Mario Grassi

Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients*

Objective:Compared with standard medical therapy (SMT), noninvasive ventilation (NIV) does not reduce the need for reintubation in unselected patients who develop respiratory failure after extubation. The goal of this study was to assess whether early application of NIV, immediately after extubation, is effective in preventing postextubation respiratory failure in an at-risk population. Design:Multiple-center, randomized controlled study. Setting:Multiple hospitals. Patients:Ninety-seven consecutive patients with similar baseline characteristics, requiring >48 hrs of mechanical ventilation and considered at risk of developing postextubation respiratory failure (i.e., patients who had hypercapnia, congestive heart failure, ineffective cough and excessive tracheobronchial secretions, more than one failure of a weaning trial, more than one comorbid condition, and upper airway obstruction). Interventions:After a successful weaning trial, the patients were randomized to receive NIV for ≥8 hrs a day in the first 48 hrs or SMT. Primary outcome was the need for reintubation according to standardized criteria. Secondary outcomes were intensive care unit and hospital mortality, as well as time spent in the intensive care unit and in hospital. Measurements and Main Results:Compared with the SMT group, the NIV group had a lower rate of reintubation (four of 48 vs. 12 of 49; p = .027). The need for reintubation was associated with a higher risk of mortality (p < .01). The use of NIV resulted in a reduction of risk of intensive care unit mortality (−10%, p < .01), mediated by the reduction for the need of reintubation. Conclusions:NIV was more effective than SMT in preventing postextubation respiratory failure in a population considered at risk of developing this complication.

Inherited Thrombophilic Disorders in Young Adults With Ischemic Stroke and Patent Foramen Ovale

Background and Purpose— The pathogenic link between patent foramen ovale (PFO) and stroke remains unknown in most cases. We investigated the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study. Methods— We investigated 125 consecutive subjects (age, 34.7±7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects. PFO was assessed in all patients with transcranial Doppler sonography with intravenous injection of agitated saline according to a standardized protocol. Genetic analyses for the factor V (FV)G1691A mutation, the prothrombin (PT)G20210A variant, and the TT 677 genotype of methylenetetrahydrofolate reductase (MTHFR) were performed in all subjects. Results— A pathogenic role of PFO was presumed in 36 patients (PFO+). Interatrial right-to-left shunt either was not detected or was considered unrelated to stroke occurrence in the remaining 89 patients (PFO−). The PTG20210A variant was more frequent in the PFO+ group compared with control subjects and the PFO− group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO−, 11% versus 1.1%; 95% CI, 1.09 to 109;P =0.047). A similar distribution was observed for subjects carrying either the PTG20210A variant or the FVG1691A mutation (PFO+ versus control subjects, 19.4% versus 5.3%; 95% CI, 0.08 to 0.75; PFO+ versus PFO−, 19.4% versus 3.3%; 95% CI, 1.45 to 26.1;P =0.021). Combined thrombophilic defects were observed in 3 subjects of the PFO+ group, in 2 control subjects (8.3% versus 1.3%; 95% CI, 0.01 to 0.66;P =0.015), and in 0 subjects in the PFO− group. A trend toward a difference in the frequency of the FVG1691A mutation between PFO+ and control subjects was found after bivariate analysis (11% versus 3.3%;P =0.068) but not after multinomial logistic regression analysis. No significant association was found in the distribution of the TT MTHFR genotype in the 3 groups. Conclusions— In young adults, the PTG20210A variant and, to a lesser extent, the FVG1691A mutation may represent risk factors for PFO-related cerebral infarcts. A role of systemic thrombophilic disorders in the pathogenesis of this specific subtype of stroke may be hypothesized.

A population based study of Helicobacter pylori infection in a European country: the San Marino Study. Relations with gastrointestinal diseases.

Helicobacter pylori is present worldwide but few large population studies exist on the epidemiology of the infection. A random cross sectional study was performed of H pylori infection in the adult population of San Marino, a European country with high gastric cancer rate, to assess its prevalence and to evaluate its relations with gastrointestinal disease. In 2237 subjects (77% of the initial sample) H pylori IgG antibodies were detected with enzyme linked immunosorbent assay (ELISA) and immunoblotting. A questionnaire including questions about occupation, place of birth, and smoking was given to all subjects. Dyspepsia, peptic ulcer, and gastric cancer in the subjects, relatives, and partners as well as use of drug, dental treatment/prostheses, and gastrointestinal endoscopies, were evaluated by multivariate analysis. H pylori prevalence was of 51%, increased with age from 23% (20-29 years) to 68% (> or = 70 years), and was higher among manual workers. H pylori was independently associated with ulcer (OR = 1.63, 95% confidence intervals (CI) = 1.16 to 2.27), H2 antagonists (OR = 1.94, 95% CI = 1.21 to 3.10), and benzodiazepines (OR = 1.57, 95% CI = 1.02 to 2.42), dental prostheses (OR = 1.25, 95% CI = 1.05 to 1.49), gastroscopy in the past five years (OR = 1.50, 95% CI = 1.05 to 2.14), peptic ulcer in siblings (OR = 1.52, 95% CI = 1.09 to 2.12), gastric cancer in father (OR = 1.61, 95% CI = 1.02 to 2.52). The association of seropositivity with history of ulcer, gastric cancer in family, gastroscopy, and H2 antagonists suggests that H pylori is an epidemiological key factor in the pathogenesis of gastroduodenal diseases in this area.

