Publications by authors named "Filomena Caria"

18 Publications

  • Page 1 of 1

Human leukocyte antigens class II in CIDP spectrum neuropathies.

J Neurol Sci 2019 Dec 23;407:116533. Epub 2019 Oct 23.

Center for Neuromuscular Diseases, Unit of Neurology, ASST "Spedali Civili" and University of Brescia, Italy. Electronic address:

CIDP spectrum encompasses several clinical variants and the reasons of the heterogeneous clinical expression and the variable response to therapy are scarcely known. HLA associations are common in dysimmune conditions. In CIDP, few studies reported no associations or HLA-DR13/DQ6 association in some populations but, to date, a clear confirmed association is lacking. We analyzed expression of HLA-DR and DQ haplotypes in 24 CIDP patients and 216 healthy subject. HLA-DR3 and DR3/DQ2 were significantly more frequent in CIDP patients than in the control group. The DR3 and DR3/DQ2 positive patients present with more frequent relapsing course, worse response to IVIg, higher inflammatory neuropathy sensory sumscore (ISS) and Rotterdam Inflammatory Neuropathy Cause and Treatment Scale (INCAT) than negative patients.
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http://dx.doi.org/10.1016/j.jns.2019.116533DOI Listing
December 2019

History of Migraine and Volume of Brain Infarcts: The Italian Project on Stroke at Young Age (IPSYS).

J Stroke 2019 09 30;21(3):324-331. Epub 2019 Sep 30.

Department of Clinical and Experimental Sciences, Neurological Clinic, University of Brescia, Brescia, Italy.

Background And Purpose: Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated.

Methods: In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status.

Results: A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P<0.001), and the largest volumes were observed in patients with migraine with aura (median, 9.0 cm3 [IQR, 3.4 to 16.6]). In a linear regression model, migraine was an independent predictor of increased log (acute infarct volumes) (median ratio [MR], 1.64; 95% confidence interval [CI], 1.22 to 2.20), an effect that was more prominent for migraine with aura (MR, 2.92; 95% CI, 1.88 to 4.54).

Conclusion: s These findings reinforce the experimental observation of larger acute cerebral infarcts in migraineurs, extend animal data to human disease, and support the hypothesis of increased vulnerability to ischemic brain injury in people suffering migraine.
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http://dx.doi.org/10.5853/jos.2019.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780016PMC
September 2019

Autosomal recessive Bethlem myopathy: A clinical, genetic and functional study.

Neuromuscul Disord 2019 09 30;29(9):657-663. Epub 2019 Jul 30.

Center for Neuromuscular Diseases, Unit of Neurology, ASST "Spedali Civili", Brescia, Italy. Electronic address:

Bethlem myopathy represents the milder form of the spectrum of Collagen VI-related dystrophies, which are characterized by a clinical continuum between the two extremities, the Bethlem myopathy and the Ullrich congenital muscular dystrophy, and include less defined intermediate phenotypes. Bethlem myopathy is mainly an autosomal dominant disorder and the causing mutations occur in the COL6A genes encoding for the α1 (COL6A1), α2 (COL6A2) and α3 (COL6A3) chains. However, few cases of recessive inheritance have been also reported. We here describe clinical, genetic and functional findings in a recessive Bethlem myopathy family harbouring two novel pathogenic mutations in the COL6A2 gene. Two adult siblings presented with muscle weakness and wasting, elbows and Achilles tendon retractions, lumbar hyperlordosis, waddling gait and positive Gowers' sign. Muscle biopsy showed a dystrophic pattern. Molecular analysis of the COL6A2 gene revealed the novel paternally-inherited nonsense p.Gln889* mutation and the maternally-inherited p.Pro260_Lys261insProPro small insertion. Fibroblast studies in both affected patients showed the concomitant reduction in the amount of normal Collagen VI (p.Gln889*) and impairment of Collagen VI secretion and assembly (p.Pro260_Lys261insProPro). Each of the two variants behave as a recessive mutation as shown by the asymptomatic heterozygous parents, while their concomitant effects determined a relatively mild Bethlem myopathy phenotype. This study confirms the occurrence of recessive inherited Bethlem myopathy and expands the genetic heterogeneity of this group of muscle diseases.
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http://dx.doi.org/10.1016/j.nmd.2019.07.007DOI Listing
September 2019

Validation and Comparison of Noncontrast CT Scores to Predict Intracerebral Hemorrhage Expansion.

