Epilepsia partialis continua: aetiology, semiology and prognosis in a Spanish adult cohort.

To describe the semiological features in patients suffering with Epilepsia Partialis Continua (EPC), also referred as Kozhevnikov syndrome and their relationship with aetiology, duration, and prognosis, as well as recurrence during follow-up. We analysed consecutive EPC patients diagnosed and followed in our centre over a seven-and-a half year period. We collected demographic and clinical data, along with neuroimaging and EEG recordings. All patients were followed for more than six months. Patients were categorised with single body area or multiple body area involvement according to the body parts affected. Recurrence was defined as a second EPC episode after one week. We collected data from 27 adult patients; 70.4% were men, the mean age was 65.2 years old (range: 17-89 years), and 40.7% had previous epilepsy. EPC causes were structural in 85.1% (stroke being the most frequent; 44.4%), metabolic in 11.1%, and of unknown origin in 7.4%. A cortical lesion on neuroimaging was shown in 70.4%. Involvement of multiple body areas was reported in 55.6% of patients. The optimal cut-off period to predict death was nine days (with a sensitivity of 62.5% and specificity of 75%; p=0.039), and this group of patients exhibited more multiple body area involvement (88.9% vs 38.9%; p=0.04). During follow-up, patients with cortical lesions had more EPC relapses (p=0.037). The most frequent aetiology of EPC in our patients was stroke. Multiple body area involvement and duration were associated with mortality. Patients with cortical lesions had more EPC relapses during follow-up.

Levetiracetam and Valproate Retention Rate in Juvenile Myoclonic Epilepsy.

BACKGROUND: Valproic acid (VPA) is an effective treatment in juvenile myoclonic epilepsy (JME), but concerns on its use during pregnancy are remarkable. Levetiracetam (LEV) is approved as second-line therapy, and used as monotherapy in clinical practice. Our objective was to analyze the outcome of LEV and VPA in JME. MATERIALS AND METHODS: We analyzed patients with JME attending our epilepsy unit between 2010 and 2014, including all patients treated with LEV and/or VPA at some point of the disease course. The primary end point was drug retention rate in monotherapy after the final analysis. RESULTS: We identified 58 patients (62% women). All had myoclonic seizures, 86% had generalized tonic-clonic seizures (GTCS) before the diagnosis, and 9% also had absences. All had generalized spike and wave on the interictal electroencephalogram, and 86% of them also had generalized polyspike and wave discharges. In total, LEV monotherapy was maintained in 15 (65%) of 23 patients, and VPA was maintained in 37 (74%) of 50 patients (P = 0.062). In women younger than 35 years, LEV had a similar retention rate with VPA (P = 0.939). More VPA patients achieved seizure freedom during follow-up (P < 0.01), whereas LEV patients showed a trend toward higher myoclonic freedom (0.085). CONCLUSIONS: Levetiracetam showed lower retention rate than VPA, primarily due to poorer seizure control during long-term follow-up. More LEV patients achieved myoclonic seizure freedom than VPA patients. In women younger than 35 years, LEV and VPA had comparable retention rate; therefore, LEV could be a good option for women with JME with prominent myoclonic seizures.

Differentiated clinical presentation of early and late-onset Alzheimer's disease: is 65 years of age providing a reliable threshold?

Early-onset and late-onset Alzheimer's disease (EOAD and LOAD) are two forms of the disease with the same characteristic neuropathological hallmarks. However, higher burdens of neuritic plaques and neurofibrillary tangles in frontal and parietal lobes have been found in EOAD than in LOAD patients. Thus, the EOAD subjects may have a differentiated clinical presentation compared to the LOAD ones. Some authors have found less hippocampal memory presentations and more focal cortical abnormalities (such as visuoconstructive or executive dysfunction) in EOAD than LOAD patients. The aim of the present study was to determine which initial clinical profiles differ between EOAD and LOAD; and to analyze whether another age cut-off could discriminate better between EOAD and LOAD clinical presentations than the conventional limit of 65. All patients fulfilling NINCDS-ADRDA criteria for probable Alzheimer's disease who referred to our Hospital between October 2007 and December 2012 were included in the study. The conventional age limit of 65 was established to distinguish between EOAD and LOAD. Baseline neuropsychological scores, adjusted for age and education, were compared between both groups. A total of 181 patients (38 EOAD, 143 LOAD) entered in the analysis. Sex distribution and time of evolution of symptoms did not differ between groups. The EOAD patients performed worse than LOAD in attentional, imitation praxis and verbal learning tests. In addition, the age cut-off of 70 was found to differentiate between early- and late-onset groups better than the standard cut-off of 65 years old. Our results support a differentiated neuropsychological impairment pattern in EOAD compared to LOAD.

