Search

Background and Purpose: Many single cases and small series of Guillain-Barré syndrome (GBS) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported during the coronavirus disease 19 (COVID-19) outbreak worldwide. However, the debate regarding the possible role of infection in causing GBS is still ongoing. This multicenter study aimed to evaluate epidemiological and clinical findings of GBS diagnosed during the COVID-19 pandemic in northeastern Italy in order to further investigate the possible association between GBS and COVID-19., Methods: Guillain-Barré syndrome cases diagnosed in 14 referral hospitals from northern Italy between March 2020 and March 2021 were collected and divided into COVID-19-positive and COVID-19-negative. As a control population, GBS patients diagnosed in the same hospitals from January 2019 to February 2020 were considered., Results: The estimated incidence of GBS in 2020 was 1.41 cases per 100,000 persons/year (95% confidence interval 1.18-1.68) versus 0.89 cases per 100,000 persons/year (95% confidence interval 0.71-1.11) in 2019. The cumulative incidence of GBS increased by 59% in the period March 2020-March 2021 and, most importantly, COVID-19-positive GBS patients represented about 50% of the total GBS cases with most of them occurring during the two first pandemic waves in spring and autumn 2020. COVID-19-negative GBS cases from March 2020 to March 2021 declined by 22% compared to February 2019-February 2020., Conclusions: Other than showing an increase of GBS in northern Italy in the "COVID-19 era" compared to the previous year, this study emphasizes how GBS cases related to COVID-19 represent a significant part of the total, thus suggesting a relation between COVID-19 and GBS., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain., Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment., Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA 2 DS 2 -VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P =0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P =0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P =0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P =0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P =0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7])., Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Considering the similarities with other pandemics due to respiratory virus infections and subsequent development of neurological disorders (e.g. encephalitis lethargica after the 1918 influenza), there is growing concern about a possible new wave of neurological complications following the worldwide spread of SARS-CoV-2. However, data on COVID-19-related encephalitis and movement disorders are still limited. Herein, we describe the clinical and neuroimaging (FDG-PET/CT, MRI and DaT-SPECT) findings of two patients with COVID-19-related encephalopathy who developed prominent parkinsonism. None of the patients had previous history of parkinsonian signs/symptoms, and none had prodromal features of Parkinson's disease (hyposmia or RBD). Both developed a rapidly progressive form of atypical parkinsonism along with distinctive features suggestive of encephalitis. A possible immune-mediated etiology was suggested in Patient 2 by the presence of CSF-restricted oligoclonal bands, but none of the patients responded favorably to immunotherapy. Interestingly, FDG-PET/CT findings were similar in both cases and reminiscent of those observed in post-encephalitic parkinsonism, with cortical hypo-metabolism associated with hyper-metabolism in the brainstem, mesial temporal lobes, and basal ganglia. Patient's FDG-PET/CT findings were validated by performing a Statistical Parametric Mapping analysis and comparing the results with a cohort of healthy controls (n = 48). Cerebrum cortical thickness map was obtained in Patient 1 from MRI examinations to evaluate the structural correlates of the metabolic alterations detected with FDG-PET/CT. Hypermetabolic areas correlated with brain regions showing increased cortical thickness, suggesting their involvement during the inflammatory process. Overall, these observations suggest that SARS-CoV-2 infection may trigger an encephalitis with prominent parkinsonism and distinctive brain metabolic alterations., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Single cases and small series of Guillain-Barré syndrome (GBS) have been reported during the SARS-CoV-2 outbreak worldwide. We evaluated incidence and clinical features of GBS in a cohort of patients from two regions of northern Italy with the highest number of patients with COVID-19., Methods: GBS cases diagnosed in 12 referral hospitals from Lombardy and Veneto in March and April 2020 were retrospectively collected. As a control population, GBS diagnosed in March and April 2019 in the same hospitals were considered., Results: Incidence of GBS in March and April 2020 was 0.202/100 000/month (estimated rate 2.43/100 000/year) vs 0.077/100 000/month (estimated rate 0.93/100 000/year) in the same months of 2019 with a 2.6-fold increase. Estimated incidence of GBS in COVID-19-positive patients was 47.9/100 000 and in the COVID-19-positive hospitalised patients was 236/100 000. COVID-19-positive patients with GBS, when compared with COVID-19-negative subjects, showed lower MRC sum score (26.3±18.3 vs 41.4±14.8, p=0.006), higher frequency of demyelinating subtype (76.6% vs 35.3%, p=0.011), more frequent low blood pressure (50% vs 11.8%, p=0.017) and higher rate of admission to intensive care unit (66.6% vs 17.6%, p=0.002)., Conclusions: This study shows an increased incidence of GBS during the COVID-19 outbreak in northern Italy, supporting a pathogenic link. COVID-19-associated GBS is predominantly demyelinating and seems to be more severe than non-COVID-19 GBS, although it is likely that in some patients the systemic impairment due to COVID-19 might have contributed to the severity of the whole clinical picture., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

