Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

Sex-Related Differences in Clinical Features, Neuroimaging, and Long-Term Prognosis After Transient Ischemic Attack.

BACKGROUND AND PURPOSE: Differences in sex in the incidence, presentation, and outcome of events after ischemic stroke have been studied in depth. In contrast, only limited data are available after transient ischemic attack (TIA). We aim to assess sex-related differences in the presentation, cause, neuroimaging features, and predictors of long-term prognosis in patients with TIA. METHODS: We carried out a prospective cohort study of consecutive patients with TIA from January 2006 to June 2010. Nondefinitive TIA events were defined by the presence of isolated atypical symptoms. The risk of stroke recurrence (SR) and composite of major vascular events were stratified by sex after a median follow-up time of 6.5 (interquartile range, 5.0-9.6) years. RESULTS: Among the 723 patients studied, 302 (41.8%) were female and 79 (10.9%) suffered a nondefinitive TIA event. Vascular territory diffusion-weighted imaging patterns (odds ratio, 1.61 [95% CI, 0.94-2.77]), and nondefinitive TIA events (odds ratio, 2.66 [95% CI, 1.55-4.59]) were associated with women, whereas active smoking (odds ratio, 0.30 [95% CI, 0.15-0.58]) and large artery atherosclerosis causes (odds ratio, 0.50 [95% CI, 0.29-0.83]) were related to men. The risk of SR was similar in both sexes (12.6% [95% CI, 8.9-16.3] for women versus 14.3% [95% CI, 11.0-17.6] for men). In contrast, the risk of major vascular events was significantly lower in women than in men (17.5% [95% CI, 13.2-21.8] versus 23.8% [95% CI, 19.7-27.9]). In both sexes, after adjusting for age, large artery atherosclerosis was associated with SR (hazard ratio, 3.22 [95% CI, 1.42-7.24] and hazard ratio, 2.00 [95% CI, 1.14-3.51]). In a Kaplan-Meier analysis, females with positive diffusion-weighted imaging (P=0.014) and definitive TIA (log-rank test P=0.022) had a significantly higher risk of SR. CONCLUSIONS: Despite similar risks of SR, there were sex-related differences in baseline characteristics, presenting symptoms, patterns of acute ischemic lesions, cause, and outcomes. These findings encourage further research into optimal preventive strategies that take into account these differences.

Risk-benefit assessment of treatment of epileptic women of childbearing age with valproic acid.

AIM: Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude. METHODS: We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient's willingness to their change treatment were analysed. RESULTS: A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA. CONCLUSIONS: Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.

MRI predicts intracranial hemorrhage in patients who receive long-term oral anticoagulation.

OBJECTIVE: We tested the hypothesis that the risk of intracranial hemorrhage (ICH) in patients with cardioembolic ischemic stroke who are treated with oral anticoagulants (OAs) can be predicted by evaluating surrogate markers of hemorrhagic-prone cerebral angiopathies using a baseline MRI. METHODS: Patients were participants in a multicenter and prospective observational study. They were older than 64 years, had a recent cardioembolic ischemic stroke, and were new users of OAs. They underwent a baseline MRI analysis to evaluate microbleeds, white matter hyperintensities, and cortical superficial siderosis. We collected demographic variables, clinical characteristics, risk scores, and therapeutic data. The primary endpoint was ICH that occurred during follow-up. We performed bivariate and multivariate Cox regression analyses. RESULTS: We recruited 937 patients (aged 77.6 ± 6.5 years; 47.9% were men). Microbleeds were detected in 207 patients (22.5%), moderate/severe white matter hyperintensities in 419 (45.1%), and superficial siderosis in 28 patients (3%). After a mean follow-up of 23.1 ± 6.8 months, 18 patients (1.9%) experienced an ICH. In multivariable analysis, microbleeds (hazard ratio 2.7, 95% confidence interval [CI] 1.1-7, p = 0.034) and moderate/severe white matter hyperintensities (hazard ratio 5.7, 95% CI 1.6-20, p = 0.006) were associated with ICH (C index 0.76, 95% CI 0.66-0.85). Rate of ICH was highest in patients with both microbleed and moderate/severe WMH (3.76 per 100 patient-years, 95% CI 1.62-7.4). CONCLUSION: Patients taking OAs who have advanced cerebral small vessel disease, evidenced by microbleeds and moderate to severe white matter hyperintensities, had an increased risk of ICH. Our results should help to determine the risk of prescribing OA for a patient with cardioembolic stroke. CLINICALTRIALSGOV IDENTIFIER: NCT02238470.

