Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

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73.1 Clinical Features

and Laboratory Findings

The acronym CADASIL stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This disease was formerly known as familial Binswanger disease or hereditary multi-infarct dementia. Although it was initially thought to be a rare disease, many families with CADASIL have now been reported worldwide.

CADASIL is the most common hereditary form of stroke leading to progressive dementia.

The clinical picture is dominated by recurrent sub- cortical ischemic infarctions, beginning somewhere between 40 and 60 years, or occasionally at a younger age. There is usually a striking absence of vascular risk factors: there is no history of hypertension, no hypercholesterolemia, and no hyperhomocysteine- mia. Migrainous headaches and psychiatric symp- toms are frequent. They are often the initial symp- toms and may precede other symptoms of the disease for many years. The neurological symptoms progress over months to years, most often in a step-like fash- ion, and may worsen in the second decade after onset.

Hemiparesis, hemianopia, dysarthria, and cerebellar ataxia may characterize these events. Other symp- toms include seizures, pseudobulbar palsy, urinary incontinence, and unexplained “CADASIL coma.”

This latter event is a subacute encephalopathy, in some cases accompanied by fever, with focal neuro- logical symptoms and seizures, eventually progress- ing to coma. The condition is reversible in most cases but may recur. In the history of nearly all the report- ed patients migraines with visual or sensory auras are present. In other patients the diagnosis “relapsing–re- mitting multiple sclerosis” was maintained for years.

Psychiatric symptoms, including confusion, severe forms of depression, and signs of frontal dysfunction, are manifest in more than 30% of the patients. A sub- cortical dementia, similar to that seen in subcortical arteriosclerotic encephalopathy, evolves. There is considerable variability in clinical symptoms and course of disease among the patients, also within fam- ilies. The median survival is 64 years for males and 69 years for females.

A definite diagnosis of CADASIL can be made on the basis of histopathological findings in skin, mus- cle, or brain biopsy or when the typical clinical find- ings can be linked to a mutation in the gene NOTCH3.

Diagnosis based on the electron microscopic demon- stration of granular osmiophilic material (GOM) ad- jacent to the basement membrane of smooth muscle cells of arterioles has a specificity of 100%, but the sensitivity is rather low (~50%). Immunostaining with antibodies against the Notch3 protein may in- crease the sensitivity of skin biopsy techniques sub- stantially; in patients with CADASIL, there is an ab- normal accumulation of the Notch3 protein in the vessel walls. Diagnosis by mutation detection is also possible. In the absence of such evidence criteria for probable CADASIL have been proposed, which are summarized in Table 73.1.

Discovery of de novo mutations in isolated pa- tients emphasizes that a possible diagnosis of CADASIL should not be rejected in the absence of a family history. Neuroimaging plays an important role in the initial diagnosis. The pattern of white matter abnormalities is highly suggestive (see below) and the MRI-based diagnosis of CADASIL can be substantiat- ed with many more details than suggested under point 5 of the above criteria. Especially involvement of the anterior temporal pole has a high sensitivity and specificity (both 85–90%). CSF analysis shows oligoclonal bands in quite a number of cases, al- though these are considered to be nonspecific.

73.2 Pathology

The primary disease process is a vasculopathy, most prominently involving the small perforating arteries of the cerebral white matter. Within the media of the

Cerebral Autosomal Dominant Arteriopathy

with Subcortical Infarcts and Leukoencephalopathy

Table 73.1. Diagnostic criteria for probable CADASIL (Davous 1998)

1. Young age at onset (<50 years)

2. At least two of the following clinical findings:

– Stroke-like episodes with permanent neurological signs

– Migrainous headaches – Major mood disturbances – Subcortical dementia

3. No vascular risk factors related to deficit

4. Evidence of inheritance with autosomal dominant transmission

5. On MRI, white matter abnormalities without cortical infarcts

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small arterial vessels, deposits of GOM are seen on electron microscopy, which displace degenerating smooth muscle cells of the arterial media in small vessels, a feature now considered the pathological hallmark of CADASIL. GOM has an extracellular location and is not membrane-bound. The chemical nature of GOM is unknown. The material usually stains with PAS, consistent with acid polysaccharide.

