Mechanosensitive receptors in migraine: a systematic review.

BACKGROUND: Migraine is a debilitating neurological disorder with pain profile, suggesting exaggerated mechanosensation. Mechanosensitive receptors of different families, which specifically respond to various mechanical stimuli, have gathered increasing attention due to their potential role in migraine related nociception. Understanding these mechanisms is of principal importance for improved therapeutic strategies. This systematic review comprehensively examines the involvement of mechanosensitive mechanisms in migraine pain pathways. METHODS: A systematic search across the Cochrane Library, Scopus, Web of Science, and Medline was conducted on 8th August 2023 for the period from 2000 to 2023, according to PRISMA guidelines. The review was constructed following a meticulous evaluation by two authors who independently applied rigorous inclusion criteria and quality assessments to the selected studies, upon which all authors collectively wrote the review. RESULTS: We identified 36 relevant studies with our analysis. Additionally, 3 more studies were selected by literature search. The 39 papers included in this systematic review cover the role of the putative mechanosensitive Piezo and K2P, as well as ASICs, NMDA, and TRP family of channels in the migraine pain cascade. The outcome of the available knowledge, including mainly preclinical animal models of migraine and few clinical studies, underscores the intricate relationship between mechanosensitive receptors and migraine pain symptoms. The review presents the mechanisms of activation of mechanosensitive receptors that may be involved in the generation of nociceptive signals and migraine associated clinical symptoms. The gender differences of targeting these receptors as potential therapeutic interventions are also acknowledged as well as the challenges related to respective drug development. CONCLUSIONS: Overall, this analysis identified key molecular players and uncovered significant gaps in our understanding of mechanotransduction in migraine. This review offers a foundation for filling these gaps and suggests novel therapeutic options for migraine treatments based on achievements in the emerging field of mechano-neurobiology.

Prevalence of myocardial injury in patients after acute ischaemic stroke according to standard criteria.

This study examined the prevalence of acute and chronic myocardial injury according to standard criteria in patients after acute ischaemic stroke (AIS) and its relation to stroke severity and short-term prognosis. Between August 2020 and August 2022, 217 consecutive patients with AIS were enrolled. Plasma levels of high-sensitive cardiac troponin I (hs-cTnI) were measured in blood samples obtained at the time of admission and 24 and 48 h later. The patients were divided into three groups according to the Fourth Universal Definition of Myocardial Infarction: no injury, chronic injury, and acute injury. Twelve-lead ECGs were obtained at the time of admission, 24 and 48 h later, and on the day of hospital discharge. A standard echocardiographic examination was performed within the first 7 days of hospitalization in patients with suspected abnormalities of left ventricular function and regional wall motion. Demographic characteristics, clinical data, functional outcomes, and all-cause mortality were compared between the three groups. The National Institutes of Health Stroke Scale (NIHSS) at the time of admission and the modified Rankin Scale (mRS) 90 days following hospital discharge were used to assess stroke severity and outcome. Elevated hs-cTnI levels were measured in 59 patients (27.2%): 34 patients (15.7%) had acute myocardial injury and 25 patients (11.5%) had chronic myocardial injury within the acute phase after ischaemic stroke. An unfavourable outcome, evaluated based on the mRS at 90 days, was associated with both acute and chronic myocardial injury. Myocardial injury was also strongly associated with all-cause death, with the strongest association in patients with acute myocardial injury, at 30 days and at 90 days. Kaplan-Meier survival curves showed that all-cause mortality was significantly higher in patients with acute and chronic myocardial injury than in patients without myocardial injury (P < 0.001). Stroke severity, evaluated with the NIHSS, was also associated with acute and chronic myocardial injury. A comparison of the ECG findings between patients with and without myocardial injury showed a higher occurrence in the former of T-wave inversion, ST segment depression, and QTc prolongation. In echocardiographic analysis, a new abnormality in regional wall motion of the left ventricle was identified in six patients. Chronic and acute myocardial injury with hs-cTnI elevation after AIS are associated with stroke severity, unfavourable functional outcome, and short-term mortality.

Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.

INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

Genetics of migraine: where are we now?

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.

Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in Patients after Acute Stroke: Relation to Stroke Severity, Myocardial Injury, and Impact on Prognosis.

BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to be associated with poor prognosis after cardiovascular events. We aimed to assess the dynamic changes in TRAIL levels and the relation of TRAIL level to stroke severity, its impact on the short-term outcomes, and its association with markers of cardiac injury in patients after acute stroke. METHODS: Between August 2020 and August 2021, 120 consecutive patients, 104 after acute ischemic stroke (AIS), 76 receiving reperfusion therapy, and 16 patients after intracerebral hemorrhage (ICH) were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 h later, and 48 h later to determine the plasma level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitive Troponin I (hs-TnI). Twelve-lead ECGs were obtained at the time of admission, 24 h later, 48 h later, and at the release of the patients. Evaluations were performed using the National Institutes of Health Stroke Scale (NIHSS) at the time of admission and using the modified Rankin Scale (mRS) 90 days following the patient's discharge from the hospital. RESULTS: We observed a connection between lower TRAIL levels and stroke severity evaluated using the NIHSS (p = 0.044) on the first day. Lower TRAIL showed an association with severe disability and death as evaluated using the mRS at 90 days, both after 24 (p = 0.0022) and 48 h (p = 0.044) of hospitalization. Moreover, we observed an association between lower TRAIL and NT-proBNP elevation at the time of admission (p = 0.039), after 24 (p = 0.043), and after 48 h (p = 0.023) of hospitalization. In the ECG analysis, lower TRAIL levels were associated with the occurrence of premature ventricular extrasystoles (p = 0.043), and there was an association with prolonged QTc interval (p = 0.052). CONCLUSIONS: The results show that lower TRAIL is associated with stroke severity, unfavorable functional outcome, and short-term mortality in patients after acute ischemic stroke. Moreover, we described the association with markers of cardiac injury and ECG changes.

Clinical and radiological factors predicting stroke outcome after successful mechanical intervention in anterior circulation.

The recanalization effect of large-vessel occlusion (LVO) in anterior circulation is well documented but only some patients benefit from endovascular treatment. We analysed clinical and radiological factors determining clinical outcome after successful mechanical intervention. We included 146 patients from the Prague 16 study enrolled from September 2012 to December 2020, who had initial CT/CTA examination and achieved good recanalization status after mechanical intervention (TICI 2b-3). One hundred and six (73%) patients achieved a good clinical outcome (modified Rankin Scale 0-2 in 3 months). It was associated with age, leptomeningeal collaterals (LC), onset to intervention time, ASPECTS, initial NIHSS, and leukoaraiosis (LA) in univariate analysis. The regression model identified good collateral status [odds ratio (OR) 5.00, 95% confidence interval (CI) 1.91-13.08], late thrombectomy (OR 0.24, 95% CI 0.09-0.65), LA (OR 0.44, 95% CI 0.19-1.00), ASPECTS (OR 1.45, 95% CI 1.08-1.95), and NIHSS score (OR 0.86, 95% CI 0.78-0.95) as independent outcome determinants. In the late thrombectomy subgroup, 14 out of 33 patients (42%) achieved a favourable clinical outcome, none of whom with poor collateral status. The presence of LC and absence of LA predicts a good outcome in acute stroke patients after successful recanalization of LVO in anterior circulation. Late thrombectomy was associated with higher rate of unfavourable clinical outcome. Nevertheless, collateral status in this subgroup was validated as a reliable selection criterion.

Headache onset after vaccination against SARS-CoV-2: a systematic literature review and meta-analysis.

