13ournal of Neurology, Neurosurgery, and Psychiatry 1995;59:138-143

Cerebral autosomal dominant arteriopathy withsubcortical infarcts and leukoencephalopathy: a

clinicopathological and genetic study of a Swissfamily

H H Jung, C Bassetti, E Tournier-Lasserve, K Vahedi, M Arnaboldi, V Blatter Arifi,J-M Burgunder

AbstractThis paper reports a Swiss familyaffected by a cerebral autosomal domi-nant arteriopathy with subcorticalinfarcts and leukoencephalopathy(CADASIL) linked to chromosome19q12. In three generations several mem-bers of this family had recurrent stroke-like episodes and, some developedsubcortical dementia, migraine-likeheadaches, and depression. The clinicallyaffected family members had multiplesubcortical infarcts and diffuse leukoen-cephalopathy on MRI. Necropsy of onepatient showed a distinctive non-amyloidand non-atherosclerotic angiopathy ofsmall cerebral and leptomeningeal arter-ies with concentric depositions of abasophilic granular material replacingthe smooth muscle cells of the media.Linkage analysis with five chromosome19 markers spanning the estimatedCADASIL interval showed the absence ofany recombinant and positive Lod scores,highly suggestive of linkage of this condi-tion to the CADASIL locus. CADASILmight be an underestimated cause offamilial stroke and should be consideredin the differential diagnosis of hereditarystroke.

Department ofNeurology, UniversityHospital Bern, Bern,SwitzerlandH H JungC BassettiV Blatter ArifiJ-M BurgunderFaculte de MedecineNecker-EnfantsMalades, Inserm U25,Paris, FranceE Tournier-LasserveK VahediDepartment ofPathology, UniversityHospital Zurich,Zurich, SwitzerlandM ArnaboldiCorrespondence to:Dr C Bassetti, Departmentof Neurology, UniversityHospital Bern, CH-3010Bern, Switzerland.

Received 3 January 1995and in final revised form7 April 1995Accepted 12 April 1995

(7 Neurol Neurosurg Psychiatry 1995;59: 138-143)

Keywords: CADASIL; leukoencephalopathy; heredi-tary stroke; chromosome 19q

Various causes have been identified for familialstroke such as hereditary dyslipoproteinaemia,thrombotic disorders, Fabry's disease, mito-chondrial myopathy with encephalopathy, lac-tic acidosis, and stroke-like episodes(MELAS), and homocystinuria.1 3 Since1977, several clinical reports have describedfamilial disorders with an autosomal domi-nant pattem of inheritance consisting ofrecurrent stroke-like episodes and the devel-opment of subcortical dementia in theabsence of major vascular risk factors, in par-ticular arterial hypertension. Similar condi-tions are known as chronic familiar vascularencephalopathy,4 hereditary multi-infarctdementia,56 familial subcortical dementia witharteriopathic leukoencephalopathy,7 familial

disorder with subcortical ischaemic strokesand leukoencephalopathy,9 and morerecently, cerebral autosomal dominant arteri-opathy with subcortical infarcts and leukoen-cephalopathy (CADASIL).1'' I All thesedisorders share similar clinical features,pathological findings, and neuroradiologicalchanges. Recently, the disease locus in twounrelated French families has been ascribedto chromosome 1 9q12 by genetic linkageanalysis. 12

In this paper we describe a Swiss familyaffected by autosomal dominant disease char-acterised by recurrent stroke-like episodes andthe development of subcortical dementiashowing the same genetic linkage to chromo-some 19.