Neurocrit Care 2020 06;32(3):804-811

Stroke Unit, IRCCS Fondazione Istituto Neurologico Nazionale C. Mondino, Pavia, Italy.

Background And Purpose: The BAT, BRAIN, and HEP scores have been proposed to predict hematoma expansion (HE) with noncontrast computed tomography (NCCT). We sought to validate these tools and compare their diagnostic performance.

Methods: We retrospectively analyzed two cohorts of patients with primary intracerebral hemorrhage. HE expansion was defined as volume growth > 33% or > 6 mL. Two raters analyzed NCCT scans and calculated the scores, blinded to clinical and imaging data. The inter-rater reliability was assessed with the interclass correlation statistic. Discrimination and calibration were calculated with area under the curve (AUC) and Hosmer-Lemeshow χ statistic, respectively. AUC comparison between different scores was explored with DeLong test. We also calculated the sensitivity, specificity, positive, and negative predictive values of the dichotomized scores with cutoffs identified with the Youden's index.

Results: A total of 230 subjects were included, of whom 86 (37.4%) experienced HE. The observed AUC for HE were 0.696 for BAT, 0.700 for BRAIN, and 0.648 for HEP. None of the scores had a significantly superior AUC compared with the others (all p > 0.4). All the scores had good calibration (all p > 0.3) and good-to-excellent inter-rater reliability (interclass correlation > 0.8). BAT ≥ 3 showed the highest specificity (0.81), whereas BRAIN ≥ 6 had the highest sensitivity (0.76).

Conclusions: The BAT, BRAIN, and HEP scores can predict HE with acceptable discrimination and require just a baseline NCCT scan. These tools may be used to stratify the risk of HE in clinical practice or randomized controlled trials.
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http://dx.doi.org/10.1007/s12028-019-00797-2DOI Listing
June 2020

A Novel Mutation Causes a Pure Hereditary Spastic Paraplegia in an Italian Family.

Front Neurol 2019 5;10:580. Epub 2019 Jun 5.

Unit of Neurology, Center for Neuromuscular Diseases, ASST Spedali Civili and University of Brescia, Brescia, Italy.

encodes calpain-1, a large subunit of μ-calpain, a calcium-activated cysteine protease widely present in the central nervous system. Mutations in have recently been identified in a complicated form of Hereditary Spastic Paraplegia (HSP) with a combination of cerebellar ataxia and corticomotor tract disorder (SPG76). Therefore, is now considered one of those genes that clinically manifest with a spectrum of disorders ranging from spasticity to cerebellar ataxia and represent a link between Spinocerebellar Ataxia and HSP, two groups of diseases previously considered separate but sharing pathophysiological pathways. We here describe clinical and molecular findings of two Italian adult siblings affected with a pure form of HSP and harboring the novel homozygote c.959delA variant (p.Tyr320Leufs73) in the gene. Although the reason why mutations in may cause heterogeneous clinical pictures remains speculative, our findings confirm that the spectrum of the -linked phenotypes includes pure HSP with onset during the third decade of life. Further studies are warrantied in order to clarify the mechanism underlying the differences in mutation clinical expression.
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http://dx.doi.org/10.3389/fneur.2019.00580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560055PMC
June 2019

Intravenous fibrinolysis plus endovascular thrombectomy versus direct endovascular thrombectomy for anterior circulation acute ischemic stroke: clinical and infarct volume results.

BMC Neurol 2019 May 29;19(1):103. Epub 2019 May 29.

Stroke Unit, Neurologia Vascolare, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, Brescia 25123, Brescia, Italy.

Background: endovascular therapy (ET) is the standard of care for anterior circulation acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). The role of adjunctive intravenous thrombolysis (IVT) in these patients remains unclear. The present study aims to investigate whether IVT followed by ET (CoT, combined therapy) provides additional benefits over direct ET for anterior circulation AIS with LVO.

