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Tobias Brandt

Publications and source records attributed to Tobias Brandt.

16 recordsLinked to original sources
PubMed2006

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.

Adolescent↗
PubMed2006

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.

Adult↗
PubMed2004

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.

Biopsy↗
PubMed2004

Leukocyte count as an independent predictor of recurrent ischemic events.

BACKGROUND AND PURPOSE: Inflammatory markers predict first-time ischemic events. We investigated whether leukocyte and differential counts predict recurrent events and ischemic events in high-risk populations, and whether such events are preceded by acutely exacerbated inflammation. METHODS: We studied 18 558 patients with ischemic stroke, myocardial infarction, or peripheral arterial disease who participated in the trial of Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), a study that compared the occurrence of ischemic stroke, myocardial infarction, or vascular death under randomized treatment with aspirin or clopidogrel. Leukocyte counts were frequently assessed during followup. RESULTS: Compared with the quartile with lowest leukocyte counts at baseline (<5.9x10(9)/L), patients in the top quartile (>8.2x10(9)/L) had higher risks for ischemic stroke (relative risk 1.30; P=0.007), myocardial infarction (relative risk 1.56, P<0.001), and vascular death (relative risk 1.51; P<0.001) after adjustment for other risk factors. Neutrophil counts contributed most to increased risk. Assessments of regression dilution effects based on replicate measurements show that these risk associations may underestimate the real associations by 30 to 50%. Treatment with aspirin or clopidogrel did not influence predictive effects by leukocytes. In the week before a recurrent event, but not at earlier time points, the leukocyte count was significantly increased over baseline levels (n=211; mean difference +0.46x10(9)/L; P=0.005). CONCLUSIONS: Leukocyte counts and mainly neutrophil counts are independently associated with ischemic events in these high-risk populations. An increase of leukocyte counts over baseline levels heralds a period of increased risk lasting about one week.

Aspirin↗
PubMed2003

Heterozygous carriers of Pseudoxanthoma elasticum were not found among patients with cervical artery dissections.

In this study of patients with spontaneous cervical artery dissections (sCAD) we searched for mutations in ABCC6, the candidate gene for Pseudoxanthoma elasticum (PXE). Genomic DNA samples from 12 sCAD patients with pronounced electron microscopic alterations in their dermal connective tissue and from 2 patients with PXE were analysed. One patient with PXE was compound heterozygous for two missense point mutations, in the second patient with PXE we did not find changes in the ABCC6 gene. We observed several missense mutations (H623Q, R3190W and R1268Q) in the patients with sCAD, but these mutations were not disease specific,since they were also detected in a series of 25 healthy control subjects.The finding of several sequence variants in sCAD patients and of disease causing mutations in one of the PXE patients suggests that our strategy of mutation search is reliable. Since we did not find disease causing mutations in our series of patients with sCAD we suggest that ABCC6 is not a candidate gene for sCAD.

Adult↗
PubMed2002

Exclusion mapping of the genetic predisposition for cervical artery dissections by linkage analysis.

Skin biopsies from a patient with a dissection of the left internal carotid artery and from four of his children were analyzed by electron microscopy. The index patient and three children showed mild but regular electron microscopic connective tissue aberrations. They were considered as carriers of an unknown autosomal dominant mutation. Thirty-four candidate genes involved in the biosynthesis of the extracellular matrix were excluded by genetic linkage analysis as possible sites of a disease-causing mutation in this family (logarithm of odds [LOD]-score less than -2.0).

Biopsy↗
PubMed2002

Analysis of the COL3A1 gene in patients with spontaneous cervical artery dissections.

