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Background

CADASIL stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. It is a disease of young adults and presents with migraines with or without an aura, mood disturbances, focal neurologic deficits, strokes, and dementia. Most patients will show symptoms by age 60 years. There are recurrent subcortical ischemic events causing permanent deficits in as many as 2/3 of patients. Unfortunately, there are no laboratory screening tests except for a mild elevation of cerebrospinal fluid protein in 25% of cases. Recently, electron microscopic studies performed upon a skin biopsy may yield the diagnostic changes (see the outline below).

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Hereditary multi-infarct dementia
Chronic familial vascular encephalopathy
Familial disorder with subcortical ischemic strokes
Agnogenic medial arteriopathy
Familial Binswanger's disease
AGE RANGE-MEDIAN 30-40 years
Death usually occurs 12-23 years after onset of symptoms

CADASIL in a North American family: clinical, pathologic, and radiologic findings.

Desmond DW, Moroney JT, Lynch T, Chan S, Chin SS, Shungu DC, Naini AB, Mohr JP.

Department of Neurology, Columbia University, College of Physicians and Surgeons, New York, NY, USA.

Neurology 1998 Sep;51(3):844-9 Abstract quote

OBJECTIVE: To expand the reported phenotypic range of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

BACKGROUND: Despite numerous patient reports, our knowledge of the phenotypic range of CADASIL remains incomplete.

METHOD: We performed clinical, pathologic, and radiologic examinations on members of a family with CADASIL.

RESULTS: The proband is a 61-year-old man with a history of migraine and depression who has experienced multiple subcortical infarctions resulting in a stepwise decline. Neuropsychological testing documented a dementia syndrome with frontal lobe features and neurologic examination noted a left hemiparesis and a right-sided palmomental reflex. Brain biopsy with light microscopy revealed a nonatherosclerotic small-vessel angiopathy with periodic acid-Schiff positive granular changes in the media and white matter gliosis, with unremarkable cortex. Genetic testing confirmed a Notch3 mutation. The proband's first cousin has a history of depression, one seizure possibly resulting from an acute stroke, and a learning disorder. Neuropsychological testing demonstrated deficits in executive function and neurologic examination noted persistent extraneous adventitial movements, poor coordination, and primitive reflexes. Skin biopsy with electron microscopy demonstrated granular osmiophilic material within the basement membrane of vascular smooth muscle cells, which is considered to be pathognomonic of CADASIL. The proband's older son and younger son have histories of migraine and depression, respectively, and both also had learning disorders. MRI revealed diffuse white matter disease extending into the temporal lobes, and lacunar infarctions in these four nonhypertensive patients. Other family members have experienced migraine, recurrent stroke, dementia, and depression.

CONCLUSIONS: CADASIL is a genetic basis for vascular dementia that may be manifest earlier in life than previously reported.

 

DISEASE ASSOCIATIONS CHARACTERIZATION

Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family.

de la Pena P, Bornstein B, del Hoyo P, Fernandez-Moreno MA, Martin MA, Campos Y, Gomez-Escalonilla C, Molina JA, Cabello A, Arenas J, Garesse R.

Departamento de Bioquimica, Instituto de Investigaciones Biomedicas "Alberto Sols" CSIC-UAM, Facultad de Medicina, Universidad Autonoma de Madrid, Spain.

Neurology 2001 Oct 9;57(7):1235-8 Abstract quote

BACKGROUND: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development.

OBJECTIVE: To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene.

METHODS: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed.

RESULTS: In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V.

CONCLUSIONS: Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.

 

PATHOGENESIS CHARACTERIZATION
NOTCH3 MUTATIONS

Short arm of chromosome 19

The function is largely unknown although a gene involved in the Notch signaling pathway has homology to the presenilin 1 gene altered in some cases of premature Alzheimer's disease


Mouse Notch 3 expression in the pre- and postnatal brain: relationship to the stroke and dementia syndrome CADASIL.

Prakash N, Hansson E, Betsholtz C, Mitsiadis T, Lendahl U.

Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77, Stockholm, Sweden.


Exp Cell Res 2002 Aug 1;278(1):31-44 Abstract quote

Mutations in the human Notch 3 gene cause the vascular stroke and dementia syndrome CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) characterized by degeneration of vascular smooth muscle cells and multiple small infarcts in the white and deep gray matter of the brain.

