Christian Stapf

Demographic, Morphological, and Clinical Characteristics of 1289 Patients With Brain Arteriovenous Malformation

BACKGROUND AND PURPOSEnThe purpose of this study was to assess demographic, clinical, and morphological characteristics of patients with brain arteriovenous malformations (AVMs).nnnMETHODSnProspectively collected data of 1289 consecutive AVM patients from 3 independent databases (1 multicenter [Berlin/Paris/Middle and Far East, n=662] and 2 single centers [New York, n=337, and Toronto, n=290]) were analyzed. The variables assessed were age at diagnosis, sex, AVM size, AVM drainage pattern, AVM location in functionally important brain areas (eloquence), and type of presentation (hemorrhage, seizure, chronic headache, or focal neurologic deficit). Comparisons were made by ANOVA, contingency tables, and log-linear models.nnnRESULTSnOverall, mean age at diagnosis was 31.2 years (95% CI 30.2 to 32.2 years), and 45% of the patients were female (95% CI 42% to 47%). AVM maximum diameter was <3 cm in 38% (95% CI 35% to 41%). Deep venous drainage was present in 55% (95% CI 52% to 59%). An eloquent AVM location was described in 71% (95% CI 69% to 74%). AVM hemorrhage occurred in 53% (95% CI 51% to 56%). Generalized or focal seizures were described in 30% (95% CI 27% to 33%) and 10% (95% CI 8% to 12%), respectively. Chronic headache was recorded in 14% (95% CI 12% to 16%). Persistent neurological deficits were found in 7% (95% CI 6% to 9%), and progressive neurological deficits in 5% (95% CI 4% to 6%). Significant differences between centers were found for age (P<0.001), sex (P=0.04), eloquence (P=0.04), size (P<0.001), hemorrhage (P=0.006), persistent neurological deficit (P<0.001), and reversible neurological deficit (P=0.013). The intercenter difference found for hemorrhage frequency did not remain after adjustment for AVM size.nnnCONCLUSIONSnBaseline characteristics differed considerably between centers. The differences found in patient age and AVM size may be explained by center-specific referral patterns and the influence of access to treatment resources, whereas those found for other characteristics may be attributable to center-specific definitions. Analysis of natural history data from tertiary referral center databases may be improved by consistent definitions applicable to the entire population of AVM patients.

Prospective Study on the Complication Rate of Carotid Surgery

Background: Randomized trials of carotid endarterectomy for high-grade stenosis have shown a benefit for surgery under the condition of low perioperative complication rates. Concerns have been expressed that the complication rates of carotid surgery are higher in everyday practice and may vary considerably between centers. We prospectively established the complication rate for carotid surgery in a single institution. Design: Prospective 2-year study. All patients received pre- and postoperative neurological evaluation. Laboratory tests included pre- and postoperative brain imaging, intracranial and neck vessel sonography, conventional angiography, magnetic resonance angiography, and intraoperative monitoring. Participants: 108 consecutive patients: 54 symptomatic patients fulfilling the inclusion criteria of the European Carotid Surgery Trial (ECST) and 54 asymptomatic patients fulfilling the inclusion criteria of the North American Trial on Asymptomatic Stenoses (ACAS). Setting: Single academic center with a high volume of carotid endarterectomies (>50 per year). Participating center in ECST. Main Outcome Measures: Stroke or death as defined in the randomized trials. Results: The overall complication rate was 8.3% (95% CI 4.1–15.6%). Complications were more frequent in patients with symptomatic stenosis (11.1%, CI 4.6–23.3%) than in asymptomatic cases (5.6%, CI 1.5–16.4%). Three patients died (2 strokes, 1 myocardial infarction). Disabling strokes were found in 2 patients (Rankin scale scores 3 and 4). Nondisabling strokes (Rankin scale score 1 and 2) occurred in 4 patients. The complication rates for symptomatic and asymptomatic patients were higher than the ones reported in the randomized trials, but 95% confidence intervals showed that the differences were not statistically significant. The point estimates of complication rates still supported a benefit of surgery for patients with symptomatic stenosis, but denied a positive effect of endarterectomy for patients with asymptomatic stenosis. Conclusion: In this center, a beneficial effect of carotid surgery for asymptomatic stenoses cannot be safely assumed.