Methods: we achieved a single center retrospective study of patients with AIS caused by anterior circulation LVO, referred to our center between January 2014 and January 2017 and treated with ET. Functional recovery (modified Rankin at 3-months follow-up), recanalization rate (thrombolysis in cerebral infarction [TICI] score) and time, early follow-up brain CT scan infarct volume (EFIV) (for recanalized patients only), symptomatic intracerebral hemorrhage (sICH) and 3-month mortality were the outcomes of interests. Independent predictors of the outcomes were explored with multivariable logistic regression.

Results: 145 subjects were included in the study, of whom 70 underwent direct ET and 75 were treated with CoT. Functional independence at 3-months was more frequent in CoT subjects compared to patients who received direct ET (mRS score 0-1: 48.5% vs 18.6%; P < 0.001. mRS score 0-2: 67.1% vs 37.3%; P < 0.001); CoT patients had also higher first-pass success rate (62.7% vs 38.6%, P < 0.05), higher recanalization rate (84.3% vs 65.3%; P = 0.009) and, in recanalized subjects, smaller EFIV (16.4 ml vs 62.3 ml; P = 0.003). Mortality and intracranial bleeding did not differ between the two groups. In multivariable regression analysis, low baseline NIHSS score (P < 0.05), vessel recanalization (P = 0.05) and CoT (P = 0.03) were independent predictors of favorable outcome at three months.

Conclusions: CoT appears more effective than ET alone for anterior circulation AIS with LVO, with similar safety profile.
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http://dx.doi.org/10.1186/s12883-019-1341-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540520PMC
May 2019

The clinical spectrum of reversible cerebral vasoconstriction syndrome: The Italian Project on Stroke at Young Age (IPSYS).

Cephalalgia 2019 Sep 6;39(10):1267-1276. Epub 2019 May 6.

1 Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy.

Introduction: To describe clinical, neuroimaging, and laboratory features of a large cohort of Italian patients with reversible cerebral vasoconstriction syndrome.

Methods: In the setting of the multicenter Italian Project on Stroke at Young Age (IPSYS), we retrospectively enrolled patients with a diagnosis of definite reversible cerebral vasoconstriction syndrome according to the International Classification of Headache Disorders (ICHD)-3 beta criteria (6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome, imaging-proven). Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of reversible cerebral vasoconstriction syndrome without typical causes ("idiopathic reversible cerebral vasoconstriction syndrome") were compared with those of reversible cerebral vasoconstriction syndrome related to putative causative factors ("secondary reversible cerebral vasoconstriction syndrome").

Results: A total of 102 patients (mean age, 47.2 ± 13.9 years; females, 85 [83.3%]) qualified for the analysis. Thunderclap headache at presentation was reported in 69 (67.6%) patients, and it typically recurred in 42 (60.9%). Compared to reversible cerebral vasoconstriction syndrome cases related to putative etiologic conditions (n = 21 [20.6%]), patients with idiopathic reversible cerebral vasoconstriction syndrome (n = 81 [79.4%]) were significantly older (49.2 ± 13.9 vs. 39.5 ± 11.4 years), had more frequently typical thunderclap headache (77.8% vs. 28.6%) and less frequently neurological complications (epileptic seizures, 11.1% vs. 38.1%; cerebral infarction, 6.1% vs. 33.3%), as well as concomitant reversible brain edema (25.9% vs. 47.6%).

Conclusions: Clinical manifestations and putative etiologies of reversible cerebral vasoconstriction syndrome in our series are slightly different from those observed in previous cohorts. This variability might be partly related to the coexistence of precipitating conditions with a putative etiologic role on disease occurrence.
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http://dx.doi.org/10.1177/0333102419849013DOI Listing
September 2019

Assessing the Role of Anti rh-GAA in Modulating Response to ERT in a Late-Onset Pompe Disease Cohort from the Italian GSDII Study Group.

Adv Ther 2019 05 16;36(5):1177-1189. Epub 2019 Mar 16.

Department of Clinical and Experimental Medicine, UOC di Neurologia e Malattie Neuromuscolari, University of Messina, Messina, Italy.