Other histochemical stains have shown that the mate- rial does not contain amyloid, elastin, chromatin, cal- cium, or iron. Immunoenzymatic and immunofluo- rescence studies have also shown absence of im- munoglobulins or complement proteins, cystatin C, transthyretin, gelsolin, fibrinogen, cathepsin D and a

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-antichymotrypsin. Although the disease manifests itself only through neurological and neuropsychiatric symptoms, it is a generalized disorder and the ultra- structural lesions of the arterial wall are also found in other organs, including the spinal cord, spleen, heart, muscle, skin, and peripheral nerves. Biopsy of these tissues can confirm the diagnosis. Skin biopsy is most often used for that purpose.

The concentric thickening of the wall leads to is- chemia, infarctions, and myelin loss, which are shown by microscopic examination of the brain. Multiple small infarcts and lacunae are seen in the basal gan- glia, thalamus, internal capsule, periventricular white matter, and brain stem. The cerebellum is less often affected. The periventricular white matter may be se- verely demyelinated. The U fibers and the cortex are usually spared. Cortical infarcts are rare and of small size. Fresh and old hemorrhages may also be found, most often in advanced stages of the disease.

73.3 Pathogenetic Considerations

CADASIL is related to dominant mutations in NOTCH3 on chromosome 19q13.1. The gene codes for a large transmembrane receptor protein. The extra- cellular portion of the Notch3 protein contains 34 tandem repeats of an epidermal growth factor (EGF) motif, each of which contains six cysteine residues binding within the domains as three cysteine–cys- teine disulfide bonds. Mutations that have been demonstrated in CADASIL occur within these EGF repeats and always involve either loss or gain of a cys- teine residue. The mutations result in altered disulfide binding within the repeats by changing the number of cysteines from six to an odd number. There is evi- dence that mutations may lead to a gain of function.

Other evidence demonstrates that some CADASIL mutations reduce the activity of the Notch3 receptor.

There is considerable phenotypic variability, which is thus far unexplained.

In normal tissue, gene expression for NOTCH3 is highly restricted to vascular smooth muscle cells. In

CADASIL, a dramatic and selective accumulation of the extracellular domain of the receptor protein occurs at the cytoplasmic membrane of vascular smooth muscle cells, in close vicinity to but not with- in GOM. This suggests that CADASIL mutations specifically impair the clearance of the notch3 ectodomain, but not the cytosolic domain, from the cell surface.

It is evident that the clinical manifestations, di- verse as they may be, are the result of the vascular changes leading to hypoperfusion, demyelination, gliosis, and lacunar infarctions. How the genetic changes translate into the vascular changes and the phenotypic variability is still incompletely under- stood.

73.4 Therapy

As in other disorders with cerebrovascular disease, strategies are directed at improving cerebral perfu- sion.Anticoagulants and thrombolytic agents, such as warfarin and heparin, are not advocated because of the risk of hemorrhage. Aspirin, despite its low effica- cy in some patients, is considered the best choice with the smallest chance of complications. Neuro- protective agents, antioxidants, N-methyl-

D

-aspartate (NMDA) antagonists, and voltage-sensitive calcium channel antagonists, for example nimodipine and flunarizine, also have been suggested. Other com- pounds, like propentofylline, a xanthine derivative with multiple actions, have been tested positively in Alzheimer disease, and might also be beneficial in vascular dementias.

73.5 Magnetic Resonance Imaging

Although there are many similarities between CADASIL, subcortical arteriosclerotic encephalopa- thy, and cerebral amyloid angiopathy, the MR pattern of fully developed CADASIL has several features that can make the MR diagnosis highly suggestive and, in combination with the clinical features and family his- tory, even diagnostic.

