Jaume Roquer

Intracerebral hemorrhage (ICH) is a complex and heterogeneous disease, and there is no effective treatment. Spontaneous ICH represents the final manifestation of different types of cerebral small vessel disease, usually categorized as: lobar (mostly related to cerebral amyloid angiopathy) and nonlobar (hypertension-related vasculopathy) ICH. Accurate phenotyping aims to reflect these biological differences in the underlying mechanisms and has been demonstrated to be crucial to the success of genetic studies in this field. This review summarizes how current knowledge on genetics and epigenetics of this devastating stroke subtype are contributing to improve the understanding of ICH pathophysiology and their potential role in developing therapeutic strategies.

Few studies have assessed the impact of the COVID-19 pandemic on non-COVID diseases and healthcare quality. We aimed to evaluate changes in rates of hospitalisations, complications, in-hospital mortality, and readmissions among patients with non-COVID diseases during a one-year period after the pandemic onset. From March 2018 to February 2021 a retrospective observational study of hospital admissions in a university hospital in Spain was conducted. Non-COVID hospitalisations admitted through the emergency department were compared between the pre-COVID period (n = 28,622) and the COVID period (n = 11,904). We assessed rate ratios (RaR), comparing the weekly number of admissions and risk ratios (RR) to examine rates of complications, in-hospital mortality, readmissions, and severity. Statistical significance was set at p < 0.05. The weekly admission rate dropped by 20.8% during the complete lockdown. We observed significant reductions in admissions related to diseases of the respir...

Background: Stroke has a great impact in functional status of patients, although there are substantial interindividual differences in recovery capacity. Apart from stroke severity, age is considered an important predictor of outcome after stroke, but aging is not only due to chronological age. There are age-related DNA-methylation changes in multiple CpG sites across the genome that can be used to estimate the biological age (b-Age), and we seek to analyze the impact of this b-Age in recovery after an ischemic stroke. Methods: We include 600 individuals with acute ischemic stroke assessed in Hospital del Mar (Barcelona). Demographic and clinical data such as chronological age (c-Age), vascular risk factors, NIHSS at admission, recanalization treatment (rtPA or endovascular treatment), previous modified Rankin scale (p-mRS) and 3 months post stroke functional status (3-mRS) were registered. Biological age (b-Age) was estimated with Hannumm algorithm, based on DNA methylation in 71 Cp...

Although, by itself, atrial fibrillation is associated with an impairment of quality of life antithrombotic therapy may play a role. To evaluate the satisfaction with anticoagulant treatment in patients with nonvalvular atrial fibrillation who attended internal medicine departments in Spain. Patients from two different cross-sectional studies were combined. To measure the satisfaction with anticoagulant treatment, the Anti-Clot-Treatment Scale (ACTS) questionnaire was completed by every patient. A multivariate analysis was performed to determine the variables associated with satisfaction of patients receiving oral anticoagulants. A total of 1,309 patients (mean age 78.5±8.4 years; 49.3% men; CHADSVASC 4.9±1.5; HAS-BLED 2.0±0.9) were included in the study, of whom 902 (68.9%) were taking vitamin K antagonists (VKA) and 407 (31.1%) direct oral anticoagulants (DOACs). Overall, satisfaction with oral anticoagulation was high (ACTS Burdens scale 49.69±9.45; ACTS Benefits scale 11.35±2.61...

The aim of the study was to confirm the safety and effectiveness of using intravenous thrombolysis (IVT) with individuals aged 80 and older in routine practice in different hospital settings. Observasional registry. Prospective multicenter population-based registry of acute stroke patients treated with reperfusion therapies in Catalonia, Spain (Sistema Online d'Informació de l'Ictus Agut). Individuals treated only with IVT (N = 3,231; 1,189 (36.8%) aged ≥80). Symptomatic intracranial hemorrhage, mortality, and favorable outcome (modified Rankin Scale (mRS) score = 0-2) at 3 months were evaluated according to hospital characteristics. Treating hospitals were classified in three categories: comprehensive stroke centers (CSCs), primary stroke centers (PSCs), and community hospitals operating a telestroke system (TS). First individuals aged 80 and older were compared with those younger than 80, and then participants aged 80 and older were focused on. Participants aged 80 and older had significantly higher baseline National Institute of Health Stroke Scale (NIHSS) scores, longer onset to treatment times, and worse outcomes than younger participants. For participants aged 80 and older, 90-day mortality was 23.2%, with 38.7% having favorable outcomes at 3 months. Symptomatic intracranial hemorrhage (SICH; Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy definition) was observed in 4.7% of subjects. None of the risk factors differed significantly between participants treated in different types of hospitals. Basal stroke severity measured according to NIHSS score was not significantly different either. The three different types of hospitals achieved similar outcomes, although the TS and PSC hospitals had significantly higher proportions of SICH (6.3% and 6.3%, respectively) than the CSC (3.2%). Older adults with acute stroke treated with IVT had similar outcomes regardless of hospital characteristics.