Correction to: Type 2 diabetes-associated carotid plaque burden is increased in patients with retinopathy compared to those without retinopathy.

The author found errors in Table 1 after publication of the original article [1].

Statins do not increase Markers of Cerebral Angiopathies in patients with Cardioembolic Stroke.

We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter study of patients naive for oral anticoagulants, who had an acute cardioembolic stroke. MRI was performed at admission to evaluate microbleeds, leukoaraiosis and superficial siderosis. We collected data on the specific statin compound, the dose and the statin intensity. We performed bivariate analyses and a logistic regression to investigate variables associated with microbleeds. We studied 470 patients (age 77.5 ± 6.4 years, 43.7% were men), and 193 (41.1%) of them received prior treatment with a statin. Microbleeds were detected in 140 (29.8%), leukoaraiosis in 388 (82.5%) and superficial siderosis in 20 (4.3%) patients. The presence of microbleeds, leukoaraiosis or superficial siderosis was not related to pre-treatment with statins. Microbleeds were more frequent in patients with prior intracerebral hemorrhage (OR 9.7, 95% CI 1.06-90.9) and in those pre-treated antiplatelets (OR 1.66, 95% CI 1.09-2.53). Prior treatment with statins was not associated with markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore, previous statin treatment should not influence the decision to initiate or withhold oral anticoagulation if these neuroimaging markers are detected.

Influence of Hospital Type on Outcomes of Individuals Aged 80 and Older with Stroke Treated Using Intravenous Thrombolysis.

OBJECTIVES: 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. DESIGN: Observasional registry. SETTING: Prospective multicenter population-based registry of acute stroke patients treated with reperfusion therapies in Catalonia, Spain (Sistema Online d'Informació de l'Ictus Agut). PARTICIPANTS: Individuals treated only with IVT (N = 3,231; 1,189 (36.8%) aged ≥80). MEASUREMENTS: 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. RESULTS: 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%). CONCLUSION: Older adults with acute stroke treated with IVT had similar outcomes regardless of hospital characteristics.

Metabolomics Predicts Neuroimaging Characteristics of Transient Ischemic Attack Patients.

BACKGROUND: Neuroimaging is essential for the diagnosis and prognosis of transient ischemic attack (TIA). The discovery of a plasmatic biomarker related to neuroimaging findings is of enormous interest because, despite its relevance, magnetic resonance diffusion weighted imaging (DWI) is not always available in all hospitals that attend to TIA patients. METHODS: Metabolomic analyses were performed by liquid chromatography coupled to mass spectrometry in order to establish the metabolomic patterns of positive DWI, DWI patterns and acute ischemic lesion volumes. We used these methods with an initial TIA cohort of 129 patients and validated them with a 2nd independent cohort of 152 patients. FINDINGS: Positive DWI was observed in 115 (40.9%) subjects and scattered pearls in one arterial territory was the most frequent lesion pattern (35.7%). The median acute ischemic lesion volume was 0.33 (0.15-1.90)cm3. We detected a specific metabolomic profile common to both cohorts for positive DWI (11 molecules including creatinine, threoninyl-threonine, N-acetyl-glucosamine, lyso phosphatidic acid and cholesterol-related molecules) and ischemic lesion volume (10 molecules including lysophosphatidylcholine, hypoxanthine/threonate, and leucines). Moreover lysophospholipids and creatinine clearly differed the subcortical DWI pattern from other patterns. INTERPRETATION: There are specific metabolomic profiles associated with representative neuroimaging features in TIA patients. Our findings could allow the development of serum biomarkers related to acute ischemic lesions and specific acute ischemic patterns.