[Figure: see text].

Complete middle cerebral artery (MCA) stroke is a life-threatening condition, which can lead to death in the form of "malignant MCA syndrome"; characterized by massive brain edema and cerebral herniation. Moreover, patients with complete MCA infarct have high mortality due to complications. The aim of this study was to evaluate the clinical predictors of in-hospital mortality in patients with complete MCA stroke. Consecutive patients with complete MCA stroke were enrolled in a prospective single center in-hospital outcome study having mortality as its end point. Among 780 ischemic stroke patients, 125 had complete MCA strokes (16%) and 44 (35.2%) of these died in hospital. A high NIHSS-score (OR 1.17 95%CI 1.03-1.34, P=0.013) and high diastolic blood pressure on admission (OR 1.05 95%CI 1.01-1.09) resulted being independent predictors of in-hospital mortality in patients with complete MCA stroke. The median value of diastolic blood pressure at admission was 90 mmHg in patients who died and 80 mmHg in survivors (P=0.01). The risk of death increased by 5% for each mmHg increase in diastolic blood pressure on admission after adjusting for other risk factors. The rate of mortality was 22% in patients with diastolic blood pressure lower than 90 mmHg, 56% for those with diastolic blood pressure between 90 and 109 mmHg and 67% for those with diastolic blood pressure higher than 110 mmHg. This study suggests that high diastolic blood pressure on admission in acute MCA stroke patients is linearly correlated with in-hospital mortality.

Stroke is the leading cause of acquired motor disability in the adult. Neuropsychological sequelae are common after vascular brain injury. While left cortical signs and symptoms are clearly evident at neurological examination, right hemispheric dysfunction must be carefully pursued and sometimes can be underrecognized. Indeed, patients with right hemispheric strokes present later to an emergency department and have a lower chance of receiving intravenous recombinant tissue plasminogen activator. For a better comprehension of clinical signs and symptoms in right acute hemispheric stroke, in this chapter we present a review of the principle clinical syndromes., (Copyright © 2012 S. Karger AG, Basel.)

In patients admitted for acute stroke, the clinical burden of acute myocardial infarction (AMI) and acute heart failure (AHF) is unclear. In these patients we evaluated: (1) the prevalence of AMI and AHF; (2) the effect of AMI and/or AHF on mortality at 3 months; (3) the risk factors for AMI and/or AHF. Consecutive patients admitted for acute stroke were prospectively assessed for the occurrence of AMI and AHF during the hospital stay. Mortality at 3 months was also assessed. Multiple logistic regression analysis was used to identify independent predictors for cardiovascular events and death. Eight hundred fourteen patients were included in the study, 685 of which had an ischemic stroke (84.2%). Fifty-three patients (6.5%) had an AMI and/or an AHF (13 AMI alone, 28 AHF alone and 12 AMI and AHF); all these events occurred in patients with ischemic stroke. At 3 months, 151 patients had died (18.8%). Among patients who had an AMI and/or AHF, 60.4% died as compared with 119 of the 750 patients who did not have these events (15.9%) (p < 0.0001). At logistic regression analysis, AMI and/or AHF were associated with increased mortality at 3 months (p = 0.001). History of angina (p = 0.003), AMI in the 3 months before admission (p < 0.0001), hyperglycemia (p = 0.047), and high NIHSS on admission (p < 0.0001) were associated with in hospital AMI and/or AHF. In acute stroke patients, AMI and AHF are common and associated with increased mortality at 3 months. Whether a timely and more careful management of these complications may improve clinical outcome should be further explored.

