Raffaella Cerqua

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

The Role of Carotid Atherosclerosis in Alzheimer's Disease Progression

The aim of this 12-month prospective study was to establish whether severe internal carotid artery stenosis is associated with faster progression of the cognitive impairment in patients with Alzheimers disease (AD). Four hundred and eleven patients with AD underwent extracranial carotid Doppler ultrasound evaluation. Cerebrovascular reactivity to hypercapnia was measured by means of the breath-holding index (BHI) in those with severe carotid artery stenosis using transcranial Doppler ultrasonography. Cognitive status was quantified with the Mini Mental State Evaluation (MMSE). Ninety-eight patients had severe carotid artery stenosis, 41 right (group 1), and 57 left (group 2), while 313 had no significant stenosis (group 3). Group 1 and 2 patients showed an increased probability compared with group 3 patients to develop severe dementia (MMSE scores < 21) during the 12-month follow-up period: OR 2.36 (95% CI: 1.14-4.87) and OR 4.90 (95% CI: 2.65-9.04), respectively (p < 0.05, multiple logistic regression analysis). A BHI value ipsilateral to the stenosis < 0.69 predicted a worse MMSE score at 12 months irrespective of the side of the stenosis. These findings suggest that severe internal carotid artery stenosis can be considered as a marker of a faster rate of progression of the cognitive decline in AD. They also indicate that cerebral hemodynamic evaluation could be applied to identify patients at higher risk of rapid cognitive decline, who may benefit from aggressive treatment, and warrant investigation of the advantages of carotid revascularization procedures in these patients.

Ultrasonographic markers of vascular risk in patients with asymptomatic carotid stenosis.

Six-hundred twenty-one subjects with unilateral asymptomatic severe internal carotid artery (ICA) stenosis were prospectively evaluated with a median follow-up of 27 months (min = 6, max = 68). Vascular risk profile, plaque characteristic, stenosis progression, and common carotid artery intima-media thickness (IMT) were investigated in all patients. Outcome measures were occurrence of ischemic stroke ipsilateral to ICA stenosis and vascular death, while myocardial infarction, contralateral strokes, and transient ischemic attack were considered as competing events. A total of 99 subjects (15.9%) suffered from a vascular event. Among them, 39 were strokes ipsilateral to the stenosis (6.3%). Degree of stenosis, stenosis progression, and common carotid artery IMT resulted as independent predictive factors of ipsilateral stroke. Considering a stenosis of 60% to 70% as reference, a degree between 71% and 90% increased the risk by 2.45, while a degree between 91% and 99% increased the risk by 3.26. The progression of stenosis was a strong risk factor (hazard ratio = 4.32). Finally, the role of carotid IMT was confirmed as crucial additional measure, with an increased risk by 25% for each 0.1 mm IMT increase. Our data suggest that IMT, stenosis progression and severity should be considered as risk factors for cerebrovascular events in asymptomatic subjects with severe ICA stenosis.

Intravenous thrombolysis for acute ischemic stroke associated to extracranial internal carotid artery occlusion: the ICARO-2 study.

Background and Purposes: In a case-control study in patients with acute ischemic stroke and extracranial internal carotid artery (eICA) occlusion, thrombolytic treatment was associated with increased mortality. The aim of this cohort study was to assess the efficacy and safety of thrombolysis in patients with eICA occlusion compared to those without eICA occlusion. Methods: Consecutive patients treated with intravenous tissue-type plasminogen activator within 4.5 h from symptom onset included in the Safe Implementation of Thrombolysis in Stroke – International Stroke Thrombolysis Registry (SITS-ISTR) in 20 Italian centres were analyzed. Acute carotid occlusion was diagnosed using ultrasound examination, angio-CT scan or angio-MRI. Since the SITS-ISTR database did not plan to report the site of vessel occlusion, each participating center provided the code of the patient with eICA occlusion. Patients were divided into 2 groups, those with and those without eICA occlusion. Main outcome measures were: death, disability (modified Rankin Scale, mRS, 3–6) and any intracranial bleeding at 3 months. Multiple logistic regression analysis was performed to reveal predictors for main outcomes. The following variables of interest were included in the analysis: presence of eICA occlusion, age, gender, diabetes mellitus, hyperlipidemia, atrial fibrillation, congestive heart failure, previous stroke, current smoking, antiplatelet treatment at stroke onset, baseline NIHSS score, baseline blood glucose, cholesterol and blood pressure, history of hypertension and stroke onset to treatment time. Results: A total of 1,761 patients without eICA occlusion and 137 with eICA occlusion were included in the study. At 3 months, 42 patients were lost to follow-up (3 with eICA occlusion). Death occurred in 30 (22.4%) patients with eICA occlusion and in 175 (10.2%) patients without (p < 0.0001). Death or disability at 3 months occurred in 91 of 134 patients with eICA occlusion (67.9%) compared with 654 of 1,722 patients without eICA occlusion (37.9%, p < 0.0001). No or minimal disability at 3 months (mRS 0–1) was reported in 25 (18.7%) patients with eICA occlusion and in 829 (48.2%) patients without (p < 0.0001). Any intracranial bleeding detected by CT or MRI at posttreatment imaging was seen in 16 (11.7%) patients with eICA occlusion and in 314 (17.8%) of those without (p = 0.09). The proportion of symptomatic intracerebral hemorrhage was 5.8% for patients with eICA occlusion and 8.0% for patients without (p = 0.16). At logistic regression analysis, eICA occlusion was associated with mortality (odds ratio, OR 5.7; 95% confidence interval, CI 2.9–11.1) and mortality or disability (OR 5.0; 95% CI 2.9–8.7) at 90 days. Conclusions: This cohort study in patients with acute ischemic stroke treated with thrombolysis showed an association between eICA occlusion and adverse outcome.