Objective:To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke.Methods:We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.Results:After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01–1.07]), nullifying c-age. Stepwise regression kept b-age, basal NI...

Objective:To analyze the effect of previous antiplatelet (AP) and vitamin K antagonist (VKA) treatments on outcome in patients with primary intracerebral hemorrhage (ICH).Methods:In this prospective observational study, we analyzed 529 patients according to antithrombotic pretreatment: none, AP, or VKA. Very-early (24-hour) death, 3-month mortality, and functional independence were analyzed.Results:Of 236 (44.6%) pretreated patients, 147 (27.8%) patients were taking AP and 89 (16.8%) VKA. Very-early death was observed in 13.4% and was increased in pretreated patients: 19.0% for AP and 27.0% for VKA treatment, compared to 6.5% in non-pretreated patients, p < 0.0001. Three-month mortality was 40.8% overall (49.7% for AP pretreated, 58.4% for VKA pretreated, and 31.1% for non-pretreated patients, p < 0.0001). The adjusted odds of very-early and 3-month mortality were 2.55 (p = 0.004) and 1.56 (p = 0.046) for AP-pretreated patients and 4.24 (p < 0.0001) and 2.34 (p = 0.01) for ...

The main structures involved in the control of vertical gaze, both saccades, smooth pursuit and oculovestibular reflexes, are the rostral interstitial nucleus of medial longitudinal fasciculus, posterior commissure, interstitial nucleus of Cajal, oculomotor complex and trochlear nerve nucleus. Despite knowing the functions of these nuclei, and their main interconnections, afferents and efferents, there is no definitive and contrasted model of vertical gaze control in humans. Through the description of three cases, and as described in scientific literature, our aim is to review the models described to date. The control of vertical saccades generates in the rostral interstitial nucleus of medial longitudinal fasciculus, projecting to the pertinent oculomotor nuclei ipsilaterally for the inferior gaze, and bilaterally for the superior gaze. The double cross-innervation of the nuclei responsible for superior gaze, implies that unilateral lesions predominantly affect the inferior gaze.

1. Med Clin (Barc). 2005 Nov 26;125(19):759. [Multiple sclerosis after treatment with anti-TNF-alpha antibodies]. [Article in Spanish]. Munteis-Olivas E, Pérez-García C, Roquer-González J, Maymo-Guarch J. PMID: 16324476 [PubMed - indexed for MEDLINE]. ...

We report 3 cases of dorsal ischemic myelopathy indicative of aneurysm of the abdominal aorta. In 2 cases the aneurysm was dissecting and in all patients medullary symptoms were preceded by sudden lumbar or abdominal pain. Neurological symptoms were slightly different in each case. One patient experienced 3 episodes of acute paraparesis and rapid regression evoking transitory medullary ischemic accidents (intermittent medullary claudication). Another patient suffered progressive asymmetric paraparesis which first stabilized and later improved partially after surgical treatment of the aneurysm. The third suffered acute paraplegia related to irreversible ischemia of the anterior 2/3 of the medulla. The great variety of clinical manifestations of spinal cord ischemia related to aneurysms of the descending aorta can be explained by the topography of the aneurysm, pecularities of medullary vascularization and, especially, by the diversity of etiopathogenetic mechanisms that give rise to ...

A case of multiple sclerosis and Hashimoto's thyroiditis confirmed by cytology is reported. The association of multiple sclerosis with other autoimmune diseases is infrequent but supports the immune hypothesis of the pathogenesis of multiple sclerosis. The authors suggest the inclusion of immunological tests in the screening of all patients diagnosed as having multiple sclerosis.

