Stroke genetics and how it Informs novel drug discovery.

INTRODUCTION: Stroke is one of the main causes of death and disability worldwide. Nevertheless, despite the global burden of this disease, our understanding is limited and there is still a lack of highly efficient etiopathology-based treatment. It is partly due to the complexity and heterogenicity of the disease. It is estimated that around one-third of ischemic stroke is heritable, emphasizing the importance of genetic factors identification and targeting for therapeutic purposes. AREAS COVERED: In this review, the authors provide an overview of the current knowledge of stroke genetics and its value in diagnostics, personalized treatment, and prognostication. EXPERT OPINION: As the scale of genetic testing increases and the cost decreases, integration of genetic data into clinical practice is inevitable, enabling assessing individual risk, providing personalized prognostic models and identifying new therapeutic targets and biomarkers. Although expanding stroke genetics data provides different diagnostics and treatment perspectives, there are some limitations and challenges to face. One of them is the threat of health disparities as non-European populations are underrepresented in genetic datasets. Finally, a deeper understanding of underlying mechanisms of potential targets is still lacking, delaying the application of novel therapies into routine clinical practice.

Association between Left Atrial Appendage Morphology and Clot Histology in Patients with Embolic Ischemic Stroke: An Exploratory Study.

BACKGROUND: Acute embolic ischemic stroke poses a significant healthcare challenge. Histological clot features' variability among patients with acute ischemic stroke treated by mechanical thrombectomy has potential implications for determining treatment and etiology. This study investigated the clot histological feature differences among patients who experienced cardioembolic stroke and embolic stroke of undetermined source with different left atrial appendage (LAA) morphologies. METHODS: We conducted a prospective observational study involving 79 patients with acute embolic ischemic stroke undergoing mechanical thrombectomy. Computed tomography angiography images were used to classify LAA morphologies. An artificial intelligence algorithm assessed the clot fibrin and red blood cell contents. RESULTS: Patients with chicken-wing LAA morphology exhibited lower mean clot fibrin proportions than did those with non-chicken-wing morphology (p < 0.001). Linear regression analysis showed that chicken-wing LAA was significantly associated with a lower clot fibrin proportion (estimate, -0.177; 95% CI [-0.259, -0.096]; p < 0.001). The successful recanalization rate and first-pass effect between the groups did not differ significantly. CONCLUSIONS: The chicken-wing LAA morphological type is associated with lower clot fibrin contents, suggesting potentially different embolism mechanisms or diverse embolic sources, compared with the non-chicken-wing LAA types. Further studies are required to investigate this association.

Posterior Circulation Stroke Patients Receive Less Reperfusion Therapy Because of Late Arrival and Relative Contraindications: A Retrospective Study.

BACKGROUND: Reperfusion treatment (RT) is administered to individuals with posterior circulation strokes (PCS) later and less frequently. We aimed to study the impact of demographic and clinical factors on the decision for RT in PCS. METHODS: We conducted a retrospective analysis of the data from 500 subjects admitted to the tertiary stroke centre's emergency department between 2018 and 2020 due to PCS. Demographic and clinical factors were analysed among three groups: the RT group, the group with no RT because of absolute contraindications (ACI), and the group with no RT because of relative contraindications (RCI). RESULTS: Of the patients, 202 (40.3%) were female. The median NIHSS was four (4), and the subjects' median age was 69 (18). RT was performed on 120 (24%) subjects. FAST symptoms (OR-5.62, 95% CI [2.90-12.28]) and higher NIHSS (OR-1.13, 95% CI [1.09-1.18]) at presentation, atrial fibrillation (OR-1.56, 95% CI [1.02-2.38]), hypertension (OR-2.19, 95% CI [1.17-4.53]) and diabetes (OR-1.70, 95% CI [1.06-2.71]) increased the chance of RT. Late arrival was the most prevalent ACI for 291 (58.2%) patients. FAST-negative subjects (OR-2.92, 95% CI [1.84-4.77]) and males (OR-1.58, 95% CI [1.11-2.28]) had a higher risk of arriving late. Because of RCI, 50 (10%) subjects did not receive RT; the majority were above 80 and had NIHSS ≤ 5. Subjects with RCI who received the RT had a higher NIHSS (4 vs. 3, p < 0.001), higher hypertension (59 (92.2%) vs. 35 (77.8%), p = 0.032) and heart failure (23 (35.9%) vs. 7 (15.6%), p = 0.018) prevalence. There was a trend for less RT in females with RCI. CONCLUSIONS: Late arrival was the most common barrier to RT, and the male gender increased this risk. because of relative contraindications, 10% of subjects were not considered for RT. The presence of FAST symptoms, vascular risk factors, and a higher NIHSS increased the chance of RT.