MRI shows extensive white matter abnormalities in the absence of cortical infarcts (Figs. 73.1–73.3).

There is a tendency to symmetry. The centrum semi- ovale is involved, with relative sparing of the U fibers.

The abnormalities extend downwards into the exter- nal and extreme capsules. In the frontal lobes the white matter abnormalities extend into the U fibers.

The white matter of the temporal lobes is involved in typical cases (Figs. 73.1–73.5). Moderate to severe in- volvement of the temporal lobes has a sensitivity of 89% and a specificity of 83%. Involvement of the ex- treme and external capsule has a sensitivity of 93%,

Chapter 73 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy 542

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but a low specificity of 45%. To differentiate between small lacunar infarctions and other white matter ab- normalities, such as demyelination and gliosis, FLAIR images are very useful (Figs. 73.2–73.5). They show

the white matter changes with high signal intensity, whereas cystic infarctions have very low signal inten- sity. Diffusion-weighted imaging may demonstrate the relatively fresh infarctions.

Fig. 73.1. Images of a 45-year-old woman with CADASIL, showing most of the typical MR features. The T2-weighted im- ages (first row, middle and right; second row, left and middle) show nearly symmetrical involvement of the white matter in the centrum semiovale,with extensions into the arcuate fibers, the external capsules, and the temporal lobes. The corpus callosum is relatively spared. The involvement of the basal gan-

glia, thalamus, pons, and cerebellum is also more or less sym- metrical. The CT scan (first row, left) and the T1-weighted im- ages (third row) show multiple small hemorrhages in the cen- trum semiovale and the posterior temporal lobe on the right.

The T1-weighted images, including the sagittal image (second row, right), show the widened perivascular spaces in the cen- trum semiovale and the basal ganglia.

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Good quality images show that, apart from the sig- nal changes in the white matter, the Virchow–Robin spaces are widened (Fig. 73.1). This leads to an état criblé of the basal ganglia. The widening of the perivascular spaces may also involve the centrum semiovale and the temporal lobes.

In longer-standing cases of CADASIL signal changes may occur in the basal ganglia. Apart from

the often multiple small or lacunar infarctions in the basal ganglia, one may see a more generalized low sig- nal intensity on T

2

-weighted images, in particular in the globus pallidus (Figs. 73.3 and 73.4). CT does not show calcification in the basal ganglia, so that the ex- planation must be deposition of other substances, for example iron.

Fig. 73.2. The MR pattern in a 61-year-old woman with CADASIL is similar to the pattern seen in Fig. 73.1, although the white matter abnormalities are more confluent. There is cere-

bellar atrophy. Courtesy of Dr. K. Demuth, Department of Neu- rology, Marien Hospital, Stuttgart, Germany

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Fig. 73.3.

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Abnormalities in the mesencephalon, pons, and cerebellum are often less symmetrical than lesions in the cerebral hemispheres. One may find an occasion- al infarction in the mesencephalon, pons, and cerebel- lum, and a high signal in the transverse fibers of the pons (Figs. 73.1, 73.2, and 73.4).

MR angiography usually does not show the changes in the small vessels that cause the problems in CADASIL. At the same time intra-arterial DSA seems contraindicated because of the unexplained extremely high complication rate of up to 50% in in- tra-arterial DSA in CADASIL patients.

After contrast injection there is no enhancement seen in any of the lesions, unlike, for example, Bin- swanger disease, where new infarcts will display en- hancement in the subacute phase, or multiple sclero- sis, where acute plaques show enhancement.

Gradient refocused T

2

*-weighted images show in many cases spots of low signal intensity, representing microhemorrhages. This feature is also seen in other small vessel diseases. Small hemorrhages may also be seen on CT and T

1

-weighted images (Fig. 73.1).