The dose of warfarin needed to obtain a therapeutic anticoagulation level varies widely among patients and can undergo abrupt changes for unknown reasons. Drug interactions and genetic factors may partially explain these differences. Intestinal flora produces vitamin K2 (VK2) and patients with small intestinal bacterial overgrowth (SIBO) rarely present reduced INR values due to insufficient dietary vitamin K. The present study was undertaken to investigate whether SIBO occurrence may affect warfarin dose requirements in anticoagulated patients. Based on their mean weekly dose of warfarin while on stable anticoagulation, 3 groups of 10 patients each were defined: low dose (LD, or=70 mg/wk). Each patient underwent a lactulose breath test to diagnose SIBO. Plasma levels of warfarin and vitamin K-analogues were also assessed. Patients with an altered breath test were 50% in the VHD group, 10% in the HD group, and none in the LD group (P=0.01). Predisposing factors to SIBO were more frequent in the VHD group, while warfarin interfering variables were not. VHD patients were younger and had a higher plasma vitamin K1 (VK1) concentration (P>0.05). On the contrary, the plasma VK2 levels tended to be lower. This pilot study suggests that SIBO may increase a patient's warfarin dose requirement by increasing dietary VK1 absorption through the potentially damaged intestinal mucosa rather than increasing intestinal VK2 biosynthesis. Larger studies are needed to confirm these preliminary data and to evaluate the effects of SIBO decontamination on warfarin dosage., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Stroke has a greater effect on women than men owing to the fact that women have more stroke events and are less likely to recover. Age-specific stroke rates are higher in men; however, because of women's longer life expectancy and the much higher incidence of stroke at older ages, women have more stroke events than men overall. The aims of this prospective study in consecutive patients were to assess whether there are gender differences in stroke risk factors, treatment or outcome. Consecutive patients with ischemic stroke were included in this prospective study at four study centers. Disability was assessed using a modified Rankin Scale score (>or=3 indicating disabling stroke) in both genders at 90 days. Outcomes and risk factors in both genders were compared using the chi(2) test. Multiple logistic regression analysis was used to identify any independent predictors of outcome. A total of 1136 patients were included in this study; of these, 494 (46%) were female. Women were statistically older compared with men: 76.02 (+/- 12.93) and 72.68 (+/- 13.27) median years of age, respectively. At admission, females had higher NIH Stroke Scale scores compared with males (9.4 [+/- 6.94] vs 7.6 [+/- 6.28] for men; p = 0.0018). Furthermore, females tended to have more cardioembolic strokes (153 [30%] vs 147 [23%] for men; p = 0.004). Males had lacunar and atherosclerotic strokes more often (146 [29%] vs 249 [39%] for men; p = 0.002, and 68 [13%] vs 123 [19%] for men; p = 0.01, respectively). The mean modified Rankin Scale score at 3 months was also significantly different between genders, at 2.5 (+/- 2.05) for women and 2.1 (+/- 2.02) for men (p = 0.003). However, at multivariate analysis, female gender was not an indicator for negative outcome. It was concluded that female gender was not an independent factor for negative outcome. In addition, both genders demonstrated different stroke pathophysiologies. These findings should be taken into account when diagnostic workup and treatment are being planned.