Combining statins with tissue plasminogen activator treatment after experimental and human stroke: a safety study on hemorrhagic transformation.

AIMS: Statins may afford neuroprotection against ischemic injury, but it remains controversial whether combined treatment with tissue plasminogen activator (tPA) after stroke increases the risk of hemorrhagic transformation (HT), the major tPA-related complication. We evaluated the safety of combining statin with tPA administration during the acute phase of both experimental and human stroke. METHODS: The occurrence and severity of HT, infarct volume, and neurological outcome were evaluated in spontaneous hypertensive rats (SHR) subjected to embolic middle cerebral arterial occlusion (MCAO), which received vehicle or simvastatin (20 mg/kg), 15 min after ischemia and tPA (9 mg/kg) 3 h after ischemia. Additionally, HT rate was evaluated in stroke patients who were treated with tPA (0.9 mg/kg) within 3 h after symptom onset, considering whether or not were under statins treatment when the stroke occurred. RESULTS: In the experimental study, no differences in HT rates and severity were found between treatment groups, neither regarding mortality, neurological deficit, infarct volume, or metalloproteinases (MMPs) brain content. In the clinical study, HT rates and hemorrhage type were similar in stroke patients who were or not under statins treatment. CONCLUSION: This study consistently confirms that the use of statins does not increase HT rates and severity when is combined with tPA administration.

Selecting endovascular treatment strategy according to the location of intracranial occlusion in acute stroke.

BACKGROUND: Selection of endovascular approaches for acute stroke patients remains unclear. The efficacy of intra-arterial therapy (IAT) has been demonstrated in the past. However, in the last years, the use of mechanical thrombectomy by retrievers (RET) is increasing at the expense of IAT. We aimed to compare several clinical outcomes between patients treated with IAT or RET. METHODS: In a 6-year period, acute stroke patients (<8 h) with confirmed internal carotid artery (ICA) occlusion or middle cerebral artery (MCA) occlusion undergoing endovascular therapy were prospectively included in our database. Patients who underwent intra-arterial tissue plasminogen activator (tPA) ± microguidewire mechanical clot disruption (IAT group) were compared with those who underwent thrombectomy with the Solitaire® or Trevo® retrievers (RET group). Recanalization (REC) was considered if at the end of the endovascular procedure thrombolysis in cerebral infarction score was 2a-3. Dramatic clinical improvement (DCI) was defined as a decrease of ≥10 NIHSSS points from baseline to discharge or 7 days. RESULTS: One hundred and eighty patients were included, 100 (55.6%) patients in the IAT group and 80 patients (44.4%) in the RET group. There were no differences in baseline characteristics (age, gender, risk factors profile, previous treatment with i.v. tPA, baseline NIHSS, extracranial ICA angioplasty and time to REC). Rates of REC, DCI and symptomatic intracranial hemorrhage were also similar between groups. Among patients with ICA occlusions (41 IAT, 34 RET), REC was significantly higher with RET (83.9 vs. 61%; p = 0.04).There was a trend towards a higher DCI rate in the RET group (32.3%) compared with the IAT group (14.6%; p = 0.06). According to MCA occlusions, there were no major differences in the main outcome variables. The number needed to treat to achieve one additional DCI with RET compared with IAT was 12 for MCA occlusions, and only 5 for ICA occlusions. CONCLUSIONS: Among acute stroke patients undergoing endovascular therapies, the benefits of RET over IAT are greater in ICA occlusions. Retrievers may be considered as the first therapeutic option in these patients.

Role of the MMP9 gene in hemorrhagic transformations after tissue-type plasminogen activator treatment in stroke patients.

