Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.

Cladribine vs other drugs in MS: Merging randomized trial with real-life data.

OBJECTIVE: Cladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data. METHODS: Data from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity. RESULTS: All weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis. CONCLUSION: In patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

Long-term outcome in multiple sclerosis patients treated with fingolimod.

BACKGROUND AND PURPOSE: Ongoing disease activity during treatment has been associated to worse disability outcomes in patients with Multiple Sclerosis (MS). The aim of this study was to assess the 5-year response to fingolimod (FTY) treatment in patients with relapsing-remitting (RRMS) in a real-life setting. METHODS: We included RRMS patients who received FTY for at least 6 months and had a follow-up ≥ 60 months. Treatment response was assessed through the No Evidence of Disease Activity (NEDA)-3 status. RESULTS: Eighty-eight patients were included, of which 51 (58.0%) were NTZ-naïve and 37 (42.0%) NTZ-switchers. The mean age was 38.9 (9.5) years and 58 (65.9%) were females. The proportion of patients on FTY treatment who maintained the NEDA-3 status at 5 years was 55.9% among NTZ-naïve patients and 35.0% among NTZ-switchers (p=0.138). Predictors of NEDA-3 status were lower Expanded Disability Status Scale score at baseline (adjOR=0.28, 95% CI 0.10-0.77; p=0.013) in NTZ-naïve patients and fewer relapses in the 12 months before starting FTY in NTZ-switchers (adjOR=0.05, 95% CI 0.003-0.79; p=0.034). CONCLUSIONS: This study supports the potential of FTY as a disease-modifying treatment for the long-term management of RRMS patients. Patients with milder disability and fewer clinical relapses before treatment may achieve a better disease control.

Cerebral hemodynamics in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Although the currently predominant view is that of an autoimmune inflammatory condition, changes in brain vasculature can occur and contribute to pathophysiology. The aim of this study was to evaluate cerebral hemodynamics in patients with MS and explore its relationship with disease status. METHODS: Patients with MS and age- and sex- matched healthy controls were recruited. All participants underwent assessment of cerebral hemodynamics through transcranial Doppler ultrasonography. Cerebral vasomotor reactivity (CVR) to hypercapnia was measured by the breath-holding index (BHI). RESULTS: A total of 80 patients with MS and 80 healthy controls were recruited. BHI values obtained in healthy controls, relapsing-remitting (RR)-MS and secondary progressive (SP)-MS patients were 1.15±0.11, 0.87±0.18 and 0.51±0.20, respectively (p<0.001). Group-wise, patients showed decreased CVR in comparison to controls and BHI values were significantly lower in SP-MS than in RR-MS patients. At linear regression analysis, the disease form was significantly associated with cerebral hemodynamics being the SP phenotype an independent predictor of lower BHI values [ß=-0.36, 95% confidence interval (CI): -0.44 to -0.27, p<0.001; adjusted ß=-0.37, 95% CI: -0.50 to -0.23, p<0.001). CONCLUSIONS: Cerebrovascular hemodynamic insufficiency in MS may be secondary to the downstream effects of neuro-inflammatory cascades.

Effects of THC/CBD oromucosal spray on spasticity-related symptoms in people with multiple sclerosis: results from a retrospective multicenter study.

INTRODUCTION: The approval of 9-δ-tetrahydocannabinol (THC)+cannabidiol (CBD) oromucosal spray (Sativex®) in Italy as an add-on medication for the management of moderate to severe spasticity in multiple sclerosis (MS) has provided a new opportunity for MS patients with drug-resistant spasticity. We aimed to investigate the improvement of MS spasticity-related symptoms in a large cohort of patients with moderate to severe spasticity in daily clinical practice. MATERIALS AND METHODS: MS patients with drug-resistant spasticity were recruited from 30 Italian MS centers. All patients were eligible for THC:CBD treatment according to the approved label: ≥ 18 years of age, at least moderate spasticity (MS spasticity numerical rating scale [NRS] score ≥ 4) and not responding to the common antispastic drugs. Patients were evaluated at baseline (T0) and after 4 weeks of treatment (T1) with the spasticity NRS scale and were also asked about meaningful improvements in 6 key spasticity-related symptoms. RESULTS: Out of 1615 enrolled patients, 1432 reached the end of the first month trial period (T1). Of these, 1010 patients (70.5%) reached a ≥ 20% NRS score reduction compared with baseline (initial responders; IR). We found that 627 (43.8% of 1432) patients showed an improvement in at least one spasticity-related symptom (SRSr group), 543 (86.6%) of them belonging to the IR group and 84 (13.4%) to the spasticity NRS non-responders group. CONCLUSION: Our study confirmed that the therapeutic benefit of cannabinoids may extend beyond spasticity, improving spasticity-related symptoms even in non-NRS responder patients.