Increased Burden of Cerebral Small Vessel Disease in Patients With Type 2 Diabetes and Retinopathy.

OBJECTIVE: We sought to examine the presence and severity of brain small vessel disease (SVD) in patients with type 2 diabetes and diabetic retinopathy (DR) compared with those without DR. RESEARCH DESIGN AND METHODS: We evaluated 312 patients with type 2 diabetes without previous cardiovascular disease (men 51%; mean age 57 years; age range 40-75 years); 153 patients (49%) had DR. MRI was performed to evaluate the presence and severity (age-related white matter changes scale) of white matter lesions (WMLs) and lacunes, and transcranial Doppler ultrasound was used to measure the Gosling pulsatility index (PI) of the middle cerebral artery (MCA). RESULTS: The prevalence of lesions of cerebral SVD (WML and/or lacunes) was higher in patients with DR (40.2% vs. 30.1% without DR, P = 0.04). Age (P < 0.01) and systolic blood pressure (P = 0.02) were associated with the presence of SVD. The severity of SVD was associated with age and the presence of DR (P < 0.01 and P = 0.01, respectively). Patients with DR showed a higher MCA PI compared with those without DR (P < 0.01). Age, systolic and diastolic blood pressure, and retinopathy and its severity were associated with an increased MCA PI (P < 0.01 for all variables). A positive correlation was found between MCA PI values and the presence and severity of SVD (P < 0.01 for both variables). CONCLUSIONS: Patients with type 2 diabetes who have DR have an increased burden of cerebral SVD compared with those without DR. Our findings suggest that the brain is a target organ for microangiopathy, similar to other classic target organs, like the retina.

Type 2 diabetes-associated carotid plaque burden is increased in patients with retinopathy compared to those without retinopathy.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality among subjects with type 2 diabetes (T2D), and diabetic retinopathy (DR) has been associated with an increased risk for CVD. The present study was designed to test the concept that T2D patients with DR, but without previous cardiovascular (CV) events and with normal renal function, have an increased atherosclerotic burden compared with patients without DR. METHODS: A cross-sectional study was performed using patients with normal renal function (estimated glomerular filtration rate (eGFR) >60 ml/min) and without previous CV events. A total of 312 patients (men, 51%; mean age, 57 yrs; age range 40-75 yrs) were included in the study; 153 (49%) of the patients had DR. B-mode carotid ultrasound imaging was performed for all of the study subjects to measure the carotid intima-media thickness (cIMT) and carotid plaques in the common carotid artery (CCA), bifurcation and internal carotid artery (ICA). RESULTS: The percentage of carotid plaques in T2D patients with DR was higher than in T2D patients without DR (68% vs. 52.2%, p = 0.0045), and patients with DR had a higher prevalence of ≥2 carotid plaques (44.4% vs. 21.4%; p < 0.0001). No differences were observed in the cIMT measured at different carotid regions between the patients with or without DR. Using multivariate logistic regression (adjustment for major risk factors for atherosclerosis), DR was independently associated with mean-internal cIMT (p = 0.0176), with the presence of carotid plaques (p = 0.0366) and with carotid plaque burden (≥2 plaques; p < 0.0001). CONCLUSIONS: The present study shows that DR in T2D patients without CVD and with normal renal function is associated with a higher atherosclerotic burden (presence and number of plaques) in the carotid arteries. These patients may be at a higher risk for future CV events; therefore, an ultrasound examination of the carotid arteries should be considered in patients with DR for more careful and individualised CV assessment and follow-up.

Metabolomics predicts stroke recurrence after transient ischemic attack.

