Optimizing the Definition of Ischemic Core in CT Perfusion: Influence of Infarct Growth and Tissue-Specific Thresholds.

BACKGROUND AND PURPOSE: CTP allows estimating ischemic core in patients with acute stroke. However, these estimations have limited accuracy compared with MR imaging. We studied the effect of applying WM- and GM-specific thresholds and analyzed the infarct growth from baseline imaging to reperfusion. MATERIALS AND METHODS: This was a single-center cohort of consecutive patients (n = 113) with witnessed strokes due to proximal carotid territory occlusions with baseline CT perfusion, complete reperfusion, and follow-up DWI. We segmented GM and WM, coregistered CTP with DWI, and compared the accuracy of the different predictions for each voxel on DWI through receiver operating characteristic analysis. We assessed the yield of different relative CBF thresholds to predict the final infarct volume and an estimated infarct growth-corrected volume (subtracting the infarct growth from baseline imaging to complete reperfusion) for a single relative CBF threshold and GM- and WM-specific thresholds. RESULTS: The fixed threshold underestimated lesions in GM and overestimated them in WM. Double GM- and WM-specific thresholds of relative CBF were superior to fixed thresholds in predicting infarcted voxels. The closest estimations of the infarct on DWI were based on a relative CBF of 25% for a single threshold, 35% for GM, and 20% for WM, and they decreased when correcting for infarct growth: 20% for a single threshold, 25% for GM, and 15% for WM. The combination of 25% for GM and 15% for WM yielded the best prediction. CONCLUSIONS: GM- and WM-specific thresholds result in different estimations of ischemic core in CTP and increase the global accuracy. More restrictive thresholds better estimate the actual extent of the infarcted tissue.

The I/D polymorphism of the ACE1 gene is not associated with ischaemic stroke in Spanish individuals.

BACKGROUND: The angiotensin-converting enzyme 1 (ACE1) gene has been extensively studied in stroke, yet generating conflicting results. The goal of our study was thus to clarify the influence of the ACE1 on the risk of suffering an ischaemic stroke (IS). METHODS: We genotyped the rs4341 (in linkage disequilibrium with the I/D polymorphism) of the ACE1 gene in 531 patients with IS and 549 healthy controls, and the rs1799752 (I/D polymorphism) in a subset of 68 patients with IS and 27 controls. We also performed functional studies by measuring serum ACE protein levels and enzymatic activity in 27 controls, 68 patients with IS at baseline and 35 patients with IS 24 h after onset of stroke symptoms. RESULTS: There was no association of the ACE1 variant with IS, although it affected ACE protein levels (P = 0.001). Indeed, patients with IS showed lower ACE levels than controls in the acute phase (115.9 } 38.9 vs. 174.1 } 56.1 ng/ml, P < 0.001), but not in the chronic phase (168.2 } 51.2, P = 0.673), and ACE protein levels did not differ between IS etiologies. Similar results were found for ACE activity. CONCLUSIONS: The D allele of the ACE1 I/D and ACE protein levels was not associated with a higher risk of IS in Spanish individuals.

Leukoaraiosis May Confound the Interpretation of CT Perfusion in Patients Treated with Mechanical Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Leukoaraiosis frequently coexists in patients with acute stroke. We studied whether leukoaraiosis could confound the interpretation of CTP findings in patients treated with mechanical thrombectomy. MATERIALS AND METHODS: We analyzed 236 patients with stroke treated with mechanical thrombectomy and studied with CTP, of whom 127 (53.8%) achieved complete reperfusion. Periventricular white matter hyperintensities on MR imaging and hypodensities on NCCT were assessed through the Fazekas score. CTP-predicted nonviable tissue was defined as relative CBF <30%, and final infarct volume was quantified in DWI. We estimated mean MTT, CBV, and CBF in the asymptomatic hemisphere. In patients achieving complete reperfusion, we assessed the accuracy of nonviable tissue to predict final infarct volume using the intraclass correlation coefficient across periventricular hyperintensity/hypodensity Fazekas scores and variable relative CBF cutoffs. RESULTS: MTT was longer (Spearman ρ = 0.279, P < .001) and CBF was lower (ρ = -0.263, P < .001) as the periventricular hyperintensity Fazekas score increased, while CBV was similar across groups (ρ = -0.043, P = .513). In the subgroup of patients achieving complete reperfusion, nonviable tissue-final infarct volume reliability was excellent in patients with periventricular hyperintensity Fazekas score grade 0 (intraclass correlation coefficient, 0.900; 95% CI, 0.805-0.950), fair in patients with periventricular hyperintensity Fazekas scores 1 (intraclass correlation coefficient, 0.569; 95% CI, 0.327-0.741) and 2 (intraclass correlation coefficient, 0.444; 95% CI, 0.165-0.657), and poor in patients with periventricular hyperintensity Fazekas score 3 (intraclass correlation coefficient, 0.310; 95% CI, -0.359-0.769). The most accurate cutoffs were relative CBF <30% for periventricular hyperintensity Fazekas score grades 0 and 1, relative CBF <25% for periventricular hyperintensity Fazekas score 2, and relative CBF <20% for periventricular hyperintensity Fazekas score 3. The reliability analysis according to periventricular hypodensity Fazekas score grades on NCCT was similar to that in follow-up MR imaging. CONCLUSIONS: In patients with stroke, the presence of leukoaraiosis confounds the interpretation of CTP despite proper adjustment of CBF thresholds.

