The familial nature of the process may not be appreciated because genetic penetrance is not complete until after 60 years of age. On MRI, clinically unaffected family members may show substantial changes in the white matter well before strokes or dementia arises (Fig. 33-22). A syndrome of early alopecia and lumbar spondylosis with the white matter changes typical of CADASIL has been identified as a recessively inherited disease (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy [CARASIL]) and is discussed separately below.
The MRI and CT appearance is of multiple confluent white matter lesions of various sizes, many quite small and concentrated around the basal ganglia and periventricular areas. Lesions anterior to the temporal horns of the lateral ventricles are particularly characteristic of the entity. When the affected regions are asymmetrical and periventricular, they are difficult to distinguish from the lesions of multiple sclerosis. In the autopsy cases studied by Jung and colleagues, numerous partially cavitated infarctions were found in the white matter and basal ganglia. Small vessels in the regions of these infarctions, 100 to 200 mm diameters, contained basophilic granular deposits in the media with degeneration of smooth muscle fibers. Attribution of the white matter lesions to these vascular changes presents the same problems as in Binswanger disease, particularly in view of patency of most of the many small vessels in the examined material. Nevertheless, CADASIL is probably the main cause of sporadic instances of what otherwise passes for Binswanger disease; the anterior temporal changes, however, are typical of the former. Also, migraine headaches are not a component of Binswanger disease.
The responsible mutation is a missense change on chromosome 19 of the NOTCH 3 gene, in the same locus as the gene for familial hemiplegic migraine, and has been characterized by Joutel and colleagues; this provides a diagnostic test that can be performed on the blood or skin. The gene may now be sequenced in commercial laboratories. The diagnosis can also be confirmed by finding eosinophilic inclusions in the arterioles of a skin biopsy (osmophilic with electron microscopy).
An entirely different vasculopathy with widespread white matter signal change has been reported in Japan. Migraine is not a component of the syndrome, and the NOTCH gene, implicated in CADASIL, is normal. Inheritance is as a recessive trait (hence, CARASIL) from a mutation in the HTAR1 gene (see Hara et al). The result is fragmentation and duplication of the internal elastic lamina of cerebral vessels with narrowing of their lumens. As intriguing from this mutation is an associated osteoid growth that causes severe lumbar stenosis and alopecia.
An interesting mutation of the COL4A1 gene for type 4 collagen leads to familial small vessel disease and intracerebral hemorrhage in mice and humans (Gould et al). More often, as in the cases described by Verreault and colleagues, there are numerous white matter infarctions that are not explained by hypertension and similar lesions may be found in family members by MRI.
Under the terms HERNS (hereditary endotheliopathy, retinopathy, nephropathy, and strokes) and CRV (cerebroretinal vasculopathy), rare dominantly inherited conditions have been described that cause subcortical white matter degeneration, presumably on a microvascular occlusive basis. Ocular symptoms and retinopathy are the main features and the neurologic aspects. Awareness of these vascular forms of white matter degenerations adds to the list of inherited leukoencephalopathies discussed in Chap. 37 and the action of the implicated genes reveals novel mechanisms of damage to small cerebral vessels.