Inflammatory Disorders of the Central Nervous System Vessels: Narrative Review.

Inflammatory disorders of the central nervous system (CNS) vessels, also called CNS vasculitides, can cause substantial disability or even be fatal. Inflammation of the CNS vessels can be caused by primary angiitis of the CNS (PACNS), inflammatory cerebral amyloid angiopathy, or systemic inflammatory disorders. Clinical symptoms of these disorders are often non-specific, such as encephalopathy, cognitive and affective abnormalities, headache and focal neurological symptoms. Diagnostic workup includes a thorough neuropsychiatric examination, blood and cerebrospinal fluid analysis and magnetic resonance imaging (MRI) of the brain and its vessels. Biopsy of the brain remains the gold standard diagnostic test. Timely diagnosis and treatment initiation is of high importance, as it might prevent severe complications, such as ischemic and hemorrhagic stroke. In this review, we describe the specific characteristics of primary and secondary non-infectious CNS vasculitides which help to establish the diagnosis, discuss the peculiarities of the diagnostic workup and present current treatment recommendations.

Intracerebral Hemorrhage Genetics.

Intracerebral hemorrhage (ICH) is a devastating type of stroke, frequently resulting in unfavorable functional outcomes. Up to 15% of stroke patients experience ICH and approximately half of those have a lethal outcome within a year. Considering the huge burden of ICH, timely prevention and optimized treatment strategies are particularly relevant. Nevertheless, ICH management options are quite limited, despite thorough research. More and more trials highlight the importance of the genetic component in the pathogenesis of ICH. Apart from distinct monogenic disorders of familial character, mostly occurring in younger subjects, there are numerous polygenic risk factors, such as hypertension, neurovascular inflammation, disorders of lipid metabolism and coagulation cascade, and small vessel disease. In this paper we describe gene-related ICH types and underlying mechanisms. We also briefly discuss the emerging treatment options and possible clinical relevance of the genetic findings in ICH management. Although existing data seems of more theoretical and scientific value so far, a growing body of evidence, combined with rapidly evolving experimental research, will probably serve clinicians in the future.

High Prevalence of Atrial Fibrillation in a Lithuanian Stroke Patient Cohort.

Background and Objectives: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a five-fold increased risk for acute ischemic stroke (AIS). We aimed to estimate the prevalence of AF in a Lithuanian cohort of stroke patients, and its impact on patients regarding case fatality, functional outcome, and health-related quality of life (HRQoL) at 90 days. Materials and Methods: A single-center prospective study was carried out for four non-consecutive months between December 2018 and July 2019 in one of the two comprehensive stroke centers in Eastern Lithuania. A telephone-based follow-up was conveyed at 90 days using the modified Rankin Scale (mRS) and EuroQoL five-dimensional three-level descriptive system (EQ-5D-3L) with a self-rated visual analog scale (EQ-VAS). One-year case fatality was investigated. Results: We included 238 AIS patients with a mean age of 71.4 ± 11.9 years of whom 45.0% were female. A striking 97 (40.8%) AIS patients had a concomitant AF, in 68 (70.1%) of whom the AF was pre-existing. The AIS patients with AF were at a significantly higher risk for a large vessel occlusion (LVO; odds ratio 2.72 [95% CI 1.38−5.49], p = 0.004), and had a more severe neurological impairment at presentation (median NIHSS score (interquartile range): 9 (6−16) vs. 6 (3−9), p < 0.001). The LVO status was only detected in those who had received computed tomography angiography. Fifty-five (80.9%) patients with pre-existing AF received insufficient anticoagulation at stroke onset. All patients received a 12-lead ECG, however, in-hospital 24-h Holter monitoring was only performed in 3.4% of AIS patients without pre-existing AF. Although multivariate analyses found no statistically significant difference in one-year stroke patient survival and favorable functional status (mRS 0−2) at 90 days, when adjusted for age, gender, reperfusion treatment, baseline functional status, and baseline NIHSS, stroke patients with AF had a significantly poorer self-perceived HRQoL, indicated by a lower EQ-VAS score (regression coefficient ± standard error: ß = −11.776 ± 4.850, p = 0.017). Conclusions: In our single-center prospective observational study in Lithuania, we found that 40.8% of AIS patients had a concomitant AF, were at a higher risk for an LVO, and had a significantly poorer self-perceived HRQoL at 90 days. Despite the high AF prevalence, diagnostic tools for subclinical AF were greatly underutilized.

Interactive Training of the Emergency Medical Services Improved Prehospital Stroke Recognition and Transport Time.