The response to IV rt-PA in very old stroke patients.

The use of rtPA in stroke patients aged >80 years remains controversial and it is debated whether there are sex-based differences in the response to rtPA. We assessed the clinical value of thrombolytic therapy in patients aged >80 years (elderly group) in comparison with a non-elderly group, and evaluated the existence of sex differences in the response to rtPA. All consecutive patients (n = 157) treated with rtPA were prospectively assessed since July 2001, including 49 elderly patients who fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria. Changes of the National Institute of Health Stroke Scale (NIHSS) score at 1 h, 24 h, and 7 days after rtPA administration, favourable outcome at day 90 [(modified Rankin Scale) mRS 0-1, or 2 if mRS = 2 before the stroke], symptomatic bleedings, and death rates were compared between elderly and non-elderly patients. Using logistic regression, baseline NIHSS score [odds ratio (OR) 0.59, 95% confidence interval (CI) 0.41-0.84] was an independent predictor of favourable outcome, but not sex (OR 0.72, 95% CI 0.33-1.56), or age >80 years (OR 0.74, 95% CI 0.32-1.70). The rates of clinical improvement, mortality, or symptomatic CNS bleeding were also unrelated to age and sex. In conclusion, the response to IV rtPA is not impaired in elderly stroke patients and male and female are equally responsive.

Influence of antiplatelet pre-treatment on the risk of symptomatic intracranial haemorrhage after intravenous thrombolysis.

BACKGROUND: The influence of antiplatelet agents (AP) in the development of a symptomatic intracranial haemorrhage (SICH) after intravenous rt-PA is not well known. We assessed the hypothesis that pre-treatment with AP may increase that risk. METHODS: We studied data from consecutive patients with ischaemic stroke treated with intravenous rt-PA within the first 3 h after symptom onset. We recorded the antecedent of any AP therapy previous to thrombolysis. A follow-up CT was performed routinely 24-36 h after the infusion of rt-PA. Intracranial bleeding was categorized according to the criteria of the European Cooperative Acute Stroke Study II (ECASS II) into haemorrhagic infarction type 1 and 2 and parenchymal haemorrhage type 1 and 2. SICH was diagnosed if it was of the parenchymal haemorrhage type, occurred within the first 36 h and was associated with neurological deterioration. RESULTS: Of a total of 605 patients, 137 (22.6%) were pre-treated with AP, most of them (n = 106) with aspirin. Any type of intracranial haemorrhage was observed in 119 patients (19.7%), without differences between the AP (18.4%) and the non-AP (20.2%) groups. Parenchymal haemorrhage was observed in 41 patients (8.5%) and SICH in 26 (4.3%). There was a non-significant rise in the frequency of SICH in the AP group compared with the non-AP group (6.6 vs. 3.6% p = 0.10). CONCLUSIONS: Pre-treatment with AP non-significantly increases the risk of SICH and therefore this antecedent should not be a contraindication for intravenous thrombolysis.

Interleukin 10, monocytes and increased risk of early infection in ischaemic stroke.

BACKGROUND AND PURPOSE: The pathophysiology of stroke-associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI. METHODS: The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)alpha and IL10 were measured in plasma. RESULTS: 17 (15%) patients developed infection and showed time-dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNFalpha and the TNFalpha/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection. CONCLUSIONS: SAI is associated with stroke severity, excessive IL10-mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood-borne anti-inflammatory response that decreases the antimicrobial drive of the immune system.