First therapy choice in newly diagnosed Multiple Sclerosis patients: A multicenter Italian study.

BACKGROUND: The approval of an increasing number of disease modifying drugs for the treatment of Multiple Sclerosis (MS) creates new challenges for patients and clinicians on the first treatment choice. The main aim of this study was to assess factors impacting first therapy choice in a large Italian MS cohort. METHODS: Newly diagnosed relapsing-remitting (RR) MS patients (2010-2018) followed in 24 Italian MS centres were included in the study. We evaluated the association of baseline demographics, clinical and MRI characteristics to the first treatment choice by logistic regression models applied to pre-defined binary alternatives: dimethyl fumarate vs injectables (interferon and glatiramer acetate), teriflunomide vs injectables, fingolimod vs dimethyl fumarate and fingolimod vs natalizumab. RESULTS: We enrolled 3025 patients in the period between January 2010 and June 2018. Relapses in the previous year (OR = 2.75; p = 0.001), presence of spinal cord lesions (OR = 1.80; p = 0.002) and higher number (>9) of T2 lesions on the baseline brain MRI scan (OR = 1.65; p = 0.022) were the factors associated to dimethyl fumarate choice as first therapy vs an injectable drug. Older age (OR = 1.06; p < 0.001), male sex (OR = 2.29; p = 0.001) and higher EDSS (OR = 1.36; p < 0.001) were the factors associated with the choice of teriflunomide vs injectables. In more recent years, dimethyl fumarate (OR = 3.23; p < 0.001) and teriflunomide (OR = 2.53; p < 0.001) were chosen more frequently than injectables therapies. The main determinant for the choice of fingolimod as compared with dimethyl fumarate was a higher EDSS (OR = 1.56; p = 0.001), while there was a weak association with a longer disease duration (p = 0.068) and a longer time from onset to diagnosis (p = 0.085). Compared to fingolimod, natalizumab was preferred in patients with a younger age (OR = 0.95; p = 0.003) and higher EDSS (OR = 1.45; p = 0.007) and a shorter disease duration (OR = 0.52; p = 0.076). CONCLUSION: Many factors guided therapeutic decision for our Italian cohort of MS patients; they are mainly related to MS disease activity, baseline EDSS, disease duration and age.

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.

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.

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 ß, 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.

Persistence to oral disease-modifying therapies in multiple sclerosis patients.

Dimethyl fumarate (DMF), fingolimod (FTY) and teriflunomide (TFN) are oral disease-modifying therapies (DMTs) approved for relapsing-remitting multiple sclerosis (RRMS) whose efficacy and tolerability have been separately assessed in phase III trials. Conversely, little evidence exists about their head-to-head comparison. The aim of the study was to evaluate the 1-year persistence to DMF, FTY and TFN in patients with RRMS. Patients affected by RRMS who started treatment with DMF, FTY or TFN were identified. The study end-point was 12-month drug persistence as time to discontinuation and proportion of patients who discontinued medication within 1-year. A total of 307 patients were included (DMF = 114, FTY = 129, TFN = 64). The mean times to discontinuation were 144 (84), 189 (72) and 138 (120) days in the DMF, FTY and TFN cohorts (p = 0.036). At 12-month, the proportion of patients discontinuing medication was lower for subjects taking FTY (9.8%) compared with those starting DMF (21.9%) and TFN (23.6%) (p = 0.020). Compared to FTY cohort, DMF [adjOR = 3.26 (1.38-7.70); p = 0.007] and TFN [adjOR = 2.89 (1.10-7.63); p = 0.032] treated patients were more likely to have discontinued their drug at 1-year since initiation. In patients with RRMS, FTY was associated with a better persistence profile as compared to DMF and TFN.