Migraine Mediates the Influence of C677T MTHFR Genotypes on Ischemic Stroke Risk With a Stroke-Subtype Effect

Background and Purpose— The objective was to investigate the role of C677T MTHFR polymorphism in migraine pathogenesis and in the migraine–ischemic stroke pathway. Methods— A first genotype–migraine association study was conducted on 100 patients with migraine with aura (MA), 106 with migraine without aura (MO), and 105 subjects without migraine, which provided evidence in favor of association of the TT677 MTHFR genotype with increased risk of MA compared with both control subjects (OR, 2.48; 95% CI, 1.11 to 5.58) and patients with MO (OR, 2.21; 95% CI, 1.01 to 4.82). Based on these findings, mediational models of the genotype–migraine–stroke pathway were fitted on a group of 106 patients with spontaneous cervical artery dissection, 227 young patients whose ischemic stroke was unrelated to a spontaneous cervical artery dissection (noncervical artery dissection), and 187 control subjects, and a genotype–migraine partial mediation model was selected. Results— Both migraine and the TT genotype were more strongly associated to the subgroup of patients with spontaneous cervical artery dissection (OR, 4.06; 95% CI, 1.63 to 10.02 for MA; OR, 5.45; 95% CI, 3.03 to 9.79 for MO; OR, 2.87; 95% CI, 1.45 to 5.68 for TT genotype) than to the subgroup of patients with noncervical artery dissection ischemic stroke (OR, 2.22; 95% CI, 1.00 to 4.96 for MA; OR, 1.81; 95% CI, 1.02 to 3.22 for TT genotype) as compared with controls. Conclusions— Migraine may act as mediator in the methylenetetrahydrofolate reductase–ischemic stroke pathway with a more prominent effect in the subgroup of patients with spontaneous artery dissection.

History of Migraine and the Risk of Spontaneous Cervical Artery Dissection

The pathophysiology of spontaneous cervical artery dissection (sCAD) is largely unknown. An association with migraine has been suggested, but not definitively proven. In the setting of a hospital-based prospective case-control study we assessed personal and family history of migraine in 72 patients with sCAD, 72 patients with cerebral infarct unrelated to a CAD (non-CAD) and 72 control subjects. Personal history of migraine was significantly associated to sCAD compared to non-CAD (59.7% vs. 30.6%; OR 3.14; 95% CI 1.41-7.01) and controls (18.1%; OR 7.41; 95% CI 3.11-17.64). As opposed to migraine with aura, migraine without aura was significantly more frequent among sCAD than among non-CAD (56.9% vs. 25.0%; OR 3.91; 95% CI 1.71-8.90) and controls (12.5%; OR 9.84; 95% CI 3.85-25.16). Similar results were observed when the frequencies of family history of migraine were compared. These findings are consistent with the hypothesis that migraine may represent a predisposing condition for sCAD.

Cumulative Effect of Predisposing Genotypes and Their Interaction With Modifiable Factors on the Risk of Ischemic Stroke in Young Adults

Background and Purpose— Combinations of multiple predisposing polymorphisms and their interactions with modifiable factors may result in synergistic effects on the risk of ischemic stroke. These mechanisms are more likely to play a relevant role in younger individuals. Methods— The cumulative effect of the 20210A variant of prothrombin gene, the 1691A variant of factor V gene, the TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR) gene, and the &egr;4-carriership of the apolipoprotein (APOE) gene, as well as their interactions with modifiable predisposing factors, were determined in a series of 163 stroke patients aged younger than 45 years and 158 controls. Results— Odds ratios (ORs) for stroke were 1.73 (95% confidence interval [CI], 1.20 to 2.51) in subjects with 1 polymorphism and 3.00 (95% CI, 1.43 to 6.30) in those with ≥2. Compared with nonsmokers with none of the studied polymorphisms, ORs for stroke were 1.88 (95% CI, 1.18 to 3.00) and 3.55 (95% CI, 1.40 to 8.98) for nonsmokers with 1 and 2 polymorphisms, respectively, and 3.99 (95% CI, 2.00 to 7.96) and 15.99 (95% CI, 4.01 to 63.3) for smokers. Compared with nonhypertensive subjects bearing no polymorphisms, ORs were 1.91 (95% CI, 1.28 to 2.87) and 3.68 (95% CI, 1.64 to 8.26) for nonhypertensive subjects with 1 and 2 polymorphisms, 3.28 (95% CI, 1.01 to 10.7) and 10.79 (95% CI, 1.01 to 115.4) for hypertensive. Conclusions— These data suggest a gene–dose effect of the examined prothrombotic and proatherogenic gene variants and a synergistic effect of these polymorphisms and modifiable risk factors in the pathogenesis of cerebral ischemia in young adults.