The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial.

BACKGROUND AND PURPOSE: Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. OBJECTIVE AND METHODS: The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. RESULTS: Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). CONCLUSIONS: Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke.

Alpha(1)-antichymotrypsin gene polymorphism in patients with stroke.

BACKGROUND AND PURPOSE: A role for proteolytic enzymes has been suggested in the pathogenesis of stroke. In a search for new genetic factors, we investigated the gene polymorphism of the serine protease inhibitor alpha(1)-antichymotrypsin (ACT) in patients with stroke. METHODS: Two hundred twenty patients with acute ischemic stroke (n=182) and primary intracerebral hemorrhage (n=38) and 70 control subjects without clinical cerebrovascular disease were genotyped for the ACT polymorphism. RESULTS: The ACT-TT genotype was more frequent in patients with primary intracerebral hemorrhage than in patients with ischemic stroke (31.6% versus 16.4%, P:<0.05) or in control subjects (21.4%, P:=0.1). After adjusting for age, gender, and vascular risk factors, the ACT-TT genotype was associated with primary intracerebral hemorrhage, with an OR of 2.3 (95% CI 1.0 to 5. 2) compared with ischemic stroke and an OR of 1.8 (95% CI 0.85 to 9. 65) compared with controls. CONCLUSIONS: Pending confirmation in a larger study, our results suggest that the ACT-TT genotype might be a risk factor for primary cerebral hemorrhage.

alpha(1)-antichymotrypsin polymorphism: a risk factor for hemorrhagic stroke in normotensive subjects.

BACKGROUND AND PURPOSE: Although genetic factors may be important in the pathogenesis of ischemic stroke (IS), little is known on the potential role of genes in most cases of hemorrhagic stroke (HS). Preliminary data showed that the TT genotype of the alpha(1)-antichymotrypsin (ACT) gene polymorphism was associated with HS, although it remained unsettled whether prevalence of this polymorphism might differ between hypertensive and normotensive HS. METHODS: Ninety-nine patients with HS, 182 patients with IS (symptomatic control subjects), and 80 asymptomatic control subjects were genotyped for the ACT polymorphism using polymerase chain reaction amplification. Chronic hypertension was recorded in 66 patients with HS. RESULTS: The ACT-TT genotype was more prevalent in patients than in asymptomatic or symptomatic control subjects: 26%, 15%, and 16%, respectively. The ACT-TT genotype was obtained in 33% of HS who lacked arterial hypertension (P<0.05). After adjustment for age, gender, and vascular risk factors, the ACT-TT genotype remained independently associated with HS (OR 2.80, 95% CI 1.19 to 6.58, compared with asymptomatic control subjects; OR 1.79, 95% CI 0.95 to 3.40, compared with symptomatic control subjects). In analyses restricted to HS in normotensive patients, the ORs were 3.10 (95% CI 1.10 to 8.68) and 2.53 (95% CI 1.04 to 6.18), respectively. CONCLUSIONS: These findings confirm in a larger series of patients the association between the ACT-TT genotype and HS. This polymorphism is more prevalent in normotensive bleedings. Pathological studies will be required to establish whether the ACT-TT genotype facilitates proteolytic rupture of vessels that harbor amyloidotic changes or another form of nonhypertensive cerebral angiopathy.

Alpha1-antichymotrypsin gene polymorphism and susceptibility to Parkinson's disease.

OBJECTIVE: To determine whether the alpha1-antichymotrypsin AA genotype (ACT-AA) confers susceptibility for developing Parkinson's disease (PD) in the Spanish population. BACKGROUND: A correlation between the ACT-AA genotype and the risk of developing PD has been recently reported in the Japanese population. METHODS: The ACT genotypes of 71 patients diagnosed with clinically definite PD were compared with those of 109 age-matched healthy control subjects. RESULTS: The authors found that the ACT-AA polymorphism frequency was not increased significantly in the PD group (31%) compared with the control group (28.4%). The ACT allelic distribution was also similar for familial and sporadic PD, for female and male patients, and for the different clinical subtypes of PD. The age at onset of PD was significantly lower in the ACT-AA patients compared with non-ACT-AA patients. When the actual age was considered, the ACT-AA frequency was higher in PD patients < or =50 years old (50%) compared with that present in patients >50 years old (26.8%), but the same effect was found in control subjects. CONCLUSIONS: The ACT-AA polymorphism is not related to an increased risk of developing PD in the Spanish population. The ACT-AA overrepresentation in PD and control subjects < or =50 years old suggests that this polymorphism could be associated with life-threatening conditions other than PD.