BACKGROUND: Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are used to reduce the risk of developing Coronavirus Disease 2019 (COVID-19). Despite the significant benefits in terms of reduced risk of hospitalization and death, different adverse events may present after vaccination: among them, headache is one of the most common, but nowadays there is no summary presentation of its incidence and no description of its main features. METHODS: We searched PubMed and EMBASE covering the period between January 1st 2020 and August 6th, 2021, looking for record in English and with an abstract and using three main search terms (with specific variations): COVID-19/SARS-CoV-2; Vaccination; headache/adverse events. We selected manuscript including information on subjects developing headache after injection, and such information had to be derived from a structured form (i.e. no free reporting). Pooled estimates and 95% confidence intervals were calculated. Analyses were carried out by vaccine vs. placebo, by first vs. second dose, and by mRNA-based vs. "traditional" vaccines; finally, we addressed the impact of age and gender on post-vaccine headache onset. RESULTS: Out of 9338 records, 84 papers were included in the review, accounting for 1.57 million participants, 94% of whom received BNT162b2 or ChAdOx1. Headache was generally the third most common AE: it was detected in 22% (95% CI 18-27%) of subjects after the first dose of vaccine and in 29% (95% CI 23-35%) after the second, with an extreme heterogeneity. Those receiving placebo reported headache in 10-12% of cases. No differences were detected across different vaccines or by mRNA-based vs. "traditional" ones. None of the studies reported information on headache features. A lower prevalence of headache after the first injection of BNT162b2 among older participants was shown. CONCLUSIONS: Our results show that vaccines are associated to a two-fold risk of developing headache within 7 days from injection, and the lack of difference between vaccine types enable to hypothesize that headache is secondary to systemic immunological reaction than to a vaccine-type specific reaction. Some descriptions report onset within the first 24 h and that in around one-third of the cases, headache has migraine-like features with pulsating quality, phono and photophobia; in 40-60% of the cases aggravation with activity is observed. The majority of patients used some medication to treat headache, the one perceived as the most effective being acetylsalicylic acid.

Nationwide screening for Fabry disease in unselected stroke patients.

BACKGROUND AND AIMS: Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. METHODS: A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males-enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. RESULTS: 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02-0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08-2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. CONCLUSIONS: The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

Hemichorea in ketotic hyperglycemia with hyperdense striatum mimicking hemorrhagic transformation in a patient using apixaban.

INTRODUCTION: Diabetic striatopathy is a rare condition characterized by unilateral hemichorea and/or hemiballismus in the settings of uncontrolled nonketotic diabetes mellitus. Imaging studies usually reveal striatal abnormality - subtle hyperdensity on CT and T1 hyperintensity on MRI. The resolution of clinical symptoms is prompt when optimal glycaemic control is achieved. CASE REPORT: We present the case of a 90-year-old male who came to our attention for acute involuntary choreiform movements of his left-sided extremities lasting two-weeks. Apart from that neurological examination was unremarkable. His medical history included hypertension, atrial fibrillation, previous stroke with no residual disability and poorly controlled type 2 diabetes mellitus on metformin treatment. There was no history of movement disorders or exposure to neuroleptics. His glucose level on admission was 512.6 mg/dL, glycated hemoglobin was 14%. CT scan of the head demonstrated an abnormally increased intensity within the right striatum. Treatment consisted of symptomatic treatment of chorea and improvement of blood glucose control. Tiapride was started with a dose of 100 mg 4 times a day. The patient was initiated on intensive insulin therapy which included insulin glargine 10 units every evening and 12 units of insulin glulisine 3 times a day with meals. Abnormal movements resolved after normoglycemia was achieved approximately 7 days after admission. Though striatal hyperdensity was still present at follow-up CT scan after 10 days, it was less pronounced. CONCLUSION: Diabetic striatopathy is a rare but treatable disorder and should be considered in patients with poorly controlled diabetes who present with hemichorea.

Left ventricle cardiac myxoma as a cause of ischaemic stroke in young patient treated by mechanical thrombectomy.