Introduction: Patients with late-onset Pompe disease (LOPD) receiving enzyme replacement therapy (ERT) may develop IgG antibodies against alglucosidase alpha (anti-rhGAA) in the first 3 months of treatment. The exact role of these antibodies in modulating efficacy of ERT in this group of patients is still not fully understood. To assess whether anti rh-GAA antibodies interfere with ERT efficacy, we studied a large Italian cohort of LOPD patients.

Methods: We analyzed clinical findings and performed serial measurements of IgG anti rh-GAA antibody titers from 64 LOPD patients treated with ERT. The first examination (T0) was completed on average at 17.56 months after starting ERT, while the follow-up (T1) was collected on average at 38.5 months. Differences in T0-T1 delta of the six-minute walking test (6MWT), MRC sum score (MRC), gait, stairs and chair performance (GSGC) and forced vital capacity (FVC) were considered and then related to the antibody titers.

Results: Almost 22% of the patients never developed antibodies against GAA, while 78.1% had a positive titer (31.2% patients developed a low titer, 43.8% a medium titer and 3.1% a high titer). No statistical significance was found in relating the T0-T1 delta differences and antibody titers, except for MRC sum score values in a subgroup of patients treated < 36 months, in which those with a null antibody titer showed a greater clinical improvement than patients with a positive titer.

Conclusion: Our results confirm that in a large cohort of LOPD patients, anti rh-GAA antibody generation did not significantly affect either clinical outcome or ERT efficacy. However, in the first 36 months of treatment, a possible interference of low-medium antibody titers with the clinical status could be present. Therefore, a careful and regular evaluation of antibody titers, especially in cases with evidence of clinical decline despite ERT, should be performed.
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http://dx.doi.org/10.1007/s12325-019-00926-5DOI Listing
May 2019

Late and Severe Myopathy in a Patient With Glycogenosis VII Worsened by Cyclosporine and Amiodarone.

Front Neurol 2019 7;10:77. Epub 2019 Feb 7.

Department of Clinical and Experimental Medicine, UOC di Neurologia e Malattie Neuromuscolari, University of Messina, Messina, Italy.

Glycogenosis VII (GSD VII) is a rare autosomal recessive glycogen storage disorder caused by mutations in the gene encoding the phosphofructokinase (PFK) enzyme. A classical form with exercise intolerance, contractures, and myoglobinuria, a severe multisystem infantile form, an hemolytic variant and a late-onset form usually presenting with muscle pain and mild fixed proximal weakness have been reported. We describe a 65-year-old man affected by muscle PFK deficiency who, since the age of 33, presented with exercise intolerance and myoglobinuria. Muscle biopsy showed a vacuolar myopathy with glycogen storage. The biochemical assay of PFK-M showed very low residual activity (6%). Genetic analysis of gene evidenced the presence of the heterozygote c.1817A>C (p.Asp543Ala) and c.488 G>A (p.Arg100Gln) pathogenic mutations. In his fifth decade, he started cyclosporine after liver transplantation for hepatocellular carcinoma and, then, amiodarone because of atrial fibrillation. In the following years, he developed a progressive and severe muscle weakness, mainly involving lower limbs, up to a loss of independent walking. Muscle MRI showed adipose substitution of both anterior and posterior thigh muscles with selective sparing of the medial compartment. Marked signs of adipose substitution were also documented in the legs with a selective replacement of gemelli and peroneus muscles. The temporal relationship between the patient's clinical worsening and chronic treatment with cyclosporine and amiodarone suggests an additive toxic damage by these two potentially myotoxic drugs determining such an unusually severe phenotype, also confirmed by muscle MRI findings.
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http://dx.doi.org/10.3389/fneur.2019.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374292PMC
February 2019

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

Neurol Sci 2019 Mar 3;40(3):561-570. Epub 2019 Jan 3.

Cerebrovascular Unit, Neurological Institute "C. Besta" IRCCS Foundation, Milan, Italy.

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results.

Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies.

Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed.

Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.
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http://dx.doi.org/10.1007/s10072-018-3664-zDOI Listing
March 2019

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE-MTDPS1).

J Clin Med 2018 Oct 26;7(11). Epub 2018 Oct 26.