Histogram-based characterization of healthy and ischemic brain tissues using multiparametric MR imaging including apparent diffusion coefficient maps and relaxometry

Decreased, renormalized, or increased values of the calculated apparent diffusion coefficient (ADC) are observed in stroke models. A quantitative description of corresponding tissue states using ADC values may be extended to include true relaxation times. A histogram‐based segmentation is well suited for characterizing tissues according to specific parameter combinations irrespective of the heterogeneity found for human healthy and ischemic brain tissues. In a new approach, navigated diffusion‐weighted images and ADC maps were incorporated into voxel‐based parameter sets of relaxation times (T1, T2), and T1‐ or T2‐weighted images, followed by a supervised histogram‐based analysis. Healthy tissues were segmented by incorporating T1 relaxation into the data set, ischemic regions by combining T2‐ or diffusion‐weighted images with ADC maps. Mean values of healthy and pathologic tissues were determined, spatial distributions of the parameter vectors were visualized using color‐encoded overlays. One to six days after stroke, ischemic regions exhibited reduced relative mean ADC values. Magn Reson Med 43:52–61, 2000.

LOCALIZATION, DIFFERENTIAL EXPRESSION AND RETROGRADE AXONAL TRANSPORT SUGGEST PHYSIOLOGICAL ROLE OF FGF-2 IN SPINAL AUTONOMIC NEURONS OF THE RAT

Fibroblast growth factor‐2 (FGF‐2) has marked pharmacological neurotrophic effects on lesioned spinal autonomic neurons following target removal of the adrenal medulla, yet expression and axonal transport in autonomic neurons remain to be shown. We show here FGF‐2 and FGF receptor type 1 (FGFR1) protein and mRNA expression in preganglionic intermediolateral neurons of the rat thoracic spinal cord. While immunoreactivity of both FGF‐2 and FGFR1 co‐localize to intermediolateral neurons, mRNA transcripts of FGFR1, but not of FGF‐2, are detectable in intermediolateral preparations by RNase protection analysis, suggesting protein translocation in viva Unilateral microinjection of 125iodinated FGF‐2 into the adrenal medulla (a major target of intermediolateral neurons) results in significant accumulation of specific radioactivity in thoracic spinal cord tissue, including the intermediolateral neurons, and the ipsilateral splanchnic nerve. Emulsion autoradiography demonstrated labelling over ipsilateral intermediolateral neurons only. Neuronal co‐localization of FGF‐2/FGFR1 protein, differential mRNA expression, specific retrograde axonal transport and the known neurotrophic actions in vivo, strongly suggest unique physiological roles of FGF‐2 in the autonomic nervous system.

Presentation and Prognosis of Bilateral Infarcts in the Territory of the Superior Cerebellar Artery

Unilateral cerebellar infarcts in the territory of the superior cerebellar artery (SCA) have been studied in recent years to delineate the clinical presentation and stroke mechanism, but most studies excluded bilateral infarctions. We have studied patients with bilateral SCA infarctions to provide data on clinical findings, stroke distribution and outcome. We collected data of 8 patients with bilateral SCA infarctions recognized by computed tomography and/or magnetic resonance imaging. The most common clinical presentation of patients with bilateral SCA infarctions were nausea, vomiting or vertigo (6 patients), often associated with ataxia and dysarthria (5 patients). Further symptoms were variable and depended on additional infarcts in other vascular territories. Infarcts were often partial or scattered with equal distribution between the medial and lateral branches of the SCA. Complete infarction within the SCA area occurred in less than half of the cases. Clinical outcome was either benign (full recovery in 3 patients) or fatal (5 patients). Predictors for a good clinical recovery were young age, few vascular risk factors, only partial involvement of the SCA territory without involvement of other vascular territories, and absent limb weakness on clinical presentation.

