Otto Busse

Complications following Acute Ischemic Stroke

The objective of this study was to assess typical early-onset complications following ischemic stroke in a large, hospital-based cohort to provide clinical data for future randomized trials and quality standards in clinical routine. 3,866 patients with acute ischemic stroke were prospectively documented in 14 Neurology Departments with an acute stroke unit. Within the first week after admission, increased intracranial pressure (7.6%) and recurrent cerebral ischemia (5.1%) were the most frequent neurological complications. Fever >38°C (13.2%), severe arterial hypertension (7.5%) and pneumonia (7.4%) were the most frequent medical complications. Multivariate regression analysis yielded brain stem infarction and large-artery atherosclerosis as independent predictors for early recurrent ischemic stroke. This study provides representative data on onset and severity of early neurological and medical complications as well as possible predictors for early recurrent cerebral ischemia following acute ischemic stroke.

Adherence to Secondary Stroke Prevention Strategies - Results from the German Stroke Data Bank

Only very limited data are available concerning patient adherence to antithrombotic medication intended to prevent a recurrent stroke. Reduced adherence and compliance could significantly influence the effects of any stroke prevention strategies. This study from a large stroke data bank provides representative data concerning the rate of stroke victims adhering to their recommended preventive medication. During a 2-year period beginning January 1, 1998, all patients with acute stroke or TIA in 23 neurological departments with an acute stroke unit were included in the German Stroke Data Bank. Data were collected prospectively, reviewed, validated and processed in a central data management unit. Only 12 centers with a follow-up rate of 80% or higher were included in this evaluation. 3,420 patients were followed up after 3 months, and 2,640 patients were followed up one year after their stroke. After one year, 96% of all patients reported still adhere to at least one medical stroke prevention strategy. Of the patients receiving aspirin at discharge, 92.6% reported to use that medication after 3 months and 84% after one year, while 81.6 and 61.6% were the respective figures for clopidogrel, and 85.2 and 77.4% for oral anticoagulation. Most patients who changed medication switched from aspirin to clopidogrel. Under the conditions of this observational study, adherence to stroke prevention strategies is excellent. The highest adherence rate is noticed for aspirin and oral anticoagulation. After one year, very few patients stopped taking stroke preventive medication.

Management Patterns and Health Care Use after Intracerebral Hemorrhage

Background: The German cost-of-illness study of stroke is a multicenter study in 6 departments of internal medicine, 9 departments of general neurology and 15 departments of neurology with an acute stroke unit. The aims of this study are to describe the management patterns, cost of treatment and overall resource utilization after intracerebral hemorrhage (ICH) as well as the major differences to ischemic stroke (IS). Methods: During a 12-month period, 30 participating centers with a special interest in stroke prospectively included 586 patients with ICH which were collected in a joint data bank. About 75% of all patients could be centrally followed up via structured telephone interviews after 3 and 12 months to assess further acute hospital and rehabilitation stays, outpatient resource utilization, functional outcome and quality of life. Results: Mortality after 3 months (33.5%) was markedly higher than in patients with IS from the same hospitals. Accordingly, only 30.9% of patients had regained independent functional status after 3 months. Cumulative cost of treatment amounted to 5,301 EUR for inpatient stay in the documenting hospital and 8,920 EUR for the overall hospital stay including rehabilitation. Mean direct cost after discharge during the first year amounted to 4,598 EUR and the loss of work force was equivalent to 5,537 EUR in all surviving patients. Conclusion: This study provides a comprehensive overview of patient characteristics, treatment strategies and health care cost of ICH from a societal perspective in Germany.

Vertebral Body Infarction as a Confirmatory Sign of Spinal Cord Ischemic Stroke Report of Three Cases and Review of the Literature

BACKGROUND Acute spontaneous spinal cord syndromes often remain etiologically ambiguous despite extensive diagnostic efforts. In the previous literature five cases are described with acute spinal cord syndromes interpreted as spinal cord ischemic strokes because of association with vertebral body infarctions on MRI. CASE DESCRIPTIONS Three cases are presented, and the literature is reviewed. In addition to an extensive diagnostic battery including an initial MRI without pathological signs, follow-up MRI at different time intervals from the onset of symptoms showed T2 hyperintense signals in vertebral bodies. Patient 1, who had plaques in the abdominal aorta, had suffered a thoracolumbar spinal infarction; this and a concomitant infarction of the left portion of T-12 could be demonstrated on follow-up MRI on day 12. Patient 2, who had incomplete transverse spinal artery syndrome below T-3, had an abnormal signal at the T-2 level of the spinal cord on follow-up MRI on day 5; this was one segment above infarction of the dorsal area of T-3, corresponding to the ascending course of the medullary artery. The spinal cord of patient 3, who had a posterior spinal artery syndrome below T-11, was unremarkable on follow-up MRI on day 14, but a T2 hyperintense signal was noted in the dorsal area of T-10. CONCLUSIONS Vertebral body infarction represents the only confirmatory sign for the otherwise exclusionary diagnostic procedure for spinal cord ischemic stroke and must be searched for on follow-up MRI as a key to correct diagnosis.