The etiology of spontaneous cervical artery dissection (sCAD) is unknown. An underlying connective tissue disorder has been suggested. As a collagen disease is conceivable several genes encoding fibrillar collagens have been condsidered as candidate genes for sCAD. We analysed the COL3A1 gene in patients with spontaneous cervical artery dissection (sCAD) and in healthy controls, using three different genetic methods. 1) The promoter region, the 5' and 3' untranscribed regions and the N- and C- peptide encoding regions were studied by direct sequencing analysis of DNA from 12 patients. 2) A possible association of sCAD and the COL3A1 gene was tested for with 5 different DNA polymorphisms in 45 patients and 50 healthy control subjects. 3) DNA samples from a father and his two daughters, all suffering from spontaneous dissections of a cervical artery, were analysed with CA-repeat markers that flank the COL3A1 locus. No disease-causing mutations were found in an extended sequence analysis of the COL3A1 gene in patients with sCAD. However, we identified a single nucleotid polymorphism (SNP) in the promotor region in 2 patients and a 2 bp deletion in the 3' UTR in 7 patients. These sequence variants were also found among 50 healthy subjects. An analysis of multiple DNA polymorphisms of the COL3A1 locus in patients and healthy control persons did not indicate a significant association of sCAD with COL3A1. A deletion polymorphism in the 3' UTR was, however, found more often amongst patients with sCAD. The possible linkage of a hypothetical disease mutation with the COL3A1 locus was tested in a small family with three affected patients. As the affected daughters did not inherit the same COL3A1 allele from their affected father (LOD < - 2.3) COL3A1 was excluded as a disease gene in this family. This study confirms and extends earlier work which suggests that COL3A1 mutations are not a major cause for isolated sCAD.

Adult↗
PubMed2002

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.

Adult↗
PubMed2001

Spontaneous Arterial Dissection.

There is no controlled study for the best treatment or management of cervico-cerebral artery dissection (CAD). Rationale initial empiric treatment in acute CAD to prevent secondary embolism is partial thromboplastin time (PTT)-guided anticoagulation by intravenous heparin followed by anticoagulation with warfarin. Carotid surgery for treatment of CAD is not recommended anymore with the possible exception of persisting severe stenosis of the proximal internal carotid artery (ICA). There could be use of carotid angioplasty by balloon dilatation and stenting in selected cases of severe cerebral hemodynamic impairment by bilateral CAD. Duration of secondary prophylaxis by anticoagulation is best guided by Doppler sonography follow-up, and should be continued until normalization of blood flow or until at least 1 year after the vessel is occluded. There is no evidence that pseudoaneurysms increase the risk for embolic complication, and there is no evidence for surgery or continuation of anticoagulation in patients with pseudoaneurysms. Caution should be recommended for exercises that involve excessive head movements (eg, bungee jumping, trampoline jumping, and chiropractic maneuvers). The patient should be informed that recurrent rate is low in nonfamilial cases. Doppler sonography is a low-cost and high-sensitivity method for patients at risk.

Journal Article↗
PubMedDate not supplied

Diagnosis and thrombolytic therapy of acute basilar artery occlusion: a review.

Acute basilar artery (BA) occlusion is associated with an extremely high mortality. The pathogenesis in younger patients is usually embolism form cardiac sources or less frequently from vertebral artery dissection. Local atherothrombosis is more common in elderly patients. Differently to the carotid territory, for the vertebrobasilar territory there are no placebo controlled studies proving efficacy of thrombolytic treatment. Furthermore, neither the best route of administration nor the best fibrinolytic agent have been evaluated. Several uncontrolled series, however, indicate that intraarterial thrombolysis reduces mortality of patients with BA occlusion. Recanalization rates average 60% and are associated with occlusions of embolic etiology. Mortality with an average rate of 40-60% is significantly lower in the recanalization group in most series. Other independent variables affecting mortality are identified as length of obstruction, proximal BA occlusion, collateralization, high age, and initial poor clinical state. Time from onset of symptoms to start of intraarterial thrombolysis, however, is not associated with recanalization or mortality rate. This indicates that differently from thrombolytic treatment in the anterior circulation there is no fixed time window in BA thrombosis. Rate ofparenchymal hemorrhage seems to be lower with an average of 6% compared with systemic thrombolytic therapy in hemispheric stroke. Recanalization of the BA is clinically beneficial under certain circumstances only: (1) BA occlusion should affect only one segment; (2) an effective collateral supply is essential; and (3) the patient should not already be tetraplegic or comatose for a longer period of time. Clinical outcome and assessment of quality of life on follow-up of survivors with successful recanalization encourage thrombolysis in acute BA occlusions of embolic origin.

Acute Disease↗