Rocco Totaro

Contribution of Atrial Fibrillation to Incidence and Outcome of Ischemic Stroke Results From a Population-Based Study

Background and Purpose— Atrial fibrillation (AF) is a major risk factor for ischemic stroke and its prevalence increases steeply with age. Population-based data on its influence on stroke outcome are scarce. Methods— We evaluated the prevalence of AF and its influence on prognosis in patients with a first-ever ischemic stroke from a population-based registry. Results— The presence of AF at stroke onset and during the acute phase was confirmed by a standard electrocardiogram in 869 (24.6%) of 3530 patients with ischemic stroke. With respect to patients without the arrhythmia, those with AF were more frequently women, aged 80 years and older, with coronary heart disease and peripheral arterial disease. The presence of AF was associated with high 30-day (32.5%; 95% CI, 29.3 to 35.6) and 1-year case-fatality rates (49.5%; 95% CI, 46.2 to 52.8), with a higher stroke recurrence rate within the first year of follow-up (6.6% versus 4.4%; P=0.046) and with the worst survival after an average follow-up of 45.2 months (P<0.0001). At the multivariate Cox regression analysis, AF was an independent predictor of 30-day and 1-year mortality. Approximately 17% of all deaths were attributable to the presence of AF. Conclusions— We found a high prevalence of AF in patients with a first-ever ischemic stroke, especially among elderly women. The overall contribution of AF to stroke mortality was relevant, suggesting that together with new strategies to prevent the development of the arrhythmia more appropriate treatments are needed, mostly in elderly women.

Stroke in young adults in the community-based L'Aquila registry: incidence and prognosis.

Background and Purpose— Stroke type in the young may influence the outcome and may have a dramatic impact on the quality of life in survivors. This study aimed to evaluate the incidence and prognosis of first-ever stroke in the young and to make comparisons with older patients within a well-defined population. Methods— All first-ever strokes occurring in the L’Aquila district, central Italy, were traced by active monitoring of inpatient and outpatient health services. Incidence rates were standardized to the 1996 European population according to the direct method. Long-term survival was estimated by the Kaplan-Meier method; outcome in survivors was evaluated by the modified Rankin scale. Results— Of 4353 patients who had a first-ever stroke, 89 patients <45 years of age (55 men and 34 women) (2%) were identified in a 5-year period. Mean age±SD was 36.1±8.1 years. Twenty patients (22.5%) had a subarachnoid hemorrhage, 18 (20.2%) an intracerebral hemorrhage, and 51 (57.3%) a cerebral infarction. The corresponding proportions in patients >45 years of age were 2.4%, 13.3%, and 83.1%. Neuroimaging studies of the brain detected 14 intracranial aneurysms and 6 arteriovenous malformations in 20 of 38 patients (52.6%) with either subarachnoid (n=17) or intracerebral (n=3) hemorrhage. The crude annual incidence rate was 10.18/100 000 (95% CI, 8.14 to 12.57) and 10.23/100 000 when standardized to the 1996 European population. The 30-day case-fatality rate was 11.2% (95% CI, 6.2 to 19.4). Patients with subarachnoid hemorrhage had the highest proportion of good recovery (60%), patients with intracerebral hemorrhage had the highest mortality (44%), and patients with cerebral infarction had the highest proportion of severe disability (47%). Conclusions— Stroke patients <45 years of age showed a disproportionate cumulative high prevalence (42.7%) of subarachnoid and intracerebral hemorrhage with respect to older patients (15.7%), mainly (52.6%) due to aneurysms and arteriovenous malformations. Therefore, screening procedures and preventive strategies in the young should also be addressed to subjects at risk of subarachnoid and intracerebral hemorrhage.

A population-based study of the incidence and prognosis of lacunar stroke

Objective: To evaluate incidence and prognosis of lacunar stroke in a prospective, population-based patient registry. Methods: The authors included first-ever strokes occurring between 1994 and 1998. They assessed incidence, risk factors, mortality, and recurrence in patients with lacunar stroke. Results: The authors identified 491 patients (15.3%) with lacunar stroke (252 men and 239 women) and 2,153 patients (67.3%) with nonlacunar stroke (998 men and 1,155 women). Crude annual incidence rate for a first-ever lacunar stroke was 33.0/100,000 (95% CI 30.2 to 36.0). At the univariate logistic regression analysis among patients with lacunar stroke there was a higher proportion of cigarette smoking and hypercholesterolemia and a lower proportion of chronic atrial fibrillation than in patients with nonlacunar stroke. For lacunar stroke, the 30-day case-fatality rate was 4.3% (95% CI 2.5 to 6.1) and the 1-year case-fatality rate was 13.0% (95% CI 10.0 to 16.0). During the first year of follow-up the average annual stroke recurrence rate was lower in patients with lacunar (2.83%; 95% CI 1.36 to 4.30) than in those with nonlacunar stroke (5.10%; 95% CI 4.17 to 6.03) while from the second year onward, rates were similar in both groups. Conclusion: In the short term, patients with nonlacunar stroke had more vascular events, but in the long term, the risk of death and of stroke recurrence was similar.

