Thomas Gattringer

Clinical Presentation, Etiology, and Long-Term Prognosis in Patients With Nontraumatic Convexal Subarachnoid Hemorrhage

Background and Purpose— Nontraumatic subarachnoid hemorrhage at the convexity of the brain (cSAH) is an incompletely characterized subtype of nonaneurysmal subarachnoid bleeding. This study sought to systematically describe the clinical presentation, etiology, and long-term outcome in patients with cSAH. Methods— For a 6-year period, we searched our radiological database for patients with nontraumatic nonaneurysmal subarachnoid hemorrhages (n=131) seen on CT or MRI. By subsequent image review, we identified 24 patients with cSAH defined by intrasulcal bleeding restricted to the hemispheric convexities. We reviewed their medical records, analyzed the neuroimaging studies, and followed up patients by telephone or a clinical visit. Results— The 24 patients with cSAH had a mean age of 70 years (range, 37–88 years), 20 (83%) were >60 years, and 13 (54%) were women. Patients often presented with transient sensory and/or motor symptoms (n=10 [42%]) and seizures (n=5 [21%]), whereas headaches typical of subarachnoid hemorrhage were rare (n=4 [17%]). MRI provided evidence for prior bleedings in 11 patients (microbleeds in 10 and parenchymal bleeds in 5) with a bleeding pattern suggestive of cerebral amyloid angiopathy in 5 subjects. At follow-up (after a mean of 33 months), 14 patients (64%) had an unfavorable outcome (modified Rankin scale score 3–6), including 5 deaths. We did not observe recurrent cSAH. Conclusions— Our data suggest that cSAH often presents with features not typical for subarachnoid bleeding. In the elderly, cSAH is frequently associated with bleeding-prone conditions such as cerebral amyloid angiopathy. Recurrence of cSAH is rare but the condition itself is a marker of poor prognosis.

Dynamics of brain iron levels in multiple sclerosis A longitudinal 3T MRI study

Objective: We investigated longitudinal changes in iron concentration in the subcortical gray matter (caudate nucleus, globus pallidus, putamen, thalamus) of patients with clinically isolated syndrome (CIS) and definite multiple sclerosis (MS) and their relation to clinical and other morphologic variables. Methods: We followed 144 patients (76 CIS; median Expanded Disability Status Scale [EDSS] 1.0 [interquartile range (IQR) 0.0–2.0]; 68 MS; median EDSS 2.0 [IQR 1.0–3.3]) clinically and with 3T MRI over a median period of 2.9 (IQR 1.3–4.0) years. Iron concentration was determined by R2* relaxometry at baseline and last follow-up. Results: At baseline, subcortical gray matter iron deposition was higher in MS compared to CIS. In CIS, R2* rates increased in the globus pallidus (p < 0.001), putamen (p < 0.001), and caudate nucleus (p < 0.001), whereas R2* rates in the thalamus decreased (p < 0.05). In MS, R2* rates increased in the putamen (p < 0.05), remained stable in the globus pallidus and caudate nucleus, and decreased in the thalamus (p < 0.01). Changes in R2* relaxation rates were unrelated to changes in the volume of respective structures, of T2 lesion load, and of disability. Conclusions: Iron accumulation in the basal ganglia is more pronounced in the early than later phases of the disease and occurs independent from other morphologic brain changes. Short-term changes in iron concentration are not associated with disease activity or changes in disability.

Sex-Related Differences of Acute Stroke Unit Care: Results From the Austrian Stroke Unit Registry

Background and Purpose— Sex-related differences in quality of acute stroke care are an important concern with limited data available, specifically regarding stroke unit (SU) setting. We used the prospective nationwide Austrian SU registry to address this issue. Methods— Our analysis covered an 8-year time period (January 2005 to December 2012) during which all patients with transient ischemic attack or ischemic stroke admitted to 1 of 35 Austrian SU had been captured in the registry. These data were analyzed for age-adjusted preclinical and clinical characteristics and quality of acute stroke care in men and women. In addition, we assessed the outcome at 3 months in multivariate analysis. Results— A total of 47 209 individuals (47% women) had received SU care. Women were significantly older (median age: 77.9 versus 70.3 years), had higher pre-existing disability and more severe strokes. Correcting for age, no significant sex-related differences in quality of care were identified with comparable onset-to-door times, times to and rates of neuroimaging, as well as door-to-needle times and rates of intravenous thrombolysis (14.5% for both sexes). Despite equal acute stroke care and a comparable rate of neurorehabilitation, women had a worse functional outcome at 3-month follow-up (modified Rankin scale 3–5: odds ratio, 1.26; 95% confidence interval [1.17–1.36]), but a lower mortality (odds ratio, 0.70; 95% confidence interval [0.78–0.88]) after correcting for confounders. Conclusions— We identified no disproportions in quality of care in the acute SU setting between men and women, but the outcome was significantly different. Further studies on the poststroke period including socioeconomic aspects are needed to clarify this finding.

