Christian Tanislav

Lifestyle Risk Factors for Ischemic Stroke and Transient Ischemic Attack in Young Adults in the Stroke in Young Fabry Patients Study

Background and Purpose— Although many stroke patients are young or middle-aged, risk factor profiles in these age groups are poorly understood. Methods— The Stroke in Young Fabry Patients (sifap1) study prospectively recruited a large multinational European cohort of patients with cerebrovascular events aged 18 to 55 years to establish their prevalence of Fabry disease. In a secondary analysis of patients with ischemic stroke or transient ischemic attack, we studied age- and sex-specific prevalences of various risk factors. Results— Among 4467 patients (median age, 47 years; interquartile range, 40–51), the most frequent well-documented and modifiable risk factors were smoking (55.5%), physical inactivity (48.2%), arterial hypertension (46.6%), dyslipidemia (34.9%), and obesity (22.3%). Modifiable less well-documented or potentially modifiable risk factors like high-risk alcohol consumption (33.0%) and short sleep duration (20.6%) were more frequent in men, and migraine (26.5%) was more frequent in women. Women were more often physically inactive, most pronouncedly at ages <35 years (18–24: 38.2%; 25–34: 51.7%), and had high proportions of abdominal obesity at age 25 years or older (74%). Physical inactivity, arterial hypertension, dyslipidemia, obesity, and diabetes mellitus increased with age. Conclusions— In this large European cohort of young patients with acute ischemic cerebrovascular events, modifiable risk factors were highly prevalent, particularly in men and older patients. These data emphasize the need for vigorous primary and secondary prevention measures already in young populations targeting modifiable lifestyle vascular risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00414583.

Frequency of Fabry disease in patients with small‐fibre neuropathy of unknown aetiology: a pilot study

Background:  Early occurrence of small‐fibre neuropathy (SFN) is a common feature of Fabry disease (FD) – an X‐linked storage disorder caused by reduced activity of the α‐galactosidase A (α‐GAL). Although SFN may result from different disorders, the cause is often unclear. Therefore, we investigated the frequency of FD in patients with SFN of unknown aetiology.

Effect of daytime, weekday and year of admission on outcome in acute ischaemic stroke patients treated with thrombolytic therapy.

Background:  Since doubts were raised, if a challenging medical procedure such as acute stroke treatment including thrombolysis with recombinant tissue plasminogen activator (rTPA) is available with identical standard and outcome 24 h and 7 days a week our aim was to examine if acute stroke patients defined by onset‐admission time (OAT) of ≤ 3 h were treated differently or had distinct outcome when admitted during off duty hours (day versus night and weekend versus weekdays) and if any differences in treatment or outcome were apparent when comparing patients admitted in the year 2003 with patients admitted in the year 2006.

MRI in acute cerebral ischemia of the young: The Stroke in Young Fabry Patients (sifap1) Study

Objective: We focused on cerebral imaging findings in a large cohort of young patients with a symptomatic ischemic cerebrovascular event (CVE) to extract relevant pathophysiologic and clinical information. Methods: We analyzed the scans of 2,979 patients (aged 18–55 years) enrolled in the sifap1 project with clinical evidence of ischemic stroke (IS) or clinically defined TIA in whom MRI, including diffusion-weighted imaging, was obtained within 10 days of the CVE. Age groups were categorized as 18–34, 35–44, and 45–55 years. We compared age- and sex-specific proportions of infarct features, white matter hyperintensities, and old microbleeds. Results: Acute infarcts were identified in 1,914 of 2,264 patients (84.5%) with IS and 101 of 715 patients (14.1%) with TIA. Among patients with IS, younger age was significantly associated with acute infarcts in the posterior circulation, while anterior circulation infarcts and acute lacunar infarcts were more frequent in older age groups. One or more old infarcts were present in 26.8% of IS and 17.1% of TIA patients. This rate remained high even after excluding patients with a prior CVE (IS, 21.7%; TIA, 9.9%). The prevailing type of old infarction was territorial in patients younger than 45 years and lacunar in those aged 45 years or older. The frequency of white matter hyperintensities (46.4%) and their severity was positively associated with age. Old microbleeds were infrequent (7.2%). Conclusions: Young adults show a high frequency of preexisting and clinically silent infarcts and a relative preference for acute ischemia in the posterior circulation. Findings suggesting small-vessel disease become apparent at age 45 years and older.