OBJECTIVE: To discover, by using metabolomics, novel candidate biomarkers for stroke recurrence (SR) with a higher prediction power than present ones. METHODS: Metabolomic analysis was performed by liquid chromatography coupled to mass spectrometry in plasma samples from an initial cohort of 131 TIA patients recruited <24 hours after the onset of symptoms. Pattern analysis and metabolomic profiling, performed by multivariate statistics, disclosed specific SR and large-artery atherosclerosis (LAA) biomarkers. The use of these methods in an independent cohort (162 subjects) confirmed the results obtained in the first cohort. RESULTS: Metabolomics analyses could predict SR using pattern recognition methods. Low concentrations of a specific lysophosphatidylcholine (LysoPC[16:0]) were significantly associated with SR. Moreover, LysoPC(20:4) also arose as a potential SR biomarker, increasing the prediction power of age, blood pressure, clinical features, duration of symptoms, and diabetes scale (ABCD2) and LAA. Individuals who present early (<3 months) recurrence have a specific metabolomic pattern, differing from non-SR and late SR subjects. Finally, a potential LAA biomarker, LysoPC(22:6), was also described. CONCLUSIONS: The use of metabolomics in SR biomarker research improves the predictive power of conventional predictors such as ABCD2 and LAA. Moreover, pattern recognition methods allow us to discriminate not only SR patients but also early and late SR cases.

Prognostic value of plasma ß-amyloid levels in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: It has been proposed that the deposition of the ß-amyloid peptide (Aß) in the brain parenchyma and brain blood vessels has deleterious effects. We tested the hypothesis that the levels of plasma Aß are related to the outcome in patients with intracerebral hemorrhage. METHODS: In a multicenter study, we prospectively included patients with spontaneous intracerebral hemorrhage within the first 24 hours after onset. At admission, we measured plasma Aß40 and Aß42 levels using ELISA techniques. Also, we recorded age, sex, vascular risk factors, National Institutes of Health Stroke Scale score, presence of intraventricular hemorrhage, localization, cause, and volume of the hematoma. We obtained the modified Rankin scale and defined a unfavorable outcome as modified Rankin scale >2 at 3 months. Bivariate and multivariate regression analyses were performed. RESULTS: We studied 160 patients (mean age, 73.8±11.3 years; 59.4% of them were men). A favorable outcome was observed in 64 (40%) of the patients. In the bivariate analyses, unfavorable outcome was associated with high age, female sex, diabetes mellitus, presence of intraventricular hemorrhage, high blood glucose, high National Institutes of Health Stroke Scale score, high volume, and high plasma levels of Aß42 and Aß40. The multivariate analysis showed that increased age (odds ratio, 1.07; 95% confidence interval, 1.035-1.21; P<0.0001), high admission National Institutes of Health Stroke Scale score (odds ratio, 1.29, 95% confidence interval, 1.17-1.42; P<0.0001), presence of diabetes mellitus (odds ratio, 4.15; 95% confidence interval, 1.21-14.1; P=0.02), and Aß42 levels >9.7 pg/mL (odds ratio, 4.11; 95% confidence interval, 1.65-10.1; P=0.02) were independently associated with an increased likelihood of an unfavorable outcome. CONCLUSIONS: High levels of plasma Aß42 in patients with acute intracerebral hemorrhage are associated with a poor functional prognosis.

Microbleed burden and hematoma expansion in acute intracerebral hemorrhage.

BACKGROUND: Intracranial amyloid and hypertensive angiopathy have been related to impaired blood vessel function and the etiology of intracerebral hemorrhage (ICH). Microbleeds (MBs) are surrogate radiological markers that are associated with these underlying angiopathies. We assessed the hypothesis that MBs are associated with hematoma expansion (HE) in patients with hyperacute ICH. METHODS: We studied patients with spontaneous supratentorial ICH within the first 6 h after onset. HE was defined as an increase≥33% in the volume of hematoma on the follow-up CT in comparison with the admission CT. The volume was calculated using the ABC/2 formula. MBs were detected by specific magnetic resonance sequences (gradient-echo). The presence, number and distribution of MBs were analyzed. RESULTS: Our study included 44 patients. Their mean age was 68.9±11.1 years, and 70.5% of them were men. HE was observed in 14 of the patients (31.8%). HE was more prevalent in patients with more than 10 MBs compared with patients with 1-10 MBs (60 vs 12.5%; p=0.03). CONCLUSION: A high burden of MBs is associated with an increased risk of HE in patients with ICH. This is probably a marker of a more severe underlying angiopathy.