BACKGROUND AND PURPOSE: Despite the benefits of tissue-type plasminogen activator treatment, some stroke patients experience adverse hemorrhagic transformations (HT). Plasma protein levels of MMP9 have been associated with HT occurrence. We aimed to analyze the association of the MMP9 gene with HT occurrence. METHODS: We analyzed the MMP9 gene in blood samples from 885 stroke patients treated with tissue-type plasminogen activator by tag-SNP, imputed SNP, direct sequencing, and RNA expression. RESULTS: We did not observe any significant association between MMP9 genetic variations or MMP9 expression and HT occurrence. Moreover, no association was found between MMP9 expression and MMP9 polymorphisms. CONCLUSIONS: Genetic variations in the MMP9 gene are not associated with HT occurrence in tissue-type plasminogen activator-treated patients.

Plasma VAP-1/SSAO activity predicts intracranial hemorrhages and adverse neurological outcome after tissue plasminogen activator treatment in stroke.

BACKGROUND AND PURPOSE: Vascular adhesion protein-1 (VAP-1) is a cell surface and circulating enzyme involved in recruitment of lymphocytes and neutrophils through its semicarbazide-sensitive amine oxidase (SSAO) activity. We aimed to study plasma VAP-1/SSAO activity in relation to the risk for intracranial bleeding complications in patients with stroke treated with tissue plasminogen activator (tPA), the greatest safety concern with this treatment. METHODS: In 141 patients with ischemic stroke, we measured VAP-1/SSAO activity in plasma taken before tPA administration. Hemorrhagic events were classified according to brain CT criteria and functional outcomes evaluated using the National Institutes of Health Stroke Scale. We also assessed the potential therapeutic effect of blocking VAP-1/SSAO activity in a rat embolic stroke model treated with tPA. RESULTS: We saw significantly higher levels of plasma VAP-1/SSAO activity in patients who subsequently experienced hemorrhagic transformation. Elevated plasma VAP-1/SSAO activity also predicted worse neurological outcome in these patients. In the rat model, we confirmed that use of the inhibitor semicarbazide prevented adverse effects caused by delayed tPA administration, leading to a smaller infarct volume. CONCLUSIONS: Our data demonstrate that baseline VAP-1/SSAO activity predicts parenchymal hemorrhage after tPA, suggesting the safety of thrombolytic agents could be improved by considering VAP-1/SSAO activity. Furthermore, anti-VAP-1/SSAO drugs given with tPA may prevent neurological worsening in patients with ischemic stroke.

Triflusal and aspirin have different effects on inflammatory biomarkers measured in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Triflusal is a 4-fluoromethyl derivative of salicylic acid used for secondary prevention of ischemic stroke. Recent experimental data (permanent middle cerebral artery occlusion in rats) have shown a possible role of triflusal in neuroprotection through inhibition of inflammatory pathways. METHODS: To explore whether triflusal may modulate those pathways in human stroke, evolution of several inflammation markers (pro-inflammatory, adhesion molecules, chemokines, metalloproteinases, apoptosis and angiogenesis-related biomarkers) and neurological outcome were evaluated at baseline, and at days 1, 3, 7 and 90 in a pilot study in which 30 patients with acute ischemic stroke were randomly allocated to receive triflusal or aspirin. RESULTS: An increase in IL-6 level was found in the aspirin group when compared to the triflusal group at the third and seventh day (p < 0.05). FGF-basic level was significantly increased at days 1 and 90 in the triflusal group (p = 0.040). The triflusal group also had higher levels of MIP-1alpha and MIP-1beta (p < 0.05) at day 1. Also among triflusal-treated patients, MCP-1 and TARC levels were increased as compared with the aspirin group at day 90 (p < 0.05). Interestingly, some of those markers modified by triflusal (MCP-1 and IL-6) were associated with neurological outcome: higher MCP-1 measured at day 3 among patients who improve at day 7 [462.3 (419.2-735.2) vs. 285 (242.1-428.2), p < 0.05], and lower levels of IL-6 at day 3 among patients who improve at day 90 [24.8 (5.6-77.3) vs. 5.4 (2.0-13.8), p < 0.05]. CONCLUSION: Triflusal modulates additional mechanisms to those of aspirin [pro-inflammatory (IL-6) and chemokine (MIP-1 and MCP-1) pathways] that could participate in the ischemic damage process following human acute stroke.

Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers.

BACKGROUND AND PURPOSE: Because there is no biologic marker offering precise information about stroke etiology, many patients receive a diagnosis of undetermined stroke even after all available diagnostic tests are done, precluding correct treatment. METHODS: To examine the diagnostic value of a panel of biochemical markers to differentiate stroke etiologies, consecutive acute stroke patients were prospectively evaluated. Brain computed tomography, ultrasonography, cardiac evaluations, and other tests were done to identify an etiologic diagnosis according to TOAST classification. Blood samples were drawn on Emergency Department arrival (<24 hours) to test selected biomarkers: C-reactive protein, D-dimer, soluble receptor for advanced glycation end products, matrix metalloproteinase-9, S-100b, brain natriuretic peptide (BNP), neurotrophin-3, caspase-3, chimerin, and secretagogin (assayed by ELISA). RESULTS: Of 707 ischemic stroke patients included, 36.6% were cardioembolic, 21.4% atherothrombotic, 18.1% lacunar, and 23.9% of undetermined origin. High levels of BNP, soluble receptor for advanced glycation end products, and D-dimer (P<0.0001) were observed in patients with cardioembolic stroke. Independent predictors (odds ratios with CIs are given) of cardioembolic stroke were as follows: atrial fibrillation 15.3 (8.4-27.7, P<0.001); other embolic cardiopathies 14.7 (4.7-46, P<0.001); total anterior circulation infarction 4 (2.3-6.8, P<0.001); BNP >76 pg/mL 2.3 (1.4-3.7, P=0.001); and D-dimer >0.96 microg/mL 2.2 (1.4-3.7, P=0.001). Even among patients with transient symptoms (n=155), a high BNP level identified cardioembolic etiology (6.7, 2.4-18.9; P<0.001). A model combining clinical and biochemical data had a sensitivity of 66.5% and a specificity of 91.3% for predicting cardioembolism. CONCLUSIONS: Using a combination of biomarkers may be a feasible strategy to improve the diagnosis of cardioembolic stroke in the acute phase, thus rapidly guiding other diagnostic tests and accelerating the start of optimal secondary prevention.

Perfil de los pacientes ingresados en UCI con cetoacidosis diabética / Profile of patients with diabetic ketoacidosis in the intensive care unit

Objetivo: Valoración de pacientes ingresados en una unidad de cuidados intensivos (UCI) con el diagnóstico de cetoacidosis diabética (CAD). Método: Revisión de los casos ingresados durante 5 años. Se analizan características clínicas, factores contribuyentes, datos de laboratorio y factores pronósticos. Resultados: Treinta pacientes han justificado 38 episodios de CAD. Hay un predominio de los varones, de los ingresos en primavera y otoño y de antecedentes de diabetes mellitus. Los factores precipitantes son: desconocidos (28,9%), infecciosos (28,9%), omisión o inadecuado tratamiento con insulina (15,8%), drogadicción (15,8%) y enfermedad intercurrente (10,4%). Ningún paciente presentó al ingreso un índice de Glasgow Coma Score (GCS) < 9. Un 7,9% presentó hipotensión, sin necesidad de fármacos vasoactivos. Los valores bioquímicos medios al ingreso fueron: glucemia, 649 ± 304 mg/dl; pH, 7,04 ± 0,12; bicarbonato, 6,26 ± 3,9 mEq/l; leucocitos, 16.532 ± 6.948 µl; sodio, 135 ± 8 mEq/l; potasio, 4,9 ± 1,2 mEq/l; creatinina, 1,9 ± 0,9 mg/dl. Los días de estancia media en UCI fueron 3, con menos de 2 días en la mitad de los pacientes. Las complicaciones graves más frecuentes fueron edema cerebral (2,6%), accidente cerebrovascular agudo (ACVA) (2,6%), pancreatitis (2,6%) e insuficiencia respiratoria (5,3%). Falleció el 13,2% de los ingresados. Los pacientes que desarrollaron edema cerebral, insuficiencia respiratoria y ACVA justifican el 80% de las muertes. Otras variables relacionadas fueron edad, potasio y pH al ingreso, y días de estancia. Conclusiones: En nuestro entorno la CAD predomina en varones, y en primavera y otoño. La mayoría de los pacientes son diabéticos conocidos con una causa conocida de precipitación. El control de los pacientes es bueno y la evolución, adecuada, salvo que aparezcan complicaciones como edema cerebral/ACVA o insuficiencia respiratoria (AU)