Circulating Dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease

OBJECTIVES Previous data suggest that Dickkopf-1 (Dkk-1), an inhibitor of the canonical/β-catenin cascade of the Wnt pathway, is upregulated in carotid atherosclerosis and acute myocardial ischemia. It is currently unclear if such upregulation also occurs in cerebral ischemia. METHODS We measured plasma levels of Dkk-1 in patients with acute ischemic stroke (n=57) within 24h from symptom onset, in patients with clinically stable cerebrovascular disease (n=29) and in healthy controls (n=29). Stroke severity on admission was determined by the National Institutes of Stroke Scale (NIHSS). The modified Rankin Scale (mRS) served to define outcome at day 90. Ischemic stroke subtype and cause was determined by the Oxfordshire Community Stroke Project (OCSP) criteria and the Causative Classification of Stroke System (CCS). RESULTS Dkk-1 plasma levels were significantly higher in acute stroke patients (median 727.1 pg/ml) as compared to patients with stable cerebrovascular disease (median 534.2 pg/ml; p=0.017) or healthy controls (median 371.3 pg/ml; p<0.001). The difference of Dkk-1 levels between patients with stable cerebrovascular disease and healthy controls was also significant (p=0.005). No significant differences in Dkk-1 plasma levels were found between different causes or subtypes of ischemic stroke. No correlation of Dkk-1 levels was found with stroke severity on admission and outcome at day 90. CONCLUSION Our study provides for the first time evidence for a release of Dkk-1 into the circulation in patients with acute ischemic stroke and also in patients with clinically stable cerebrovascular disease.

Vascular Risk Factors, White Matter Hyperintensities and Hippocampal Volume in Normal Elderly Individuals

Background/Aims: Hippocampal atrophy has been identified as marker for the development of Alzheimer’s dementia (AD). To what extent vascular risk factors and white matter hyperintensities (WMH) affect hippocampal volume (HV) in asymptomatic elderly subjects and thus may impact such a predictive capacity is controversial. Methods: We analysed 287 participants of the Austrian Stroke Prevention Study (mean age 66.6 ± 6.6 years) with a Mini Mental State Examination score ≧27 who were free of neuropsychiatric disease and had undergone MRI including coronal T1-weighted sequences allowing for semi-automatic assessment of HV. Global brain volume (BV) was measured using SIENAX. WMH were rated according to the Fazekas scale and segmented to obtain WMH volumes. Results: Higher age was associated with lower absolute and normalized HV, a lower BV and higher WMH volume. None of the vascular risk factors had an impact on HV except for high-density lipoprotein. This effect disappeared after normalization of HV. WMH severity and volume did not affect HV either. Conclusion: Our data indicate HV loss in parallel with the whole brain and suggest no specific vulnerability towards vascular risk factors or age-related WMH in a cognitively intact normal elderly population. This also supports the utility of HV measurements to identify impending AD.

High-Grade Internal Carotid Artery Stenosis and Chronic Brain Damage: A Volumetric Magnetic Resonance Imaging Study

Background: Experimental data suggest that high-grade vascular stenosis may induce chronic cerebral tissue damage. Methods: We tested this hypothesis in 97 patients with a ≧70% unilateral internal carotid artery (ICA) stenosis (mean age: 69.1 ± 10.2 years), comparing intraindividual side-to-side differences in hemispheric brain and white matter hyperintensity (WMH) volumes. Patients with a supratentorial infarct exceeding 1.5 cm in diameter were excluded. Results: Overall, the median WMH volume was greater in the hemisphere ipsilateral to the stenotic ICA (1.13 ± 2.65 vs. 0.77 ± 2.26 cm3; p = 0.005), but there were no differences in hemispheric brain volumes between the stenotic and nonstenotic sides. In the subgroup of patients with moderate and severe WMH (n = 41), the hemispheric volume ipsilateral to the stenotic ICA was significantly smaller (543.46 ± 22.17 vs. 548.66 ± 26.7 cm3; p = 0.03). Multivariate linear regression analysis revealed an independent effect of WMH grade on interhemispheric volume differences relative to the side of stenosis. Conclusions: Chronic tissue damage may occur in a subset of individuals with ≧70% ICA stenosis, globally exhibiting more extensive WMH.