Background: Data on the correlation between blood pressure (BP) on admission and clinical outcome in patients with acute stroke are conflicting. The aims of the present study in consecutive patients with acute ischemic stroke were to evaluate: (a) the relationship between systolic or diastolic BP on admission and mortality at 3 months; (b) the role of carotid artery disease ipsilateral to the index stroke on this relationship., Methods: Consecutive patients admitted to four Italian hospitals with objectively diagnosed ischemic stroke were included in this prospective study., Results: A total of 1467 patients (mean age 72.6+/-13.2 years; males 53.3%) with acute ischemic stroke were evaluated. At 3 months, 13 patients were lost at follow-up and 133 had died (9.2%). In patients with systolic BP <140mmHg, mortality was 11% (40/362), in patients with systolic BP between 140 and 179mmHg 8.3% (68/823) and in patients with systolic BP >or=180mmHg 9.2% (25/269). Patients with systolic BP <140mmHg were more likely to die within 90 days (OR 3.4; 95% CI 1.4-8.5, p=0.008, after adjusting for other risk factors) when compared to those with systolic BP between 140 and 179mmHg (reference group with OR=1.0). Systolic BP >or=180mmHg was not associated with increased mortality (OR 0.4; 95% CI 0.1-1.3, p=0.13). Two-hundred and thirty patients out of 1278 with anterior circulation stroke had a stenosis (>or=50% on ultrasonography) or an occlusion of the internal carotid ipsilateral to the index stroke. At 3 months, 29 patients had died (12.7%). In patients with systolic BP <140mmHg, mortality was 20.4% (11/54), in those with systolic BP between 140 and 179mmHg 13.0% (16/123) and in those with systolic BP >or=180mmHg 3.9% (2/51). Patients with systolic BP >or=180mmHg were less likely to die within 90 days (OR 0.1; 95% CI 0.0-0.5, p=0.022 after adjusting for other risk factors) compared to those with systolic BP between 140 and 179mmHg. Systolic BP <140mmHg was not associated with increased mortality (OR 6.3; 95% CI 0.8-48.0, p=0.08)., Conclusions: In the overall population, low BP was an independent risk factor for mortality. In patients with stenosis >/=50% or occlusion of the carotid ipsilateral to the index stroke, high BP was associated with a lower mortality at 3 months.

Adult's mastocytosis is usually associated with persistent systemic involvement and c-kit 816 mutation, while pediatrics disease is mostly limited to the skin and often resolves spontaneously. We prospectively included 142 adult patients with histologically proven mastocytosis. We compared phenotypic and genotypic features of adults patients whose disease started during childhood (Group 1, n = 28) with those of patients whose disease started at adult's age (Group 2, n = 114). Genotypic analysis was performed on skin biopsy by sequencing of c-kit exons 17 and 8 to 13. According to WHO classification, the percentage of systemic disease was similar (75 vs. 73%) in 2 groups. C-kit 816 mutation was found in 42% and 77% of patients in groups 1 and 2, respectively (p<0.001). 816 c-kit mutation was associated with systemic mastocytosis in group 2 (87% of patients with systemic mastocytosis vs. 45% with cutaneous mastocytosis, p = 0.0001). Other c-kit activating mutations were found in 23% of patients with mastocytosis' onset before the age of 5, 0% between 6 and 15 years and 2% at adults' age (p<0.001). In conclusion, pathogenesis of mastocytosis significantly differs according to the age of disease's onset. Our data may have major therapeutic relevance when considering c-kit-targeted therapy.

