow-up were identified. Kruskal Wallis Test and Fisher's Exact Test were used to identify statistically significant differences between progressive and stable patients concerning demographic, clinical, laboratory, and radiographic features. RESULTS: Our cohort comprised 63 patients with initially unilateral MMA. Fourteen (22.2%) had an ipsi- (n = 3, 21.4%) or contralateral (n = 11, 78.6%) progression. Mean age of patients with progressive MMA at symptom onset was 32 ± 14.1 years. The ratio of women to men in this subgroup was 2.5:1. Mean follow-up period was 5.4 ± 3.7 years, mean age at progression was 39.9 ± 12.7 years. Mean time interval between penultimate follow-up and progression was 4.8 ± 4.5 years. Patients with progression showed affection of the posterior cerebral artery (p = 0.009) and suffered from vertigo (p = 0.009) significantly more often. CONCLUSION: Unilateral MMA progresses in a substantial proportion in European Caucasians. Long-term follow-up is required due to potential late progression with consecutive symptoms and the need for bypass surgery.

How does moderate hypocapnia affect cerebral autoregulation in response to changes in perfusion pressure in TBI patients?

In traumatic brain injury, the hypocapnic effects on blood pressure autoregulation may vary from beneficial to detrimental. The consequences of moderate hypocapnia (HC) on the autoregulation of cerebral perfusion pressure (CPP) have not been monitored so far.Thirty head injured patients requiring sedation and mechanical ventilation were studied during normocapnia (5.1 ± 0.4 kPa) and moderate HC (4.4 ± 3.0 kPa). Transcranial Doppler flow velocity (Fv) of the middle cerebral arteries (MCA), invasive arterial blood pressure, and intracranial pressure were monitored. CPP was calculated. The responsiveness of Fv to slow oscillations in CPP was assessed by means of the moving correlation coefficient, the Mx autoregulatory index. Hypocapnic effects on Mx were increasing with its deviation from normal baseline (left MCA: R (2) = 0.67; right MCA: R (2) = 0.51; p < 0.05). Mx indicating normal autoregulation (left: -0.23 ± 0.23; right: -0.21 ± 0.24) was not significantly changed by moderate HC. Impaired Mx autoregulation, however, (left: 0.37 ± 0.13; right: 0.33 ± 0.26) was improved (left: 0.12 ± 0.25; right: -0.0003 ± 0.19; p < 0.01) during moderate HC. Mx was adjusted to normal despite no significant change in CPP levels. Our study showed that short-term moderate HC may optimize the autoregulatory response to spontaneous CPP fluctuations with only a small CPP increase. Patients with impaired autoregulation seemed to benefit the most.

Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic moyamoya angiopathy.

BACKGROUND: The etiology and genetic susceptibility of Moyamoya angiopathy (MMA) (Moyamoya disease, Moyamoya syndrome and unilateral type of MMA) still remain unclear. In Asian patient cohorts several HLA markers were described to be associated with MMA, but in Caucasians very little is known about genetic susceptibility of this angiopathy. METHOD: We analysed DNA of 33 Caucasian patients with MMA for HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 markers, respectively. HLA frequencies of all 33 patients with MMA were compared with HLA-frequencies of Caucasian controls. Additionally, subgroup analysis of 22 patients with Moyamoya disease (MMD) and 11 patients with unilateral type of MMA was performed. FINDINGS: Significant association was observed for HLA-DRB1*03 and HLA-DRB1*13 in all 33 patients (P (c) < 0.001 and P (c) < 0.001, respectively). Moreover, HLA-A*02 (P (c) = 0.009); HLA-B*08 (P (c) = 0.009), and HLA-DQB1*03 (P (c) = 0.003) frequencies were higher in all patients with MMA when compared with the controls. In addition, in 22 patients with MMD a higher frequency of HLA-DRB1*03 (P (c) < 0.001) was observed when compared with controls. CONCLUSIONS: The results of this study indicate a putative association of HLA markers with MMA in Caucasian patients. Further studies are needed to elucidate the role of human MHC in the pathogenesis of this angiopathy.

Differential diagnosis between cerebral ischemia, focal seizures and limb shaking TIAs in moyamoya disease.

We describe the clinical course of a young female Caucasian patient with bilateral moyamoya disease in whom we could diagnose the simultaneous occurrence of cerebral ischemia, TIAs, limb shaking TIAs and focal Jacksonian seizures. It is the second clinical communication in the literature elaborating limb shaking TIAs in moyamoya disease.

Microembolic signals and antiplatelet therapy in Moyamoya angiopathy.