Fibroblast growth factor-2 (FGF-2) and FGF-receptor (FGFR-1) immunoreactivity in embryonic spinal autonomic neurons

Abstract.The development of the nervous system appears to be under the control of multiple growth factors, neurotrophins and cytokines, which may be expressed either continuously or transiently throughout defined stages of cellular generation, proliferation or differentiation. Fibroblast growth factor (FGF) cytokines and their receptors are abundantly expressed in the embryonic nervous system but their localization at autonomic levels in the fetal spinal cord has not yet been detailed. Immunoreactivity to FGF-2, probably the best characterized member of the FGF family (FGF-1 to FGF-10) and of one of its high affinity receptors, FGFR-1, was found in autonomic neurons at embryonic day E14, the peak day of generation and proliferation in the common ventral motoneuron pool. It was also continuously present throughout the investigated subsequent stages (E15 to postnatal day P30). Immunogold electron microscopy revealed the cytoplasmic localization of FGF-2 and FGFR-1 in intermediolateral neurons, the major group of sympathetic preganglionic neurons in the spinal cord. In these neurons, immunocytochemistry from E14 onwards showed the co-distribution of both markers at the period of axonal outgrowth to peripheral targets, e.g. the adrenal medulla. Our findings suggest autocrine and/or paracrine actions of FGF-2 for sympathetic preganglionic development but do not support its role as a target-derived neurotrophic factor for autonomic neuron development.

Co-existence of NADPH-diaphorase, fibroblast growth factor-2 and fibroblast growth factor receptor in spinal autonomic system suggests target-specific actions

In the rat spinal cord, we found substantial co-existence of fibroblast growth factor-2, fibroblast growth factor receptor (type-1 or flg) immunoreactivity and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity (a histochemical marker for neuronal nitric oxide synthase) in preganglionic autonomic cell groups of intermediate layers VI, VII and X. Anti-fibroblast growth factor-2 and anti-nitric oxide synthase binding sites were confined to the cytoplasm of reactive neurons as judged by immunogold electron microscopy. Within the major autonomic nucleus, i.e. intermediolateral column, three different populations were identified: (i) fibroblast growth factor and fibroblast growth factor receptor, (ii) fibroblast growth factor/NADPH-diaphorase and (iii) NADPH-diaphorase-only stained cell groups. Sympathoadrenal neurons were prelabelled with fluorescent tracer Fast Blue and co-stained for fibroblast growth factor-like protein and NADPH-diaphorase, suggesting heterologous diversification of neuronal phenotypes and functional organization in the spinal autonomic system. Our findings suggest intriguing roles for nitric oxide and fibroblast growth factor-2 cytokine in the preganglionic sympathetic spinal cord system: The short-term diffusible messenger nitric oxide may act as tonic and/or phasic signal within rostrocaudally oriented function-specific preganglionic units necessary for integrated target control. The long-term messenger fibroblast growth factor-2 may be involved in, for example, cytokine-dependent regulation of neuronal NADPH-diaphorase/nitric oxide synthase. Furthermore, co-existence of NADPH-diaphorase, fibroblast growth factor-2 and receptor in sympathoadrenal neurons suggest mutual target-specific regulatory functions, e.g. hormone release and blood perfusion or maintenance of phenotype and plasticity responsiveness of adrenal medullary tissue.

Assoziation von Hypertonie und Diabetes mellitus mit mikroangiopathischen Hirninfarktmustern