To the Editor: Compressive neuropathy is the most frequent complication of the peripheral nervous system after heroin consumption. Plexopathies, radiculopathies, and neuropathies without a traumatic cause are also described but are very uncommon and their prognoses are uncertain. We present a case of an acute atraumatic pluriradiculopathy after heroin use. A 31-year-old man with regular drug abuse was admitted in the emergency department after suffering an abruptly right upper extremity weakness 2 hours after injecting intravenous heroin on his limb. The patient did not complain about pain or any sensory disorder and did not refer loss of consciousness after consumption, history of trauma, or other situations that could cause compression of the extremity. Physical examination revealed an areflectic flaccid paralysis proximally in the right upper extremity, without sensory disturbance. Creatine kinase (CK) levels were of 18,000 U/L, with a decrease to 8600 U/L a few hours later. Human immunodeficiency virus and hepatitis B virus serologies were negative, being positive for hepatitis C virus. The motor deficit still was remaining 2 weeks later, and a slight atrophy of the right infraspinatus muscle was already visible. A neurophysiological study was performed 23 days after the onset of symptoms showing fibrillation potentials and positive sharp waves in the biceps, extensor digitorum, extensor carpi radialis, palmaris longus, deltoid, and supraspinatus muscles with a neurogenic recruitment that was very poor in supraspinatus and deltoid muscles. Sensory nerve conduction studies were normal. This suggested a preganglionic involvement, affecting C5, C6, and C7 nerve roots. A magnetic resonance image of the brachial plexus and cervical spinal cord was performed, without compressive pathology at any point of the nerve pathway. Symptoms persisted for 1 month, and then progressively improved until complete recovery after 2 months. Heroin-related neuropathies without a traumatic cause are very uncommon. The clinical picture is acute, asymmetric, predominantly proximal, painful, and associated with a sensory disorder. There is no specific treatment, and the functional prognosis is variable. Symptoms appear 3–36 hours after consumption. There have been cases reported after sniffed heroin, and in cases of intravenous abuse, the affected side does not always coincide with the side of the puncture. There are very few reports described, being the largest series of 6 patients, 4 with a plexus involvement (2 brachial and 2 lumbosacral) and 2 with an acute sensorimotor axonal neuropathy. All but one of these patients had elevated levels of creatine kinase. The prognosis was variable, and 2 patients underwent nerve biopsy showing axonal loss with Wallerian degeneration. It has been proposed that there is a direct toxic effect either of the drug itself or its adulterants, as the mechanism of neurotoxicity or rhabdomyolysis. Proximal regions of peripheral nerves lack perineurium, therefore nerve fibers are in contact with blood vessels in the absence of the blood–neural barrier. This anatomical consideration favors the liability at these locations of the peripheral nervous system (ie, roots) to certain immunologic (eg, Guillain–Barré syndrome) or toxic (eg, cisplatin) phenomena. In summary, we describe a pluriradicular affectation after heroin consumption, which is very infrequent and poorly described. The reversibility of the deficit demonstrates the toxic, and sometimes transient, effect of the heroin and its adulterants in the peripheral nervous system. The peculiarity of our case is the absence of pain and sensory disorder, and the excellent and early recovery. This may suggest that in cases of heroin toxicity, the existence of a preganglionic disorder may be associated with a better prognosis.

Background Since atherogenesis is related to oxidative stress, our objective was to study the association of oxidative stress markers with the vascular recurrence in non-cardioembolic stroke. Methods Atherosclerotic and oxidative stress markers were evaluated on admission, in 477 patients suffering from a first non-cardioembolic stroke. Patients were followed at 6 and 12 months after inclusion, recording cardiovascular events. As markers of endothelial oxidative stress we used oxidized LDL, Cu/Zn superoxide dismutase and 8-OH deoxiguanosine. 136 patients were being treated with statins at the moment of serum samples acquisition. Results Patients who suffered vascular recurrence or vascular-origin death had higher levels of 8-OHDG (40.06±24.70vs33.11±15.18;p=0.003). We also found associations between vascular recurrence or vascular origin death and Cu/ZnSOD (OR,1.02; 95%CI,1.00-1.03;p=0.0001) and 8-OHDG (OR,1.12;95%CI,1.08-1.16;p<0.0001) in a subgroup of 333 patients that were not...

OBJECTIVE We present an update of the Spanish Society of Neurology's recommendations for prevention of both primary and secondary stroke in patients with dyslipidaemia. DEVELOPMENT We performed a systematic review to evaluate the main aspects of the management of dyslipidaemias in primary and secondary stroke prevention and establish a series of recommendations. CONCLUSIONS In primary prevention, the patient's vascular risk should be determined in order to define target values for low-density lipoprotein cholesterol. In secondary prevention after an atherothrombotic stroke, a target value <55mg/dL is recommended; in non-atherothombotic ischaemic strokes, given the unclear relationship with dyslipidaemia, target value should be established according to the vascular risk group of each patient. In both primary and secondary prevention, statins are the drugs of first choice, and ezetimibe and/or PCSK9 inhibitors may be added in patients not achieving the target value.

Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-anal...

Background:CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the receptor, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, as executive function is characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further.Methods:Agenome-wide transcriptome study(four casespaired with three healthysiblings)was carried out,in addition toa qRT-PCR for validation purposes(ten new cases and eight new controls).Neuropsychological tests were performedto evaluateverbal memory, attention and information processing speed (IPS), motor speed and dexterity, executive function and visuoconstructional skills. The Single-nuclei Brain RNA-seq expression browser (SNBREB) and the GTExPortalwere used to study brain expressionof the significant mRNAs found.Results: The two most significant differentially expressed mRNAs (...

Hematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH. We conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with <5×10 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, resp...

To describe the design and rationale for the genetic analysis of acute and chronic cerebrovascular neuroimaging phenotypes detected on clinical MRI in patients with acute ischemic stroke (AIS) within the scope of the MRI-GENetics Interface Exploration (MRI-GENIE) study. MRI-GENIE capitalizes on the existing infrastructure of the Stroke Genetics Network (SiGN). In total, 12 international SiGN sites contributed MRIs of 3,301 patients with AIS. Detailed clinical phenotyping with the web-based Causative Classification of Stroke (CCS) system and genome-wide genotyping data were available for all participants. Neuroimaging analyses include the manual and automated assessments of established MRI markers. A high-throughput MRI analysis pipeline for the automated assessment of cerebrovascular lesions on clinical scans will be developed in a subset of scans for both acute and chronic lesions, validated against gold standard, and applied to all available scans. The extracted neuroimaging pheno...

To investigate whether the correlation of age and sex with the risk of recurrence and death seen in patients with previous ischemic stroke is also evident in patients with embolic stroke of undetermined source (ESUS). We pooled datasets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. We performed Cox regression and Kaplan-Meier product limit analyses to investigate whether age (<60, 60-80, >80 years) and sex were independently associated with the risk for ischemic stroke/TIA recurrence or death. Ischemic stroke/TIA recurrences and deaths per 100 patient-years were 2.46 and 1.01 in patients <60 years old, 5.76 and 5.23 in patients 60 to 80 years old, 7.88 and 11.58 in those >80 years old, 3.53 and 3.48 in women, and 4.49 and 3.98 in men, respectively. Female sex was not associated with increased risk for recurrent ischemic stroke/TIA (hazard ratio [HR] 1.15, 95% confidence interval [CI...

Vascular recurrence occurs in 11% of patients during the first year after ischemic stroke (IS) or transient ischemic attack. Clinical scores do not predict the whole vascular recurrence risk; therefore, we aimed to find genetic variants associated with recurrence that might improve the clinical predictive models in IS. We analyzed 256 polymorphisms from 115 candidate genes in 3 patient cohorts comprising 4482 IS or transient ischemic attack patients. The discovery cohort was prospectively recruited and included 1494 patients, 6.2% of them developed a new IS during the first year of follow-up. Replication analysis was performed in 2988 patients using SNPlex or HumanOmni1-Quad technology. We generated a predictive model using Cox regression (GRECOS score [Genotyping Reurrence Risk of Stroke]) and generated risk groups using a classification tree method. The analyses revealed that rs1800801 in the MGP gene (hazard ratio, 1.33; P=9×10(-)(03)), a gene related to artery calcification, was...

Microvascular endothelial cells at the blood–brain barrier exhibit a protective phenotype, which is highly induced by biochemical and biomechanical stimuli. Amongst them, shear stress enhances junctional tightness and limits transport at capillary-like levels. Abnormal flow patterns can reduce functional features of macrovascular endothelium. We now examine if this is true in brain microvascular endothelial cells. We suggest in this paper a complex response of endothelial cells to aberrant forces under different flow domains. Human brain microvascular endothelial cells were exposed to physiological or abnormal flow patterns. Physiologic shear (10–20 dyn/cm2) upregulates expression of tight junction markers Zona Occludens 1 (1.7-fold) and Claudin-5 (more than 2-fold). High shear stress (40 dyn/cm2) and/or pulsatility decreased their expression to basal levels and altered junctional morphology. We exposed cells to pathological shear stress patterns followed by capillary-like condition...

Objective In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods We performed two candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1149 ICH cases and 1238 controls from 3 studies, followed by replication in 1625 cases and 1845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk. Results Twelve variants within CETP demonstrated nominal association with ICH, with ...

Remote parenchymal hemorrhage (rPH) after intravenous thrombolysis with recombinant tissue-type plasminogen activator may be associated with cerebral amyloid angiopathy, although supportive data are limited. We aimed to investigate risk factors of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator. This is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator and were included in a multicenter prospective registry. rPH was defined as any extraischemic hemorrhage detected in the follow-up computed tomography. We collected demographic, clinical, laboratory, radiological, and outcome variables. In the subset of patients who underwent a magnetic resonance imaging examination, we evaluated the distribution and burden of cerebral microbleeds, cortical superficial siderosis, leukoaraiosis, and recent silent ischemia in regions anatomically unrelated to the ...

Background and Purpose— Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods— We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma v...