The Responses to CGRP in the Territory of the Posterior Cerebral Artery in Migraine.

Calcitonin gene-related peptide (CGRP) is important in trigeminovascular (TMV) sensitization with neurogenic inflammation which might be involved in CGRP-induced headache (CGRP-IH). Distribution of white matter lesions, migraine aura, and functional neuroimaging indicate that posterior circulation is especially exposed to TMV sensitization. The transcranial Doppler (TCD) is able to detect changes in the posterior cerebral artery (PCA) during CGRP stimulation. Thus, we studied CGRP-induced hemodynamic changes in PCA and frequency of CGRP-IH. Twenty healthy subjects and 20 patients with migraine participated in our study. TCD was used to monitor mean arterial velocity in posterior cerebral artery (vmPCA). Simultaneously, end-tidal carbon dioxide (Et-CO2), mean arterial pressure (MAP), and heart rate (HR) were measured. During the experiment, we monitored the frequency of CGRP-IH. We determined the values of vmPCA, Et-CO2, MAP, and HR and calculate the response of vmPCA, Et-CO2, MAP, and HR to CGRP. To test the differences and relationships, statistical methods were applied using SSPS. We found significant decrease in vmPCA in migraine and control groups and found the vmPCA response to be significantly lower in migraine (p = 0.018). Et-CO2 decreases in both groups, and it is significantly lower in migraine (p < 0.001). MAP is significantly higher in migraine (p = 0.001), while HR is not significantly higher in migraine (p = 0.570). CGRP-IH is significantly associated with vmPCA responses (p = 0.003) and migraine (p < 0.001). We concluded that hemodynamic changes in PCA are significantly related to CGRP-IH. The TMV sensitization might be pronounced in posterior circulation explaining clinical and morphologic issues in migraine.

The Vasodilatory Response to CGRP of the Anterior and Posterior Cerebral Circulation in Migraine.

Introduction: Migraine aura can be associated with headache or it may occur without one, which suggests an independent mechanism for the aura and for migraine headache. The role of CGRP in migraine headache is well established, but the connection between CGRP and the aura is still lacking an explanation. Exogenous CGRP can induce CGRP headaches and migraine auras in patients with migraine. The results of our recent study suggest differences in the vascular response to CGRP stimulation between migraine without aura and migraine with aura. Therefore, we hypothesized that the magnitude of the posterior cerebral circulation response in migraine with aura is greater than in migraine without aura and that CGRP stimulation has different effects on the anterior and posterior circulation in migraine with aura and migraine without aura. Methods: By using transcranial doppler, we studied the hemodynamic effects of CGRP intravenous infusion at a rate of 1.5 mcg/min in 20 min on the mean arterial velocity in the middle cerebral artery and in the posterior cerebral artery in twenty patients with migraine and in a control group of twenty healthy subjects. The same CGRP effects on cerebral hemodynamics were analyzed separately for the group of patients with migraine with aura and the group of patients with migraine without aura. Fifteen patients with migraine (75%) had migraine without aura and 5 patients (25%) had migraine with aura. Results: We found that migraine has a significant impact on the vasodilatory response of the anterior (B = 4,249, SE = 1.023, r = 0.363, p < 0.001) and posterior cerebral circulation (B = 3.634, SE = 1.461, r = 0.227, p = 0.014). Migraine with aura was significantly associated with changes in the anterior (B = 2.558, SE = 0.880, r = 0.275, p = 0.005) and posterior cerebral circulation (B = 7.565, SE = 2,368, r = 0.359, p = 0.002), while migraine without aura was only significantly associated with changes in the anterior circulation. In addition, we established a significant impact of migraine with aura on VR PCA (B = 5.901, SE = 2,546, r = 0.291, p = 0.024). Conclusion: We conclude that TVR in the posterior cerebral circulation might be enhanced in MA and that aura might be a consequence of TVR enhancement.

Calcitonin gene-related peptide-induced hemodynamic changes in migraine with and without aura.