BACKGROUND: Embolism as a cause of stroke is widely neglected in Moyamoya angiopathy (MMA), and recommendations for use of antiplatelet therapy (APT) vary. We examined the presence of microembolic signals (MES) during transcranial Doppler (TCD) monitoring and assessed the effects of APT on the occurrence of MES in MMA. PATIENTS AND METHODS: We retrospectively analysed patients with MMA treated at our centre between 2011 and 2021. TCD was performed at first presentation and at most visits, while number of visits varied between individual patients. TCD was performed for 30 min bilaterally. Patient demographics, vascular risk factors, and antiplatelet treatment were collected from each clinic visit and ischemic and haemorrhagic episodes were captured as recorded during follow-up visits. RESULTS: 209 patients were included in the analysis (mean age 38.7 ± 15.3, 28% male). 21 patients with 27 MES-positive TCD examinations were identified (10%). Patient characteristics were similar in MES-positive and MES-negative groups. However, recent ischemic events were detected at a significantly higher rate in MES-positive patients (42.9% vs 4.8%, p < 0.001). After MES detection, change of antiplatelet drug regime was performed, leading to loss of MES in all cases. Dual APT was preferably used in the MES-positive group (p < 0.001) but no significant difference of haemorrhage during follow-up-visits was observed. Reduction of APT before bypass-surgery triggered MES in four patients. CONCLUSION: APT is required in patients with MMA. MES monitoring may help to identify risk patients in need of intensified APT.

The influence of vasovagal response on the coagulation system.

BACKGROUND: Vasovagal response (VVR) is provoked by a reduced venous blood return to the heart as a reaction to orthostatic stress and to haemorrhage. Recently, two cases were reported showing elevated plasma concentration of von-Willebrand-factor (VWF) and factor VIII (FVIII) after VVR due to venapuncture. Although the effect of epinephrine as trigger for VWF liberation is known, a connection between VVR and activation of the coagulation system has not been studied systematically. METHODS: We examined 21 subjects with lower body negative pressure. We measured the plasma concentration of von-Willebrand-factor-antigen (VWF:Ag), the activity of von-Willebrand-factor-Ristocetin-Cofactor (VWF:RiCo) and FVIII at several stress-levels and consecutively split up the different VWF-multimers. RESULTS: In 16 of 21 subjects VVR could be induced. These subjects showed a significant increase of VWF:Ag concentration in plasma and an increase of FVIII and VWF:RiCo activity. The five individuals who experienced all stress-levels without VVR did not show any changes in their clotting factor levels. CONCLUSION: VVR leads to measurable changes in the coagulation system. This might be a further diagnostic tool in treating patients with syncope.

Moyamoya angiopathy: early postoperative course within 3 months after STA-MCA-bypass surgery in Europe-a retrospective analysis of 64 procedures.

BACKGROUND: Despite the consensus on the necessity of revascularizing surgery in Moyamoya angiopathy in Asia, the indication in Caucasian Moyamoya patients is discussed controversially. OBJECTIVE: The safety of revascularizing surgery in Europe should be clarified. METHODS: This study retrospectively analyzed the rate of complications as well as clinical symptoms within the first 3 months after bypass surgery between superficial temporal artery and middle cerebral artery (STA-MCA). RESULTS: 64 direct bypass procedures in 45 patients (95.5% Caucasians) were analyzed. The magnetic resonance imaging at day 6 showed subdural hematoma in 60.3%. The mean diameter of these hematomas on magnetic resonance imaging was 5.1 mm (SD 3.4 mm) and increased in 25% at follow-up. No difference was found between those patients with early (day 1) or late (day 7) restarts of antiplatelet therapy. Magnetic resonance imaging at day 6 revealed hyperperfusion syndrome after six of 64 procedures (9.3%). Three of these six had clinical symptoms; two-thirds were transient within seconds. Magnetic resonance imaging depicted stroke after seven procedures (10.9%). Five of these seven patients had no new symptoms. Altogether, after ten procedures (15%), patients complained about clinical symptoms. These were all transient. No new transient ischemic attacks occurred during the 3 month follow-up and no new lesions were detected in magnetic resonance imaging. Only two patients underwent surgery for asymptomatic subdural hematoma. All other subdural hematomas resolved spontaneously. CONCLUSION: Revasculating surgery is a safe procedure in Caucasian patients with Moyamoya angiopathy. The observed complications have a good prognosis.

Is there a direct link between cerebrovascular activity and cerebrospinal fluid pressure-volume compensation?

BACKGROUND AND PURPOSE: Cerebral blood flow is coupled to brain metabolism by means of active modulation of cerebrovascular resistance. This homeostatic vasogenic activity is reflected in slow waves of cerebral blood flow velocities (FV) which can also be detected in intracranial pressure (ICP). However, effects of increased ICP on the modulation of cerebral blood flow are still poorly understood. This study focused on the question whether ICP has an independent impact on slow waves of FV within the normal cerebral perfusion pressures range. METHODS: Twenty patients presenting with communicating hydrocephalus underwent a diagnostic intraventricular constant-flow infusion test. Blood flow velocities in the middle cerebral artery and posterior cerebral arteries were measured using Transcranial Doppler. Pulsatility index, FV variability of slow vasogenic waves (3 to 9 bpm), ICP, and arterial blood pressure were simultaneously monitored. RESULTS: During the test, ICP increased from a baseline of 11 (6) mm Hg to a plateau value of 21 (6) mm Hg (P=0.00005). Although the infusion did not induce significant changes in cerebral perfusion pressures, FV, pulsatility index, or index of autoregulation, the magnitude of FV vasogenic waves at plateau became inversely correlated to ICP (middle cerebral artery: r=-0.58, P<0.01; posterior cerebral arteries: r=-0.54, P<0.01). CONCLUSIONS: This study shows that even moderately increased ICP can limit the modulation of cerebral blood flow in both vascular territories within the autoregulatory range of cerebral perfusion pressures. The exhaustion of cerebrospinal fluid volume buffering reserve during infusion studies elicits a direct interaction between the cerebrospinal fluid space and the cerebrovascular compartment.