Patients and methodsTwelve members belonging to two genera-tions of a family originating from the easternpart of Switzerland were examined. Eight ofthem were females and four were males. Fourwere aged between 13 and 19 and eightbetween 31 and 40. All members gaveinformed consent to the examinations.Clinical and paraclinical data available frommedical records of deceased members of thefamily were also reviewed. Figure 1 shows thepedigree of family members aged over 30.Table 1 summarises the clinical and radiologi-cal findings of the affected family members.Cerebral MRI was carried out in 10 of the 12examined members (General Electric Signa,1-5 Tesla, TI and T2 weighted transversaland sagittal sections). Brain MRI was notdone in two members because of claustropho-bia. All those examined had standard labora-tory investigations (red and white blood cellcounts, erythrocyte sedimentation rate, pro-tein electrophoresis, activated partial throm-boplastin time and prothrombin time tests,serum electrolytes, renal and liver functiontests, glycaemia, cholesterol, tryglycerides),determination of several antibodies (antinu-clear antibodies and antibodies directedagainst double and single strand DNA, mito-chondria, SS-A, SS-B, c-ANCA, and p-ANCA, cardiolipin/phospholipid), andscreening for lipids, mucopolysaccharides,and arylsulphatase A in the urine. The indexpatient underwent further examination asdescribed next.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a clinicopathological and genetic study ofa Swissfamily 139

I

III

IV

1 2 3 4 5 6 7 8 9 10

H L H C H LH M H M M M

L L L H H LA A A H C AD D D D C D

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Figure 1 Pedigree of thefamily overfour generations (flled symbols represent affected patients, empty symbols non-affected subjects, and hatched symbolssubjects not examined). Markers spanning the interval containing the CADASIL gene are indicated below the examined informative members due to theirestimated position on the short arm ofchromosome 19

INDEX PATIENT (IV 5)The patient was referred to our service withpossible multiple sclerosis. At the age of 38 hehad suddenly developed a right sided facialpalsy that recovered with only minor residualsymptoms. Two years later he experiencedacute paraesthesia and dysaesthesia of the leftside. The first clinical examination showed a

residual right sided facial palsy, hyperpathy ofthe left side, slight hypaesthesia on the lefthand, and a depressive mood with cryingspells. Neuropsychological testing showedmild amnesia and concentration and atten-tional deficits. There was no history ofheadache and major cardiovascular risk fac-tors were absent.

Table 1 Clinical and radiologicalfeatures ofseven patients in generations II to IV

Patients(onset age) Clinicalfeatures Radiologicalfeatures

II 1 (45) Recurrent stroke-like episodes, progressive subcortical No radiological examination performeddementia

III 1 (40) Migraine accompagnee. At age 50 progressive subcortical CT: multiple bilateral hypodensities indementia. At 55 recurrent stroke-like episodes the white ganglia, leukoaraiosis

III 2 (53) Transient stroke-like episode. At age 59 progressive CT: multiple bilateral hypodensities insubcortical dementia. At 62 stroke-like episode with the white matter and in the basalpersistent right sided hemiplegia. Death at 63 ganglia, leukoaraiosis

Im 4 (40) Episodes of major depression. At age 52 first transient CT: multiple bilateral hypodensities instroke-like episode. At 54 multiple stroke-like episodes the white matter and in the basaland progressive subcortical dementia. Death at 60 ganglia, leukoaraiosis

IV 1 (33) Migraine-like headaches. Two episodes of migraine MRI: multiple bilateral lesions in theaccompagn6e. One transient stroke-like episode. white matter and basal ganglia;No neurological deficits leukoencephalopathy

IV 3 (35) Recurrent attacks of migraine since youth. At 35 migraine MRI: multiple bilateral lesions in theaccompagnee. At 37 first transient stroke-like episode. white matter and basal ganglia,No neurological deficits thalamus and centrum semiovale;

leukoencephalopathyIV 5 (38) Several stroke-like episodes. Clinically left sided MRI: multiple bilateral lesions in the

hyposensibiliy, motor aphasis and apraxia of the white matter, basal ganglia corpusright hand. Mild neuropsychological deficits callosum, and right thalamus;

leukoencephalopathy

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10ung, Bassetti, Tournier-Lasserve, Vahedi, Arnaboldi, Blatter Arzifi, et al