Here we have analyzed the expression pattern of the Notch 3 gene in the pre- and postnatal mouse brain. Prenatal Notch 3 expression is restricted to a scattered population of cells within the vessel wall of all major blood vessels in the developing embryo, including those that form the perineural vascular plexus.

Expression in the postnatal brain is confined to a scattered cell population within the vessel wall of small to medium-sized penetrating arteries, which are the vessel type primarily affected in CADASIL patients. In contrast, no expression was observed in capillaries and veins. Notch 3 is most likely expressed in a subset of vascular smooth muscle cells, and the expression pattern of one of the Notch ligands, Serrate 1, was very similar to that observed for Notch 3.

The Notch 3 expressing pattern was not significantly altered in platelet-derived growth factor B- (PDGF-B) deficient mouse embryos, demonstrating that Notch 3 expression is not under direct control of PDGF-B. These data show that Notch 3 expression is conserved between mouse and human and suggest that the mouse is a valid system for analysis of CADASIL.

C455R notch3 mutation in a Colombian CADASIL kindred with early onset of stroke.

Arboleda-Velasquez JF, Lopera F, Lopez E, Frosch MP, Sepulveda-Falla D, Gutierrez JE, Vargas S, Medina M, Martinez De Arrieta C, Lebo RV, Slaugenhaupt SA, Betensky RA, Villegas A, Arcos-Burgos M, Rivera D, Restrepo JC, Kosik KS.

Center for Neurological Diseases, Brigham and Women's Hospital-Harvard Medical School, Boston, MA, USA.

Neurology 2002 Jul 23;59(2):277-9 Abstract quote

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the notch3 epidermal growth factor-like repeats. A Colombian kindred carries a novel C455R mutation located in the predicted ligand-binding domain.

Stroke occurred in the patients at an unusually early age (median age: 31 years) in comparison to the more frequent onset in the fourth decade of life in other CADASIL populations, including a second Colombian kindred with an R1031C mutation.


Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Phenotypic and mutational spectrum.

Dichgans M.

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universitat, Marchioninistrasse 15, D-81377, Munich, Germany

J Neurol Sci 2002 Nov 15;203-204(C):77-80 Abstract quote

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) an inherited small vessel disease leading to subcortical strokes and dementia.

Since the vascular pathology is clearly defined, CADASIL may provide important insights into the mechanisms underlying lacunar infarcts, ischemic white matter changes, and vascular dementia. Evidence from different sources suggests a central role for vascular smooth muscle cells (VSMC) in the pathophysiology of the disease.

This article gives a brief overview on the phenotypic spectrum of the disease and discusses some of the relevant disease mechanisms that lead from Notch3 mutations to ischemic infarcts.

VASCULAR DAMAGE  
Primary damage to vascular smooth muscle cells (VSMC)

Damaged cells leak or extrude material which forms GOM

GOM may impede the delivery of nutrients leading to damage of the surrounding tissue

GOM progressively impedes contact between astrocytic foot processes and VSMC

Primary damage to the endothelial cells

Endothelial cell alterations including condensation of cytoplasm with progressive packing of microfilaments in skin arterioles and capillaries

May have altered pinocytosis

Primary proliferation of elastic lamina and basement membrane material
Could inhibit nutrient passage

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION
MRI

Lesions usually symmetrically situated within the white matter and deep gray nuclei-periventricular white matter is preferentially involved

Usually in the frontal lobe, temporal lobe, subinsular white matter, and internal and external capsules with relative sparing of the inferior frontal and occipital white matter in the early stages

Brainstem affected in 45% of cases


Subcortical lacunar lesions: an MR imaging finding in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

van Den Boom R, Lesnik Oberstein SA, van Duinen SG, Bornebroek M, Ferrari MD, Haan J, van Buchem MA.

Department of Radiology, Leiden University Medical Center, Albinusdreef 2, C2S, the Netherlands

Radiology 2002 Sep;224(3):791-6 Abstract quote

PURPOSE: To assess the prevalence and distribution of subcortical lacunar lesions (SLLs) in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to determine whether SLLs are an abnormal finding by studying their prevalence in healthy subjects, and to assess whether SLLs occur in other conditions associated with small vessel disease and white matter areas of high signal intensity (WMH).

MATERIALS AND METHODS: The presence of SLLs, their location, and their relation to other abnormalities were assessed on magnetic resonance (MR) images (T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery) obtained in 34 CADASIL patients and 20 healthy family members. Three additional control groups of healthy volunteers, elderly patients with vascular risk factors, and patients with another hereditary small vessel disease were also screened for the presence and location of SLLs. Sensitivity and specificity of the presence of SLLs for the diagnosis of CADASIL were assessed.

