Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)is an increasingly recognized adult-onset autosomal dominant vascular dementia, caused by highly stereotyped mutations in the Notch3 receptor. CADASIL is a widespread angiopathy characterized by a degeneration of vascular smooth muscle cells (VSMCs) and the abnormal accumulation of electron-dense granular material called GOM and Notch3 protein, because of an impaired clearance. Evidence that VSMCs are the primary target of the pathogenic process is supported by the restricted expression of Notch3 in these cells but mechanisms of their degeneration remain essentially unknown. We generated transgenic mice in which the SM22␣ promoter drove, in VSMCs, the expression of a full-length human Notch3 carrying the Arg90Cys mutation, a CADASIL archetypal mutation.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by a cerebral non-atherosclerotic, nonamyloid angiopathy mainly affecting the small arteries penetrating the white matter. In the brain vessels of two patients with CADASIL, abnormal patches of granular osmiophilic material have recently been described. Here we report the observation of similar granular osmiophilic material within the vessel walls of muscle and skin biopsies from a 54-year-old woman belonging to a CADASIL family, who suffered from subcortical dementia with leukoencephalopathy demonstrated on neuroimaging. Postmortem examination disclosed changes of the vessel walls in all the organs chiefly leading to cerebral lesions. Ultrastructural study showed destruction of the vascular smooth muscle cells (VSMC) and the granular osmiophilic material already found in muscle and skin biopsies in this patient. Both changes were found all along the arterial tree. The findings of this study indicate that CADASIL is a systemic vascular disease involving arterial VSMC and that the lesions are different in each organ and vessel wall, depending on their fine structure. Moreover, it emphasizes that skin and muscle biopsies might be useful for diagnosis of and research into CADASIL.

A significant proportion of children with OPT can avoid radiotherapy after prolonged chemotherapy. Deferring irradiation with chemotherapy protocols did not compromise overall survival of the entire population or visual function.

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.

Parkinsonian tremor may be suppressed by thalamic stimulation. For an equivalent clinical efficacy, its obvious advantage over micro-thalamotomy is its reversibility. This patient experienced postural tremor at the age of 44 years and akineto-rigid syndrome 8 years later. At the age of 60 years, intrathalamic stimulation was applied over a long-term period of 43 months until death and was efficient on tremor with low stimulation. This case is the first with anatomic verification. The extent of the lesion provoked by the electrode is very small. The location of the stimulation site was in the medio-inferior part of the intermedius complex at the entrance of cerebello-thalamic fibers. The stimulation of the cerebellar afferent axons could be the cause of the clinical effect. The stimulation site corresponds to the thalamic source of the precentral and accessory motor cortex, which correlates with changes observed in our PET study showing a regional cerebral blood flow decrease in cerebellar nuclei and also in precentral and accessory motor cortex. The places and mechanisms of the effects of stimulations and lesions could be different.