Center for Neuromuscular Diseases, Unit of Neurology, ASST Spedali Civili and University of Brescia, 25100 Brescia, Italy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE-MTDPS1) is a devastating autosomal recessive disorder due to mutations in , which cause a loss of function of thymidine phosphorylase (TP), nucleoside accumulation in plasma and tissues, and mitochondrial dysfunction. The clinical picture includes progressive gastrointestinal dysmotility, cachexia, ptosis and ophthalmoparesis, peripheral neuropathy, and diffuse leukoencephalopathy, which usually lead to death in early adulthood. Other two MNGIE-type phenotypes have been described so far, which are linked to mutations in and genes. Therapeutic options are currently available in clinical practice (allogeneic hematopoietic stem cell transplantation and carrier erythrocyte entrapped thymidine phosphorylase therapy) and newer, promising therapies are expected in the near future. Since successful treatment is strictly related to early diagnosis, it is essential that clinicians be warned about the clinical features and diagnostic procedures useful to suspect diagnosis of MNGIE-MTDPS1. The aim of this review is to promote the knowledge of the disease as well as the involved mechanisms and the diagnostic processes in order to reach an early diagnosis.
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http://dx.doi.org/10.3390/jcm7110389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262582PMC
October 2018

Migraine improvement after spontaneous cervical artery dissection the Italian Project on Stroke in Young Adults (IPSYS).

Neurol Sci 2019 Jan 21;40(1):59-66. Epub 2018 Sep 21.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, P.le Spedali Civili, 1,, 25123, Brescia, Italy.

Objective: Whether migraine modifies after spontaneous cervical artery dissection (sCeAD) more than after other stroke etiologic subtypes has never been adequately investigated.

Methods: In the setting of the Italian Project on Stroke in Young Adults (IPSYS), we compared the course of migraine before and after acute brain infarct in a group of migraine patients with sCeAD and a group of migraine patients whose ischemia was due to a cause other than CeAD (non-CeAD IS), matched by sex, age (± 3 years), and migraine subtype.We applied linear mixed models to evaluate pre-event vs post-event changes and differences between sCeAD and non-CeAD IS patients.

Results: Eighty-seven patients per group (migraine without aura/migraine with aura, 67/20) qualified for the analysis. After the acute event, migraine headaches disappeared in 14.0% of CeAD patients vs 0.0% of non-CeAD IS patients (p ≤ 0.001). Migraine frequency (patients suffering at least 1 attack, from 93.1 to 80.5%, p = 0.001), pain intensity (from 6.7 ± 1.7 to 4.6 ± 2.6 in a 0 to 10 pain scale, p ≤ 0.001), and use of acute anti-migraine medications (patients taking at least 1 preparation, from 81.6 to 64.4%, p = 0.007) also improved significantly after CeAD as opposed to that observed after non-CeAD IS.

Conclusion: The spontaneous improvement of migraine after sCeAD reinforces the hypothesis of a pathogenic link between the two conditions.
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http://dx.doi.org/10.1007/s10072-018-3578-9DOI Listing
January 2019

Alcohol intake and the risk of intracerebral hemorrhage in the elderly: The MUCH-Italy.

Neurology 2018 07 13;91(3):e227-e235. Epub 2018 Jun 13.

