CADASIL: skin biopsy allows diagnosis in early stages

Ebke, Markus; Dichgans, Martin; Bergmann, Markus; Voelter, Hans-Ulrich; Rieger, Peter; Gasser, Thomas; Schwendemann, G.

doi:10.1111/j.1600-0404.1997.tb00224.x

Cited by 89 publications

(41 citation statements)

References 17 publications

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“…All but 1 individual had developed Ն1 of the following manifestations: migraine with aura (nϭ8 patients), transient ischemic attacks and/or stroke (nϭ13), dementia (nϭ1), or depression (nϭ3). In all cases, the diagnosis had been confirmed either by skin biopsy (nϭ10) [21][22][23] or by demonstration of a Notch3 mutation (nϭ14): R90C (nϭ4), C93F, R110C, R133C, R169C (nϭ2), R182C (nϭ2), C194F, or delD239-D253 (nϭ2). 24,25 Control subjects consisted of 16 age-matched healthy subjects (5 men, 11 women; mean age, 49.7Ϯ9.4 years; range, 32 to 63 years).…”

Section: Study Populationmentioning

confidence: 99%

Cerebral Microbleeds in CADASIL

Dichgans

Holtmannspötter

Herzog

et al. 2002

Stroke

241

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Background and Purpose-An increased frequency of clinically silent microbleeds (MB) has recently been observed in patients with sporadic small-vessel disease related to vascular amyloid deposition or hypertension. In this study, we searched for cerebral MBs in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a unique type of small-vessel disease caused by mutations in the Notch3 gene. Our purposes were (1) to determine the frequency, extent, and pattern of MBs in CADASIL; (2) to analyze the relationship between MBs and T2-hyperintense lesions; and (3) to evaluate the histopathology of brain tissue affected by MBs. Methods-Gradient-echo, T2/PD-weighted dual-echo, and T1-weighted MRI scans of the brain were obtained from 16 consecutive CADASIL subjects and 16 age-matched control subjects. T2-lesion volume measurements were made with a semiautomated segmentation technique based on local thresholding. Postmortem examinations were performed on the brains of 7 additional CADASIL subjects. Results-Focal areas of signal loss on gradient-echo images suggesting past MBs were found in 11 CADASIL individuals (69%) and no control subjects (PϽ0.001). The average number of MBs was 5.9Ϯ7.3 (range, 0 to 22) in individual CADASIL patients. MBs were associated with age (rϭ0.71, Pϭ0.002) and total lesion volume (rϭ0.75, Pϭ0.001). However, after correction for age, the correlation with lesion volume was no longer significant. MBs were located simultaneously in various parts of the brain with a preference for cortical-subcortical regions (38%), white matter (20%), thalamus (13%), and brainstem (14%). Eighty-two percent of the MBs were located outside areas appearing hyperintense on T2-weighted images. Postmortem examination revealed focal accumulations of hemosiderin-containing macrophages in 6 of the 7 brains (86%). They were always found outside ischemic lesions. Key Words: angiopathy Ⅲ CADASIL Ⅲ echo-planar imaging Ⅲ intracerebral hemorrhage C erebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease of small blood vessels caused by mutations in the Notch3 gene. 1,2 Clinical manifestations include recurrent ischemic episodes, cognitive deficits, and migraine mostly with aura, as well as psychiatric disorders. 3,4 There have been single reports of intracerebral hemorrhages (ICHs), 5,6 but the meaning of these observations remains unclear given the absence of ICH in large patient series. 3,4 MRIs show lacunar infarcts and less well demarcated subcortical T2 hyperintensities that may show different degrees of hypointensity on T1-weighted scans. 7-9 These alterations are caused by a unique type of nonarteriosclerotic, amyloid-negative angiopathy involving small arteries and capillaries primarily in the brain but also in other organs. 10 Ultrastructural examination reveals characteristic granular osmiophilic material within the vascular basal lamina, which is often seen in close association with vascular smooth muscle ...

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Section: Study Populationmentioning

confidence: 99%

Cerebral Microbleeds in CADASIL

Dichgans

Holtmannspötter

Herzog

et al. 2002

Stroke

241

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“…1 Ultrastructural examination of small arteries reveals degenerating vascular smooth muscle cells along with characteristic granular deposits. 2,3 Such arteriopathic changes have been documented in virtually all organs of patients with CADASIL, but they are more pronounced in the brain, where they can result in small circumscribed subcortical infarcts and confluent areas of diffuse white matter abnormalities. 4 As shown by a number of MRI studies, [5][6][7][8][9][10][11] conventional T2-weighted scans of the brain are very sensitive in detecting the presence of such lesions in the brain from individuals with CADASIL.…”

mentioning

confidence: 99%

Correlations Between Clinical Findings and Magnetization Transfer Imaging Metrics of Tissue Damage in Individuals With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Iannucci

Dichgans

Rovaris

et al. 2001

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Background and Purpose-We obtained magnetization transfer imaging (MTI) scans from individuals with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (1) to investigate the presence, extent, and nature of pathology in white and gray matter outside proton density (PD)-visible lesions; (2) to quantify the degree of tissue damage occurring in lesions seen on PD-weighted scans; and (3) to correlate MTI-derived measures of disease burden with age, physical disability, and cognitive performance. Methods-Dual-echo, T1-weighted, and MTI scans of the brain were obtained from 33 individuals with CADASIL and 12 control subjects. Magnetization transfer ratio (MTR) values from PD-visible lesions, normal-appearing white matter (NAWM), and normal-appearing gray matter (NAGM) were measured. Histograms of MTR from the whole brain and normal-appearing brain tissue were also produced. Results-All MTR values from NAWM and NAGM regions studied were significantly lower for individuals with CADASIL than for control subjects, with the exception of those obtained from the NAWM of the infratentorial structures and the NAGM of the occipital cortex. The average MTR from PD lesions in individuals with CADASIL was significantly lower than that from all the NAWM regions. Average MTR and peak location from whole-brain and normal-appearing brain tissue histograms were significantly lower for individuals with CADASIL than for control subjects. MTR values from NAWM were strongly correlated with the extent of macroscopic lesions and their average MTR. Apart from NAGM, average MTR from all other tissues studied significantly decreased with increasing age, physical disability, and cognitive impairment. Conclusions-PD

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“…Although GOM has not been detected in any other disease and the specificity is considered to be 100% (Ebke et al, 1997, Mayer et al, 1999, Markus et al, 2002, Razvi et al, 2003 the reports on the sensitivity of detecting GOM in skin biopsy of patients with genetically verified CADASIL have been contradictory. Two earlier studies on a smaller number of patients suggested 100% sensitivity (Ebke et al, 1997, Mayer et al, 1999 in which Ebke et al analysed one family with 8 patients (mutation not specified) and 5 controls suffering from sporadic leukoencephalopathies and Mayer et al examined 14 patients (mutation not specified) from three unrelated families.…”

Section: Em Analysismentioning

confidence: 99%

“…Two earlier studies on a smaller number of patients suggested 100% sensitivity (Ebke et al, 1997, Mayer et al, 1999 in which Ebke et al analysed one family with 8 patients (mutation not specified) and 5 controls suffering from sporadic leukoencephalopathies and Mayer et al examined 14 patients (mutation not specified) from three unrelated families. Two more recent papers have reported a low sensitivity: Markus et al (2002) reported GOM detected only in 8 patients out of 18, thus giving a sensitivity of only 44.4%.…”

Section: Em Analysismentioning

confidence: 99%