Abstract
Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder being recognized during the past two decades. It is characterized by multiple abrupt severe headaches ...and widespread cerebral vasoconstrictions, with potential complications such as ischemic stroke, convexity subarachnoid hemorrhage, intracerebral hemorrhage and posterior reversible encephalopathy syndrome. The clinical features, imaging findings, and dynamic disease course have been delineated. However, the pathophysiology of RCVS remains elusive. Recent studies have had substantial progress in elucidating its pathogenesis. It is now believed that dysfunction of cerebral vascular tone and impairment of blood–brain barrier may play key roles in the pathophysiology of RCVS, which explains some of the clinical and radiological manifestations of RCVS. Some other potentially important elements include genetic predisposition, sympathetic overactivity, endothelial dysfunction, and oxidative stress, although the detailed molecular mechanisms are yet to be identified. In this review, we will summarize what have been revealed in the literature and elaborate how these factors could contribute to the pathophysiology of RCVS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Objective
To evaluate human glymphatics and meningeal lymphatics noninvasively.
Methods
This prospective study implemented 3‐dimensional (3D) isotropic contrast‐enhanced T2 fluid‐attenuated inversion ...recovery (CE‐T2‐FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood–brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg 0.2ml/kg) was administered intravenously in all study subjects.
Results
In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para‐arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase‐ or condition‐specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours.
Interpretation
This large‐scale in vivo study successfully demonstrated the putative human para‐arterial glymphatic transports and meningeal lymphatics by clear depiction of para‐arterial, parasinus, and paravenous meningeal contrast enrichment using high‐resolution 3D isotropic CE‐T2‐FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111–124
Whether blood transfusion exacerbates cancer outcomes after surgery in humans remains inconclusive. We utilized a large cohort to investigate the effect of perioperative blood transfusion on cancer ...prognosis following colorectal cancer (CRC) resection. Patients with stage I through III CRC undergoing tumour resection at a tertiary medical center between 2005 and 2014 were identified and evaluated through August 2016. Propensity score matching was used to cancel out imbalances in patient characteristics. Postoperative disease-free survival (DFS) and overall survival (OS) were analysed using Cox regression model. A total of 4,030 and 972 patients were analysed before and after propensity score matching. Cox regression analyses demonstrated blood transfusion associated with shorter DFS and OS before and after matching (hazard ratio: 1.41, 95% CI: 1.2-1.66 for DFS; 1.97, 95% CI: 1.6-2.43 for OS). Larger transfusion volume was linked to higher overall mortality (≤4 units vs. nil, HR = 1.58; >4 units vs. nil, HR = 2.32) but not more cancer recurrence. Preoperative anemia was not associated with decreased survival after adjusting covariates. Perioperative blood transfusion was associated with worse cancer prognosis after curative colorectal resection, independently of anemia status. Strategies aimed at minimizing transfusion requirements should be further developed.
Migraine is among the most prevalent and disabling neurological diseases in the world. Cortical spreading depression (SD) is an intense wave of neuronal and glial depolarization underlying migraine ...aura, and a headache trigger, which has been used as an experimental platform for drug screening in migraine. Here, we provide an overview of novel therapeutic targets that show promise to suppress SD, such as acid‐sensing ion channels, casein kinase Iδ, P2X7‐pannexin 1 complex, and neuromodulation, and outline the experimental models and essential quality measures for rigorous and reproducible efficacy testing.
Spreading depression (SD) is a slowly propagating wave of near-complete depolarization of neurons and glial cells across the cortex. SD is thought to contribute to the underlying pathophysiology of ...migraine aura, and possibly also an intrinsic brain activity causing migraine headache. Experimental models of SD have recapitulated multiple migraine-related phenomena and are considered highly translational. In this review, we summarize conventional and novel methods to trigger SD, with specific focus on optogenetic methods. We outline physiological triggers that might affect SD susceptibility, review a multitude of physiological, biochemical, and behavioral consequences of SD, and elaborate their relevance to migraine pathophysiology. The possibility of constructing a recurrent episodic or chronic migraine model using SD is also discussed.
Bisphenol A (BPA) is an estrogen‐like compound, and an environmental hormone, that is commonly used in daily life. Therefore, it may enter the human body through food or direct contact, causing BPA ...residues in blood and urine. Because most studies focused on the analysis of BPA in reproductive cells or tissues, regarding evidence the effect of BPA on human retinal pigment epithelium (ARPE‐19) cells unavailable. Accordingly, the present study explored the cytotoxicity of BPA on ARPE‐19 cells. After BPA treatment, the expression of Bcl‐XL an antiapoptotic protein, in the mitochondria decreased, and the expression of Bax, a proapoptotic protein increased. Then the mitochondrial membrane potential was affected. BPA changed in mitochondrial membrane potential led to the release of cytochrome C, which activated caspase‐9 to promote downstream caspase‐3 leading to cytotoxicity. The nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and heme oxygenase 1 (HO‐1) pathway play a major role in age‐related macular degeneration. Our results showed that expression of HO‐1 and Nrf2 suppressed by BPA. Superoxide dismutase and catalase, which Nrf2 downstream antioxidants, were degraded by BPA. AMP‐activated kinase (AMPK), which can regulate the phosphorylation of Nrf2, and the phosphorylation of AMPK expression was reduced by BPA. Finally, BPA‐induced ROS generation and cytotoxicity were reduced by N‐acetyl‐l‐cysteine. Taken together, these results suggest that BPA induced ARPE‐19 cells via oxidative stress, which was associated with down regulated Nrf2/HO‐1 pathway, and the mitochondria dependent apoptotic signaling pathway.