OBJECTIVES: Exogenous calcitonin gene-related peptide (eCGRP) can induce CGRP-induced headaches (CGRP-IH) and aura in migraine with aura (MA). This implies a common pathophysiological mechanism of trigeminovascular sensitization (TVS) in migraine headaches and aura. The aim was to assess hemodynamic changes in cerebral circulation induced by eCGRP. We predicted that cerebral hemodynamic changes may differ between migraine without aura (MO) and MA. MATERIALS AND METHODS: We included twenty participants with migraine, of whom 15 (75%) had MO, and 5 (25%) had MA. An intravenous infusion of eCGRP was administered. Polymodal recording of mean arterial velocity in MCA (vm MCA) and PCA (vm PCA), end-tidal carbon dioxide partial pressure (Et-CO2 ), mean arterial pressure (MAP), and heart rate (HR) was employed using transcranial Doppler sonography (TCD). The parameters were determined at different time points with single responses vm MCAtot , vm PCAtot , Et-CO2tot , MAPtot , and HRtot . RESULTS: The CGRP-IH appeared in five participants with MA (100%) and in 11 participants with MO (73.3%) (p = .530). The difference of changes in vm MCAtot (p = .014) and vm PCAtot (p = .004) was significant, whereas in Et-CO2tot (p = .658), MAPtot (p = .392), and HRtot (p = .686), it appeared to be non-significant. We found significant associations between vm MCAtot and MA (p = .023; OR = 0.88; 95%C.I. 0.78-0.98), and vm PCAtot and MA (p = .018; OR = 0.85; 95%C.I. 0.74-0.97). CONCLUSIONS: Cerebral hemodynamics differs between MO and MA, indicating a pronounced vasodilatation and TVS in MA, which could induce aura.

The Influence of Calcitonin Gene-Related Peptide on Cerebral Hemodynamics in Nonmigraine Subjects with Calcitonin Gene-Related Peptide-Induced Headaches.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is regarded as an important molecule in trigeminovascular sensitization (TVS). CGRP-induced headaches (CGRP-IH) are evoked by intravascular administration of CGRP in nonmigraine and migraine subjects. CGRP might be associated with vasodilatation of the middle cerebral artery (MCA). It is unclear whether CGRP-induced hemodynamic changes relate to CGRP-IH in nonmigraine subjects. METHODS: Twenty healthy subjects participated in our study. Polymodal recording of mean arterial velocity in MCA (vm MCA), end-tidal carbon dioxide partial pressure (Et-CO2), mean arterial pressure (MAP), and heart rate (HR) was employed using transcranial Doppler (TCD) sonography. During the experiment, we administered intravenous infusion of CGRP at a rate of 1.5 mcg/min. The vm MCA, Et-CO2, HR, and MAP were determined at time points T 0, T 1, T 2, and T 3. We calculated the responses at different time points and combined them into a single response vm MCAtot, Et-CO2tot, HRtot, and MAPtot. RESULTS: We found significant differences along the time points in vm MCA (p = <0.001), Et-CO2 (p = 0.003), MAP (p < 0.001), and HR (p < 0.001). The relationship between vm MCAtot and Et-CO2tot was significant and positive (p = 0.005). The t-test showed significant differences between CGRP-IH and non-CGRP-IH subjects in vm MCAtot (p = 0.021) but not in Et-CO2tot (p = 0.838), MAPtot (p = 0.839), and HRtot (p = 0.198). Only vm MCAtot showed a significant relationship with CGRP-IH (p = 0.028). CONCLUSIONS: Our study provides evidence for vasodilatation of MCA in relation to CGRP-IH due to intravascular CGRP detected by multimodal TCD. In the context of TVS induced by CGRP, MCA vasodilatation seems to represent an epiphenomenon of the underlying TVS.

Enhanced Hemodynamic and Clinical Response to αCGRP in Migraine Patients-A TCD Study.

Introduction: Sensitisation of the nervous system in a patient with migraine is supposed to be associated with calcitonin gene-related peptide (CGRP) activity. Therefore, the vascular response to human αCGRP (hαCGRP) could be a surrogate marker for the sensitization. We hypothesize that vascular response to hαCGRP is augmented in a patient with migraine. Methods: Twenty healthy subjects and 20 patients with migraine participated in our study. TCD was used to monitor mean arterial velocity in the middle cerebral artery (vm MCA). Simultaneously, end-tidal CO2 (Et-CO2), mean arterial pressure (MAP), and heart rate (HR) were measured. The reconstruction of the signals was made for basal conditions, during and after CGRP infusion which were compared using statistics. Results: In both groups, we found significant decrease between measurement points of vm MCA and Et-CO2 during and after hαCGRP infusion. MAP did not show significant trends during the infusion, but it was significantly increased after the infusion in migraine patients only. Responses to hαCGRP, defined as differences between two measurement points, were significantly higher for vm MCA and Et-CO2 in patients with migraine. A significant difference between groups was found in MAP response. Significant relationships were found between migraine and vm MCA, Et-CO2, and MAP. Conclusion: In patients with migraine, vm MCA responses to hαCGRP are significantly higher and are associated with CGRP-induced headache which indicates that patients with migraine are more prone to sensitization.