MR diffusion-weighted imaging is capable of quantitative estimation of the structural damage of the brain, which in its turn may relate to the clinical severity of the disorder. Changes in diffusion-weight- ed imaging consist of an up to 60% increase in diffu- sivity in lesions with high signal intensity on FLAIR or T

2

-weighted images, with loss of diffusion aniso- tropy in those areas. In normal-appearing white mat- ter, however, changes in diffusivity were also found.

These findings do not explain one of the most in- triguing MRI aspects of CADASIL, namely that many

of the above-mentioned findings may already be pre- sent in clinically unaffected members of patients’

families.

In the early stages of the disease, the pattern of MRI abnormalities is less characteristic and more dif- ficult to differentiate from other vascular disorders (Fig. 73.5). Abnormalities of the anterior temporal white matter and the external capsule are early find- ings and, in the presence of multiple small infarc- tions, suggestive of CADASIL.

The differential diagnosis of CADASIL includes other familial disorders presenting with multiple recurrent incidents and white matter lesions. Other familial disorders, in which recurrent incidents or step-like progression is a prominent symptom, in- clude multiple sclerosis, the dyslipoproteinemias (e.g., familial hypercholesterolemia), disorders of connective tissue (Ehlers–Danlos syndrome, Marfan syndrome), hyperhomocysteinemia, amyloid an- giopathy, and mitochondrial encephalopathies. Re- current strokes in young adults may also be due to cerebral vasculitis, systemic lupus erythematosus, drug abuse (especially cocaine), cardiac diseases, sickle cell disease, etc. Most of these diseases can be ruled out by the mode of inheritance, the clinical ap- pearance and course, biological tests, and laboratory findings. MRI of these diseases and disorders shows a pattern of irregular cortical and subcortical infarc- tions, lacking the tendency towards symmetry seen in CADASIL. In the disorders mentioned, the infarcts may involve both cortex and white matter, whereas CADASIL involves white matter and basal ganglia, without cortical infarctions. Temporal lobe involve-

Fig. 73.3. (continued). Series of FLAIR images in a 59-year-old woman, a representative of a known CADASIL family. In this series many MR characteristics of CADASIL are present: more or less symmetrical involvement of the centrum semiovale, external capsules, temporal lobes, and basal ganglia; multiple lacunar infarctions; some involvement of the cerebellum. Even on the FLAIR images the basal ganglia have a relatively low

signal intensity.The sagittal (fourth row) and coronal (fifth row) FLAIR images further illustrate and complete this pattern. The frontal cortico-subcortical involvement is depicted, as are the multiple lacunar infarctions and the extension of the lesions into the external capsules and the temporal lobes. There is also involvement of the corpus callosum and the fornix (mid- sagittal image, fourth row, right)

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ment also argues strongly for CADASIL. The differen- tial diagnosis of white matter disorders with cogni- tive impairment and possible severe temporal lobe involvement is from myotonic dystrophy. Familial

hemiplegic migraine can be confused with the begin- ning of CADASIL, but does not show white matter abnormalities comparable to those of CADASIL.

Fig. 73.4. In this 48-year-old man, a representative of another large family with CADASIL, the MR pattern is difficult to distin- guish from that of other vascular disorders.The involvement of the centrum semiovale is patchy and less symmetrical than in more advanced CADASIL.There is incipient involvement of the

external capsules and evident involvement of the temporal lobes.There are many lacunar infarctions, which, together with the dark appearance of the globus pallidus, often seen in patients with CADASIL, indicate the correct diagnosis

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Fig. 73.5. A 31-year-old male member of the same family as the patient in Fig. 73.4. Without knowing the diagnosis in the family, it would be difficult to diagnose this patient with

CADASIL. The images show multiple lacunar infarctions. In addition, there is incipient involvement of the external capsules and the white matter of the anterior temporal lobes 073_Valk_CerebralAutosomal 08.04.2005 16:31 Uhr Seite 548