T1 weighted brain MRI showed multiplewell delineated lesions in the white matter,corona radiata, and centrum semiovale as wellas in the basal ganglia and right thalamus.There was also one lesion in the corpus callo-sum. T2 weighted brain MRI showed conflu-ent white matter hyperintensities. Laboratoryexamination as mentioned yielded normalresults. Coagulation variables (thrombocytes,protein C and S, thrombin time test, fibrino-gen, factors II, V, VII, and X, and fibrin/fib-rinogen degradation products), serum lactate,and subanaerobic threshold exercise test(SATE test) were within the normal range.Examination of CSF gave normal results forcell count, protein, and glucose; CSFimmunoglobulins were normal by isoelectricfocusing. Duplex and Doppler sonographicexamination of the cerebral arteries, a pco,reactivity test, four vessel cerebral angiogra-phy, chest radiographs, ECG, trans-oesophageal echocardiography, and visual andmotor evoked potentials were normal.Somatosensory evoked potentials showed alow amplitude of early cortical responses onthe right side due to the thalamic lesion.Biopsy of the quadriceps muscle showed aslightly augmented intracellular lipid accumu-lation of unknown origin. Biopsy of the suralnerve showed slight axonal and demyelinatingdamage without alterations of endoneural andperineural vessels at light microscopy. A trialprophylactic treatment with aspirin wasstarted. Six months later another stroke-likeepisode occurred with symptoms of motoraphasia and ideomotor apraxia. There wasworsening of the right sided facial paresis withnewly developed complete left sided hemi-hypaesthesia.

PATIENT IV 1This woman reported a history of allergicasthmoid reaction, rhinitis, and urticaria. Atthe age of 33 she experienced for the first timeseveral attacks of severe migraine-like

Figure 2 Brain MRI ofpatient IV l; T2 weightedMRI showing multiple,well delineated lesions ofthe white matterpredominantly adjacent tothe ventricles and in thebasal ganglia, andextended confluent whitematter lesions

headaches in the left hemicranium with nau-sea, photophobia, and phonophobia. Twoepisodes of 10 minutes duration were accom-panied by paraesthesia and hypaesthesia ofthe left arm and face without motor symp-toms. One short episode of sudden paraesthe-sia of the left hand without headaches wasalso reported. Clinical and laboratory exami-nations were normal. Brain MRI showed mul-tiple, well delineated lesions in Ti weightedimages in the white matter and basal ganglia.T2 weighted images showed confluent whitematter lesions (fig 2).

RECORDS OF DECEASED FAMILY MEMBERSA history of stroke-like episodes was docu-mented in four deceased members in genera-tion II and III in the absence of majorcardiovascular risk factors (table 1). Themean age of onset was 51. In addition, allpatients developed symptoms of subcorticaldementia with a documented mean age ofonset of 55. One of the deceased patients (III1) showed symptoms of hemiplegic migrainein his 40s. Another patient was admitted tohospital several times due to major depressionbetween his third to sixth decade. In three ofthe deceased affected members (III 1, III 2,and III 4) brain CT was available. Theseshowed multiple small circumscribed hypo-densities without contrast enhancementlocalised predominantly in the basal gangliaand the adjacent white matter together withdiffuse low densities in the white matter.

HISTOPATHOLOGICAL EXAMINATIONNecropsy had been performed on one familymember (III 2, aged 59) after his death in1986. His brain weighed 1360 g. Macroscopicexamination showed multiple ischaemiclesions of the cerebral cortex in the left tem-poro-occipital region and the right cerebel-lum. The basal ganglia and the adjacent whitematter showed multiple small cystic lesions.Only a minor stenosing atherosclerosis of thebasal cerebral arteries was found.

Archived paraffin embedded brain tissuewas used to prepare new slices, which werestained with haematoxylin-eosin, elastica vanGieson, congo red, and thioflavine. Selectedareas were examined immunohistochemicallywith monoclonal antibodies directed againstsmooth muscle actin.