Time Delay From Onset to Diagnosis of Migraine

(Headache 2011;51:232‐236)

Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study

Objective: To assess whether the presence of concomitant diseases at multiple sclerosis (MS) diagnosis is associated with the choice and the treatment persistence in an Italian MS cohort. Methods: We included newly diagnosed patients (2010–2016) followed in 20 MS centers and collected demographic and clinical data. We evaluated baseline factors related to the presence of comorbidities and the association between comorbidities and the clinical course of MS and the time to the first treatment switch. Results: The study cohort included 2,076 patients. Data on comorbidities were available for 1,877/2,076 patients (90.4%). A total of 449/1,877 (23.9%) patients had at least 1 comorbidity at MS diagnosis. Age at diagnosis (odds ratio 1.05, 95% confidence interval [CI] 1.04–1.06; p < 0.001) was the only baseline factor independently related to the presence of comorbidities. Comorbidities were not significantly associated with the choice of the first disease-modifying treatment, but were significantly associated with higher risk to switch from the first treatment due to intolerance (hazard ratio 1.42, CI 1.07–1.87; p = 0.014). Association of comorbidities with risk of switching for intolerance was significantly heterogeneous among treatments (interferon β, glatiramer acetate, natalizumab, or fingolimod; interaction test, p = 0.04). Conclusions: Comorbidities at diagnosis should be taken into account at the first treatment choice because they are associated with lower persistence on treatment.

Prediction of disability progression in fingolimod-treated patients.

PURPOSE The aim of the study was to evaluate whether early disease activity during fingolimod treatment could predict disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS We included RRMS patients who received fingolimod for at least 12 months with a ≥36 months of follow-up. Early disease activity was assessed by the modified Rio score (MRS). Association between MRS at 12 months and time to disability progression over the following two years was assessed using Kaplan-Meier survival curves analysis and Cox proportional hazards model. RESULTS At 1 year from starting treatment, 14 (58.3%), 5 (20.8%), 3 (12.5%) and 2 (8.3%) subjects had a MRS=0, 1, 2, and 3, respectively. The risk of disability progression in the next 2 years was associated to the MRS and increased from 21.1% in patients with MRS=0-1 to 80% in those with MRS≥2 (adjusted HR=19.67; 95% CI=2.30-167.79; p=0.006). CONCLUSIONS Early disease activity is suggested to be associated with the risk of disease progression in patients receiving fingolimod and MRS could be a reliable tool to identify the subjects at higher risk of unfavorable course.

Instrumental Exams Performance Can Be a Contributing Factor to the Delay in Diagnosis of Migraine

Background: Diagnostic delay is a recognized drawback for a correct management of migraine patients. The aim of this study was to investigate the possible relationship among number and type of examinations performed and diagnostic delay in migraine diagnosis. Methods: We enrolled 500 subjects referred to our Headache Center for a migraine without aura. We analyzed the relationship among diagnostic delay, number of examinations performed and performance of each single test by a Cox regression model and an ordinal logistic regression model. Results: Each individual exam increased a diagnostic delay of at least 12 months (p < 0.05, Cox regression model). Brain CT as the first diagnostic approach had a reduced risk of delay of more than 5 years (OR 0.632, 95% CI 0.71-0.56, p < 0.05, ordinal regression model). Conclusions: The number of instrumental examinations seems to significantly influence the diagnostic delay. This aspect contributes to increase health care costs, the risk of pain chronicization and pharmacological treatment misuse.

Predicting the profile of increasing disability in multiple sclerosis

Background: Effective therapeutic strategies to preserve function and delay progression in multiple sclerosis (MS) require early recognition of individual disease trajectories. Objectives: To determine the profiles of disability evolution, identify their early predictors and develop a risk score of increasing disability. Methods: We analysed demographic, clinical and magnetic resonance imaging (MRI) data from patients with relapsing MS, Expanded Disability Status Scale (EDSS) score of 3.0–4.0 and follow-up ≥ 2 years. Attaining EDSS = 6.0 defined increasing disability; relapses and/or MRI defined disease activity. Results: In total, 344 out of 542 (63.5%) patients reached EDSS ≥ 6.0; of these, 220 (64.0%) showed disease activity. In patients with activity, the number of relapses before reaching EDSS 3.0–4.0 predicted increasing disability; age > 45 at baseline predicted increasing disability without activity. Combining age and number of relapses increased the risk of and shortened the time to EDSS = 6.0. Conclusion: Increasing disability is frequently associated with persistent activity. The high number of relapses identifies early those patients worsening in the presence of activity. Age predicts increasing disability in the absence of activity. The presence of both factors increases the risk of developing severe disability. As this study likely describes the transition to progression, our findings contribute to improving patient management and stratification in trials on progressive MS.

Determinants of therapy switch in multiple sclerosis treatment-naïve patients: A real-life study:

Background: With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. Objectives: To identify prognostic factors for early switch after first therapy choice. Methods: Newly diagnosed relapsing–remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. Results: We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baseline Expanded Disability Status Scale (HR = 1.17; p = 0.001), and spinal cord lesions (HR = 1.46; p = 0.001) were independently associated with higher inefficacy switch rates. We found lower switch for intolerance/safety with glatiramer acetate (HR = 0.61; p = 0.001), fingolimod (HR = 0.35; p = 0.002), and dimethyl-fumarate (HR = 0.57; p = 0.022) as compared to interferons, while it increased with natalizumab (HR = 1.43; p = 0.022). Comorbidities were associated with intolerance switch (HR = 1.28; p = 0.047). Conclusion: Several factors are associated with higher switch risk in patients starting a first-line therapy and could be integrated in the decision-making process of first treatment choice.