Cerebral vein thrombosis: clinical manifestation and diagnosis

BackgroundCerebral venous thrombosis (CVT) is a disease with a wide spectrum of symptoms and severity. In this study we analysed the predictive value of clinical signs and symptoms and the contribution of D-dimer measurements for diagnosis.MethodsWe evaluated consecutive patients admitted with suspected CVT receiving non-invasive imaging. Symptoms and symptom combination as well as D-dimer levels were evaluated regarding their diagnostic value.Results239 patients were included in this study, 170 (71%) were females. In 39 patients (16%) a CVT was found. For identifying a CVT patients underwent either a venous CT-angiography or MR-angiography or both. No combination of symptoms either alone or together with the D-dimer measurements had a sensitivity and positive predictive value as well as negative predictive value and specificity high enough to serve as red flag. D-dimer testing produced rates of 9% false positive and of 24% false negative results. For D-dimer values a Receiver Operating Characteristic curve (ROC) and the area under the curve (AUC = 0.921; CI: 0.864 - 0.977) were calculated. An increase of sensitivity above 0.9 results in a relevant decrease in specificity; a sensitivity of 0.9 matches a specificity value of 0.9. This corresponds to a D-dimer cut-off level of 0.16 μg/ml.ConclusionImaging as performed by venous CT-angiography or MR-angiography has a 1 to 2 in 10 chance to detect CVT when typical symptoms are present. D-dimer measurements are of limited clinical value because of false positive and negative results.

cAMP controls the restoration of endothelial barrier function after thrombin-induced hyperpermeability via Rac1 activation.

Inflammatory mediators like thrombin disrupt endothelial adherens junctions (AJs) and barrier integrity leading to oedema formation followed by resealing of AJs and a slow recovery of the barrier function. The molecular mechanisms of this process have not yet been fully delineated. The aim of the present study was to analyse the molecular mechanism of endothelial barrier recovery and thrombin was used as model inflammatory mediator. Thrombin caused a strong increase in endothelial permeability within 10 min accompanied by loss of Rac1 but not cdc42 activity, drop in cellular cAMP contents, and a strong activation of the endothelial contractile machinery mainly via RhoA/Rock signalling. Activation of RhoA/Rock signalling precedes and is dependent upon a rise in the cytosolic Ca2+ concentration. Inhibition of cytosolic Ca2+ rise but not MLCK or Rock enhances the recovery of endothelial barrier function. The cellular cAMP contents increased gradually during the barrier recovery phase (30–60 min after thrombin challenge) accompanied by an increase in Rac1 activity. Inhibition of Rac1 activity using a specific pharmacological inhibitor (NSC23766) abrogated the endothelial barrier recovery process, suggesting a Rac1‐dependent phenomenon. Likewise, inhibition of either adenylyl cyclase or the cAMP‐effectors PKA and Epac (with PKI and ESI‐09, respectively) caused an abrogation of Rac1 activation, resealing of endothelial AJs and recovery of endothelial barrier function. The data demonstrate that endothelial barrier recovery after thrombin challenge is regulated by Rac1 GTPase activation. This Rac1 activation is due to increased levels of cellular cAMP and activation of downstream signalling during the barrier recovery phase.

Fabry Disease – Underestimated in the Differential Diagnosis of Multiple Sclerosis?

Objective Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings. Methods Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease. Results Four patients were identified as having a “possible” history of MS, and 7 patients as “definite” cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load. Conclusion There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.