Histologically, the main abnormalities werefound in small arteries up to a diameter of 2mm, in some meningeal arteries, in most ofthe vessels of the basal ganglia and thalamus,and in practically all vessels of the white mat-ter. There were few arterial changes in thecortex of the cerebrum and the cerebellum.The abnormalities consisted of concentricdepositions of granular material in a slightlythickened media. The granules werebasophilic, replaced the smooth muscle cells,and were found in widely varying amounts (fig3). The loss of smooth muscle cells was con-firmed by the immunohistochemical examina-tion with a monoclonal antibody directedagainst smooth muscle actin (fig 4). Somecerebral arteries also showed a loss of their

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a clinicopathological and genetic study ofa Swiss family 141

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Figure 3 Granular degeneration of the media and splitting of the laminain small arteries of the white matter. Depositions ofgranules of basophilic a(haematoxylin and eosin; bar represents 50 jm).

normal texture and a splitting celastica intema, in rare cases accodiffuse hyalinosis of the media. Itypical signs of a long lasting atension or signs of vasculitis.after thioflavine staining and co:negative for amyloid depositi(with occlusions or thrombosis (

detected. There were no abnvenous vessels.

In general the brain tissue sho'

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9^* partially cystic transformed infarcts, lying pre-dominantly in the white matter and the basalganglia often with centrally located altered

/ g vessels. There was a diffuse loss of ganglion cellsin the adjacent tissue with a mild lymphocyticinfiltration, iron pigment deposition in macro-phages, and a pronounced astrocytic gliosis.

LINKAGE ANALYSISGenetic linkage analysis was conducted asdescribed.12 Briefly, all clinically symptomatic

+* patients with the typical alterations on brainMRI were considered as affected. Asympto-matic subjects with normal cerebral MRI wereconsidered as having an unknown status whenaged below 35. Six were fully informative.Three of them (IV1, IV3, and IV5) were con-

- sidered as affected and three of them (IV2,IV4, and IV8) as healthy. Those belonging to

elastica interna generation V were considered as non-infor-aspect mative and were not analysed. DNA was

extracted from peripheral blood lymphocytesof all potentially informative subjects. Fivechromosome 19 markers were selected for

)f the lamina their informativity-namely, D19S221,)mpanied by a D19S226, D19S244, D19S 199, and[here were no Dl 9S215."3 14 The examined markers haverterial hyper- previously been shown to span a 14 cM inter-Fluorescence val containing the CADASIL locus.'2 Theyngo red were are drawn on fig 1 according to their esti-ons. Arteries mated position on the short arm of chromo-could not be some 19. D19S244 is located at e = 0 fromLormalities of D19S226 and D19S199 is centromeric to

D19S226 and located at i9 = 2cM fromwed multiple, Dl 9S226 (Weissenbach et al 14 and J Weber,

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Figure 4 Immunhistochemical examination ofsmooth muscle actin in the media using a monoclonal antibody (arrow).(A) granular degeneration of the media with nearly total loss ofsmooth muscle cell actin; (B) normal amount ofsmoothmuscle cell actin in a patient with vascular encephalopathy associated with hypertension (haematoxylin and eosin; barsrepresent 100 jm)

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2Jung, Bassetti, Tournier-Lasserve, Vahedi, Arnaboldi, BlatterArifi, et al

Table 2 Lod scores obtainedfor various values of recombination fractions (9) offivemarkers spanning the CADASIL interval

'9

Marker 0 01 0-2 03 04 05

D19S221 1 71 1-36 0-97 0-56 0-17 0-00D19S226 -0-06 -0-04 -0-02 -0-01 -0-003 0 00D19S244 0-85 0-73 0-55 0-33 0-10 0-00D19S199 1-12 0-89 0-62 0-33 0-09 0-00D19S215 0-46 0.32 0-19 0-08 0 01 0 00

personal communication). Linkage analysiswas conducted with the allele frequenciesfound for the selected markers in the CEPHfamilies as previously described.'2 Table 2shows Lod scores for various values of recom-bination fractions. No recombinant was foundwith any of the markers (fig 1). These com-

bined data strongly suggest the linkage of thedisorder present in this family with theCADASIL locus.