Objective: To determine the clinical characteristics of patients admitted to the intensive care unit (ICU) with a diagnosis of diabetic ketoacidosis (DKA). Method: We performed a retrospective chart review of all patients admitted to our ICU over a 5-year period with a diagnosis of DKA. The medical records were analyzed to identify clinical presentations, contributory factors, laboratory data, and outcomes. Results: Data on 30 patients with 38 DKA episodes were included. Patients were predominantly men. Episodes were more frequent in the spring and fall. Most patients had established diabetes. Precipitating factors of DKA were unknown in 28.9%, infections in 28.9%, omission of insulin therapy or inadequate insulin therapy in 15.8%, polysubstance abuse in 15.8%, and medical illness in 10.4%. All patients had a Glasgow Coma Scale >= 9. Mild hypotension was found in 7.9%, without the need for vasoactive drugs. The mean laboratory values at admission were as follows: glucose 649 ± 304 mg/dl; pH 7.04 ± 0.12; bicarbonate 6.26 ± 3.9 mEq/l; white blood cell count 16,532 ± 6,948 µl; sodium 135 ± 8 mEq/l; potassium 4.9 ± 1.2 mEq/l; creatinine 1.9 ± 0.9 mg/dl. The mean length of stay in the ICU was 3 days and more than half the patients were admitted for less than 2 days. The most frequent severe complications were cerebral edema in 2.6%, ischemic cerebrovascular disease in 2.6%, pancreatitis in 2.6%, and respiratory failure in 5.3%. A total of 13.2% of the patients died in the ICU. The main predictors of mortality were cerebral edema, respiratory failure and ischemic cerebrovascular disease, accounting for 80% of deaths. Mortality was also influenced by age, potassium levels, pH, and length of stay. Conclusions: In our environment, DKA was more frequent in men and in the spring and fall. Most patients had established diabetes and a known precipitating factor. Outcome was favorable in patients without complications such as cerebral edema, ischemic cerebrovascular disease, or respiratory failure (AU)

Prior statin use may be associated with improved stroke outcome after tissue plasminogen activator.

BACKGROUND AND PURPOSE: Statins may exert some neuroprotection, because use before stroke onset has been related to better outcome and reduced mortality. The purpose of this study was to evaluate whether patients who receive tissue plasminogen activator have better outcome when statins were taken before stroke. METHODS: We evaluated 145 patients with a stroke involving the middle cerebral artery (who received tissue plasminogen activator treatment (<3 hours). RESULTS: Fifty-eight patients (40%) became functionally independent at 3 months. Factors associated with good outcome were age (68 versus 74.4 years, P<0.001), baseline National Institutes of Health Stroke Scale score (13 versus 18, P<0.001), and proximal middle cerebral artery occlusion (56.1% versus 84.3%, P<0.001). Statins were the only drug taken before stroke that conditioned neurologic outcome. In fact, among patients who were functionally independent, 27.3% were under statins at the time of the index stroke as compared with 13.6% among the group of patients who were dependent or dead by the end of the study period (P=0.046). A logistic regression model identified baseline National Institutes of Health Stroke Scale score <15 (OR: 5.8, 95% CI: 2.05 to 16.36, P=0.001), age <70 years (OR: 2.93, 95% CI: 1.13 to 7.59, P=0.027), and previous treatment with statins (OR: 5.26, 95% CI: 1.48 to 18.72, P=0.027) as independent predictors of good functional outcome. CONCLUSIONS: Patients under statins at the moment of stroke who received thrombolytics had an improved neurologic outcome.

[Usefulness of urgent combined carotid/transcranial ultrasound testing in early prognosis of TIA patients]. / Efectividad del estudio ultrasonográfico precoz en el pronóstico a corto plazo de los pacientes con un accidente vascular cerebral isquémico transitorio.