RESULTS: SLLs were found in 20 (59%) of CADASIL patients. Incidence of SLLs increased with age (20%, <30 years; 50%, 30-50 years; 80%, >50 years). SLLs invariably occurred in the anterior temporal lobes and in areas where diffuse WMH expanded into arcuate fibers. From the anterior temporal lobe, the lesions could extend dorsally into the temporal lobes and rostrally into the frontal lobes. Lesions were not found in the parietal and occipital lobes. None of the control subjects had SLLs. Specificity and sensitivity of SLLs for CADASIL were 100% and 59%, respectively.

CONCLUSION: SLLs are an abnormal finding at MR imaging that frequently occur in CADASIL patients. Copyright


CADASIL imitating multiple sclerosis: the importance of MRI markers.

O'Riordan S, Nor AM, Hutchinson M.

Department of Neurology, St Vincent's University Hospital, Dublin, Ireland.

Mult Scler 2002 Oct;8(5):430-2 Abstract quote

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can mimic multiple sclerosis (MS), leading to diagnostic confusion.

We report a family with CADASIL in which the index case and the daughter of the index case were initially erroneously diagnosed with MS.

Relatively specific magnetic resonance imaging (MPI) markers of CADASIL include involvement of the anterior temporal lobes and external capsules and, as illustrated in this report, these MRI findings may aid in the differentiation of the two conditions.

PET and SPECT scanning May identify regions of hypoperfusion correlating with MRI findings
ULTRASOUND  


Prolonged cerebral transit time in CADASIL: a transcranial ultrasound study.

Liebetrau M, Herzog J, Kloss CU, Hamann GF, Dichgans M.

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Munchen, Germany.

 

Stroke 2002 Feb;33(2):509-12 Abstract quote

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary angiopathy caused by mutations in Notch3. Cerebral microvessels show an accumulation of granular osmophilic material in the vicinity of degenerating vascular smooth muscle cells. In this study, we measured the arteriovenous cerebral transit time (CTT) to identify changes related to the microangiopathy in CADASIL.

METHODS: CTT is the time that a contrast agent needs to pass from a cerebral artery to its corresponding vein. CTT was measured in 17 CADASIL individuals (mean age, 50.2+/-12.3 years) and an equal number of age- and sex-matched control subjects (mean age, 48.9+/-13.0 years) with transcranial color-coded duplex sonography. The intensity curves were recorded in the P2 segment of the posterior cerebral artery and the vein of Galen after injection of the ultrasound contrast agent Levovist.

RESULTS: CTT was significantly prolonged in individuals with CADASIL (4.4+/-1.9 seconds) compared with control subjects (1.3+/-0.5 seconds, P<0.0001). This difference was also significant when only nondisabled CADASIL individuals (Rankin score=0, n=9) were analyzed (P<0.0001). There was a nonsignificant trend for a correlation between Rankin score and CTT (r=0.39, P=0.11).

CONCLUSIONS: The prolonged CTT likely reflects microvascular changes in CADASIL. Measurements of the CTT may be used clinically to disclose small-vessel disease. Studies comparing CADASIL subjects with other patient populations seem warranted to determine possible differences in CTT between different types of small-vessel disease.

SCREENING FOR GENETIC MUTATIONS  


Diagnostic strategies in CADASIL.

Markus HS, Martin RJ, Simpson MA, Dong YB, Ali N, Crosby AH, Powell JF.

Department of Clinical Neuroscience, St. George's Hospital Medical School, London, UK.

Neurology 2002 Oct 22;59(8):1134-8 Abstract quote

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited autosomal dominant condition characterized by migraine, recurrent stroke, and dementia. It results from mutations in the notch3 gene but mutations may occur at multiple sites making molecular diagnosis time consuming. It has been suggested that the presence of granular osmiophilic material (GOM) on skin biopsy and involvement of the anterior temporal lobe and external capsule on MRI may help in diagnosis.

METHODS: The authors identified 83 potential index cases from the British population and screened exons 2 to 23 of notch3. MRI scans were scored using a modified Scheltens scale. Skin biopsy was performed in a subgroup.

RESULTS: Fifteen different point mutations were identified in 48 families, 73% of which were in exon 4, 8% in exon 3, and 6% in each of exons 5 and 6. Moderate or severe involvement of the anterior temporal pole on MRI had a sensitivity of 89% and specificity of 86% for diagnosis of CADASIL, whereas external capsule involvement had a high sensitivity of 93% but a low specificity of 45%. Skin biopsy, performed in 18 cases, had a sensitivity of 45% and specificity of 100%.

