Skin Biopsy Value and Leukoaraiosis

Abstract

In the field of leukoaraiosis, the identification of CADASIL and its link to Notch 3 mutation has shed light on the pathogenesis of white matter (WM) abnormalities related to small-vessel disease. Since 1993, its systemic vascular involvement allows skin biopsy diagnosis and research on tissues before postmortem examination. We received 160 skin biopsies from patients presenting subcortical dementia, recurrent strokes, behavioral disturbances or migraines, and suspected CADASIL. Almost all the patients lacked the well-known vascular risk factors. The ultrastructural study was systematically carried out looking at the vessel walls and the other components found in skin. In a third, we found endothelial changes, destruction of vascular smooth muscle cells (VSMCs), and characteristic granular osmiophilic material (GOM). In these cases, the genetic analysis confirmed the Notch 3 mutation. Curiously, the skin biopsies from the other two thirds presented marked alterations within the vessel walls. Such changes included destruction of VSMCs, lack of GOM, and replacement of these cells by an extracellular matrix. Frequently, we noticed endothelial pathological changes as well as other tissue impairments. By now, we are able to describe eight different groups of lesions according to either the prevalence of a lesion or the association of different lesions. The skin biopsy ultrastructural study seems to be highly informative given that we can observe vessel lesions and association of impairments in various tissues that might, in part, explain the brain vessel involvement and then the leukoaraiosis and probably some clinical symptoms. Moreover, these vessel lesions often belonged to young people (30-50 years old), and many of them seemed to run in families. These new data associated with early onset of clinical symptoms and leukoaraiosis would be extremely valuable in clarifying the wide field of leucoencephalopathy and might provide genetic research with new issues.

Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review

“…29 Interestingly, there is now evidence pointing to a systemic endothelial dysfunction in patients with cerebral SVD, as indicated by several studies in which endothelial changes have been measured in other vascular beds other than the brain. This association has been documented with the kidney, 30,31 with the skin, 32 and the sublingual microvasculature. 33 Impairment of endothelial function in systemic vessels, investigated by means of flow-mediated dilatation in the brachial artery, has also been associated with lacunar stroke.…”

Polymorphisms in Genes of the Endothelin System and Cerebral Small-Vessel Disease

“…Neuropathologic studies demonstrate endothelial disruption. 3 Neuroimaging studies demonstrate reduced white-matter blood flow and autoregulatory capacity. 4,5 Nitric oxide, derived from the endothelium, is responsible for the maintenance of cerebral blood flow 6 and autoregulation.…”

CADASIL, artériopathie cérébrale et systémique autosomale dominante associée à des accidents ischémiques sous-corticaux et à une leucoencéphalopathie: une revue

“…Une absence des facteurs de risque habituels de maladie cérébrovasculaire a été notée chez la plupart des patients atteints de CADASIL [24]. L'imagerie cérébrale, en particulier l'IRM, montre des anomalies de la substance blanche et des noyaux gris centraux qui, en soi, ne sont pas typique de l'affection.…”

“…L'existence de GOM dans la musculature squelettique et en particulier dans les artérioles sous- cutanées ( fig. 4a et b) revêt une importance particulière puisqu'elle permet de poser ou de confirmer le diagnostic de CADASIL du vivant du patient à partir de prélèvements de muscle et de peau (punch biopsies) [8,9,24]. Le diagnostic de CADASIL a également été confirmé dans quelques cas par l'examen ultrastructural de biopsies de nerf periphérique (nerf sural) [34,35].…”