BACKGROUND AND OBJECTIVE: Although patients with ischemic attacks (TIA) experience cardiovascular events frequently within the first 90 days after symptoms onset, strong clinical predictors of early recurrence are lacking. We investigate the value of combined carotid/transcranial ultrasound testing (UST) on the prognosis of TIA patients. PATIENTS AND METHOD: UST was performed < 24 h after symptoms onset among 311 consecutive TIA patients. Stroke recurrence, myocardial infarction, or any vascular event was recorded at 7 and 90 days of follow-up. RESULTS: A total of 20 patients suffered an stroke within 7 days of symptoms onset. During the next 90 days after index TIA, 58 (18.6%) patients experienced an endpoint: 51 cerebral ischemic events, one peripheral arterial disease, 5 myocardial infarctions and one cerebellum hemorrhage. Cox proportional hazards multivariate analyses identified the presence of intracranial stenoses (HR = 3.05; 95% CI, 1.21-7.70; p = 0.018) and carotid territory implication (HR = 15.91; 95% CI, 2.11-120.04; p = 0.007) as independent predictors of stroke within the first 7 days after index TIA. Moreover, at 90 days of follow-up, large-artery occlusive disease was an independent predictor of stroke (HR = 3.07; 95% CI, 1.76-5.38; p < 0.001). CONCLUSIONS: TIA patients with moderate to severe intracranial or extracranial stenoses have a higher risk of stroke recurrence. The routine use of UST within the first 24 h after index TIA can be useful for identifying those patients at high risk in order to plan aggressive prevention therapies.

Efectividad del estudio ultrasonográfico precoz en el pronóstico a corto plazo de los pacientes con un accidente vascular cerebral isquémico transitorio / Usefulness of urgent combined carotid/transcranial ultrasound testing in early prognosis of TIA patients

Fundamento y objetivo: Los pacientes con un accidente vascular cerebral isquémico transitorio (AIT) y estenosis tanto intracraneal como extracraneal de grado moderado a importante tienen mayor riesgo de recurrencia de ictus. Investigamos el valor de realizar un estudio ultrasonográfico (EUS) transcraneal/carotídeo precoz en el pronóstico de estos pacientes. Pacientes y método: Estudiamos de forma prospectiva a 311 pacientes con AIT atendidos en el servicio de urgencias a los que se realizó un EUS transcraneal/carotídeo dentro de las primeras 24 h. Resultados: Durante los primeros 90 días, 58 pacientes tuvieron un episodio vascular (isquemia cerebral, 51; isquemia coronaria, 5; hemorragia cerebelosa, 1, y arteriopatía periférica, 1); 20 pacientes presentaron un infarto cerebral durante la primera semana. El análisis multivariable (regresiones de Cox) identificó como predictores independientes de infarto cerebral, a los 7 días, los episodios de territorio carotídeo (razón de riesgos [RR] = 15,91; intervalo de confianza [IC] del 95%, 2,11-120,04; p = 0,007) y la presencia de estenosis intracraneal (EIC) (RR = 3,05; IC del 95%, 1,21-7,70; p = 0,018), mientras que la etiología aterotrombótica se identificó como predictor independiente para ictus isquémico a los 90 días (RR = 3,07; IC del 95%, 1,76-5,38; p < 0,001). Conclusiones: Los pacientes con AIT y estenosis intracraneal o extracraneal de grado moderado a importante tienen mayor riesgo de recurrencia de ictus. El EUS es útil para identificar a los pacientes de mayor riesgo e instaurar sin demora el tratamiento más adecuado