Background: Antiplatelet treatment remains the first choice for primary and secondary prevention of vascular diseases; even so, expected benefits may be offset by risk of bleeding, particularly cerebral hemorrhage. The aim of this study was to assess the influence of antiplatelet treatment on clinical outcome at hospital discharge., Materials and Methods: Consecutive patients with first-ever stroke due to a primary intraparenchymal hemorrhage were prospectively identified over a 4-year period (2000-2003). Data on hemorrhage location, vascular risk factors, and antiplatelet and anticoagulant treatment were collected. At discharge, outcome was measured using the modified Rankin Scale (disabling stroke > or =3). Patients treated with anticoagulant therapy were excluded from the study., Results: Of 457 consecutive patients with cerebral hemorrhage, 94 (20.5%) had been taking antiplatelet agents. The treated patients (mean age for antiplatelet group 78.9 +/- 9.0 years) were older than the nontreated patients (73.8 +/- 9.4, p = 0.02). In-hospital mortality was 23.4 and 23.1% (p = n.s.) for patients who had been taking antiplatelet agents or no treatment. Poor outcome at discharge was found in 52.1 and 59.7% (p = n.s.), respectively. Univariate analysis showed that age and coma at admission were predictors of disability at discharge, but antiplatelet treatment was not. Additionally, age and coma were shown to be determinants of disability at discharge after multivariate analysis: OR 1.03 per year (95% CI: 1.018-1.049), p < 0.001 and OR 1.68 (95% CI: 1.138-2.503), p = 0.009, respectively., Conclusions: Hemorrhagic stroke continues to be responsible for a high percentage of disability and death. Furthermore, it was seen here that functional outcome was independent of previous antiplatelet treatment.

To understand the etiopathogenetic mechanisms of stroke and to target prevention, we need to know how risk factors differ among etiological subtypes. Our aims were to determine the different profile of risk factors for ischemic and hemorrhagic stroke subtypes in our cohort from the Perugia Hospital-Based Stroke Registry. We analyzed the characteristics and the different risk factors of 2,395 first-ever consecutive stroke patients admitted to the Perugia Hospitals in the period between January 1, 1998 and December 31, 2002. The prevalence of cerebrovascular risk factors in each stroke subtype was analyzed independently and compared with other subtypes of stroke pooled together by means of univariate analysis and logistic regression models. Hypertension occurred in 61% of patients; familial history of stroke in 41.6%; vascular disease in 27.2%; embolic heart disease in 22.3%; cigarette smoking in 21.6%. Different potentially modifiable risk factors profiles were identified for each ischemic subtype of stroke, while in hemorrhagic lobar stroke subtypes, only male gender was an independent risk factor.

Predictors of poor outcome after first-ever stroke within 3 months in consecutive patients admitted to our Stroke Unit were defined. Factors included age, sex, risk factors, occurrence of transient ischemic attacks, extension of cerebral infarction, presumed cause of stroke, clinical findings, and demographic characteristics. Multiple regression models were used to analyze predictors of mortality, dependency and stroke recurrence. A total of 435 patients with first-ever stroke were included. Of these, 358 patients had ischemic stroke and 77 hemorrhagic stroke. Three-month mortality rate was 20.5%. After the same period, 24.6% of survivors were dependent (mRS > or = 3) and 5.0% of patients had recurrent stroke. Age, the presence of atrial fibrillation, impaired consciousness on admission, and stroke severity were related to mortality. The presence of stroke due to an undetermined cause or small vessel disease was associated with lower mortality. Partial anterior circulation syndrome or lacunar syndrome were both related to better outcome. The best predictors for dependency after 3 months were age and stroke severity. The only variable identified as the best predictor for recurrence was the presence of diabetes mellitus.