Familial Cervical Artery Dissections Clinical, Morphologic, and Genetic Studies

Background and Purpose— Genetic risk factors are thought to play a role in the etiology of spontaneous cervical artery dissections (CAD). However, familial CAD is extremely rare. In this study we analyzed patients with familial CAD and asked the question whether familial CAD has particular features. Methods— Seven families with 15 CAD patients were recruited. All patients were carefully investigated by a neurologist, a neuroradiologist, and a dermatologist for clinical characteristics. From 11 patients a skin biopsy was performed to study the morphology of the connective tissue and to analyze the coding sequences of COL3A1, COL5A1, COL5A2, and part of COL1A1. Results— The mean age of the patients (n=15, 9 women) at their first dissection was 36.2 years (median age 32 years, range 18 to 59). Two patients had bilateral CAD. One patient had a right and a left internal carotid artery dissection in successive weeks, another patient had 5 dissections over a period of 8 years. A high intrafamilial correlation was found between the affected vessels (ie, the carotid and the vertebral arteries) and between ages at the first dissection. In 1 patient we found clear and reproducible ultrastructural abnormalities in the skin biopsy, but the second patient from the family was not studied, because he died as a result of CAD before this study. The dermal connective tissue aberrations in the examined patient were similar to mild findings in patients with vascular Ehlers-Danlos syndrome (EDS type IV), but might be iatrogenic and related to long-term corticosteroid inhalation therapy. All other analyzed patients showed normal connective tissue morphology. In patients from 6 families we analyzed the whole coding sequence of COL3A1, COL5A1, and COL5A2, and from part of COL1A1. A missense mutation in the COL3A1 gene (leading to a G157S substitution in type III procollagen) was detected in both patients from 1e family. Two patients from another family carried a rare nonsynonymous coding polymorphism in COL5A1 (D192N); 1 of them carried also a rare variant in COL5A2 (T12337). Conclusions— Familial CAD patients are young and probably are at high risk for recurrent or multiple CAD. Ultrastructural alterations of the dermal connective tissue might not be an important risk factor for familial CAD. However, the finding of a COL3A1 mutation revealed the presence of an inherited connective tissue disorder in 1 family.

Different types of connective tissue alterations associated with cervical artery dissections

This study describes the technical handling and the diagnostic evaluation of skin biopsies in order to standardize the assessment of the delicate morphologic abnormalities that are found in patients with spontaneous cervical artery dissections (sCAD). Skin biopsies from 126 patients with sCAD and from 29 healthy relatives were analyzed. The morphology of the connective tissue was normal in 54 patients with sCAD (43%) and aberrant in 72 patients with sCAD (57%). These latter patients were classified into three groups: in 43 patients, we repeatedly observed composite collagen fibrils and elastic fibers with fragmentation and minicalcifications. In 13 further patients, the dermis was significantly thinner than in healthy subjects. The collagen fibers contained fibrils with highly variable diameters. In a third group of 16 sCAD patients, the abnormalities were restricted to the elastic fibers (with fragmentation and minicalcifications) without significant alterations in the morphology of the collagen fibrils. The finding of different morphologic classes of aberrations among patients suggests that the connective tissue defects are genetically heterogeneous. The segregation of the connective tissue phenotype in three families suggested an autosomal dominant pattern of inheritance.