Objective
To investigate the evolution and clinical significance of vasoconstriction on magnetic resonance angiography (MRA) in patients with reversible cerebral vasoconstriction syndromes (RCVS).
...Methods
Patients with RCVS were recruited and followed up with MRA examinations until normalization of vasoconstriction or for 6 months. The vasoconstriction severity of the major cerebral arterial segments (M1, M2, A1, A2, P1, P2, and basilar artery) was scored on a 5‐point scale: 0 (0–<10%), 1 (10–<25%), 2 (25–<50%), 3 (50–<75%), and 4 (≥75%). Subjects with at least 1 segment with a vasoconstriction score ≥2 were eligible for the study. Initial mean scores of single or combined arterial segments were used to predict ischemic complications.
Results
Seventy‐seven patients with RCVS (8 men/69 women; average age 47.7 ± 11.6 years) finished the study with a total of 225 MRAs performed. The mean number of arterial segments involved was 5.3 ± 3.0 in the initial MRA. Vasoconstriction scores reached their maximum 16.3 ± 10.2 days after headache onset, close to the average timing of headache resolution (16.7 ± 8.6 days). Vasoconstriction evolved in a parallel trend among different arterial segments. Seven (9.1%) patients developed posterior reversible encephalopathy syndromes (PRES). Six (7.8%) patients had ischemic stroke. A logistic regression model demonstrated that the M1–P2 combined score was associated with highest risk of PRES (odds ratio OR, 11.6, p = 0.005) and ischemic stroke (OR, 3.4; p = 0.026).
Interpretation
MRA evaluation in patients with RCVS is valid. Vasoconstriction was pervasive and outlasted headache resolution. Vasoconstrictions in M1 and P2 are important determinants for PRES and ischemic stroke. ANN NEUROL 2010;67:648–656
Objective
To review and discuss the literature on the role of cortical structure and function in migraine.
Discussion
Structural and functional findings suggest that changes in cortical morphology ...and function contribute to migraine susceptibility by modulating dynamic interactions across cortical and subcortical networks. The involvement of the cortex in migraine is well established for the aura phase with the underlying phenomenon of cortical spreading depolarization, while increasing evidence suggests an important role for the cortex in perception of head pain and associated sensations. As part of trigeminovascular pain and sensory processing networks, cortical dysfunction is likely to also affect initiation of attacks.
Conclusion
Morphological and functional changes identified across cortical regions are likely to contribute to initiation, cyclic recurrence and chronification of migraine. Future studies are needed to address underlying mechanisms, including interactions between cortical and subcortical regions and effects of internal (e.g. genetics, gender) and external (e.g. sensory inputs, stress) modifying factors, as well as possible clinical and therapeutic implications.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS).
Methods
We ...prospectively recruited 3 independent cohorts of patients with RCVS and age‐matched and sex‐matched controls in a single medical center. Next‐generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross‐validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis.
Results
We identified a panel of miRNAs including miR‐130a‐3p, miR‐130b‐3p, let‐7a‐5p, let‐7b‐5p, and let‐7f‐5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve AUC was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let‐7a‐5p, let‐7b‐5p, and let‐7f‐5p, but not miR‐130a‐3p nor miR‐130b‐3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor‐β signaling pathway and endothelin‐1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients’ cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR‐130a‐3p was associated with imaging‐proven disruption of the blood‐brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model.
Interpretation
We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459–473
This study was undertaken to investigate migraine glymphatic and meningeal lymphatic vessel (mLV) functions.
Migraine patients and healthy controls (HCs) were prospectively recruited between 2020 and ...2023. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) index for glymphatics and dynamic contrast-enhanced magnetic resonance imaging parameters (time to peak TTP/enhancement integral EI/mean time to enhance MTE) for para-superior sagittal (paraSSS)-mLV or paratransverse sinus (paraTS)-mLV in episodic migraine (EM), chronic migraine (CM), and CM with and without medication-overuse headache (MOH) were analyzed. DTI-ALPS correlations with clinical parameters (migraine severity numeric rating scale/disability Migraine Disability Assessment (MIDAS)/bodily pain Widespread Pain Index/sleep quality Pittsburgh Sleep Quality Index (PSQI)) were examined.
In total, 175 subjects (112 migraine + 63 HCs) were investigated. DTI-ALPS values were lower in CM (median interquartile range = 0.64 0.12) than in EM (0.71 0.13, p = 0.005) and HCs (0.71 0.09, p = 0.004). CM with MOH (0.63 0.07) had lower DTI-ALPS values than CM without MOH (0.73 0.12, p < 0.001). Furthermore, CM had longer TTP (paraSSS-mLV: 55.8 12.9 vs 40.0 7.6, p < 0.001; paraTS-mLV: 51.2 8.1 vs 44.0 3.3, p = 0.002), EI (paraSSS-mLV: 45.5 42.0 vs 16.1 9.2, p < 0.001), and MTE (paraSSS-mLV: 253.7 6.7 vs 248.4 13.8, p < 0.001; paraTS-mLV: 252.0 6.2 vs 249.7 1.2, p < 0.001) than EM patients. The MIDAS (p = 0.002) and PSQI (p = 0.002) were negatively correlated with DTI-ALPS index after Bonferroni corrections (p < q = 0.01).
CM patients, particularly those with MOH, have glymphatic and meningeal lymphatic dysfunctions, which are highly clinically relevant and may implicate pathogenesis for migraine chronification. ANN NEUROL 2024;95:583-595.
PDF
