Small arterial granular degeneration in familial Binswanger's syndrome

103

Background and Purpose-There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss. Methods-We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis. Results-We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries. Conclusions-These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO 2 levels and systemic blood pressure in CADASIL.

Section: Methodsmentioning

confidence: 99%

Arterial Changes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Relation to Pathogenesis of Diffuse Myelin Loss of Cerebral White Matter

Okeda

Arima

Kawai

2002

103

“…10,11,29,30 Moreover, some authors have described Charcot-Bouchard aneurysms. 31 It is conceivable that these changes may affect the vulnerability of blood vessels in CADASIL.…”

Section: Dichgans Et Al Cerebral Microbleeds In Cadasil 69mentioning

confidence: 99%

Cerebral Microbleeds in CADASIL

Dichgans

Holtmannspötter

Herzog

et al. 2002

240

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 ...

“…1 These lesions consisted of a nonatheromatous, nonamyloid angiopathy characterized by the presence within the media of a granular, electron-dense, osmiophilic material. Although these lesions were mostly localized to the brain, 2 they have occasionally been found in the spinal cord 3 and in other organs such as the spleen 3 and heart, 2 raising the possibility of a more generalized vascular disease, as already suspected by Sourander and Walinder. 4 To further investigate this issue, we reexamined muscle (deltoid) biopsies performed in 6 patients belonging to our first study family (subjects III4, III5, III19, III21, III23, IV22; 4 males and 2 females aged 33 to 66 years), 3 the family in which we located the responsible gene on chromosome 19.…”

Section: To the Editormentioning

confidence: 98%

Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL.

Mm¹,

Chabriat²,

Bousser³

et al. 1994

134

ResponseWe are grateful to Drs Norris and Bladin for their interest in our review of the relative merits of ticlopidine and aspirin, 1 but we are not sure whether there is a baby in the bathwater at all. We feel less confident than they do that the point estimate of the overall advantage of ticlopidine over aspirin (8% with 3500 patients) would remain the same with greater numbers and would then reach statistical significance. This is what 95% confidence intervals (-4% to 19%) are all about: we simply don't know. By the way, we could not find a P of <.OO7 in the paper about the Ticlopidine Aspirin Stroke Study (nor indeed any significant difference for any outcome event that included more than stroke alone) 2 ; is this perhaps a subgroup analysis that did not survive the final stages of publication? What the report does contain is a table of side effects, totalling 62% in the ticlopidine group and 53% in the aspirin group (with 1300 mg!). These proportions have not been weighted for severity, but this uncertainty can be interpreted both ways, as it can for efficacy.