Background: The clinical outcome in patients with stroke associated with internal carotid artery (ICA) occlusion is poor, although a minority may recover without dependency. The purposes of this study were (1) to assess the predictive factors of adverse outcome in patients with stroke associated with an occlusion of the ICA and (2) to evaluate the rate of spontaneous recanalization of an occluded ICA., Methods: A total of 177 consecutive patients with first-ever ischemic stroke associated with ICA occlusion were prospectively examined from the Perugia Stroke Registry. Mean age was 71.4 +/- 14.3 years; 53% were males. Multiple regression models were used to analyze predictors of mortality, dependency and ipsilateral stroke recurrence., Results: The most probable cause of occlusion was atherosclerosis in 65%, cardioembolism in 22%, dissection in 9% and other causes in 4%. Thirty percent of the patients died within 30 days. After a mean follow-up of 420 days (range 1-1,970 days), 45% of the patients had died and 75% had died or were disabled. Another 6% of the patients had a recurrent stroke ipsilateral to the occluded carotid artery. Age was the only predictor of 30-day mortality (77.7 +/- 9.7 vs. 68.7 +/- 15.2 years; p = 0.03) and of long-term mortality or disability (p < 0.003). Hypertension (OR 0.42; 95% CI 0.17-1.00; p = 0.05) was associated with a better outcome within 30 days from stroke onset. Previous ipsilateral transient ischemic attack (OR 0.24; 95% CI 0.06-0.89; p = 0.03) and hyperlipidemia (OR 0.38; 95% CI 0.15-0.99; p = 0.049) were predictors of a better outcome with respect to long-term mortality or disability. No predictors of ipsilateral stroke recurrence were found. One hundred and five out of 177 patients had adequate follow-up ultrasound data. After a mean follow-up of 1.8 years, 10 patients had recanalization of the occluded ICA (2/71 atherosclerosis, 3/19 cardioembolism and 5/15 dissection)., Conclusions: After a mean follow-up of 1.2 years, 45% of the patients with stroke associated with ICA occlusion had died, while 75% had died or were functionally dependent. The presence of either previous ipsilateral transient ischemic attack, hypertension or hyperlipidemia was associated with a favorable outcome. Recanalization of an occluded ICA occurred in a minority of patients and it was associated with cardioembolism and with arterial dissection., (Copyright (c) 2005 S. Karger AG, Basel.)

Background: Dysphagia is common after stroke. We aimed to study the prognosis of dysphagia (assessed clinically) over the first 3 months after acute stroke and to determine whether specific neurovascular-anatomical sites were associated with swallowing dysfunction., Methods: We prospectively examined consecutive patients with acute first-ever stroke. The assessment of dysphagia was made using standardized clinical methods. The arterial territories involved were determined on CT/MRI. All patients were followed up for 3 months., Results: 34.7% of 406 patients had dysphagia. Dysphagia was more frequent in patients with hemorrhagic stroke (31/63 vs. 110/343; p = 0.01). In patients with ischemic stroke, the involvement of the arterial territory of the total middle cerebral artery was more frequently associated with dysphagia (28.2 vs. 2.2%; p < 0.0001). Multivariate analysis revealed that stroke mortality and disability were independently associated with dysphagia (p < 0.0001)., Conclusions: The frequency of dysphagia was relatively high. Regarding anatomical-clinical correlation, the most important factor was the size rather than the location of the lesion. Dysphagia assessed clinically was a significant variable predicting death and disability at 90 days., (Copyright 2004 S. Karger AG, Basel)

This study reports the characteristics of stroke patients admitted to our hospital in the period Jan 1st, 1998-Dec 31st 1999. Seven hundred and ninety seven consecutive subjects (412 males; mean age 71 +/- 13 years) with a first-ever stroke were registered. Two-thirds of patients (65%) were admitted to the Stroke Unit (SU). The remaining part was managed in six general medicine wards (GM) or other services [neurosurgery and intensive care units (ICU+ NS)]. Ischemic stroke occurred in 534 subjects (67%). The high prevalence (30.1%) of haemorrhages can be partly explained by the presence of specialized neurosurgical services. Athero-thrombotic infarctions occurred in 21.7% of patients, lacunar in 24.7%, cardioembolic in 18.1%, other determined in 6.1%, and other undetermined in 27.5%. Overall hospital mortality was 10%. In cerebral hemorrhage mortality was 18% (44/240) vs. 6.3% (32/534) in ischemic stroke (p < 0.05). The distribution of stroke types and mortality was similar to other previous reports.