CONCLUSIONS: The spectrum of mutations in this study can be used to plan appropriate screening protocols; a suggested protocol is to screen exon 4, and proceed to exons 3, 5, and 6 where indicated. GOM on skin biopsy is diagnostic but can be negative. Anterior temporal pole involvement on MRI is a useful diagnostic marker.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
BRAIN

May have mild generalized brain atrophy with enlargement of the ventricular spaces and widening of the perivascular spaces

White matter shows areas of patchy demyelination
Lacunar infarcts


CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia.

Kalimo H, Ruchoux MM, Viitanen M, Kalaria RN.

Department of Pathology, Turku University Hospital, Finland.

Brain Pathol 2002 Jul;12(3):371-84 Abstract quote

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline and dementia. CADASIL usually begins with migraine in about one third of the patients.

More severe manifestations, transient ischemic attacks or recurrent strokes, appear between 30 and 50 years of age. CADASIL, however, may be diagnosed well before the first stroke on the basis of characteristic white matter hyperintensities upon magnetic resonance imaging and presence of pathognomonic granular osmiophilic material in arterial walls, including dermal arteries, since the arteriopathy is generalized.

Gradual destruction of vascular smooth muscle cells (VSMC) leads to progressive wall thickening and fibrosis and luminal narrowing in small and medium-sized penetrating arteries. The reduced cerebral blood flow finally causes lacunar infarcts, mainly in the basal ganglia and fronto-temporal white matter, which lead to cognitive deficits and dementia of the subcortical vascular type. CADASIL is caused by single missense mutations or small deletions in Notch3 gene encoding a transmembrane receptor Notch3, of which upon ligand binding a nuclear signaling protein is generated by regulated intramembrane proteolysis. Notch signaling is essential during development, regulating cellular differentiation.

In adults Notch3 is expressed only in VSMCs and it may promote cell survival by inhibiting apoptosis, but its exact function is unknown. Mutations result in either a gain or loss of one (or rarely, 3) cysteine residue(s) in one of the 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of Notch3. It is as yet unclear which disturbance in the Notch signaling pathway leads to the characteristic vascular pathology of CADASIL.

VARIANTS  

The phenotypic spectrum of CADASIL: clinical findings in 102 cases.

Dichgans M, Mayer M, Uttner I, Bruning R, Muller-Hocker J, Rungger G, Ebke M, Klockgether T, Gasser T.

Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians-Universitat, Munich, Germany.

Ann Neurol 1998 Nov;44(5):731-9 Abstract quote

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood.

This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups.

The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL

Small to medium sized arteries are affected but smaller arteries, arterioles,a and capillaries may be affected

Degeneration of the arterial wall with deposition in the media of the vessels of a nonatheromatous, nonamyloidotic substance

Destruction of the media is accompanied with loss of vascular smooth muscle cells

Under the electron microscope, it is a granular osmiophilic material (GOM), which is pathognomonic for the disease

BRAIN Most severely affected vessels are accompanied by lacunar infarcts


Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter: examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case.

Okeda R, Arima K, Kawai M.

Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

Stroke 2002 Nov;33(11):2565-9 Abstract quote

BACKGROUND AND PURPOSE: There is little information regarding the pathogenesis underlying diffuse myelin loss in the cerebral white matter and sparing of the U fibers in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), in which the medial smooth muscle cells of systemic arteries are characteristically involved. We sought to examine the precise extent and severity of changes in the cerebral arteries in an autopsy case of CADASIL in relation to pathogenesis of the diffuse myelin loss.

METHODS: We reconstructed 1000 serial sections of the frontal cerebral medullary arteries of an autopsy subject, which was the first identified Japanese case of CADASIL, as confirmed by the presence of ultrastructural deposits of granular osmiophilic material in the media of some visceral arteries and by genetic analysis.

RESULTS: We reconstructed 11 medullary arteries of the frontal lobe showing diffuse myelin loss and atrophy of the white matter with sparing of the U fibers. All of these showed complete loss of medial smooth muscle cells over their entire length and severe adventitial fibrosis. Although intimal fibrosis or hyalinosis was present, luminal occlusion was scarce. These changes were also observed in the small and large arachnoidal arteries but were relatively mild in the latter and in the cortical and subcortical medullary arteries.

