The crosstalk between Stroke and Cancer: Incidence of cancer after a first-ever cerebrovascular event in a population-based study.

OBJECTIVES: To determine the cancer incidence after the first-ever cerebrovascular event (CVE) and compare it to the cancer incidence in the population from the same region. METHODS: We evaluated 1069 patients with a first-ever CVE (Ischaemic or haemorrhagic stroke and Transient Ischaemic Attack) from a prospective population registry of stroke and transient focal neurological attacks, diagnosed between 2009 and 2011. We conducted a structured search to identify cancer-related variables and case-fatality for a period of 8 years following CVE. Cancer incidence in CVE patients was compared to the North Region Cancer Registry (RORENO). RESULTS: We found that 90/1069 (8.4%) CVE patients developed cancer after a first-ever CVE. Overall cancer annual incidence rate was higher after a CVE (820/100,000, 95%CI: 619-1020) than in general population (513/100,000, 95%CI: 508-518). In the 45-54 age group cancer incidence post-CVE was 3.2-fold (RR, 95%CI: 1.6-6.4) higher compared to the general population, decreasing gradually in older age-groups. Median time between CVE and cancer was 3.2 years (IQR = 1.4-5.2). Lower respiratory tract and colorectal were the most frequent cancer types. In univariable models, male sex (sHR = 1.78, 95%CI: 1.17-2.72, p = 0.007), tobacco use (sHR = 2.04, 95%CI: 1.31-3.18, p = 0.002) and peripheral artery disease (sHR = 2.37, 95%CI: 1.10-5.13, p = 0.028) were associated to higher cancer risk after CVE. After adjustment, tobacco use (sHR = 1.84, 95%CI: 1.08-3.14, p = 0.026) remained associated to a higher risk of cancer. CONCLUSIONS: At the population level, patients presenting a first-ever CVE have higher cancer incidence, that is particularly prominent in younger age-groups. Higher cancer incidence, delayed cancer diagnosis and increased mortality post-CVE warrants further research on long-term cancer surveillance in first-ever CVE survivors.

MuSK myasthenia gravis and pregnancy.

Muscle specific kinase (MuSK) myasthenia gravis (MG, MuSK-MG) is a rare subgroup of MG affecting mainly women during childbearing years. We investigated the influence of pregnancy in the course of MuSK-MG and pregnancy outcomes in females with MuSK-MG. A multicentre cohort of 17 women with MuSK-MG was studied retrospectively; 13 of them with ≥1 pregnancy. MuSK-MG onset age was 35,4 years; 23,0% had other autoimmune disorder; 46,2% were treatment refractory. Thirteen women experienced 27 pregnancies, either after MG onset (group I) (n = 4; maternal age at conception = 29.8 years) or before MG onset (group II) (n = 23; maternal age at conception = 26.2 years). In group I pregnancy occurred in average 9.8 years after the MG onset; it occurred in average 17.0 years before MG in group II. In group I, all were on steroids at time of conception, one on azathioprine and another receiving IVIG regularly. There were mild exacerbations that responded to treatment adjustments. There were no relapses in the 12 months following the delivery. There was no pre-eclampsia, birth defects or stillbirths in either group; 3 miscarriages in group II. One case of neonatal MG was recorded. In this small series, pregnancy did not seem to precipitate MuSK-MG or to have a major influence in the MuSK-MG course, and there was no apparent negative impact in pregnancy outcomes in those where pregnancy followed the MG onset. The weight was lower in the newborn of the group I mothers, although none had low birth weight.

Epidemiology of myasthenia gravis in Northern Portugal: Frequency estimates and clinical epidemiological distribution of cases.

INTRODUCTION: In this study we estimated the prevalence, incidence, and mortality of myasthenia gravis (MG) in northern Portugal and characterized the clinical features of the patients identified. METHODS: We used 2 data sources: clinical records from the hospitals and pyridostigmine prescription registers. RESULTS: On December 31, 2013, we estimated a point prevalence of 111.7 patients per million population. The highest prevalence was observed in the group >65 years of age, especially in men (288.1 per million). During 2013, we estimated an incidence rate of 6.3 per million per year. Among women, the incidence rate was highest in the 15-49-year age group; in men, incidence increased with age up to 22.1 per million in those >65 years old. The MG-related mortality rate was 0.5 per million. CONCLUSIONS: These figures are in keeping with similar studies and emphasize the importance of diagnosis and management of MG in elderly populations. Muscle Nerve 54: 413-421, 2016.

Stroke types in rural and urban northern portugal: incidence and 7-year survival in a community-based study.