Blink reflex in patients with Wallenberg's syndrome.

Knowledge of the neural circuits involved in Wallenberg's syndrome (WS) is incomplete. Study of the blink reflex (BR) in patients with WS can help in reaching a better understanding of the physiopathology underlying clinical symptoms and may help in the prediction of clinical outcome. We evaluated the BR in response to supraorbital nerve electrical stimuli in 20 patients with WS. All patients were studied within the 1st week after onset of symptoms, and 10 of them were also studied repeatedly during a follow-up period of 3-12 months. At the first examination the long latency bilateral responses (R2 and R2c) to stimulation of the supraorbital nerve of the affected side were absent in 11, delayed in 4, and normal in 5 patients. At follow-up, there was a normalization of the BR in all patients who had absent or delayed responses at the first examination except for one patient whose responses remained absent at the 9th month. Late responses elicited on the side of the lesion by stimulation of the non-affected supraorbital nerve were normal in all but one patient. This patient died from cardiorespiratory arrest within the 1st month of the illness. One patient with normal BR responses also died in the acute phase. The BR is abnormal in most patients with acute WS and tends to normalize in a mean period of 7 months. BR pattern is not a predictor of early fatal complications in patients with this syndrome.

No evidence of linkage to 6p markers in spanish families with juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is a common subtype of hereditary generalized epilepsy with an uncertain pattern of inheritance. Different studies in multiple families have provided evidence for and against linkage of the disease to chromosome 6p. We performed linkage analysis using microsatellite markers from 6p (D6S109, D6S248, D6S291, D6S426, D6S272, D6S466, D6S294, D6S257) and from centromeric 6q region (D6S402) in seven small families of Spanish origin. The highest LOD scores were obtained under an autosomal dominant inheritance model with a penetrance of 70% but a significant positive LOD score (Z>3) was not reached. LOD scores<-2 were obtained at different markers in three of our families. These results support the concept of genetic heterogeneity in the disease.

Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients.

We initiated the present work in order to determine if the Ala53Thr mutation of the alpha-synuclein gene previously described by Polymeropoulos et al. [Science, 276 (1997) 2045-2047] could be detected in Spanish early onset Parkinson's disease (PD) patients. Thirty-four PD patients were evaluated. Of these, 13 were considered early onset patients (six familial and seven sporadic) and were included in the genetic study. We detected the presence of genetic anticipation in four kindreds with early onset PD members. The Ala53Thr mutation of the alpha-synuclein gene was absent in all patients. The results do not support a role for this mutation in our patients with early onset PD and, in agreement with the results previously reported, indicate that the Ala53Thr mutation of the alpha-synuclein gene is a rare cause of PD.

Dopamine receptor D2 intronic polymorphism in patients with Parkinson's disease.

An association between the intronic allele 3 of the dopamine receptor D2 (DRD2) gene and European Parkinson's disease (PD) cases has been reported recently. We initiated the present work in order to determine whether this association between the DRD2 locus and PD is also present in our population from Spain. The DRD2 gene polymorphism has been genotyped in 154 patients and in 125 controls. The allele 3 is present in 60.3% of the patients and in 55.2% of the controls. The genotype 3/3 is present in 36.3% of the patients and in 34.4% of the controls. No statistical differences in the genotype and allelic frequencies between the two groups have been found. No differences were also found when the patients were classified according to different criteria such as onset, family history, gender or clinical presentation. Thus our results do not support a role for the DRD2 locus to develop PD.

Comparison of the acute-phase response in patients with ischemic stroke treated with high-dose heparin or aspirin.