From U.O. Neurologia (P.C.), Istituto Ospedaliero Poliambulanza, Brescia; Dipartimento di Scienze Cliniche e Sperimentali (A. Pezzini, L.P., V.D.G., F.C., A. Padovani), Clinica Neurologica, Università degli Studi di Brescia; Dipartimento di Scienze del Sistema Nervoso e del Comportamento (M. Grassi), Unità di Statistica Medica e Genomica, Università di Pavia; Laboratorio di Epidemiologia Molecolare e Nutrizionale (L.I., A.D.C., G.d.G.), Dipartimento di Epidemiologia e Prevenzione, IRCCS Istituto Neurologico Mediterraneo, NEUROMED, Pozzilli; S.C. Neurologia (M.Z.), Arcispedale Santa Maria Nuova, IRCCS, Reggio Emilia; Neurologia d'Urgenza and Stroke Unit (S.M.), IRCCS Istituto Clinico Humanitas, Rozzano-Milano; Stroke Unit (G.S.), Dipartimento di Neuroscienze, Ospedale Carlo Poma, Mantova; Unità di Neurologia (M.L.D.), Ospedale di Circolo, Università dell'Insubria, Varese; U.O. Neurologia (M.S.), Istituti Ospedalieri di Cremona, Cremona; Stroke Unit (A.Z.), Clinica Neurologica, Nuovo Ospedale Civile, "S. Agostino Estense," AUSL Modena; Stroke Unit and Divisione di Medicina Cardiovascolare (M.P., G.A.), Università di Perugia; Stroke Unit (C.A., A.D.V.), Divisione di Neurologia, Dipartimento di Neuroscienze e Riabilitazione, Azienda Ospedaliero-Universitaria di Ferrara; Stroke Unit (M. Gamba), Neurologia Vascolare, Spedali Civili di Brescia; Unità di Neurologia (M.D.S.), E.O. Ospedali Galliera, Genova; U.O.C. Neurologia (A.T., N.P.), A.O. Universitaria "San Giovanni di Dio e Ruggi d'Aragona," Salerno; Dipartimento di Neuroscienze (C.G.), Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università di Genova; U.O. Neurologia (D.M.B.), Azienda Ospedaliera "Cà Foncello," Treviso; Stroke Unit (R.T., G.M.), AOU Senese, Siena; Stroke Unit (A. Cavallini, A.M.), IRCCS Fondazione Istituto Neurologico Nazionale "C. Mondino," Pavia; Neurologia (A. Chiti), Azienda Ospedaliero Universitaria Pisana, Pisa; Istituto di Ricovero e Cura a Carattere Scientifico (R.S.C.), Centro Neurolesi Bonino-Pulejo, Messina; Dipartimento di Neuroscienze (F.G.), Scienze Psichiatriche e Anestesiologiche Clinica Neurologica, Università di Messina; USD Stroke Unit (P.B., G.T.), DAI di Neuroscienze, Azienda Ospedaliera Universitaria Integrata Verona; Centro Trombosi (C.L.), IRCCS Istituto Clinico Humanitas, Rozzano-Milano; Divisione di Biologia e Genetica (M.R., M.C.), Dipartimento di Medicina Molecolare e Traslazionale, Università degli Studi di Brescia; and Dipartimento di Specialità Medico-Chirurgiche (C.C.), Scienze Radiologiche e Sanità Pubblica, Clinica Neurochirurgica, Università degli Studi di Brescia, Italy.

Objective: To investigate the role of alcohol as a causal factor for intracerebral hemorrhage (ICH) and whether its effects might vary according to the pathogenic mechanisms underlying cerebral bleeding.

Methods: We performed a case-control analysis, comparing a cohort of consecutive white patients with ICH aged 55 years and older with a group of age- and sex-matched stroke-free controls, enrolled in the setting of the Multicenter Study on Cerebral Haemorrhage in Italy (MUCH-Italy) between 2002 and 2014. Participants were dichotomized into excessive drinkers (>45 g of alcohol) and light to moderate drinkers or nondrinkers. To isolate the unconfounded effect of alcohol on ICH, we used causal directed acyclic graphs and the back-door criterion to select a minimal sufficient adjustment set(s) of variables for multivariable analyses. Analyses were performed on the whole group as well as separately for lobar and deep ICH.

Results: We analyzed 3,173 patients (1,471 lobar ICH and 1,702 deep ICH) and 3,155 controls. After adjusting for the preselected variables in the minimal sufficient adjustments, heavy alcohol intake was associated with deep ICH risk (odds ratio [OR], 1.68; 95% confidence interval [CI], 1.36-2.09) as well as with the overall risk of ICH (OR, 1.38; 95% CI, 1.17-1.63), whereas no effect was found for lobar ICH (OR, 1.01; 95% CI, 0.77-1.32).

Conclusions: In white people aged 55 years and older, high alcohol intake might exert a causal effect on ICH, with a prominent role in the vascular pathologies underlying deep ICH.
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http://dx.doi.org/10.1212/WNL.0000000000005814DOI Listing
July 2018

Vulnerability to Infarction During Cerebral Ischemia in Migraine Sufferers.