ZusammenfassungZiel der Untersuchung: Prüfung der Hypothese einer positiven Assoziation von Hypertonie und Diabetes mellitus mit mikroangiopathischen Hirninfarktmustern (Lakunen und/oder Leukoaraiosis). Methode: Aus dem Patientenkollektiv einer prospektiven Schlaganfalldatenbank wurden 152 Patienten mit computertomographisch gesicherten, mikroangiopathischen zerebralen Läsionen einer Vergleichsgruppe von 106 Patienten mit Territorialinfarkten gegenübergestellt. Die Häufigkeiten von Hypertonie und Diabetes mellitus wurden zuerst mittels univariater Tests (odds ratios) verglichen. Im Anschluß erfolgte eine multivariate Prüfung mit einem logistischen Regressionsmodell. Letzteres schloß die zusätzlichen Variablen Hypercholesterinämie, Zigarettenrauchen, Stenosen der Karotiden, Vorhofflimmern und linkskardiale Thromben mit ein. Ergebnisse: In der multivariaten Prüfung waren Hypertonie und Diabetes mellitus signifikant mit multiplen mikroangiopathischen Defekten assoziiert (Hypertonie: Odds-Ratio 2,0; 95 %-Konfidenzintervall 1,04–3,7. Diabetes: Odds-Ratio 1,9; 95 %-Konfidenzintervall 1,01–3,8), während sich für die Gesamtgruppe von Patienten mit Lakunen und/oder Leukoaraiosis keine signifikante Assoziation ergab. Von den anderen geprüften Variablen zeigten lediglich Vorhofflimmern bzw. linkskardiale Thromben eine signifikante negative Assoziation mit mikroangiopathischen Defekten (Odds-Ratio 0,5; 95 %-Konfidenzintervall 0,2–0,9). Schlußfolgerung: Unabhängig von anderen Risikofaktoren der Arteriosklerose und anderen möglichen Hirninfarktursachen finden sich Hypertonie und Diabetes mellitus häufiger bei Patienten mit computertomographisch belegten multiplen Lakunen und/oder Leukoaraiosis. Dieses Ergebnis stützt die Hypothese einer engen Kausalbeziehung zwischen Hypertonie bzw. Diabetes und disseminierter zerebraler Mikroangiopathie.SummaryObjective: To test the hypothesis of a positive association of hypertension and diabetes mellitus with cerebral small-vessel disease infarct patterns.nn Methods: Using a prospective stroke database, the 152 patients with computertomographic signs of small-vessel disease (lacunes and/or leucoaraiosis) – including as a subgroup of 85 cases with multiple lacunes and/or leucoaraiosis – were compared with 106 patients featuring pial artery infarcts. Statistical analyses of the rates of hypertension and diabetes included univariate tests (odds ratios) and a logistic regression model comprising the additional variables hypercholesterolemia, cigarette smoking, carotid stenosis, atrial fibrillation, and left cardiac thrombus.nn Results: Multivariate testing revealed a significant association of hypertension and diabetes with multiple lacunar infarcts and/or leucoaraiosis (hypertension: odds ratio 2,0; 95 % confidence interval 1,04–3,7; diabetes: odds ratio 1,9; 95 % confidence interval 1,01–3,8), whereas for the total group of patients with small-vessel disease lesions no such effect was found. Among the other tested variables, only atrial fibrillation/left cardiac thrombus showed a significant negative association (odds ratio 0,5; 95 % confidence interval 0,2–0,9) with lacunes/leucoaraiosis.nn Conclusion: Independent of other risk factors and other possible causes of stroke, both hypertension and diabetes appear to be strong determinants of multiple lacunar infarcts and/or leucoaraiosis.

Cluster Analysis of Multiparametric MR Imaging including ADC Maps and Relaxometry for Spatially High-Resolved Differentiation of Healthy and Ischemic Human Brain Tissue

In experimental stroke models and ischemic human brain tissue the apparent diffusion coefficient (ADC) decreases in the acute phase, may normalize after reperfusion or may increase in the chronic stage, suggesting that the ADC may be used to monitor the physiologic state of affected tissue. However, a spatially high-resolved determination of the ADC for human brain tissue, required for the transfer of experimental results, is a complex task: (a) ischemic regions in human brain are often small, heterogeneous or irregularly shaped; (b) examination conditions and the complex human brain anatomy lead to widely scattered ADC values. To improve characterization of healthy and pathologic tissues, navigated diffusion-weighted images and ADC maps were incorporated in a new approach into a multidimensional parameter set of relaxation times (T1, T2) and T1-/T2-weighted images. Volunteers and patients with different neurologic deficits were examined. A supervised histogram-based analysis enabled the segmentation of healthy and pathologie tissue classes and the determination of their mean values and standard deviations. Healthy brain tissue was segmented by incorporating T1 relaxation in the data set. Acute and chronic ischemic regions were best differentiated by combining T2- or diffusion-weighted images with ADC maps. The results support findings that within the first week the mean ADC of human ischemic regions is reduced before approaching or exceeding normal values.