Background and objective: Although patients with ischemic attacks (TIA) experience cardiovascular events frequently within the first 90 days after symptoms onset, strong clinical predictors of early recurrence are lacking. We investigate the value of combined carotid/transcranial ultrasound testing (UST) on the prognosis of TIA patients. Patients and method: UST was performed < 24 h after symptoms onset among 311 consecutive TIA patients. Stroke recurrence, myocardial infarction, or any vascular event was recorded at 7 and 90 days of follow-up. Results: A total of 20 patients suffered an stroke within 7 days of symptoms onset. During the next 90 days after index TIA, 58 (18.6%) patients experienced an endpoint: 51 cerebral ischemic events, one peripheral arterial disease, 5 myocardial infarctions and one cerebellum hemorrhage. Cox proportional hazards multivariate analyses identified the presence of intracranial stenoses (HR = 3.05; 95% CI, 1.21-7.70; p = 0.018) and carotid territory implication (HR = 15.91; 95% CI, 2.11-120.04; p = 0.007) as independent predictors of stroke within the first 7 days after index TIA. Moreover, at 90 days of follow-up, large-artery occlusive disease was an independent predictor of stroke (HR = 3.07; 95% CI, 1.76-5.38; p < 0.001). Conclusions: TIA patients with moderate to severe intracranial or extracranial stenoses have a higher risk of stroke recurrence. The routine use of UST within the first 24 h after index TIA can be useful for identifying those patients at high risk in order to plan aggressive prevention therapies

ACE gene polymorphisms influence t-PA-induced brain vessel reopening following ischemic stroke.

Angiotensin converting enzyme (ACE) influences vessels tone and the coagulation/fibrinolysis system. The ACE gene I/D polymorphism has been linked with PAI-1 and fibrinogen levels and with Factors VII and X activities. Therefore, we aimed to test whether I/D polymorphism could be related to thrombolysis safety and efficacy. We studied strokes involving the middle cerebral artery (MCA) territory of patients who received t-PA <3 h of stroke onset. Blood samples were obtained before t-PA administration to measure fibrinogen, PAI-1, Factors VII and X. I/D polymorphism was determined by polymerase chain reaction and agarose electrophoresis. Recanalization rates were serially evaluated by Transcranial Doppler. Among 96 included patients the genotype frequency was: DD=33.3%, ID=57.3% and II=9.4%. A strong association was found between DD homozygous and successful recanalization rates (DD=69.2%, ID+II=31.6%, p=0.002 at 1 h; DD=91.3%, ID+II=51%, p=0.001 at 6 h; DD=100%, ID+II=72.3%, p=0.003 at 24 h post-t-PA administration). In fact, DD genotype was an independent predictor of recanalization (OR=4.3 95% CI 1.35-13.49, p=0.013). No relation was found between I/D polymorphism and symptomatic hemorrhagic complications (p=0.237). No association between ACE genotypes and Factor VII or Factor X activities, neither with fibrinogen or PAI-1 levels was observed. DD homozygous is strongly associated with MCA recanalization following t-PA treatment. Mechanisms of benefit remain unknown since I/D polymorphism had similar FVII and X activities and PAI-1 and fibrinogen levels in our stroke population.

Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome.

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) are related to blood-brain barrier disruption, and some members of this family have been recently involved in brain bleedings. We aimed to investigate the temporal profile of MMPs and their natural inhibitors (TIMPs) after acute intracerebral hemorrhage (ICH) and to study its influence on neuroimaging and clinical outcome. METHODS: MMP-2, MMP-9, and MMP-3, as well as TIMP-1 and TIMP-2, were serially determined by enzyme-linked immunosorbent assay on admission (<12 hours), and at 24 hours, 48 hours, 7 days, and 3 months in 21 ICH patients. ICH and perihematomal edema (PE) volumes were serially measured on baseline and follow-up computed tomography (48 hours, 7 days, and 3 months), just at the time of neurological assessment. RESULTS: Deep ICH was found in 62% patients. Baseline ICH volume did not influence MMP-TIMP level. Highest levels of MMP-2 and TIMP-2 were found at baseline, for MMP-9 and TIMP-1 at 24 hours, and for MMP-3 at 24 to 48 hours. Baseline MMP-9 was positively correlated to PE volume (r=0.67, P=0.004) and, conversely, its inhibitor TIMP-1 was negatively correlated to PE (r=-0.51, P=0.04). Mortality reached 35% and MMP-3 was the only MMP/TIMP related to mortality (7.5 versus 2.4 ng/mL; P=0.035) and its most powerful baseline predictor (odds ratio = 22, confidence interval: 1.5 to 314.2). Both MMP-9 and MMP-3 correlated to the residual scar volume at 3 months (r=0.68, P=0.01 for baseline MMP-9, and r=0.86, P<0.001 for 24-hour MMP-3). CONCLUSIONS: A characteristic temporal profile of MMP/TIMP release exists in ICH. Increased MMP-9 is associated with PE, and increased MMP-3 is associated with mortality. Both molecules are related to residual cavity volume.

