74.1 Clinical and Laboratory Findings
This disease was first described in 1976 by Maeda et al. as a “familial unusual encephalopathy of Bin- swanger’s type without hypertension” in four pa- tients, two of whom were brothers. In nearly all cases reported after this first publication, the parents were consanguineous, often first cousins, providing evi- dence for an autosomal recessive mode of inheri- tance. Over the years the syndrome has crystallized sufficiently to allow definition of the clinical picture.
The disease occurs predominantly in males, with a male:female ratio of 7.5:1. So far, all patients de- scribed are Japanese. The disease has a relatively ear- ly age of onset, most often between 25 and 30 years.
The course of the disease is relatively rapid and is characterized by step-like or chronic-progressive pyramidal and extrapyramidal symptoms, pseudo- bulbar palsy, and cognitive deterioration. The neuro- logical symptoms are associated with alopecia from youth. There is diffuse hair-thinning with similarities to what is seen in radiation injury and systemic lupus erythematosus. Patients experience acute lumbago.
The lumbago is caused by kyphotic and spondylotic changes of the vertebrae, often in an unusual location, the lower thoracic and higher lumbar region. Patients lack vascular risk factors, especially hypertension.
Diffuse white matter disease is seen on MRI or at autopsy. The disease is often compared to Binswanger disease, but the MR images more closely mimic the MRI characteristics of CADASIL (see below). Life ex- pectancy in these relatively young patients is short- ened considerably. Most patients die within 10 years after onset of the disease in a vegetative state.
Laboratory examinations are unrevealing. There are no biochemical changes in blood or urine samples.
74.2 Pathology
The cortex is intact. There is diffuse demyelination of the cerebral white matter, with relatively well pre- served U fibers. Within the affected white matter and within the basal ganglia, there are small softened and cystic foci. The corpus callosum is affected in about half of the patients. In the abnormal white matter arteriosclerosis is seen involving arteries of 100- to 400-mm caliber, with fibrous intimal proliferation, severe hyalinosis, and splitting of the intima and the
elastic membrane. The thickened vessel walls do not stain with PAS stain or Congo red, there is no ultra- structural granular osmiophilic material in the vessel walls, and there is no b-amyloid immunoreactivity in vascular walls. The presence of PAS-positive material and the ultrastructural finding of granular osmio- philic material in the vessel walls are considered to be the hallmarks of CADASIL, making CARASIL distinct from CADASIL. There is also no increase of amyloid plaques or neurofibrillary tangles. Large arteries at the base of the brain display no or mild atheromatous changes; severe changes are rare. In visceral organs arterial changes are less severe. A muscle biopsy, however, may show the described vessel changes. The superficial temporal arteries are often involved, pos- sibly explaining the alopecia.
74.3 Pathogenetic Considerations
In CARASIL the brain damage is caused by narrowing of the lumina of arterioles, especially of long perforat- ing arteries supplying the periventricular and deep white matter. There is an obvious similarity to other diseases in which systemic narrowing of penetrating small medullary vessels is at the core of the patho- physiology. The resulting decrease in cerebral perfu- sion leads to white matter pallor, demyelination, glio- sis, preinfarct status, and lacunar infarctions. The dis- ease is hereditary, but not linked to the NOTCH 3 gene, which is responsible for CADASIL. The genetic basis of CARASIL has not yet been elucidated.
74.4 Therapy
So far no therapy has been applied aimed at improve- ment of cerebral blood flow and counteracting is- chemia, as described in the chapter on CADASIL.
Treatment is mainly symptomatic. Disc herniation and lumbar stenosis may demand surgical interven- tion.
74.5 Magnetic Resonance Imaging
MRI shows a pattern of white matter involvement similar to that of CADASIL. The white matter lesions are confluent and more or less symmetrical (Figs. 74.1
Cerebral Autosomal Recessive Arteriopathy
with Subcortical Infarcts and Leukoencephalopathy
Chapter 74
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Chapter 74 Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy 550
Fig. 74.1.
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and 74.2). They involve the cerebral hemispheric white matter and both internal and external capsules.
The temporal lobes are affected as well, including the temporal poles. The U fibers are relatively spared, but
certainly not completely spared (Fig. 74.1), and be- come extensively affected in later stages (Fig. 74.2).
The corpus callosum tends to be spared. There are small focal lesions in the basal ganglia, thalami, and brain stem (Figs. 74.1 and 74.2). FLAIR images show small lacunae (Fig. 74.1), whereas diffusion-weighted images may reveal small fresh infarctions (Fig. 74.1).
Over time, the white matter becomes increasingly atrophic (Fig. 74.2).
The pattern of confluent periventricular and deep white matter involvement in combination with multi- focal small lesions of the basal ganglia, thalami, and brain stem is typically the pattern seen in vascular disorders. However, the white matter abnormalities are more homogeneously confluent than in Bins- wanger disease. Unlike in CADASIL, there are no petechial hemorrhages.
74.5 Magnetic Resonance Imaging 551
Fig. 74.1. A 39-year-old woman with CARASIL. The MRI was obtained 17 months after the onset of neurological symp- toms. There are symmetrical abnormalities in the cerebral hemispheric white matter and both internal and external cap- sules. The U fibers are partially spared. The corpus callosum is intact. There are small additional lesions in the basal ganglia and brain stem.The diffusion-weighted image (first row,middle image) shows a small fresh infarction.The FLAIR images (fourth row) reveal many small lacunae. From Yanagawa et al. (2002), with permission; additional images courtesy of Dr. S. Yana- gawa, Department of Neurology, and Dr. S. Ikeda,Third Depart- ment of Medicine, Shinsu University School of Medicine, Mat- sumoto, Japan
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Fig. 74.2. A 42-year-old male patient with CARASIL. The MRI was obtained 16 years after the onset of the disease. Note the extensive cerebral white matter abnormalities, which do not spare the U fibers. The internal and external capsules are af- fected as well.The cerebral white matter is atrophic; the corpus
callosum is thin but seems to have a normal signal. There are many small lesions in the basal ganglia and brain stem. The T1-weighted images do not show evidence of small hemor- rhages. From Fukutake and Hirayama (1995), with permission 074_Valk_Cerebral_Auto 08.04.2005 16:32 Uhr Seite 551