Contribution of high-b-value diffusion-weighted imaging in determination of brain ischemia in transient ischemic attack patients.

BACKGROUND AND PURPOSE: High-b-value diffusion-weighted imaging (DWI) (b = 2,000 and b = 3,000 second/mm(2)) offers theoretical advantages over DWI examinations at b = 1,000 second/mm(2) for detection of acute ischemic stroke. The purpose of this study was to determine whether high-b-value DWI are better than b = 1,000 images in TIA patients. METHODS: We compared DWI obtained with 3 different b-values (1,000, 2,000, and 3,000 second/mm(2)) and fluid-attenuated inversion recovery (FLAIR) sequences in 75 consecutive TIA patients. DWI examinations were performed within 3.25 ± 1.5 days after the onset of symptoms. Presence of ischemic lesion, volume, lesion conspicuity, and lesion distinction were determined. RESULTS: A total of 40 (53.3%) patients revealed ischemic acute lesions with b = 1,000 while 34 (45.3%) were positive on FLAIR. High-b-value DWI did not increase the sensitivity for the detection of acute brain ischemia. The median lesion value increased as the b-value did: .17 mL (interquartile range [IQR] .12-.78) at b = 1,000; .19 mL (IQR .13-1.00) at b = 2,000; .29 mL (IQR .14-1.02) at b = 3,000; and .12 mL (IQR .04-.62 mL) on FLAIR (P < .001). As b-value increased, we observed hyperintensities in white matter that could erroneously be considered as acute ischemia. CONCLUSION: High-b-value DWI did not improve the conspicuity and distinction of the ischemic lesions.

Higher carotid intima media thickness predicts extracranial vascular events and not stroke recurrence among transient ischemic attack patients.

BACKGROUND: Increased common carotid artery intima-media thickness has been associated with an increased risk of vascular ischemic events. We investigated the relationship between common carotid artery intima-media thickness and extracranial vascular events (coronary heart disease and peripheral arterial disease) or stroke recurrence in a cohort of transient ischemic attack patients from the REGITELL registry. METHODS: High-resolution B-mode ultrasonographic measurements of the common carotid artery intima-media thickness were performed in a series of 283 consecutive transient ischemic attack patients. Clinical, neuroimaging, ultrasonographic, and etiological data were collected. Patients were followed prospectively for six-months or more. Extracranial vascular events and stroke recurrence were recorded. RESULTS: Fifteen extracranial vascular events (12 coronary heart disease and three peripheral arterial disease) and 29 recurrent strokes occurred during a median follow-up period of 12.3 months. Patients who experienced extracranial vascular events had significantly (P < 0.001) higher common carotid artery intima-media thickness values (1.087 (standard deviation 0.189) mm) than subjects who were free of extracranial vascular events (0.887 (standard deviation 0.195) mm). Nevertheless, common carotid artery intima-media thickness was not found to correlate with stroke recurrence. Cox proportional hazards multivariate analyses identified hypercholesterolemia (hazard ratio 6.87, 95% confidence interval: 1.93-24.39, P = 0.003) and common carotid artery intima-media thickness > 0.939 mm (hazard ratio 8.90, 95% confidence interval: 2.00-39.49, P = 0.004) as independent predictors of extracranial vascular events after transient ischemic attack. Almost one of every three patients with hypercholesterolemia and high common carotid artery intima-media thickness had extracranial vascular events. CONCLUSIONS: An elevated common carotid artery intima-media thickness value was associated with a higher long-term risk of extracranial vascular events but no with stroke recurrence. Hypercholesterolemia was the main risk factor for extracranial vascular events. The combination of hypercholesterolemia and common carotid artery intima-media thickness > 0.939 mm justify the establishment of aggressive therapies and the study of subclinical coronary heart disease and peripheral arterial disease.

Biaryl analogues of teriflunomide as potent DHODH inhibitors.