Contribution of Convexal Subarachnoid Hemorrhage to Disease Progression in Cerebral Amyloid Angiopathy

Background and Purpose— Cerebral amyloid angiopathy–related cortical superficial siderosis (cSS) seems to indicate an increased risk of subsequent intracerebral hemorrhage (ICH). We wanted to identify the mechanisms and sequence of hemorrhagic events which are responsible for this association. Methods— During a 9-year-period, we identified patients with spontaneous convexal subarachnoid hemorrhage (cSAH) and performed a careful longitudinal analysis of clinical and neuroimaging data. A close imaging–histopathologic correlation was performed in one patient. Results— Of 38 cSAH patients (mean age, 77±11 years), 29 (76%) had imaging features of cerebral amyloid angiopathy on baseline magnetic resonance imaging. Twenty-six (68%) had cSS. Sixteen subjects underwent postcontrast magnetic resonance imaging. Extravasation of gadolinium at the site of the acute cSAH was seen on all postcontrast scans. After a mean of 24±22 (range 1–78) months of follow-up, 15 (39%) had experienced recurrent cSAHs and 14 (37%) had suffered lobar ICHs. Of 22 new ICHs, 17 occurred at sites of previous cSAHs or cSS. Repeated neuroimaging showed expansion of cSAH into the brain parenchyma and evolution of a lobar ICH in 4 patients. Propagation of cSS was observed in 21 (55%) patients, with 14 of those having experienced recurrent cSAHs. In the autopsy case, leakage of meningeal vessels affected by cerebral amyloid angiopathy was noted. Conclusions— In cerebral amyloid angiopathy, leakage of meningeal vessels seems to be a major cause for recurrent intrasulcal bleedings, which lead to the propagation of cSS and indicate sites with increased vulnerability for future ICH. Intracerebral bleedings may also develop directly from or in extension of a cSAH.

Myocardial Infarction as a Complication in Acute Stroke: Results from the Austrian Stroke Unit Registry

Background: Patients with transient ischemic attack (TIA) and stroke have an increased risk for subsequent cardiac events including myocardial infarction (MI), which might be associated with a worse clinical outcome. Rapid identification of stroke patients at higher risk for MI might foster intensified cardiac monitoring or certain therapeutic strategies. However, information regarding acute MI as a complication of stroke in the very acute phase is limited. Moreover, there are no systematic data on the occurrence of MI following intracerebral hematoma. We thus aimed to assess the frequency, clinical characteristics and short-term outcome of patients suffering from acute MI in the stroke unit setting. Methods: We analyzed 46,603 patients from 32 Austrian stroke units enrolled in the prospective Austrian Stroke Unit Registry because of TIA/acute stroke over a 6-year period (January 1, 2007 to January 13, 2013). A total of 41,619 patients (89.3%) had been treated for TIA/ischemic stroke and 4,984 (10.7%) for primary intracerebral hemorrhage (ICH). Acute MI was defined according to clinical evaluation, ECG findings and laboratory assessments. Patients with evidence for MI preceding the cerebrovascular event were not considered. Results: Overall, 421 patients (1%) with TIA/ischemic stroke and 17 patients (0.3%) with ICH suffered from MI during stroke unit treatment for a median duration of 3 days. Patients with TIA/ischemic stroke and MI were significantly older, clinically more severely affected and had more frequently vascular risk factors, atrial fibrillation and previous MI. Total anterior circulation and left hemispheric stroke syndromes were more often observed in MI patients. Patients with MI not only suffered from worse short-term outcome including a higher mortality (14.5 vs. 2%; p < 0.001) at stroke unit discharge, but also acquired more stroke complications like progressive stroke and pneumonia. Multivariate analyses identified previous MI and stroke severity at admission (according to the National Institutes of Health and Stroke Scale score) as factors independently associated with the occurrence of MI on the stroke unit. Conclusions: While quite rare in the acute phase after stroke, MI is associated with a poor short-term outcome including a higher mortality. Patients with previous MI and severe stroke syndromes appear to be at particular risk for MI as an early complication in the stroke unit setting. Further studies are needed to determine whether increased vigilance and prolonged (cardiac) monitoring or certain therapeutic approaches could improve the outcome in these high-risk patients.

Impact of small vessel disease in the brain on gait and balance

Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71–74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity – WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients’ performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

Serum neurofilament light is sensitive to active cerebral small vessel disease

Objective: To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner. Methods: In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls. Results: Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up. Conclusions: Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.