DiscussionThe diagnosis of an autosomal dominant arte-riopathy with stroke-like episodes andleukoencephalopathy (CADASIL) in the fam-ily presented here is established by the typicalclinical courses, the neuroradiological find-ings, the arteriopathic alterations, and theresults of the genetic linkage analysis thatstrongly suggests the disease locus on chro-mosome 19. Similar syndromes have beencharacterised clinically in several reports dur-ing the past two decades.41 The characterisa-tion of a genetic entity has been made possibleby the recent determination of a genetic dis-ease locus.'2The neurological manifestations of

CADASIL are characteristic and could alsobe found in the affected family members pre-sented in this paper.4 " The age of onset offirst symptoms ranges between 30 and 50.The key feature consists of recurrent stroke-like episodes. The progressive development ofa subcortical dementia after a history of recur-rent stroke-like episodes has been found inmost of the reported cases as well as in all ofour deceased patients. Only one of our livingpatients (mean age 38) had mild neuropsy-chological deficits suggesting that dementiamight be a late symptom. In 20% of thepatients reported previously clinical presenta-tion consisted of a progressive course ofdementia without stroke-like episodes.'0Migraine-like headaches with or withoutaccompanying neurological symptoms are

described as an early symptom of the diseaseand occurred in three of our patients. Finally,the frequency of psychiatric problems, espe-cially depressive mood disorders, seemed tobe increased in the reported patients.

Brain MRI and CT typically show multiplewell delineated subcortical white matterlesions and diffuse leukoencephalopathy.Lesions can also be found in the basal ganglia,thalamus, corpus callosum, and infratentorialbrain structures. Neuroradiological changes

are present in all clinically affected personsbut do not correlate with the degree of neuro-logical impairment.68 0 12 17 No alterations inthe cerebral MRI were found in two offspringof affected members younger than 20 in thepresented family. This finding is consistentwith those reported in the medical literaturethat carriers of the disease might only bedetected at the end of the third decade.'0 12Noteworthy, typical neuroradiological alter-ations can be detected before the onset ofclinical symptoms.The underlying cause of CADASIL is a

characteristic angiopathy of small and middlesized cerebral arteries as shown in one of ourpatients and reported in the medical litera-ture.47 1116 This angiopathy consists of deposi-tion of basophilic granular material replacingthe smooth muscle cells of the media withoutappreciable atherosclerotic alterations or amy-loid depositions. The angiopathic alterationsare predominantly localised in the white matterbut to a lesser extent they are also found inthe basal ganglia, thalamus, leptomeninges,and cortical cerebral and cerebellar arteries.Our immunohistochemistry results show thatthe depositions replace or destroy the smoothmuscle cells of the media in affected cerebralvessels. Due to the lack of necropsy materialwe were not able to perform histopathologicalexaminations of extracerebral organs. Nerveand muscle biopsy of our index patientshowed only non-specific findings at lightmicroscopy. Nevertheless, some specific alter-ations have been described in vessels of thespinal cord,4 16 myocardium," and morerecently, skin and muscle'8 suggesting the pos-sibility that CADASIL is a more generalisedvascular disease. No extracerebral clinicalmanifestations of CADASIL have beendescribed, however, and the reliability ofextracerebral biopsies remains to be estab-lished.The results of the genetic analysis strongly

suggest the linkage of the disorder to theCADASIL locus on chromosome 19q12 asdescribed in two unrelated French families.'2In the presented family, most of the markersspanning the CADASIL interval were infor-mative and no recombinant was found. Thelimited number of informative meiosis avail-able did not allow us to obtain higher lodscores and the negative lod score obtainedwith D19S226 reflects the poor informativityof this marker in this family. In turn, thegenetic homogeneity of CADASIL stronglyincreases the value of the obtained lod scores.Up to now three unrelated families includingours have been reported to show a linkage tothe CADASIL locus on chromosome 19q. Inaddition preliminary data showed a positivelinkage in 12 unrelated families.'6 To ourknowledge there is no report of an unlinkedfamily showing the typical clinical, neuroradio-logical, and histopathological pattern ofCADASIL. All these data form increasing evi-dence that CADASIL is a geneticallyhomogenous disorder and might be morewidespread than presently thought.