Caspases play a crucial role as apoptotic effectors; their potential implication in tumorigenesis remains to be clarified. We investigated the expression and function of caspases 7, 8, and 9 in colon cancer tissues and cell lines. Immunohistochemistry (IHC) showed downregulation of caspase 7 (22 of 26 cases) and caspase 9 (12 of 26 cases) in colonic cancer samples compared with normal mucosa on the same tissue section. Caspase 8 expression was unchanged or slightly upregulated (19 of 27 cases). The combination of IHC and Western blot analysis showed expression of the proforms of caspases 7, 8, and 9 in HT29-19A and HT29-16E colonic carcinoma cell lines. Apoptosis could be induced by staurosporine in both HT29 cell lines, with a sensitivity similar to that of the HGT cell line, but lower than that of the DAUDI cell line. Apoptosis induction in HT29 cells was concomitant with processing of caspases 3, 7, 8, and 9 and was inhibited by the caspase inhibitor ZVAD. Our data show that (1) human colon cancer cells downregulate caspase 7 and, to a smaller extent, caspase 9 in vivo and (2) in vitro staurosporine-induced apoptosis of colonic cancer cells involves caspases 7 and 9. Caspase 7 deficiency thus appears as a new immunohistochemical marker of colonic neoplasia; its correction represents a potential basis for new therapies.

The present review focuses on recent insights into the regulation of caspases by other components of the apoptotic pathway, including the mechanisms by which caspase activation influence the death of lymphoma cells. In the light of our recent findings and similar observations of other investigators, it is likely that lymphoma cells possess the complete caspase machinery required for the apoptotic process. Inhibition of caspases activation appears as a potential mechanism to explain apoptotic defects of malignant B-cells, and thus may constitute the basis for new cancer therapies.

Lymphoma cells often display in vitro resistance to FAS-induced apoptosis, in which caspases act as crucial cell death effectors. Following FAS stimulation, caspase-8 activates caspase-3, which in turn activates the caspase-activated DNAse (CAD) by proteolysis of its inhibitor (ICAD). To investigate the mechanism of FAS resistance, the expression of caspase-8 was analysed by immunohistochemistry, together with that of the substrates caspase-3 and ICAD, in 52 representative samples from non Hodgkin's lymphoma (NHL), 12 from Hodgkin's disease (HD), and eight benign lymphoid tissues. In benign tissues, caspase-8 was co-expressed with caspase-3 in the cytoplasm in germinal centre (GC) cells and was co-expressed with ICAD in the nuclei of the mantle and marginal zone cells. ICAD expression was weak or absent in GC cells. Cytoplasmic staining for both caspase-8 and caspase-3 was present in 11/12 cases of diffuse large cell B-NHL. Caspase-8 positivity was nuclear and cytoplasmic in 9/9 follicular NHLs, in 5/5 mantle cell NHLs and in 6/6 marginal zone NHLs. Five out of six peripheral T-cell NHLs expressed cytoplasmic caspase-8. Ten out of the 12 HD cases lacked significant cytoplasmic staining for caspase-3 and caspase-8 in the majority of Reed-Sternberg cells. All lymphoma cases exhibited predominant nuclear ICAD positivity. Subcellular fractionation analysis of three lymphoma samples and normal mantle zone cells confirmed that ICAD and caspase-8 were at least partly localized in the nucleus. These results show that the profile of caspase-8 expression is correlated with histological lymphoma subtypes; that caspase-8 is co-expressed with caspase-3 in GC cells and their neoplastic counterparts; that ICAD has an immunohistochemical nuclear localization in vivo; and that caspase-8 and ICAD can be co-expressed in the nuclei of mantle zone and marginal zone cells; their unexpected nuclear localization allows a reappraisal of the biochemical cascade of caspase activation., (Copyright 2000 John Wiley & Sons, Ltd.)