Cardiac myxoma is a rare cause of cardioembolic stroke, especially in young patients. Acute treatment includes intravenous thrombolysis or acute thrombectomy via mechanical recanalisation. We present a case of a young 21-year-old woman with no symptoms of dyspnoea who suddenly developed expressive aphasia and right-sided hemiparesis due to a thrombus in the left middle cerebral artery followed by the left anterior cerebral artery. She underwent acute mechanical thrombectomy with improvement of the neurological status. Bedside ultrasonography detected a suspected myxoma, which was further confirmed by a CT scan as a myxoma in the left cardiac ventricle. The patient underwent successful surgery. We stress on the importance of echocardiographic examination in young patients after ischaemic stroke and multidisciplinary team cooperation in the treatment management of such patients.

Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence.

BACKGROUND: According to the International Classification of Headache Disorders 3, post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) is a secondary headache reported to have developed within 7 days from head injury, regaining consciousness following the head injury, or discontinuation of medication(s) impairing the ability to sense or report headache following the head injury. It is one of the most common secondary headache disorders, and it is defined as persistent when it lasts more than 3 months. MAIN BODY: Currently, due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH. Despite representing a simplification of a complex disorder and displaying different limitations concerning the human condition, animal models are still a mainstay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies. Different models reproduce different types of trauma and have been ideated in order to ensure maximal proximity to the human condition and optimal experimental reproducibility. CONCLUSION: At present, despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified. Although facing limitations, animal models are needed to improve understanding of PTH. The knowledge of currently available models is necessary to all researchers who want to investigate PTH and contribute to unravel its mechanisms.

Diagnosis of cerebral venous thrombosis: a single centre experience.

OBJECTIVES: Cerebral venous thrombosis is a serious cerebrovascular disease. Due to the variability of clinical symptoms and the scarcity of occurrence, this diagnosis is often delayed. The aim of the study was to describe the risk factors, the initial findings and the imaging methods that lead to the diagnosis. METHODS: We included 34 patients treated for cerebral venous thrombosis in the years 2004-2016. We retrospectively analyzed demographic data, initial clinical symptoms, baseline D-dimer levels, risk factors, time to diagnosis, and MR findings. RESULTS: The most common initial clinical symptom was headache (28 patients, 82.4%). Focal neurological symptoms or signs of encephalopathy developed in 22 patients (64.7%). In 26 patients, we identified at least one risk factor in their history. In women of childbearing potential, 68% of patients (15/22) were taking hormonal contraceptives; in six people the diagnosis was immediately preceded by inflammation. In all patients, the diagnosis was confirmed by MR venography. Positive hereditary thrombophilic conditions were identified in 68% and acquired in 8% of 25 examined patients. In 22 cases, baseline D-dimer levels were examined and found to be increased in 86% of them. The mean time from the first onset of symptoms to diagnosis was 6.9 days. CONCLUSION: Cerebral venous thrombosis has a variable clinical course and the diagnosis is determined a relatively long time after the onset of symptoms. Atypical headache in the patient's history and a set of risk factors are the key findings for indication of imaging methods and confirmation of the diagnosis.

Comparison of an inhomogeneous orthotropic and isotropic material models used for FE analyses.

Finite element (FE) analysis has been widely used to study the behaviour of bone or implants in many clinical applications. One of the main factors in analyses is the realistic behaviour of the bone model, because the behaviour of the bone is strongly dependent on a realistic bone material property assignment. The objective of this study was to compare isotropic and orthotropic inhomogeneous material models used for FE analyses of the "global" proximal femur and "small" specimens of the bone (cancellous and cortical). Our hypothesis was that realistic material property assignment (orthotropy) is very important for the FE analyses of small bone specimens, whereas in global FE analyses of the proximal femur, this assignment can be omitted, if the inhomogeneous material model was used. The three-dimensional geometry of the "global" proximal femur was reconstructed using CT scans of a cadaveric femur. This model was implemented into an FE simulation tool and various bone material properties, dependant on bone density, were assigned to each element in the models. The "small" specimens of cortical and cancellous bone were created in the same way as the model of the proximal femur. The results obtained from FE analyses support our above described hypothesis.