Stroke 2018 03 19;49(3):573-578. Epub 2018 Feb 19.

From the Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica (A.P., L.P., F.C., V.D.G., A.P.) and Sezione di Neuroradiologia, Dipartimento di Specialità Medico-Chirurgiche, Scienze Radiologiche e Sanità Pubblica (R.G.), Università degli Studi di Brescia, Italia; Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Struttura Operativa Dipartimentale di Radiodiagnostica 2 (G.B., S.C.) and Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Struttura Operativa Dipartimentale di Neuroradiologia (E.F.), Università degli Studi di Firenze, Azienda Ospedaliero-Universitaria Careggi, Italia; Unità di Neurologia, Stroke Unit (M.Z.) and Unità di Neuroradiologia (R.P.), Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italia; Stroke Unit, Neurologia Vascolare, Spedali Civili di Brescia, Italia (M.G.); Stroke Unit, Clinica Neurologica, Nuovo Ospedale Civile S. Agostino Estense, AUSL Modena, Italia (A.Z., A.M.S.); and Unità di Neurologia, Dipartimento di Scienze Biologiche, Psichiatriche e Psicologiche, Università di Ferrara, Italia (M.P.).

Background And Purpose: Cerebral hyperexcitability in migraine experiencers might sensitize brain tissue to ischemia. We investigated whether a personal history of migraine is associated with vulnerability to brain ischemia in humans.

Methods: Multicenter cohort study of patients with acute ischemic stroke who underwent a brain computed tomography perfusion and were scheduled to undergo reperfusion therapy. In a case-control design, we compared the proportion of subjects with no-mismatch, the volume of penumbra salvaged, as well as the final infarct size in a group of patients with migraine and a group of patients with no history of migraine.

Results: We included 61 patients with migraine (34 [55.7%] men; mean age, 52.2±15.1 years; migraine without aura/migraine with aura, 44/17) and 61 patients with no history of migraine. The proportion of no-mismatch among migraineurs was significantly higher than among nonmigraineurs (17 [27.9%] versus 7 [11.5%]; =0.039) and was more prominent among patients with migraine with aura (6 [35.3%]; =0.030) while it was nonsignificantly increased in patients with migraine without aura (11 [25.0%]; =0.114). Migraine, especially migraine with aura, was independently associated with a no-mismatch pattern (odds ratio, 2.65; 95% CI, 0.95-7.41 for migraine; odds ratio, 5.54; 95% CI, 1.28-23.99 for migraine with aura), and there was a linear decrease of the proportion of patients with migraine with aura with increasing quartiles of mismatch volumes. Patients with migraine with aura had also smaller volumes of salvaged penumbra (9.8±41.2 mL) compared with patients with migraine without aura (36.4±54.1 mL) and patients with no migraine (45.1±55.0 mL; =0.056). Conversely, there was no difference in final infarct size among the 3 migraine subgroups (=0.312).

Conclusions: Migraine is likely to increase individual vulnerability to ischemic stroke during the process of acute brain ischemia and might represent, therefore, a potential new therapeutic target against occurrence and progression of the ischemic damage.
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http://dx.doi.org/10.1161/STROKEAHA.118.020554DOI Listing
March 2018

Anticoagulants Resumption after Warfarin-Related Intracerebral Haemorrhage: The Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy).

Thromb Haemost 2018 03 12;118(3):572-580. Epub 2018 Feb 12.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy.

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.
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http://dx.doi.org/10.1055/s-0038-1627454DOI Listing
March 2018

Arterial tortuosity in patients with spontaneous cervical artery dissection.

Neuroradiology 2017 Jun 11;59(6):571-575. Epub 2017 May 11.

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italy.

Purpose: The aim of this study was to test the hypothesis that patients with spontaneous cervical artery dissection (CeAD) have increased arterial tortuosity, and the objective quantification of such a tortuosity may aid in the identification of subjects at increased risk of disease.