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.

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.

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 Alzheimer's 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.

Time delay from onset to diagnosis of migraine.

OBJECTIVE: To investigate the factors involved in the delayed diagnosis of migraine without aura among patients attending a tertiary center for headache diagnosis and management. METHODS: Two hundred consecutive patients were divided into 3 groups according to the time elapsed from the first clinical manifestations and the diagnosis of migraine at our center. RESULTS: The interval was <1 year in 16.5% of patients (n = 33); from 1 to 5 years in 30% (n = 60); and >5 years in 53.5% (n = 107). Younger age at migraine onset and a lower level of education were significantly associated with a longer time to diagnosis (P = .01 and P = .0001, respectively). Longer delays were significantly associated with a larger number of specialists consulted (P < .05). CONCLUSION: Our findings suggest an insufficient awareness of the diagnostic criteria of migraine by non-specialist physicians, who often prescribe expensive and unnecessary diagnostic investigations that do not alleviate patients' symptoms while wasting health care resources.

Early activation of intracranial collateral vessels influences the outcome of spontaneous internal carotid artery dissection.

BACKGROUND AND PURPOSE: the effectiveness of different treatments for internal carotid artery (ICA) dissection has not been well defined. Lack of early prognostic indicators may represent a major problem in adequately identifying the most appropriate option for treatment. This study aimed at evaluating the influence of patients' vascular risk profiles and of early cerebral hemodynamic changes in determining the clinical evolution after ICA dissection. METHODS: sixty-six stroke patients with ICA occlusion due to spontaneous artery dissection were included. Transcranial Doppler was performed within 24 hours from symptom onset to examine cerebral arteries and the patency of the 3 major intracranial collateral vessels (ophthalmic artery and anterior and posterior communicating arteries). Possible recanalization of the occluded ICA within the first month was evaluated. Stroke severity at onset was assessed with the National Institutes of Health Stroke Scale, whereas outcome was defined according to the modified Rankin Scale score at 90 days after stroke onset. RESULTS: forty patients had at least 2 activated intracranial collateral vessels. The remaining 26 patients, with none or only 1 collateral vessel, showed a significant increased risk of poor recovery (modified Rankin Scale score ≥ 2; adjusted relative risk=14.9; 95% CI, 3.24 to 68.46). Poor recovery was not associated with the occurrence of recanalization, with stroke severity at onset, or with vascular risk profile. CONCLUSIONS: early assessment of cerebral hemodynamic status and, in particular, the activation of intracranial collateral vessels, may help in predicting the outcome of stroke patients with ICA lumen occlusion as a result of spontaneous dissection.

Carotid atherosclerosis and cognitive decline in patients with Alzheimer's disease.

Aim of the study was to explore the correlation between the progression of carotid atherosclerosis and the evolution of cognitive impairment in 66 patients with Alzheimer's disease (AD). They underwent cognitive status evaluation and ultrasonography (US) to investigate carotid arteries intima-media thickness (IMT) and plaque index (PI). After a 12-month follow-up period, neuropsychological and US examinations were repeated to assess the progression of carotid atherosclerosis and of cognitive decline [in terms of changes in Mini Mental State Examination (MMSE) scores]. MMSE score changes were related to baseline IMT (p=0.018), changes in IMT (p<0.001) and PI (p=0.006), and "antihypertensive drug intake" (p<0.001). While the first three variables correlated with increased cognitive impairment, the last one was associated with a reduced extent of MMSE score decline. Results show a link between progression of carotid wall changes and of cognitive decline, and suggest a possible protective role of antihypertensive therapy. Given the potential clinical implications, our preliminary findings could stimulate further investigations into the role of vascular impairment in patients with AD.