Wave reflection analysis of the human cerebral circulation during syncope.

Up till now, the presence of wave reflection of pressure and flow waves was not considered in studies on the cerebral circulation. This study tested the hypothesis whether the typical changes in cerebral blood flow velocity (CBFV) seen in patients during vasovagal syncope can be explained by the emergence of a wave reflection site in the cerebrovascular vessels. Continuous recordings of peripheral blood pressure (ABP, by Finapres) and CBFV (by transcranial Doppler) of 20 control subjects and 10 patients with syncope during tilt table testing were analyzed. Wave reflection analysis (WRA) consisted of a multivariate regression analysis with CBFV as dependent variable and simultaneous ABP as well as delayed ABP (by systematically varied time lags) as independent variables. The time delay yielding the best prediction of CBFV was interpreted as the reflection time. A univariate regression analysis with only simultaneous ABP as independent variable served as control method. In patients and controls CBFV during supine position could be explained sufficiently (explained variance=88-90%) by univariate regression without improvement by WRA. During syncope, multivariate regression improved the prediction of CBFV (explained variance=58% with univariate and 77% with multivariate regression) in 9 of 10 patients. The mean reflection time was 160 ms. The results can be explained by a collapse of the distal bridging veins during systemic hypotension giving rise to a pressure wave moving backward with a resulting distortion of the flow wave. In particular, the WRA model could account for the characteristic changes in the diastolic flow shape during syncope.

Bilateral vertebral artery disease: transcranial Doppler assessment of the hemodynamic vulnerability to changes in posture.

Posture changes may cause hemodynamic ischemic events, particularly in severe vertebrobasilar artery disease. It may be difficult and not without risk to prove this vulnerability to changes in posture during angiography. Therefore, TCD monitoring with passive tilting (PT) was used to evaluate cerebral hemodynamics distally to severe bilateral vertebral artery disease (BVAD). PCA flow velocity changes and dynamic cerebral autoregulation (DCA) were analyzed in supine and upright position. Despite a significant autoregulatory deficit distally to BVAD, the posterior cerebral blood supply seemed to be sufficiently maintained as long as systemic blood pressure changes were within normal limits. Posterior cerebral flow velocities, however, were significantly diminished when PT detected a systemic hypotension in upright position. This study proves the feasibility to combine PT and TCD monitoring of the PCA in patients with BVAD. In vertebrobasilar artery disease, the examination of spontaneous and tilt-induced autoregulatory responses could support the evaluation of a risk for hemodynamic ischemia.

Traumatic brain injury: increasing ICP attenuates respiratory modulations of cerebral blood flow velocity.

In vitro experiments have suggested that respiratory oscillations (R waves) in cerebral blood flow velocity are reduced as soon as the intracranial pressure-volume reserve is exhausted. Could R waves hence, provide indication for increasing ICP after traumatic brain injury (TBI)? On days 1 to 4 after TBI, 22 sedated and ventilated patients were monitored for intracranial pressure (ICP) in brain parenchyma, Doppler flow velocity (FV) in the middle cerebral arteries (MCA), and arterial blood pressure (ABP). The analysis included the transfer function gains of R waves (respiratory rate of 9-20 cpm) between ABP and FV (GainFv) as well as between ABP and ICP (GainICP). Also, the index of the intracranial pressure-volume reserve (RAP) was calculated. The rise of ICP (day 1: 14.10 ± 6.22 mmHg; to day 4: 29.69 ± 12.35 mmHg) and increase of RAP (day 1: 0.72 ± 0.22; to day 4: 0.85 ± 0.18) were accompanied by a decrease of GainFv (right MCA; day 1: 1.78 ± 1.0; day 4: 0.84 ± 0.47; left MCA day 1: 1.74 ± 1.10; day 4: 0.86 ± 0.46; p < 0.01) but no significant change in GainICP day 1: 1.50 ± 0.77; day 4: 1.15 ± 0.47; p = 0.07). The transfer of ventilatory oscillations to the intracerebral arteries after TBI appears to be dampened by increasing ICP and exhausted intracranial pressure-volume reserves. Results warrant prospective studies of whether respiratory waves in cerebral blood flow velocity may anticipate intracranial hypertension non-invasively.