Cardiac Troponin I elevation after epileptic seizure

BackgroundCardiac troponin-I (cTNI) is highly specific biomarker to prove myocardial damage, e.g. in acute coronary syndrome (ACS). However, it occurs in other conditions as well. We therefore analysed cTNI increase in patients after generalized convulsive seizure.MethodsConsecutive patients admitted with acute generalized convulsive seizure were included in case of cTNI measurement on admission. Among 898 selected cases, 53 patients were referred secondary to our department; in 845 cases cTNI measurements on admission were available. In case of multiple admissions (81 cases), only the first admission entered our analysis. In 17 patients elevated cTNI was determined due to ACS; in one patient a myocarditis was found. 5 patients suffered of relevant renal insufficiency. Finally 741 patients were included in the analysis. A cTNI cut-off level of ≥ 0.1 ng/ml was considered. Factors associated with a cTNI increase were analysed subsequently.ResultsThe mean age of the study population (n = 741) was 47.8 years (SD ± 18.6), 40.9% were female. In 50 patients (6.7%) a cTNI elevation of unknown origin was found; no obvious cardiac involvement could be detected in these patients who all remained asymptomatic. A vascular risk profile (including at least hypertension, hypercholesterolemia or diabetes) (OR = 3.62; CI: 1.59 to 8.21; p = 0.001) and elevated creatine kinase on admission (OR = 2.36; CI: 1.26 to 4.39; p = 0.002) were independent factors associated with cTNI release.ConclusioncTNI release occurs in patients with generalized convulsive seizure with predominance in patients with vascular risk profile.

High Frequency of Silent Pulmonary Embolism in Patients With Cryptogenic Stroke and Patent Foramen Ovale

Background and Purpose— Deep vein thrombosis and pulmonary embolism (PE) prove venous embolic activity and enforce the suspicion of paradoxical embolism in patients with stroke with patent foramen ovale. Because it has implications in secondary prevention, we investigated the frequency of silent PE in such a cohort of patients. Methods— Patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale who underwent a ventilation perfusion scintigraphy were identified from a stroke registry. Blinded from clinical data, ventilation perfusion scintigraphy scans were re-evaluated independently by 2 experts. Patients showing at least a subsegmental defect were considered as having silent PE. Factors potentially associated with PE were analyzed. Results— The evaluation included 151 patients. Median age was 55.2 years and 59.9% were male. In 56 (37%) patients, silent PE was found; a deep vein thrombosis was evident in 11 (7%) patients. Atrial septal aneurysm was identified in 39 patients and hypermobile atrial septum in 37 patients. Atrial septal aneurysm and hypermobile atrial septum were independently associated with PE. In females, intake of oral contraceptives showed certain association with PE (6 of 25 versus 3 of 40; P=0.07). Conclusions— Silent PE frequently occurs in patients with cryptogenic stroke and patent foramen ovale, particularly when atrial septal aneurysm or hypermobile atrial septum are present.

HbA1c in pulmonary arterial hypertension: A marker of prognostic relevance?

BACKGROUND Patients with pulmonary arterial hypertension (PAH) exhibit impaired glucose metabolism and increased insulin resistance. The clinical consequences of these metabolic changes are not known. METHODS We assessed HbA1c levels in 115 patients newly diagnosed with PAH (79 females and 36 males; mean age 49.2 years; idiopathic n = 67, collagen vascular disease n = 16, congenital heart defect n = 19, pulmonary veno-occlusive disease n = 8, portopulmonary n = 5). No patients had diabetes or were receiving anti-diabetic medication or systemic steroids. After initiation of pulmonary vasoactive treatment, patients remained in long-term follow-up. RESULTS Initially, patients were in an advanced stage of disease (mean pulmonary arterial pressure 53 ± 18 mm Hg, cardiac index 2.3 ± 0.8 liters/min/m2) with a 6-minute-walk distance of 337 ± 123 meters, and in NYHA Functional Class 3.0 ± 0.7. The HbA1c was 5.73 ± 0.75%. A moderate but statistically significant positive correlation was observed between HbA1c levels and BNP (r(p) = 0.41, p = 0.014), but no correlation was found with hemodynamics or 6-minute-walk distance. The 5-year survival rate for the entire group was 68%. Kaplan-Meier analysis and multivariate Cox proportional hazard models correcting for demographic and clinical covariates revealed that patients with HbA1c < 5.7% had a significantly better 5-year survival compared with those having higher initial values (85.1% vs. 55.9%; log rank p = 0.002). HbA1c was a predictor of all-cause mortality with a hazard ratio of 2.23 (95% CI 1.06 to 4.70; p = 0.034) per 1-unit increase of HbA1c. CONCLUSIONS In patients with pulmonary arterial hypertension, the HbA1c level at time of diagnosis is an independent predictor of long-term prognosis.