Experimental studies have suggested that unfractionated heparin (UH) has antiinflammatory properties. It is unknown whether UH also has these properties in patients with acute ischemic stroke. Within 12-24 h of treatment onset we measured the acute-phase response as reflected by the erythrocyte sedimentation rate (ESR) and total number of leukocytes (x10(9)/l) in 706 consecutive patients with acute ischemic stroke treated with full-dose UH (n=450), or 300 mg/day aspirin (n=256). Clinical outcome (Mathew scale) at hospital discharge and the effect of factors such as treatment (UH and aspirin), and acute phase response were assessed using multivariate analyses adjusted for baseline confounders and incident complications. Separate models were created for patients with lacunar and nonlacunar stroke. Whereas there were not differences at baseline between the two treatment groups, total leukocyte counts (8. 0+/-4.1 vs. 8.6+/-3.2, P<0.01) and ESR (21.7+/-20.9 vs. 25.2+/-22.9, P<0.05) were statistically significantly lower in patients treated with UH. This effect of UH was more accentuated in patients with nonlacunar stroke. Overall, leukocytes (7.2+/-2.3 vs. 8.4+/-4.0, P<0. 01), and ESR (15.7+/-17.2 vs. 24.3+/-22.2, P=0.0001) were lower in patients with complete early recovery and this effect was restricted to patients with nonlacunar stroke. Whereas baseline impairment, symptomatic bleeding and stroke recurrence were independent negative outcome predictors, the use of UH was positively associated with early recovery in all patients. This study shows that full-dose UH reduces the acute-phase reaction that follows ischemic stroke more effectively than aspirin. The prognostic implications of such effect seem more notable in patients with nonlacunar stroke.

Ex vivo response to aspirin differs in stroke patients with single or recurrent events: a pilot study.

The dose of aspirin for secondary stroke prevention and the clinical meaning of ex vivo platelet abnormalities are debated. We assessed prospectively 39 noncardioembolic stroke patients in which 300 mg/day aspirin had proved effective (n=24) or ineffective (n=15) to prevent recurrent ischemic events. We evaluated platelet aggregation induced by arachidonic acid, adenosine diphosphate and epinephrine, and the sensitivity of platelets to increasing concentrations of the synthetic thromboxane mimetic U46619. Aggregation studies were repeated while subjects received 300 (study phase 1), and 600 (study phase 2) mg/day aspirin, respectively. Overall, arachidonic acid-induced platelet aggregation was less effectively inhibited during study phase 1 compared to phase 2. Arachidonic acid and epinephrine promoted a stronger platelet aggregation in aspirin nonresponders than in aspirin responders while taking 300 mg/day aspirin. On the other hand, 600 mg/day effectively inhibited platelet function in both clinical groups. A lower sensitivity to thromboxane receptors was also found during phase 1 of the study, although the response was similar between aspirin responders and nonresponders. This pilot study suggests that 300 mg/day aspirin is less effective than 600 mg/day to block the cyclooxygenase pathway in noncardioembolic stroke and, incomplete cyclooxygenase inhibition is associated with recurrent thromboembolic events despite adequate aspirin compliance. It is likely that patients could receive a more efficacious stroke prevention if the dose of aspirin is tailored to individual needs as reflected by laboratory findings.

Sympathetic skin response in patients with lateral medullary syndrome.

We have carried out a prospective study of the sympathetic skin response (SSR) in 21 patients with lateral medullary syndrome (LMS), with the aim of identifying the most common pattern of SSR abnormalities and its possible correlation with clinical and radiological findings. The amplitude of the SSR recorded in the ipsilateral hand to the infarct was abnormally reduced in the patients as a group. However, using different stimulation and recording sites, and considering only the presence or absence of the response, we identified 5 different patterns of SSR abnormalities: 1. Normal responses; 2. Bilaterally absent responses to stimulation of the ipsilateral supraorbital nerve but not to other stimulation sites; 3. Absent responses in the side ipsilateral to the stroke, with normal responses in the contralateral side; 4. A combination of patterns 2 and 3; and 5. Absent responses to all stimuli. All patients with ipsilateral facial sensory loss had absent SSR to ipsilateral supraorbital nerve stimulation, while there was only a positive correlation between abnormal contralateral facial sensation and preservation of the SSR (Fisher's exact test P=0.003). No correlation was found between the pattern of SSR abnormalities and the infarct topography, assessed with the MRI. Our findings suggest that the damage to the SSR circuits of patients with LMS is not uniform, and follows an heterogeneous distribution independent from the MRI findings, and poorly related to the clinical sensory manifestations.

[Pyloric stenosis complicated by Wernicke-Korsakoff syndrome]. / Estenosis pilórica complicada con el síndrome de Wernicke-Korsakoff.

The Wernicke-Korsakoff syndrome (WKS) is a picture of oculomotor alterations, ataxia and confusion presented in chronic alcoholics. It has more rarely been described in non alcoholic patients with malnutrition. The case of a patient with ulcerous peptic disease of long evolution who consulted for a picture compatible with WKS following clinical manifestations of repeated vomiting secondary to complete pyloric stenosis is presented. The peculiarity of the picture and the convenience of prevention in malnourished patients receiving intravenous glucose sera is discussed.