Der Einfluß kardialer Emboliequellen auf die Genese territorialer Hirninfarkte

ZusammenfassungHintergrund: Die Mehrzahl der Patienten mit zerebralen Durchblutungsstörungen weist echo- und/oder elektrokardiographische Veränderungen – sog. kardiale Emboliequellen – auf, deren kausalgenetische Rolle oft ungeklärt ist.nn Hypothese: Kardiale Emboliequellen finden sich signifikant häufiger bei embolischen Hirninfarktmustern als bei lakunaren/mikroangiopathischen Läsionen.nn Methoden: Aus einem prospektiven zerebralen Ischämieregister wurden diejenigen Fälle analysiert, die computertomographisch belegte frische Territorialinfarkte (n=106) oder – als Vergleichsgruppe – lakunare/mikroangiopathische Läsionen (n=85) aufwiesen. Die Assoziation kardialer Emboliequellen mit Territorialinfarkten wurde mit Hilfe univariater Tests und einem logistischen Regressionsmodell geprüft. Als kardiale Emboliequellen wurden Vorhofflimmern, linkskardiale Thromben, Klappenvegetationen und andere echokardiographische Befunde wie Wandbewegungsstörungen, Vitien, linksatriale Vergrößerung, offenes Foramen ovale, Vorhofseptumaneurysma, Mitralklappenprolaps und Atherothrombose der Aorta ascendens definiert.nn Ergebnisse: Vorhofflimmern war signifikant mit Territorialinfarkten assoziiert (odds ratio 2,2; 95% Konfidenzintervall 1,01–4,8). Dieser Effekt war unabhängig von zusätzlich bestehenden Herzerkrankungen, anderen kardialen Veränderungen, gleichzeitig bestehenden Stenosen der Arteria carotis und dem Patientenalter. Für linkskardiale Thromben zeigte sich – vermutlich aufgrund der insgesamt kleinen Fallzahl – nur ein nichtsignifikanter Trend einer Assoziation mit Territorialinfarkten (odds ratio 3,0; 95% Konfidenzintervall 0,7–12,3). Für keinen der anderen untersuchten kardialen Faktoren ließ sich eine relevante größere Häufigkeit bei Territorialinfarkten erkennen.nn Schlußfolgerungen: Vorhofflimmern und linkskardiale Thromben zeigen eine Assoziation mit territorialen Hirninfarkten. Andere sogenannte kardiale Emboliequellen – mit Ausnahme der hier nicht untersuchten Faktoren wie mechanische Herzklappen und bakterielle Endokarditiden – lassen keine für den klinischen Alltag relevante Assoziation mit embolischen Hirninfarktmustern erkennen.SummaryBackground and purpose: To test the association of cardiac sources of embolism with territorial type brain infarctsnn Methods: From a prospective cerebral ischemia data base the 106 consecutive patients with territorial type cerebral infarcts on computerized tomography were analyzed. The 85 consecutive patients with lacunar lesions served as a comparison group. The association of cardiac sources of embolism with territorial types infarcts was assessed using univariate Chi Square tests and logistic regression models. Cardiac sources of embolism were defined as: atrial fibrillation, left cardiac thrombi, valvular vegetations, wall motion and valvular abnormalities, left atrial enlargement, open foramen ovale, septal aneurysm, mitral valve prolaps, and aortic arch atherothrombosis (all findings – except for atrial fibrillation – assessed by echocardiography).nn Results: Atrial fibrillation was significantly associated with territorial type infarcts (odds ratio 2.2, 95% convidence interval 1.01–4.8). This effect was independent of additional cardiac diseases, other cardiac abnormalities, carotid artery stenosis, and patient age. Most likely due to the small sample size, left cardiac thrombi only showed a non-significant trend towards an association with territorial infarcts (odds ratio 3.0, 95% confidence interval 0.7–12.3). The rate of all other cardiac findings did not differ significantly between the comparison groups.nn Conclusion: Atrial fibrillation and cardiac thrombi showed an association with territorial type infarcts. Other so-called cardiac sources of embolism – except for mechanical valves and bacterial endocarditis which were not represented in our sample – revealed no clinically relevant association with embolic brain infarct pattern.