Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry Differential Diagnosis Reference

BACKGROUND AND CLINICAL INFORMATION: Head

Characteristics: an autosomal dominant non-arteriosclerotic and non-amyloid arteriopathy which mainly affects penetrating arteries and arterioles of the white matter and leptomeningeal vessels.

Genetics: mutations of Notch 3 gene at chromosome 19q12, autosomal dominant.

Age, sex, and duration: mean age of onset is 45 years, irrespective of gender. Duration of disease varies between 10 to 30 years.

Clinical symptoms: The initial symptoms vary, but include strokes (85%), dementia (30% to 90% depending on the age of observation), migraine with aura (30%), and severe mood disturbances (20%) and hemorrhage not associated with hypertension. The main clinical presentation is recurrent subcortical events, either transient or, more often permanent. The dementia is characterized by frontal lobe symptoms and memory impairment. Dementia in these patients satifies all criteria for vascular dementia.

CADSIL is a systemic disease and the characteristic granular osmiophilic material (GOM) and balooned cells can be found in skin and other parts of the vascular tree outside the CNS.

Skin biopsy: The presence of GOM in skin biopsy may be used as a clue for making diagnosis. However, in patients younger than 30 years old, the sensitivity of skin biopsy is reduced. Detection of Notch 3 gene mutation may be the best method of diagnosis.

Diagnostic test: EM skin biopsy and genetic study. The gene is quite big and full genetic sequencing is time consuming. EM skin biopsy is most common and easiest.

NEUROIMAGING: Head

MRI is always abnormal in symptomatic patients, but signal abnormaities have been detected as early as age 20. T2-weighted images show punctated and nodular hypersignals with a symmetrical distribution; these predominate in periventricular areas and in the centrum semi-ovale, but are also found in the basal ganglia and in the pons.

Angiographic studies are usually negative.

GROSS PATHOLOGY: Head

Multiple small necroses and post-necrotic cystic lesions, particularly involving the periventricular white matter, basal ganglia, thalamus, mesencephalon and pons. The cerebral white matter is grayish-brown or granular with multiple small cystic lacunae that may be extensive and confluent. Most often the subcortical white matter is better preserved. An obvious ventricular dilation is noted.

Brain weight is usually within normal limits.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Lesions can be seen in the cerebral hemisphere and brain stem. Cerebellum is usually not affected. The cortices are usually free of lesions.

A diffuse and focally intensive pallor of myelin staining is observed throughout the white matter, partially preserving the subcortical U-fibers. Multiple infarcts in different stages of development are seen in the deep white matter and the corpus collosum. In the diffusely demyelinated areas, there are also destruction and degeneration of the nerve fiber in comparable severity to the demyelination. These lesions are nearly symmetrical in both hemispheres, and are most conspicuous in the frontal, parietal and occipital lobes.

Lacunar infarcts in the basal ganglia and thalamus are invariably seen.

Vascular changes:

Marked concentric thickening of the white matter and meningeal vessels with a peculiar smudged fibrohyalin and granular material. There may also be occlusive vascular changes with subendothelial fibrous proliferation of smudgy hyaline degeneratio within the intima, duplication-fragmentation of the internal elastica lamina, and sparse perivascular infiltration with chronic but rare pooly nuclear leukocytes. Although the thickening or thinning of the walls with fibrohyalinosis is constant, a partial or complete occlusion of vessel lumina is relatively rare, but may occur as a consequence of concentric intimal proliferation.
The smudgy and granular aspect of the media with a striking loss of musclar nuclei and the presence of a few globular cells or scattered ballooned muscle cells with a clear cytoplasm are also well described.
The vessel walls are Congo Red negative. The granular material are negative for Congo Red and thioflavine staining. They may be positive for PAS and Alcian blue staining and stained red by Masson's trichrome. Presence of PAS(+) and basophilic granules in the media is a characteristic feature of CADASIL. The granular material is readily visualized in plastic sections stained with toulidine blue (metachromatic staining).
Binswanger's subcortical arteriosclerotic encephalopaty may have all the vascular changes observed in CADASIL except for the granular material.

Electron microscopy:

Granular osmiophilic material (GOM) may be seen in the arteries and arterioles of the brain and meningeal vascular tree. They are numerous electron dense, extracellular granular deposits without filament-like profiles ranging in size from very small, barely detectable deposits to large deposits of about 0.2 to 0.8 micron.
GOM are located close to the vascular smooth muscle cells and are made of 10 to 15 nm granules.
GOM can also be seen in vessels of the nerve, muscle, skin, and other part of the body.

DIFFERENTIAL DIAGNOSIS: Head

Hereditary endotheliopathy, retinopathy, nephropathy, and strokes (HERNS): A hereditary syndrome consisting of retinopathy, nephropathy, and stroke. Initial manifestations are visual impairment and renal dysfunction; neurologic deficits occurs in the third or fourth decade. Symptoms includes migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. Neuroimaging consistently demonstrates contrast-enhancing subcortical lesions with surrounding edema. Ultrastructural studies show distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the CADASIL locus on chromosome 19. [Jen J. et al. 1997]

Binswanger's disease should be used to denote conditions characterized by a widespread degeneration of cerebral white matter having a vascular causation and observed in the context of hypertension, atherosclerosis of the small blood vessels and multiple strokes. In contrast, CADASIL is not associated with hypertension.

The distribution of pathologic changes theoretically do not distinguish CADASIL from Binswanger's disease. However, GOM and genetic changes are both absent in Binswanger. The clinical features are also different. Genetic analysis will be the final prove. [The definition of Binswanger's disease is not very clear anyway.]

REFERENCES: Head

Ruchoux and Maurage JNEN 1997 9:947

NeuroLearn NeuroHelp Vascular For Comment: KarMing-Fung@ouhsc.edu

Background Neuroimaging Gross Pathology Histopathology & Immunohistochemistry Differential Diagnosis Reference