Background and Purpose: Acute stroke treatment outcomes are predicated on reperfusion timeliness which can be improved by better prehospital stroke identification. We aimed to assess the effect of interactive emergency medical services (EMS) training on stroke recognition and prehospital care performance in a very high-risk cardiovascular risk population in Lithuania. Methods: We conducted a single-center interrupted time-series study between March 1, 2019 and March 15, 2020. Two-hour small-group interactive stroke training sessions were organized for 166 paramedics serving our stroke network. We evaluated positive predictive value (PPV) and sensitivity for stroke including transient ischemic attack identification, onset-to-door time, and hospital-based outcomes during 6-months prior and 3.5 months after the training. The study outcomes were compared between EMS providers in urban and suburban areas. Results: In total, 677 suspected stroke cases and 239 stroke chameleons (median age 75 years, 54.8% women) were transported by EMS. After the training, we observed improved PPV for stroke recognition (79.8% vs. 71.8%, p = 0.017) and a trend of decreased in-hospital mortality (7.8% vs. 12.3, p = 0.070). Multivariable logistic regression models adjusted for age, gender, EMS location, and stroke subtype showed an association between EMS stroke training and improved odds of stroke identification (adjusted odds ratio [aOR] 1.6 [1.1-2.3]) and onset-to-door ≤ 90 min (aOR 1.6 [1.1-2.5]). The improvement of PPV was observed in urban EMS (84.9% vs. 71.2%, p = 0.003), but not in the suburban group (75.0% vs. 72.6%, p = 0.621). Conclusions: The interactive EMS training was associated with a robust improvement of stroke recognition, onset to hospital transport time, and a trend of decreased in-hospital mortality. Adapted training strategies may be needed for EMS providers in suburban areas. Future studies should evaluate the long-term effects of the EMS training and identify optimal retraining intervals.

Endovascular Treatment of Basilar Artery Occlusion: What Can We Learn from the Results?

Background and Objectives: Current guidelines lack specific endovascular treatment (EVT) recommendations for posterior circulation stroke (PCS). The results of earlier studies are controversial. We aimed to compare early hospital outcomes of stroke caused by large-vessel occlusion (LVO) treated with EVT or bridging therapy (BT) in anterior circulation stroke (ACS) versus PCS (middle cerebral artery occlusion (MCAO) and basilar artery occlusion (BAO), and establish the risk factors for poor outcome. Materials and Methods: we analyzed the data of 279 subjects treated with EVT due to LVO-caused stroke in a comprehensive stroke centre in 2015−2021. The primary outcome was hospital mortality, secondary outcomes were National Institutes of Health Stroke Scale (NIHSS) after 24 h, early neurological deterioration, futile recanalization (FR), the ambulatory outcome at discharge, and complications. Results: BAO presented with higher baseline NIHSS scores (19 vs. 14, p < 0.001), and longer door-to-puncture time (93 vs. 82 min, p = 0.034), compared to MCAO. Hospital mortality and the percentage of FR were the same in BAO and almost two times higher than in MCAO (20.0% vs. 10.3%, p = 0.048), other outcomes did not differ. In BAO, unsuccessful recanalization was the only significant predictor of the lethal outcome, though there were trends for PAD and RF predicting lethal outcome. A trend for higher risk of symptomatic intracranial hemorrhage (sICH) was observed in the BAO group when BT was applied. Nevertheless, neither BT nor sICH predicted lethal outcomes in the BAO group. Conclusions: Compared to the modern gold standard of EVT in the ACS, early outcomes in BAO remain poor, there is a substantial amount of FR. Nevertheless, unsuccessful recanalization remains the strongest predictor of lethal outcomes. BT in PCS might pose a higher risk for sICH, but not the lethal outcome, although this finding requires further investigation in larger trials.

Novel In-Frame Deletion in HTRA1 Gene, Responsible for Stroke at a Young Age and Dementia-A Case Study.

Biallelic mutations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene are known to cause an extremely rare cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which belongs to the group of hereditary cerebral small vessel diseases and is mainly observed in the Japanese population. Even though this pathology is inherited in an autosomal recessive manner, recent studies have described symptomatic carriers with heterozygous HTRA1 mutations who have milder symptoms than patients with biallelic HTRA1 mutations. We present the case of a Lithuanian male patient who had a stroke at the age of 36, experienced several transient ischemic attacks, and developed an early onset, progressing dementia. These clinical symptoms were associated with extensive leukoencephalopathy, lacunar infarcts, and microbleeds based on brain magnetic resonance imaging (MRI). A novel heterozygous in-frame HTRA1 gene deletion (NM_002775.5:c.533_535del; NP_002766.1:p.(Lys178del)) was identified by next generation sequencing. The variant was consistent with the patient's phenotype, which could not be explained by alternative causes, appeared highly deleterious after in silico analysis, and was not reported in the medical literature or population databases to date.