Long-Term Prognosis of Cerebral Ischemia in Young Adults

Background and Purpose —Prognosis of ischemic stroke in young adults is reported as favorable, and transient ischemic attack (TIA) is commonly considered a benign event. We investigated long-term outcome and prognostic predictors of cerebral ischemia in patients under 45 years of age. Methods —Three hundred thirty-three patients aged 15 to 44 years who suffered from a first-ever TIA or ischemic stroke were prospectively followed up with annual clinical evaluation or complete phone interview. End points were the composite outcome event of stroke, myocardial infarction, and vascular or nonvascular death and death from all causes. The probability of event-free survival was estimated by the Kaplan-Meier method. Univariate and multivariate estimates of hazard ratios were calculated according to the Cox proportional hazards analysis. Results —An average follow-up of 96 months was available in 330 patients (99.1%). Survival was worse in patients with stroke at entry (86.5%) than in those with TIA (97.1%). Mortality in both groups was significantly higher than in the general population (standardized mortality ratio [SMR] 14.5, P P =0.002). The average annual mortality rate was higher during the first (3.94%, 95% CI 1.84 to 6.04) than in the subsequent years. The average annual incidence rate of new stroke was higher in patients with stroke than in those with TIA at entry, and it declined from 1.56% (95% CI 0.21 to 2.91) during the first year to 0.06% (95% CI 0.04 to 0.08) at the end of the follow-up. Myocardial infarction occurred later, after the first year, with similar rates in patients with stroke and TIA at entry. The average annual rates of new stroke (2.36%), myocardial infarction (1.68%), and death (3.05%) were higher in patients with the mixed atherothrombotic and cardioembolic etiology than in the remaining patients. Male gender, age >35 years, stroke at entry, and cardiac diseases were independent predictors of the composite outcome event at the Cox regression analysis, whereas only stroke at entry and cardiac diseases predicted death from all causes. Conclusions —Stroke and TIA in young adults have severe prognostic implications, because the mortality risk was highly increased with respect to the general population. Preventive measures are strongly recommended in the presence of any unfavorable prognostic profile.

Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis

Objective: To assess pregnancy and fetal outcomes after in utero exposure to interferon-β (IFNβ) in all pregnancies occurring in women with multiple sclerosis (MS) during the study period, with a specific focus on the risk of spontaneous abortion. Methods: In this cohort study, data were gathered through a standardized, semi-structured interview. Patients who discontinued IFNβ less than 4 weeks from conception (exposed) were compared with those who had discontinued the drug at least 4 weeks from conception or who were never treated (not exposed). Possible confounders were handled through multivariate analyses adjusted for propensity score (PS). Results: We collected data on 396 pregnancies in 388 women, 88 classified as exposed (mean exposure 4.6 ± 5.8 weeks). IFNβ exposure was not associated with an increased risk of spontaneous abortion (PS-adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.4 to 2.9, p = 0.88), although it was associated with both lower baby weight (PS-adjusted β −113.8, p < 0.0001) and length (PS-adjusted β −1.102, p < 0.0001). Proportion of spontaneous abortion in exposed patients fell within the range expected for the Italian population in the same period. IFNβ exposure (PS-adjusted OR 2.11, 95% CI 1.18 to 3.78, p = 0.012) and cesarean delivery were the only predictors of preterm delivery. In the exposed group, we did not observe any significant fetal complications, malformations, or developmental abnormalities over a median follow-up of 2.1 years. Conclusions: Our findings point to the relative safety of IFNβ exposure times of up to 4 weeks and can assist neurologists facing therapeutic decisions in women with MS with a pregnancy plan.