Safety profile of tissue plasminogen activator treatment among stroke patients carrying a common polymorphism (C-1562T) in the promoter region of the matrix metalloproteinase-9 gene.

BACKGROUND AND PURPOSE: Matrix metalloproteinase-9 (MMP-9) expression, related to blood-brain barrier disruption, has been implicated in the appearance of hemorrhagic transformation (HT) after tissue plasminogen activator (tPA) treatment in stroke patients. Because an in vitro functional polymorphism of the promoter region of MMP-9 gene (C-1562T) has been described, we hypothesize that patients carrying this mutation might have higher MMP-9 levels and greater susceptibility to developing HT when receiving tPA. METHODS: We studied strokes involving the middle cerebral artery territory of 61 patients who received tPA <3 hours after stroke onset. Blood samples were obtained before tPA administration. Plasmatic MMP-9 determinations were performed (enzyme-linked immunosorbent assay, ng/mL), and C-1562T genotype was determined by polymerase chain reaction. Healthy age-matched control subjects were used to study allele distribution (n=59). Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI,1 to 2] and large parenchymal hemorrhages [PH,1 to 2]). RESULTS: Allele distribution was similar in patients and control subjects (CC/CT/TT: 72.3/27.7/0% versus 79.7/20.3/0%, respectively; P=0.37). Among patients, mutation carriers (CT/TT alleles) had similar rates of HT and PH than noncarriers (HT: 23.1% versus 38.2%, P=0.49; PH: 15.4% versus 17.6%, P=1.0). Although the highest MMP-9 level corresponded to patients who later developed a PH (PH, 191.4 ng/mL; non-PH, 68.05 ng/mL; P=0.022), no relation between MMP-9 mutation presence and plasmatic levels was found (CC, 127.12 ng/mL; CT/TT, 46.31 ng/mL; P=0.11). CONCLUSIONS: Although MMP-9 level predicts PH appearance after tPA treatment, no relationship exists with the C-1562T polymorphism, probably because this mutation is not functional in response to cerebral ischemia in vivo.

Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke.

BACKGROUND: Matrix metalloproteinase (MMP) expression is related to blood brain barrier disruption after cerebral ischemia. Moreover, MMP inhibitors reduce hemorrhagic transformation (HT) after embolic ischemia in tissue plasminogen activator (t-PA)-treated animals. We aimed to correlate plasmatic MMP levels with the appearance of intracranial bleeding complications in stroke patients treated with t-PA. METHODS AND RESULTS: Serial MMP-2 and MMP-9 determinations were performed (ELISA, ng/mL) in 41 strokes involving the middle cerebral artery territory in patients who received t-PA within 3 hours of stroke onset. Blood samples were obtained at baseline (pretreatment) and at 12 and 24 hours after symptom onset. Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions [HI, 1 to 2] and large parenchymal hemorrhages [PH, 1 to 2]). Brain CT scan was obtained at 48 hours or when a neurological worsening occurred. HT was present in 36.5% of the patients (24.4% HI and 12.1% PH). MMP-2 values were unrelated to any subtype of HT. The highest baseline MMP-9 level (normal range <97 ng/mL) corresponded to patients who later developed a PH (PH: 270.2+/-87.8, non-HT: 126.3+/-127.5, HI: 94.6+/-88.7; P=0.047). A graded response was found between mean baseline MMP-9 levels and the degree of bleeding (HI-1=37.4; HI-2=111.0; PH-1=202.5; PH-2=337.8). Baseline MMP-9 was the most powerful predictor of PH appearance in the multiple logistic regression model (OR= 9.62; CI 1.31 to 70.26; P=0.025). CONCLUSIONS: Baseline MMP-9 level predicts PH appearance after t-PA treatment. Therefore, we suggest that MMP determination may increase the safety profile for thrombolysis and, in the future, anti-MMP drugs might be combined with t-PA to prevent hemorrhagic complications.