CONCLUSIONS: These arterial changes resulted in transformation of the cerebral arteries, in particular almost all the medullary arteries, to a so-called earthen pipe state. This supports the reported findings of a reduction in vascular reactivity to fluctuations in CO2 levels and systemic blood pressure in CADASIL.

SKIN

J Am Acad Dermatol 2000;43:1125-7

Electron microscopy shows numerous areas, granular, electron-dense, osmiophilic material abutted vascular smooth muscle cells

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaloapthy (CADASIL): a hereditary cerebrovascular disease, which can be diagnosed by skin biopsy electron microscopy.

Ishiko A, Shimizu A, Nagata E, Ohta K, Tanaka M.

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Am J Dermatopathol. 2005 Apr;27(2):131-4. Abstract quote  

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebrovascular disease characterized by recurrent subcortical ischemic strokes starting in the third or fourth decade as a result of mutations in the Notch3 gene. Granular osmiophilic material (GOM) deposition around the vascular smooth muscle cells is a specific feature and electron microscopic observations of skin biopsies are useful for this diagnosis.

A 39-year-old female with dizziness, abnormal visual fields, and hemiplegia, and a 42-year-old male with tinnitus and dizziness, were suspected of suffering from CADASIL based on MRI findings. Both cases were shown to have characteristic deposits of GOM, 200 to 800 nm in diameter, around the vascular smooth muscle cells of small arteries in the deep dermis, and thus the diagnoses of CADASIL were made, although there was no family history of cerebrovascular disorders or dementia.

Dermatologists should be aware of these ultra-structural findings because this disease may occur sporadically and might be more common than initially thought.


Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis.

Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, Domenga V, Cecillon M, Vahedi K, Ducros A, Cave-Riant F, Bousser MG, Tournier-Lasserve E.

INSERM EPI 99-21, Faculte de Medecine Lariboisiere, 10 Avenue de Verdun, 75010, Paris, France

Lancet 2001 Dec 15;358(9298):2049-51 Abstract quote

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is a small-artery disease of the brain caused by NOTCH3 mutations that lead to an abnormal accumulation of NOTCH3 within the vasculature.

We aimed to establish whether immunostaining skin biopsy samples with a monoclonal antibody specific for NOTCH3 could form the basis of a reliable and easy diagnostic test. We compared the sensitivity and specificity of this method in two groups of patients suspected of having CADASIL with complete scanning of mutation-causing exons of NOTCH3 (in a retrospective series of 39 patients) and with limited scanning of four exons that are mutation hotspots (prospective series of 42 patients).

In the retrospective series skin biopsy was positive in 21 (96%) of the 22 CADASIL patients examined and negative in all others; in the prospective series, seven of the 42 patients had a positive skin biopsy whereas only four had a mutation detected by limited NOTCH3 scanning. Our immunostaining technique is highly sensitive (96%) and specific (100%) for diagnosis of CADASIL.

A CADASIL case with normal skin biopsy and without mutations in exons 3 and 4 of the Notch3 gene.

de Freitas GR, Miklossy J, Christen-Zach S, Reichhart M, Bogousslavsky J.

Department of Neurology, Centre Hospitalier Universitaire Vaudois, CH1011, Lausanne, Switzerland

J Neurol Sci 2001 Dec 15;193(1):43-7 Abstract quote

The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is usually confirmed by genetic testing or skin biopsy.

We here report the case of a 69-year-old woman with recurrent transient ischemic attacks (TIAs) and strokes, seizures, and dementia without any mutations in exons 3 and 4 of the Notch3 gene and with a normal skin biopsy, but who showed characteristic CADASIL abnormalities on brain pathological examination.

Our findings suggest that negative results in these two tests do not exclude the disease and a leptomeningeal biopsy or a second skin biopsy should be considered in such cases.


CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): a neurovascular disease diagnosed by ultrastructural examination of the skin.

Kanitakis J, Thobois S, Claudy A, Broussolle E.

Department of Dermatology, Hopital Ed. Herriot, and Department of Neurology (U401-402), Hopital Neurologique Pierre Wertheimer, Lyon, France.

J Cutan Pathol 2002 Sep;29(8):498-501 Abstract quote

BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a recently recognized neurovascular disease due to mutations of the Notch3 gene, manifesting with strokes or stroke-like episodes, major psychiatric symptoms and dementia. The diagnosis can be confirmed either by molecular analysis or by ultrastructural examination of the brain or more simply the skin.