Ultrastructural Connective Tissue Aberrations in Patients With Intracranial Aneurysms

Background and Purpose— An unknown connective tissue defect might predispose for the development and rupture of intracranial aneurysms in some patients. This study of connective tissue samples of a series of patients with intracranial aneurysms investigates the morphology of the extracellular matrix with methods that are currently used in the routine diagnosis of inherited connective tissue disorders. Methods— Skin biopsies from 21 patients with intracranial aneurysms, many with multiple aneurysms, were studied by electron microscopy. None of the patients included in this study showed clinical signs of a known connective tissue disorder. Results— In 7 patients (33%), we observed repetitive aberrations in the morphology of collagen fibrils and elastic fibers of the reticular dermis. The observed ultrastructural findings were somewhat similar to those typically observed in patients with Ehlers-Danlos syndrome (EDS) and in a subgroup of patients with spontaneous cervical artery dissections. The patterns of abnormalities fell into 2 classes: 4 patients displayed abnormalities that resembled those found in patients with EDS type III, and the electron microscopic findings in the skin biopsies from 3 patients resembled those of EDS type IV patients. The sequence of the COL3A1 gene from the patients with EDS type IV–like alterations of the connective tissue morphology was analyzed. No mutation was detected. Conclusions— Connective tissue alterations were found in skin biopsies from a minority of patients with intracranial aneurysms. Electron microscopic investigation of skin biopsies from patients and their relatives might become valuable for clinical diagnostics, identification of persons at risk, and basic studies of the pathogenesis of this vascular disease.

Mutations in the COL5A1 Coding Sequence Are Not Common in Patients With Spontaneous Cervical Artery Dissections

BACKGROUND AND PURPOSE The dermal connective tissue of most patients with spontaneous cervical artery dissections (sCAD) contains abnormal collagen fibers. This suggests a predisposing connective tissue defect. The ultrastructural abnormalities in the skin of patients with sCAD have similarity with the morphological alterations in patients with Ehlers-Danlos syndrome type II, a dominant hereditary disorder that has been correlated in some patients to mutations within the genes encoding type V collagen. The aim of this study was to assess the alpha 1 chain of type V collagen (COL5A1) as a candidate gene for sCAD. METHODS We searched for mutations in the COL5A1 gene in cDNA from cultured fibroblasts of 19 patients with sCAD using single-strand conformational polymorphism analysis and nucleotide sequence analysis of polymerase chain reaction-amplified fragments of the whole COL5A1 coding sequence. RESULTS We detected 1 missense mutation leading to a predicted amino acid (192D/N) substitution within the N-terminal propeptide in 2 siblings. All other patients showed regular COL5A1 sequences with some silent polymorphisms. CONCLUSIONS Mutations in the COL5A1 gene do not appear to be a major factor in the etiology of sCAD.

Stroke Units and Stroke Services in Germany

Background/Objectives: The German stroke units are sub-intensive units with the possibility of continuous monitoring of vital parameters. This is the main difference to Scandinavian and British non-intensive combined acute and rehabilitation stroke units. Germany has 56 regional and 50 local stroke units, and standards differ between them. Nearly 30% of all strokes in Germany are treated in these units. The German stroke units are cost intensive and unfortunately their effectiveness has not been proven yet.

Genetic Analysis of Familial Connective Tissue Alterations Associated With Cervical Artery Dissections Suggests Locus Heterogeneity

Background and Purpose— Cervical artery dissections (CAD) can be associated with connective tissue aberrations in skin biopsies. The analysis of healthy relatives of patients suggested that the connective tissue phenotype is familial with an autosomal dominant inheritance. Methods— We performed genetic linkage studies in 3 families of patients with CAD. Connective tissue phenotypes for the patients and all family members were assessed by electron microscopic study of skin biopsies. A genome-wide linkage analysis of 1 family (1 patient with 8 healthy relatives) indicated 2 candidate loci. Three genes were subsequently studied by sequence analysis. Part of the genome was also studied by linkage analysis in 2 further families. Results— The genome-wide scan in a single family suggested linkage between the hypothetical mutation causing the connective tissue phenotype and informative genetic markers on chromosome 15q24 (logarithm of the odds score: Z= +2.1). A second possible candidate locus (Z=+1.9) was found on chromosome 10q26. Sequence analysis of 3 candidate genes in the suggestive locus (chondroitin sulfate proteoglycan4 [CSPG4], lysyl oxidase-like1 [LOXL1] and fibroblast growth factor receptor2 [FGFR2]) did not lead to the identification of a mutation responsible for connective tissue alterations. In 2 additional smaller families the loci on chromosome 15q24 and 10q26 were excluded by linkage analysis. Conclusions— Linkage analysis of a large family with CAD-associated connective tissue alterations suggested the presence of a candidate locus on chromosome 15q2 or on chromosome 10q26. Sequence analysis did not lead to the identification of a mutated candidate gene in 1 of these loci. The study of 2 additional pedigrees indicated locus heterogeneity for the connective tissue phenotype of CAD patients.