Several diseases have been previously

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a clinicopathological and genetic study of a Swiss family 143

mapped on chromosome 19. Among them,familial hemiplegic migraine is linked to thesame locus as CADASIL.'021 The fact thatmany patients with CADASIL report a his-tory of migraine-like episodes suggests simi-larities in the pathogenesis of the twoconditions. The late onset form ofAlzheimer's disease has also been mapped onchromosome 19. Histopathological features ofCADASIL in association with amyloidplaques and neurofibrillary tangles, however,have been reported in only one patient.17Furthermore, recurrent strokes rarely accom-pany Alzheimer's disease and dementia inAlzheimer's disease is of a vascular typewhereas dementia in CADASIL is of a sub-cortical type.22 Finally, the closest markerslinked to CADASIL and Alzheimer's disease,are at a distance of 15 cM, placing theAlzheimer's disease marker outside the inter-val of the gene probably affected inCADASIL." Therefore, the association ofCADASIL and Alzheimer's disease in thereported patient might be coincidental.By contrast with the increasing knowledge

of the clinical and genetic features, the patho-genesis of CADASIL remains unclear. Animmunopathological process has been pro-posed because of perivascular infiltrates insome cases,'7 steroid responsive peripheralblood lymphocyte abnormalities,2' and dys-globulinaemia in one patient whose conditionimproved after plasmapheresis.'0 In oneaffected family, an association of CADASILwith a hereditary protein S deficiency hasbeen reported.24 These conditions have notbeen found in most reports, including ours,and might therefore be coincidental.Consequently, other than correction of vascu-lar risk factors there is no rational treatmentfor CADASIL to date. In one of our patientsaspirin failed to prevent further stroke-likeepisodes.CADASIL turns out to be a syndrome with

distinctive clinical, neuroradiological, andhistopathological features linked to a specificchromosomal locus in several unrelated fami-lies suggesting a genetic homogeneity. Thepresent report supports the increasing evi-dence that CADASIL is a form of hereditarystroke that is not as rare as previouslythought. Brain MRI is probably the most sen-sitive diagnostic test in the early stageswhereas the role of muscle or skin biopsyremains to be established. The pathogenicmechanism leading to the characteristicangiopathy and the reason for the predilectionof cerebral vessels remain unknown.Furthermore, the underlying metabolic,immunological, or haematological causes ofthe disorder remain to be established. Thelocus assignment represents the first step indetermining the defective gene and, hopefully,the identification of a possible gene product.Further research at the molecular level isneeded to provide more insight in the under-standing of CADASIL and lead to the possi-bility of therapeutic as well as prophylacticinterventions.

We thank Professor L Egloff, Institute of Pathology,Kantonsspital Winterthur, Switzerland, for the necropsy speci-mens; Dr C Ozdoba, Department of Radiology, UniversityHospital Bern, Switzerland, for performing MRI; Professor BLkmmle, University Hospital Bern, Department ofHaematology, Switzerland, for examining the coagulation vari-ables, and Dr K Rosler, Department of Neurology, UniversityHospital Bern, Switzerland, for performing the muscle andnerve biopsies.

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3 Mudd SH, Levy HL, Skovby F. Disorders of sulfuration.In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds.The metabolic basis of inherited diseases. New York:McGraw-Hill, 1989:693-734.

4 Stevens DL, Hewlett RH, Brownell B. Chronic familialvascular encephalopathy. Lancet 1977;2: 1364-5.

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6 Sonninen V, Savontaus ML. Hereditary multi-infarctdementia. Europ Neurol 1987;27:209-15.

7 Davous P, Fallet-Bianco C. Demence sous-corticale famil-iale avec leucoencephalopathie arteriopathique: observa-tion clinico-pathologique. Rev Neurol (Paris) 1991;147:376-84.

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24 Guntert D, Hungerbihler H, Hess K. Familiares Syndrommit rezidivierenden Insulten und dementiellerEntwicklung mit subcortikaler mikroangiopathischerLeukoencephalopathie, assoziiert mit ebenfallsfamihiarem Protein-S-Mangel [abstract]. DeutscherNeurologenkongress 1994;PD69.

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and genetic study of a Swiss family.leukoencephalopathy: a clinicopathologicalwith subcortical infarcts and Cerebral autosomal dominant arteriopathy

Arifi and J M BurgunderH H Jung, C Bassetti, E Tournier-Lasserve, K Vahedi, M Arnaboldi, V B

doi: 10.1136/jnnp.59.2.1381995 59: 138-143 J Neurol Neurosurg Psychiatry

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