Noninvasive measurement of cerebral hemoglobin oxygen saturation using two near infrared spectroscopy approaches

Spatially resolved spectroscopy (SRS) is a new near infrared spectroscopy (NIRS) method that, using the multi-distance approach, measures local cerebral cortex hemoglobin oxygen saturation [J. Matcher, P. Kirkpatrick, K. Nahid, M. Cope, and D. T. Delpy, Proc. SPIE 2389, 486-495 (1995)]. Using a conventional continuous wave NIRS photometer, cerebral venous oxygen saturation (SvO2) can be calculated from oxyhemoglobin and total hemoglobin rise induced by partial occlusion of jugular vein [C. E. Elwell, S. J. Matcher, L. Tyszczuk, J. H. Meek, and D. T. Delpy, Adv. Exp. Med. Biol. 411, 453-460 (1997)]. The aim of this study was to compare direct measurements of forehead tissue oxygenation index (TOI) with the calculated SvO2 during venous occlusion in 16 adult volunteers using a clinical two-channel SRS oximeter (NIRO-300). Measured TOI and calculated SvO2 values of either right or left forehead did not significantly differ. A good agreement between the two NIRS methods was also demonstrated. On 16 other subjects, no significant differences were found between the right and left forehead TOI values measured simultaneously, and between the TOI values measured by channel 1 or 2 on the same side. The results confirm that cerebral cortex hemoglobin oxygen saturation, measured directly by the SRS method, reflects predominantly the saturation of the intracranial venous compartment of circulation.

Breastfeeding is not related to postpartum relapses in multiple sclerosis

Objective: To assess the relationship between breastfeeding and risk of puerperal relapses in a large cohort of patients with multiple sclerosis (MS). Methods: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centers, and gathered data on breastfeeding through a standardized interview. The risk of relapses after delivery was assessed using the Cox regression analysis. Results: A total of 302 out of 423 pregnancies in 298 women resulted in full-term deliveries. Patients were followed up for at least 1 year after delivery. The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not. In the multivariate analysis, adjusting for age at onset, age at pregnancy, disease duration, disability level, and relapses in the year prior to pregnancy and during pregnancy, treatment with disease-modifying drugs (DMDs), and exposure to toxics, the only significant predictors of postpartum relapses were relapses in the year before pregnancy (hazard ratio [HR] = 1.5; 95%confidence interval [CI] 1.3–1.9; p < 0.001) and during pregnancy (HR = 2.2; 95% CI 1.5–3.3; p < 0.001). Conclusions: In our sample, postpartum relapses were predicted only by relapses before and during pregnancy. Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity. Our results can assist neurologists facing the breastfeeding issue in mother counseling and shared decision-making. Especially, among patients with high risk of postpartum relapses, breastfeeding may not be feasible and early postpartum treatment should be an option.

Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study

BackgroundOnly few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion.Materials and methodsWe recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002–2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons.ResultsData on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure.ConclusionsData in our cohort show that mother’s GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.

Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study

BackgroundFew studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS.MethodsIn the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis.ResultsWe collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005).ConclusionsOur findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.

Cerebrovascular Reactivity Evaluated by Transcranial Doppler: Reproducibility of Different Methods

Transcranial Doppler is routinely used to assess the cerebrovascular reactivity, despite scarce information on its reproducibility. We evaluated the reproducibility of cerebrovascular reactivity measurements by this method utilizing different vasodilatory and vasoconstrictor stimuli. The cerebrovascular reactivity was measured in 45 healthy volunteers during hypercapnia induced by inhalation of a mixture of 5% CO2 and 95% O2, breath holding and rebreathing, and during hypocapnia induced by voluntary hyperventilation. Three sets of measurements were performed at times 0, 1, and 24 h to assess the within-observer short- and long-term reproducibility. The reproducibility was analyzed using the intraclass correlation coefficient. For the CO2 inhalation method, a good short-term (rI = 0.55; 95% CI = 0.39–0.68) and a good long-term (rI = 0.43; 95% CI = 0.25–0.59) reproducibility was found. For the breath-holding method a good short-term agreement was found (rI = 0.41; 95% CI = 0.22–0.57), while the long-term reproducibility was poor (rI = 0.17; 95% CI = –0.03–0.36). Rebreathing showed a fair (rI = 0.31; 95% CI = 0.11–0.48) short-term and a poor (rI = 0.17; 95% CI = –0.03–0.36) long-term reproducibility. For voluntary hyperventilation, the short-term reproducibility was good (rI = 0.53; 95% CI = 0.36–0.66), and the long- term reproducibility was fair (rI = 0.31; 95% CI = 0.11–0.48). In our study, CO2 inhalation and voluntary hyperventilation had the highest reproducibility and should be preferred when assessing cerebral vasoreactivity, especially in follow-up studies.