Changes in Prehospital Stroke Care and Stroke Mimic Patterns during the COVID-19 Lockdown.

The impact of COVID-19 lockdown on prehospital stroke care is largely unknown. We aimed to compare stroke care patterns before and during a state-wide lockdown. Thus, we analysed prospective data of stroke alerts referred to our stroke centre between 1 December 2019 and 16 June 2020, and compared them between two periods-15 weeks before and 13 weeks during the state-wide lockdown declared in Lithuania on 16 March 2020. Among 719 referrals for suspected stroke, there was a decrease in stroke alerts (rate ratio 0.61, 95% CI (0.52-0.71)), stroke admissions (0.63, 95% CI (0.52-0.76)), and decrease in prehospital stroke triage quality (positive predictive value 72.1% vs. 79.9%, p = 0.042) during the lockdown. The onset-to-door time was longer (153.0 vs. 120.5 min, p = 0.049) and seizures and intracranial tumours were more common among stroke mimics (16.9% vs. 6.7%, p = 0.012 and 9.6% vs. 3.0%, p = 0.037, respectively). We conclude that there was a decline in prehospital stroke triage quality during the lockdown despite low COVID-19 incidence in the country. Moreover, we observed an increase in hospital arrival delays and severe conditions presenting as stroke mimics. Our findings suggest that improved strategies are required to maintain optimal neurological care during public health emergencies.

Ischemic Stroke Genetics: What Is New and How to Apply It in Clinical Practice?

The etiology of ischemic stroke is multifactorial. Although receiving less emphasis, genetic causes make a significant contribution to ischemic stroke genesis, especially in early-onset stroke. Several stroke classification systems based on genetic information corresponding to various stroke phenotypes were proposed. Twin and family history studies, as well as candidate gene approach, are common methods to discover genetic causes of stroke, however, both have their own limitations. Genome-wide association studies and next generation sequencing are more efficient, promising and increasingly used for daily diagnostics. Some monogenic disorders, despite covering only about 7% of stroke etiology, may cause well-known clinical manifestations that include stroke. Polygenic disorders are more frequent, causing about 38% of all ischemic strokes, and their identification is a rapidly developing field of modern stroke genetics. Current advances in human genetics provide opportunity for personalized prevention of stroke and novel treatment possibilities. Genetic risk scores (GRS) and extended polygenic risk scores (PRS) estimate cumulative contribution of known genetic factors to a specific outcome of stroke. Combining those scores with clinical information and risk factor profiles might result in better primary stroke prevention. Some authors encourage the use of stroke gene panels for stroke risk evaluation and further stroke research. Moreover, new biomarkers for stroke genetic causes and novel targets for gene therapy are on the horizon. In this article, we summarize the latest evidence and perspectives of ischemic stroke genetics that could be of interest to the practitioner and useful for day-to-day clinical work.

Migraine-linked characteristics of transcranial magnetic stimulation-induced phosphenes.

Transcranial magnetic stimulation is used to explore visual cortex hyperexcitability in migraine. We hypothesized that the phosphene threshold in subjects suffering from migraines with and without aura would be lower than in controls, and this phenomenon could be linked to higher pain and disability levels. We also implied that subjects with lower phosphene threshold could see more phosphenes of different colors and shapes. Our primary objective was to compare the phosphene threshold between migraine without aura, migraine with aura, and control groups and investigate which factors contribute to different phosphene parameters in migraineurs. Secondary objectives were to compare color, shape, and number of phosphenes between groups and assess pain and disability level correlation with the phosphene characteristics. Phosphene threshold in migraine without aura, migraine with aura, and control groups were 68 ± 9.5% vs. 75 ± 12%, vs. 80 ± 11%, respectively. Other phosphene parameters (number, color and shape) did not differ between groups. Average pain level during the attack did not correlate with phosphene threshold significantly, though the non-significant trend for negative correlation of migraine disability assessment scale score and a phosphene threshold has been found the higher was migraine disability assessment scale value, the lower was phosphene threshold (ß = -0.255; P = 0.139). Other variables: gender, age, migraine subtype, migraine duration and use of hormone contraceptives - were not related to the phosphene threshold value. Our study provides additional data on visual cortex hyperexcitability in migraineurs, regarding transcranial magnetic stimulation with a figure-of-eight coil. Visual cortex excitability might be linked to higher disability.