αCGRP-Induced Changes in Cerebral and Systemic Circulation; A TCD Study.

It is known that perivascular application of CGRP induces cerebral vasodilatation. However, it is unclear whether intravenous alfa CGRP (αCGRP) induces changes in cerebral and systemic hemodynamics. Therefore, we studied the influence of an αCGRP intravenous infusion at a rate of 1.5 mcg/min in 20 min on mean arterial velocity in the middle cerebral artery (vm MCA) and in the posterior cerebral artery (vm PCA) in twenty healthy subjects using transcranial Doppler (TCD). We found out that αCGRP decreased vm MCA (p < 0.001), vm PCA (p < 0.001), mean arterial pressure (MAP) (p < 0.001) and end-tidal CO2 (Et-CO2) (p = 0.030). The heart rate (HR) increased during αCGRP infusion (p < 0.001). In addition, we found a positive relationship between Et-CO2 and vm MCA (p = 0.001) as well as vm PCA (p = 0.043). In our view, αCGRP induces changes in cerebral and systemic circulation in healthy volunteers. It might cause vasodilatation of MCA and PCA and a compensatory decrease of Et-CO2 to αCGRP related hemodynamic changes.

Enhancement of Intravenous Thrombolysis by Nationwide Telestroke Care in Slovenia: A Model of Care for Middle-Income Countries.

Background:Stroke expertise is critical for timely and appropriate intravenous thrombolysis (IVT) and affects IVT use.Introduction:In Slovenia, IVT is administered in general hospitals, which often lack on-site neurologic expertise. To overcome this obstacle, a national telestroke network, TeleKap, has been implemented. The aim of the study was to determine whether TeleKap is associated with enhanced IVT use.Materials and Methods:This investigation was a retrospective observational study comparing the number of acute ischemic stroke (AIS) patients and the use of IVT during the first 3 consecutive years. TeleKap, a decentralized hub-and-spoke telestroke model covering the entire nation, consists of one comprehensive stroke center and 12 spokes classified according to the availability of on-site neurologic expertise.Results:During the observation period, we treated a total of 1,316 patients with AIS, of which 508 (38.6%) received IVT. We found statistically significant positive trends in the number of IVT patients (142 in 2015, 158 in 2016, and 208 in 2017; B = 4.39, standard error (SE) = 1.59, p = 0.01) and the number of AIS patients (326 in 2015, 424 in 2016, and 566 in 2017; B = 14.42, SE = 5.19, p = 0.01) for all spokes. The trend in the IVT rate was numerically negative but did not reach statistical significance (43.5% in 2015, 37.3% in 2016, and 36.7% in 2017; p = 0.30).Discussion:TeleKap enhanced IVT use regardless of on-site neurologic expertise.Conclusions:TeleKap proved to be efficient. It could serve as a model of telestroke care for other similar countries.

Fatal recurrent dermatoneuro syndrome associated with systemic AL amyloidosis.

A male patient is presented with long-lasting paraproteinemia of monoclonal IgG λ, who suffered from recurrent, and until the last one, mostly reversible episodes of dermatoneuro syndrome, described exclusively in scleromyxedema. The skin biopsy revealed λ-light chain amyloid deposition instead of changes typical for scleromyxedema. Systemic AL amyloidosis was diagnosed post mortem since the patient had no clinical signs of any other organ impairment except skin and brain. Neuropathology is described and possible etiopathogenesis of brain involvement is considered.

The presence of cerebral and/or systemic endothelial dysfunction in patients with leukoaraiosis--a case control pilot study.