The structure-activity relationships of a novel series of biaryl dihydroorotate dehydrogenase (DHODH) inhibitors related to teriflunomide are disclosed. These biaryl derivatives were the result of structure-based design and proved to be potent DHODH inhibitors which in addition showed good antiproliferative activities on peripheral blood mononuclear cells and good efficacies in vivo in the rat adjuvant-induced-arthritis model.

[Validation of the ABCDI and ABCD2I scales in the registry of patients with transient ischemic attacks from Lleida (REGITELL) Spain]. / Validación de las escalas ABCDI y ABCD2I en el registro de pacientes con ataque isquémico transitorio de Lleida (REGITELL).

BACKGROUND AND OBJECTIVES: A new radiological-clinical score (ABCDI) has been recently described to predict the risk of stroke recurrence after a transient ischemic attack (TIA). We validated this score in a cohort of patients with TIA (REGITELL). PATIENTS AND METHODS: We studied 310 consecutive patients with TIA. Clinical scales (ABCD and ABCD2) and radiological-clinical scales (ABCDI and ABCD2I) were quantified. Radiological clinical scales were calculated by adding one point for the presence of ischemic brain injury in CT scan to its eponymous clinical score. We established its relationship with the risk of recurrence at 7 and 90 days, and the presence of an atheromatous etiology (AE). RESULTS: During the first week of follow-up, 18 (5.8%) patients suffered a recurrence, whereas 24 (7.7%) had a recurrence at 90 days. The multivariate study (Cox regression) identified the recurrence of episodes (hazard ratio [HR] 2.92, 95% CI 1.11 to 7.64, p=0.029) and AE (HR 3.13 95% CI: 1.17 to 8.36, p=0.023) as independent predictors of new stroke at 7 days and only AE for stroke at three months (RR 3.33, 95% CI: 1,42-7,77, p=0.006). The predictors (logistic regression) of AE were recurrence of episodes (odds ratio [OR] 3.12, 95% CI 1.58-6.14, p=0.001) and presence of ischemic lesions on CT scan (OR 2.69, 1.38-5.28, p=0.004). CONCLUSIONS: The ABCDI and ABCD2I scales are not useful in our population. The risk of recurrence after a TIA cannot only be established by clinical scores or CT scan findings.

[Diagnostic lessons of recurrence pattern after transient ischemic attacks]. / Implicaciones diagnósticas del perfil de recurrencia tras un ataque isquémico transitorio.

BACKGROUND AND OBJECTIVE: Early stroke recurrence risk alter a transient ischemic attack (TIA) is high. We studied the diagnostic implications of the recurrence pattern after TIA. METHODS: 210 consecutive TIA patients were studied. Ultrasonographic (US), neuroimaging and cardiologic data were collected. RESULTS: At 90 day follow-up, 14 patients (6.7%; 95% CI: 3.3-10.1) among 209 suffered an ischemic infarction (II), 9 (4.3%; 1.5-7.1) a TIA and 6 (2.9%; 0.6-5.1) a cardiac ischemic event. Moreover, 13 patients (6.2%; 2.8-9.6) among 210 with a seven-day follow-up had an II. Multivariate analyses only identified the presence of intracranial stenoses (HR, 23.29; 95% CI, 3.49 to 23.57; p<0.018) as independent predictors of stroke within the first 7 days, and large-artery occlusive disease (HR, 9.07; CI, 3.49 to 23.57; p<0.001) as a predictor of stroke recurrence at 90 day follow-up. A new diagnosis of atrial fibrillation was observed in 21 subjects (10.0%), and it was documented in the baseline ECG in 62% cases. Acute diffusion abnormalities were identified in 81 (44,5%) of 182 patients, and chronic ischemic lesions were observed in 110 (60.4%) on MRI vs 56 (26.7%) among 210 on CT scan. CONCLUSION: Due to very early recurrence, the routine use of ultrasonography within the first hours after an index TIA will be useful to identify those patients at high risk. The prognostic usefulness of diffusion-weighted studies will be only achieved if it is performed early. Routine noninvasive cardiac rhythm monitoring has a low detection rate.