Perfusion CT in patients with acute ischemic stroke treated with intra-arterial thrombolysis: predictive value of infarct core size on clinical outcome.

BACKGROUND AND PURPOSE: A potential role of perfusion CT (PCT) in selecting patients with stroke for reperfusion therapies has been recently advocated. The purpose of the study was to assess the reliability of PCT in predicting clinical outcome of patients with acute ischemic stroke treated with intra-arterial thrombolysis (IAT). MATERIALS AND METHODS: Twenty-seven patients with acute hemispheric ischemic stroke were investigated with PCT and treated with IAT between 3 and 6 hours of stroke onset. The infarct core was outlined on cerebral blood volume (CBV) maps by using accepted viability thresholds. The penumbra was defined as time-to-peak (TTP)-CBV mismatch. Clinical outcome was assessed by modified Rankin Scale (mRS) scores at 3 months and dichotomized into favorable (mRS score, 0–2) and unfavorable (mRS score, 3–6). Data were retrospectively analyzed by multiple regression to identify predictors of clinical outcome among the following variables: age, sex, National Institutes of Health Stroke Scale score, serum glucose level, thrombolytic agent, infarct core and mismatch size, collateral circulation, time to recanalization, and recanalization rate after IAT. RESULTS: Patients with favorable outcome had smaller cores (P = .03), increased mismatch ratios (P = .03), smaller final infarct sizes (P < .01), higher recanalization rates (P = .03), and reduced infarct growth rates (P < .01), compared with patients with unfavorable outcome. The core size was the strongest predictor of clinical outcome in an “all subset” model search (P = .01; 0.96 point increase in mRS score per any increment of 1 SD; 95% confidence interval, +0.17 to +1.75). CONCLUSIONS: PCT is a reliable tool for the identification of irreversibly damaged brain tissue and for the prediction of clinical outcome of patients with acute stroke treated with IAT.

Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy

Objective: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. Methods: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. Results: Tau form ratio was significantly reduced in patients with PSP (0.504 ± 0.284) when compared to age-matched controls (0.989 ± 0.343), and to patients with other neurodegenerative conditions (range = 0.899–1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. Conclusions: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness. GLOSSARY: AD = Alzheimer disease; AUC = area under the curve; BADL = Basic Activity of Daily Living; CBDS = corticobasal degeneration; CON = controls; DLB = dementia with Lewy bodies; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; FTD = frontotemporal dementia; IADL = Instrumental Activities of Daily Living; MMSE = Mini-Mental State Examination; MSA = multiple system atrophy; PD = Parkinson disease; PSP = progressive supranuclear palsy; ROC = receiver operating characteristic; UPDRS = Unified Parkinson’s Disease Rating Scale; VBM = voxel-based morphometry.

Arterial hypertension as risk factor for spontaneous cervical artery dissection. A case–control study

Because of the presumed non-atherosclerotic pathogenesis, the potential link between spontaneous cervical artery dissection (sCAD) and common risk factors for atherosclerosis has never been investigated systematically. Therefore, this prospective, multicentre, case–control study compared the frequency of tobacco use, hypertension, diabetes mellitus, and hypercholesterolaemia among a group of consecutive patients with sCAD (n  =  153), a group of patients with ischaemic stroke, not related to CAD (non-CAD), and a group of controls. As opposed to the other variables, a trend towards a significant association was seen when the prevalence of hypertension was compared among patients with sCAD and controls (26.8% v 17.0%; odds ratio (OR) 1.79; 95% confidence interval (CI), 0.98 to 3.27; p  =  0.058). Hypertension was also significantly associated with the subgroup of patients with sCAD and cerebral infarction (OR, 1.94; 95% CI, 1.01 to 3.70; p  =  0.045), particularly when involving the vertebral arteries (OR, 2.69; 95% CI, 1.20 to 6.04; p  =  0.017). These findings might help define the spectrum of pathogenic conditions predisposing to sCAD and provide information to help investigate the combined effect of such susceptibility factors in future studies.

Is Frontotemporal Lobar Degeneration a Rare Disorder? Evidence from a Preliminary Study in Brescia County, Italy

Frontotemporal Lobar Degeneration (FTLD) has always been considered a rare disorder, but only a few epidemiologic studies are available. The aim of the present work was to ascertain all FTLD patients in a Northern Italy area from January 2001 to December 2008, and to estimate the disease prevalence. On the census day, 213 FTD patients were still alive, resulting in an overall prevalence of 17.6 per 100,000 inhabitants. The prevalence of FTLD in patients aged 45-65 years was 22 per 100,000 inhabitants (95% CI=17-27). The prevalence of FTLD was the highest in patients aged 66-75 (78 per 100,000 inhabitants, 95% CI=56-100), and it was still high over 75 years (54 per 100,000 inhabitants, 95% CI=36-69). FTLD is a more common form of dementia than previously recognized. Our results claimed that FTLD is not only an early-onset disorder, but it is frequent in advanced age as well.