BACKGROUND/AIM: Differences in stroke incidence and mortality between regions could stem from differences in the incidence of particular stroke types and long-term prognosis. The aim of this study was to investigate whether different risk profiles and stroke types underlie the difference in stroke incidence and patient long-term survival in rural and urban populations. METHODS: All suspected first-ever-in-a-lifetime strokes occurring between October 1998 and September 2000 in 37,290 residents of rural municipalities and in 86,023 individuals living in the city of Porto were entered into a population-based registry. Standard definitions of stroke types and overlapping comprehensive sources of information were used for patient identification. Patients were examined by neurologists at 3 months, 1 year and 7 years after the index event. RESULTS: From a total of 688 patients included (226 in rural and 462 in urban areas), 76.2% had an ischaemic stroke (IS; 75.3 vs. 77.9%), 16.1% a primary intracerebral haemorrhage (PICH; 16.3 vs. 14.6%) and 3.3% a subarachnoid haemorrhage (SAH; 2.7 vs. 3.7%); in 4.4% (4.9 vs. 4.1%), the stroke type could not be determined. The annual incidence rate per 1,000 was 2.13 (95% CI, 1.95-2.31), 0.45 (95% CI, 0.37-0.53), 0.09 (95% CI, 0.06-0.14) and 0.12 (95% CI, 0.08-0.17), respectively. The age-specific rural/urban incidence rate ratios for IS in the youngest group (<55 years) was 0.27 (95% CI, 0.11-0.69), increasing to 1.47 (95% CI, 1.07-2.01) for those aged 65-74 years and to 1.87 (95% CI, 1.39-2.52) for those between 75 and 84 years. Rural compared to urban patients with an IS were predominantly men, had a prevalence ratio (PR) of 1.28 (95% CI, 1.05-1.56), were 65 years or older (PR = 1.18; 95% CI, 1.08-1.30) and had in general a lower prevalence of risk factors. There was no evidence of rural/urban differences in 28-day case fatality for the stroke types, although IS tended to be less fatal among urban patients (10.3 vs. 13.1%), whereas PICH (33.3 vs. 24.2%) and SAH (35.3 vs. 16.7%) were less fatal among rural patients. Independently of rural/urban residence, predictors of poor survival after the acute phase (28 days) were age >65 years (HR = 3.57; 95% CI, 2.6-4.9), diabetes (HR = 1.5; 95% CI, 1.2-1.9), ischaemic heart disease (HR = 1.8; 95% CI, 1.3-2.6), atrial fibrillation (HR = 1.5; 95% CI, 1.1-2.0) and smoking habits (HR = 1.6; 95% CI, 1.1-2.3). CONCLUSIONS: The age pattern of IS incidence marks the difference between rural and urban populations; the youngest urban and the oldest rural residents were at a higher risk. Although patients from rural areas were older, the relatively lower prevalence of simultaneously occurring risk and prognostic factors among them as well as the similar management of rural and urban patients may justify why rurality is not associated with long-term survival.

Psychotic aura symptoms in familial hemiplegic migraine type 2 (ATP1A2).

INTRODUCTION: Neuropsychological symptoms are rare in familial hemiplegic migraine (FHM). There are no reports of psychotic symptoms in FHM type 2 (ATP1A2). We examined a family with a FHM phenotype due to a M731T mutation in ATP1A2. A 10-year follow-up allowed us to observe complex auras, including psychotic symptoms in two siblings. CASE REPORT: Male, 48 years old, with an aura that included complex illusions with a feeling of time travelling, coincident with other aura features. The aura was regarded as mystical by the patient. Female, 38 years old, with a complex migraine aura, during which she believed she had the ability to time travel and was being followed by lobbyists who wanted to steal this ability from her. DISCUSSION: FHM type 2 must be included in the list of differential diagnoses of acute psychosis in patients with a previous history of migraine aura.

TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches.

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

Kalirin: a novel genetic risk factor for ischemic stroke.

Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.

Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patients.

BACKGROUND: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. METHODS: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. RESULTS: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. CONCLUSION: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.

Prospective community-based study of stroke in Northern Portugal: incidence and case fatality in rural and urban populations.

BACKGROUND AND PURPOSE: Mortality statistics indicate that Portugal has the highest stroke mortality in Western Europe. Data on stroke incidence in Northern Portugal, the region with the highest mortality, are lacking. This study was designed to determine stroke incidence and case fatality in rural and urban populations in Northern Portugal. METHODS: All suspected first-ever-in-a-lifetime strokes occurring between October 1998 and September 2000 in 37,290 residents in rural municipalities and 86,023 living in the city of Porto were entered in a population-based registry. Standard definitions and comprehensive sources of information were used for identification of patients who were followed-up at 3 and 12 months after onset of symptoms. RESULTS: During a 24-month period, 688 patients with a first-ever stroke were registered, 226 in rural and 462 in urban areas. The crude annual incidence was 3.05 (95% CI, 2.65 to 3.44) and 2.69 per 1000 (95% CI, 2.44 to 2.93) for rural and urban populations, respectively; the corresponding rates adjusted to the European standard population were 2.02 (95% CI, 1.69 to 2.34) and 1.73 (95% CI, 1.53 to 1.92). Age-specific incidence followed different patterns in rural and urban populations, reaching major discrepancy for those 75 to 84 years old, 20.2 (95% CI, 16.1 to 25.0) and 10.9 (95% CI, 9.0 to 12.8), respectively. Case fatality at 28 days was 14.6% (95% CI, 10.2 to 19.3) in rural and 16.9% (95% CI, 13.7 to 20.6) in urban areas. CONCLUSIONS: Stroke incidence in rural and urban Northern Portugal is high compared to that reported in other Western Europe regions. The high official mortality in our country, which could be explained by a relatively high incidence, was not because of a high case fatality rate.