BACKGROUND: In spite of high prevalence and clinical relevance of leukoaraiosis (LA), its pathophysiology is still incompletely understood. Theories of ischaemic genesis and a leaky blood-brain barrier are contradictory yet could share a common denominator-endothelial dysfunction (cerebral, systemic or both), which has not been studied thoroughly in LA. METHODS: Thirty patients with LA (58 years (SD 7)) and 30 gender- and age-matched controls without LA (55 years (SD 6)) were recruited. The vascular risk factors (VRF) were identical in both groups. Cerebral endothelial function was determined by cerebrovascular reactivity to L-arginine (CVR). Systemic endothelial function was determined by flow-mediated dilatation (FMD) of the brachial artery after hyperaemia. All participants underwent a brain MRI to search for radiological signs of LA that was classified according to the Fazekas score. Linear regression was used to explore the correlation between CVR and FMD in patients with LA. A 95 % confidence interval was used. For any statistical test used in the study, p ≤ 0.050 was regarded as statistically significant. RESULTS: We found a marked and significant decrease in both CVR (9.6 % (SD 3.2) vs. 15.8 % (SD 6.1), p < 0.001) and FMD (4.8 % (SD 3.1) vs. 7.4 % (SD 3.8), p = 0.004) in LA patients compared to controls. Both CVR (7.4 % (SD 3.1) vs. 12.2 % (SD 2.6), p = 0.001) and FMD (3.0 % (SD 2.2) vs. 6.4 % (SD 3.1), p = 0.011) were significantly decreased in LA subgroup Fazekas 3 compared to subgroup Fazekas 1. CVR and FMD significantly positively correlated (b = 0.192, 95 % CI = 0.031-0.354, p = 0.02). CONCLUSIONS: The results of our pilot study suggest that patients with LA have a significant impairment of both cerebral and systemic endothelial function that is larger than could be expected based on present VRF. Endothelial dysfunction increases in parallel with LA severity and correlates between cerebral and systemic arterial territory. Overall, our results suggest a so far unknown "intrinsic" generalised endothelial dysfunction in patients with LA that could be involved in LA pathophysiology. This interesting issue needs to be confirmed in larger samples since it could help better understand the mechanisms underlying LA.

Carotid Arterial Hemodynamic in Ischemic Levkoaraiosis Suggests Hypoperfusion Mechanism.

BACKGROUND: Leukoaraiosis (ILA) is believed to be ischaemic in origin due to its similar location as that of lacunar infarctions and its association with cerebrovascular risk factors. However, its pathophysiology is not well understood. The ischaemic injuries may be a result of increased pulsatility or cerebral hypo-perfusion. We used carotid duplex ultrasound to prove that the underlying mechanism is hypo-perfusion. METHODS: We compared 55 ILA patients to 44 risk factor-matched controls with normal magnetic resonance imaging (MRI) of the head. ILA diagnosis was based on MRI and was further categorised according to the Fazekas scale. We measured carotid artery blood flow velocity and diameter and calculated carotid blood flow and resistance indexes. RESULTS: Blood flow velocities and blood flows were significantly lower in the ILA group, including diastolic, systolic and mean pressures (p ≤ 0.05). The resistance indices were higher in the ILA group, but the differences were not statistically significant. All the velocities and blood flows showed a decreasing trend with higher Fazekas score, whereas resistance indexes showed an increasing trend. CONCLUSIONS: Lower blood flow and higher resistance of carotid arteries are consistent with the hypo-perfusion theory of ILA. Carotid ultrasound could have a diagnostic and prognostic role in ILA patients.

Ultrasound diagnosis of carotid artery stiffness in patients with ischemic leukoaraiosis.

The pathophysiology of ischemic leukoaraiosis (ILA) is unknown. It was recently found that ILA patients have increased aortic stiffness. Carotid stiffness is a more specific parameter and could have value as a non-invasive diagnostic value for ILA. Therefore, using color-coded duplex sonography, we compared local carotid stiffness parameters of 59 patients with ILA with those of 45 well-matched controls. The diagnosis of ILA was based on exclusion of other causes of white matter changes seen on magnetic resonance imaging. Pulse wave velocity ß (PWVß, m/s), pressure-strain elasticity modulus (Ep, kPa), ß index and augmentation index (Aix, %) values were higher and arterial compliance (AC, mm(2)/kPa) values were lower in the ILA group; however, only Ep and PWVß reached statistical significance (p ≤ 0.05). ß, Ep and PWVß exhibited an increasing trend with higher Fazekas score, though only Ep reached significance (p = 0.05). The main conclusion was that Ep and PWVß could have a diagnostic role in patients with ILA.

Successful treatment of brain ischemia with supplementation therapy in a patient with hyperhomocysteinemia.

The effectiveness of homocysteine-lowering therapy on stroke prevention is still unclear. Although randomized controlled epidemiological trials have yielded mixed findings, a multicenter trial did not show any beneficial effect. Genetic studies are still lacking. Therefore, we report on a female patient with transient ischemic attacks and the thermolabile variant of methylenetetrahydrofolate reductase (TT genotype), who benefited from supplemental therapy for homocysteine lowering.