Methods: In the setting of a hospital-based, case-control study, we used the vertebral tortuosity index (VTI) measured on magnetic resonance angiography, a validated method for the assessment and quantification of arterial tortuosity, to compare the degree of tortuosity in a series of consecutive patients with spontaneous CeAD and of age- and sex-matched patients with ischemic stroke unrelated to CeAD (non-CeAD IS) and stroke-free subjects.

Results: The study group was composed of 102 patients with CeAD (mean age, 44.5 ± 7.8 years; 66.7% men), 102 with non-CEAD IS, and 102 stroke-free subjects. The VTI was higher in the group of patients with CeAD (median, 7.3; 25th-75th percentile, 10.2) compared with that of non-CeAD IS (median, 3.4; 25th-75th percentile, 4.4) and of stroke-free subjects (median, 4.0; 25th-75th percentile, 2.9; p ≤ 0.001), and was independently associated to the risk of CeAD (OR, 1.18; 95% CI, 1.09-1.29) in multivariable regression analysis. The degree of tortuosity also tended to be higher in CeAD patients who experienced short-term recurrence (5.8%; median, 20.2; 25th-75th percentile, 31.2) than in those without recurrent events (median, 7.2; 25th-75th percentile, 9.4; p = 0.074).

Conclusion: CeAD patients exhibit increased arterial tortuosity. This might have potential implications for better understanding of the pathophysiology of the disease as well as clinical utility in evaluation, prognostication, and decision-making of affected individuals.
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http://dx.doi.org/10.1007/s00234-017-1836-9DOI Listing
June 2017

Association Between Migraine and Cervical Artery Dissection: The Italian Project on Stroke in Young Adults.

JAMA Neurol 2017 05;74(5):512-518

Dipartimento di Scienze Cliniche e Sperimentali, Clinica Neurologica, Università degli Studi di Brescia, Brescia, Italia.

Importance: Although sparse observational studies have suggested a link between migraine and cervical artery dissection (CEAD), any association between the 2 disorders is still unconfirmed. This lack of a definitive conclusion might have implications in understanding the pathogenesis of both conditions and the complex relationship between migraine and ischemic stroke (IS).

Objective: To investigate whether a history of migraine and its subtypes is associated with the occurrence of CEAD.

Design, Setting, And Participants: A prospective cohort study of consecutive patients aged 18 to 45 years with first-ever acute ischemic stroke enrolled in the multicenter Italian Project on Stroke in Young Adults was conducted between January 1, 2000, and June 30, 2015. In a case-control design, the study assessed whether the frequency of migraine and its subtypes (presence or absence of an aura) differs between patients whose IS was due to CEAD (CEAD IS) and those whose IS was due to a cause other than CEAD (non-CEAD IS) and compared the characteristics of patients with CEAD IS with and without migraine.

Main Outcomes And Measures: Frequency of migraine and its subtypes in patients with CEAD IS vs non-CEAD IS.

Results: Of the 2485 patients (mean [SD] age, 36.8 [7.1] years; women, 1163 [46.8%]) included in the registry, 334 (13.4%) had CEAD IS and 2151 (86.6%) had non-CEAD IS. Migraine was more common in the CEAD IS group (103 [30.8%] vs 525 [24.4%], P = .01), and the difference was mainly due to migraine without aura (80 [24.0%] vs 335 [15.6%], P < .001). Compared with migraine with aura, migraine without aura was independently associated with CEAD IS (OR, 1.74; 95% CI, 1.30-2.33). The strength of this association was higher in men (OR, 1.99; 95% CI, 1.31-3.04) and in patients 39.0 years or younger (OR, 1.82; 95% CI, 1.22-2.71). The risk factor profile was similar in migrainous and non-migrainous patients with CEAD IS (eg, hypertension, 20 [19.4%] vs 57 [24.7%], P = .29; diabetes, 1 [1.0%] vs 3 [1.3%], P > .99).

Conclusions And Relevance: In patients with IS aged 18 to 45 years, migraine, especially migraine without aura, is consistently associated with CEAD. This finding suggests common features and warrants further analyses to elucidate the underlying biologic mechanisms.
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http://dx.doi.org/10.1001/jamaneurol.2016.5704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822194PMC
May 2017