METHODS: The skin of a patient with a suspected diagnosis of CADASIL was studied by electron microscopy.

RESULTS: Characteristic granular osmiophilic material within the basement membrane surrounding pericytes and smooth muscle cells of small and medium-sized vessels of the skin were found, confirming the diagnosis of CADASIL.

CONCLUSIONS: CADASIL is an additional example of a neurologic disease that can be diagnosed thanks to electron microscopic examination of the skin. Dermatopathologists should be aware of these ultrastructural findings, all the more so since the disease could be more common than originally thought.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION
Granular material

PAS positive but staining is lost following acetylation

Negative for amyloid stains

Antibodies to aB crystallin Protein in the heat shock protein superfamily
Positive in the granular material
Electron microscopy

This is diagnostic

Pathognomonic finding of GOM in the arterial walls

These findings are found throughout the systemic circulation allowing for potential diagnosis through skin biopsies


Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications.

Brulin P, Godfraind C, Leteurtre E, Ruchoux MM.

EA 2691 MENRT, Faculte de Medecine de Lille, 59037 Lille, France.

 

Acta Neuropathol (Berl) 2002 Sep;104(3):241-8 Abstract quote

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic vascular disease caused by Notch 3 gene mutations.

On electron microscopy a specific granular osmiophilic material (GOM) is found surrounding the vascular smooth muscle cells. In 1993, we first proposed the use of skin biopsy to diagnose patients and to identify relatives of patients with CADASIL.

We analyze here our experience with skin biopsies from 50 patients with CADASIL and compare the findings with those of 20 normal skin biopsy specimens. A morphometric analysis of skin vessel morphology on electron microscopy was performed by systematic measurements of several blood vessel diameters, as well as of areas of lumen, endothelial cell and smooth muscle cell cross-sectional areas, vessel wall area, arterial media and extracellular matrix areas.

We found relative absence of stenosis but marked destruction of smooth muscle cells, resulting in decrease of vessel wall thickness and loss of extracellular matrix area, producing vessel wall weakness. Similar changes were also observed in brain arterioles from 5 patients with CADASIL. Our results suggest that hypotonicity of the arteriolar tree may constitute an important pathogenetic mechanism in CADASIL. Other than hypotonicity, the early and severe destruction of smooth muscle cells may potentially result in decreased secretion of vascular endothelial growth factor, loss of vascular permeability and damaging hemodynamic consequences. Blood vessel morphology of skin vessels correlated well with changes in brain arterioles.

Vascular morphology in skin biopsy samples contributes to our understanding of the pathogenesis of CADASIL. It could be important to perform skin biopsies in future therapeutic trials of CADASIL as a direct measure of therapeutic effectiveness.

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
MULTIPLE SCLEROSIS  
PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM  


CADASIL mimicking primary angiitis of the central nervous system.

Engelter ST, Rueegg S, Kirsch EC, Fluri F, Probst A, Steck AJ, Lyrer PA.

Neurological Clinic and Stroke Unit, University Hospital Basle, Petersgraben 4, CH-4031 Basel, Switzerland.

Arch Neurol 2002 Sep;59(9):1480-3 Abstract quote

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and primary angiitis of the central nervous system (PACNS) share several clinical and radiological features. However, digital subtraction angiogram (DSA) is generally reported as normal in CADASIL, whereas lumen irregularities in distal cerebral arteries indicate PACNS.

OBJECTIVE: To describe a potential pitfall of DSA interpretation, which led to the tentative diagnosis of PACNS in a CADASIL patient.

PATIENT AND METHODS: Single case observation.

RESULTS: A 47-year-old man sustained recurrent subcortical infarcts. He had mild hypercholesterolemia and migraine. His family history was unremarkable. The underlying cause of stroke could not be elucidated. Transcranial Doppler sonography revealed decreased intracranial blood flow velocities compatible with CADASIL. Lumen irregularities of several peripheral intracranial arteries were seen on DSA, which suggested PACNS. CADASIL was confirmed by results from skin biopsy and genetic testing.

CONCLUSIONS: First, in patients with CADASIL, DSA can show segmental lumen irregularities in distal cerebral arteries suggestive of PACNS. Second, the potential role of transcranial Doppler sonography to distinguish CADASIL from PACNS deserves further testing.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
Treatment

Acetazolamide may be useful

Anticoagulants should be avoided

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Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.


Commonly Used Terms

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences


Internet Links
Last Updated April 22, 2005

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