Dominant Arteriopathy With Subcortical Infarcts and

ISSN: 1524-4628 Copyright © 2005 American Heart Association. All rights reserved. Print ISSN: 0039-2499. OnlineStroke is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514DOI: 10.1161/01.STR.0000185678.26296.38 published online Oct 13, 2005; Stroke and Hugues Chabriat Dominique Hervé, Jean-François Mangin, Nicolas Molko, Marie-Germaine BousserDominant Arteriopathy With Subcortical Infarcts and LeukoencephalopathyShape and Volume of Lacunar Infarcts. A 3D MRI Study in Cerebral Autosomal

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Shape and Volume of Lacunar InfarctsA 3D MRI Study in Cerebral Autosomal Dominant Arteriopathy With

Subcortical Infarcts and Leukoencephalopathy

Dominique Herve, MD; Jean-Francois Mangin, PhD; Nicolas Molko, MD, PhD;Marie-Germaine Bousser, MD; Hugues Chabriat, MD, PhD

Background and Purpose—The shape and exact size of lacunar infarcts have been investigated only postmortem. Recent

imaging techniques based on triangulation and connectivity can now be used for 3D segmentation of cerebral lesions.

The shape and size of lacunar infarcts was investigated using these techniques in 10 cerebral autosomal dominant

arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients.

Methods—We segmented 102 lacunar infarcts on T1-weighted images. The surface of the corresponding set of voxels was

computed as a mesh of triangles. Thereafter, the shape of each lesion in 3D was visually analyzed by 2 investigators.

Results—The volume of lesions ranged from 10.5 to 1146 mm, with 93% of them having a volume ,500 mm; 83% lacunar

infarcts had a spheroid or ovoid shape, but 17% presented as sticks, slabs, or with a complex shape. Lesions with

multiple components appeared larger than the others, and a tail extension was noticed in 13 of 102 lesions.

Conclusions—These results suggest the following: (1) most lacunar infarcts in CADASIL have a volume far below one

third of that of a sphere of 15 mm in diameter, the upper limit currently used for their identification on 2D imaging; (2)

a significant proportion of lacunar infarcts have a shape distinct from the spheroid-ovoid morphology; and (3) lesions

with a complex shape may result from the involvement of the largest small arteries, confluence of ischemic lesions, or

secondary tissue degeneration. The segmentation of lacunar infarcts appears promising to better understand the

pathophysiology of tissue lesions secondary to small vessel diseases. (Stroke. 2005;36:2384-2388.)

Key Words: CADASIL syndrome n diagnostic methods n lacunar infarcts n MRI

Deschambre1 and Durand–Fardel2 were the first to use the

term “lacune” for small subcortical ischemic lesions

caused by the occlusion of cerebral arteries with a diameter

,300 mm. Although isolated lacunar infarcts may have an

embolic origin,3 most of these lesions are associated with

important structural changes (lipohyalinosis and sclerosis) in

the wall of small perforating cerebral arteries.4 The diagnostic

value of the so-called 4 “lacunar syndromes” first reported by

Fisher5–8 in association with these ischemic lesions was

debated after the emergence of computed tomography-scan

and MRI techniques.9,10 Nowadays, lacunar ischemic le-

sions can be easily detected with in vivo imaging, even in

the absence of neurological manifestations (so-called silent

infarcts).

The usual definition of a lacunar infarct as detected on

computed tomography scan and/or MRI is based on both the

location of the lesion and on the size of visible tissue damage.

The maximal lesion diameter of 15 mm from autopsy studies

is usually considered a key criterion for imaging diagnosis.11

However, this definition has important limitations. First, in

vivo and postmortem data are not entirely comparable. In

particular, tissue modifications resulting from the fixation

process and removal of cerebrospinal fluid can change the

size of the cavity on pathological examination.12 Second, the

use of the largest diameter calculated on axial planes on 2D

imaging is appropriate only if these cavities are actually

ball-shaped. If this is not true, such a definition may lead to

diagnostic errors.13 Fisher11 already reported that lacunar

infarcts were frequently round or ovoid in the white matter

but linear with irregularities in the gray matter. Recently,

lacunar infarcts were distinguished from Virchow–Robin

spaces also based on the diameter and shape using 2D MRI

analysis.12,14–16

Recent imaging techniques based on triangulation and

connectivity of imaging data have been developed for 3D

segmentation of circumscribed cerebral regions. We thought

that such methods are now ready for in vivo analysis of the

shape and size of cerebral ischemic lesions, particularly to

reassess the characteristic features of lacunar infarcts. For this

purpose, we chose to analyze the shape and size of these

Received June 15, 2005; final revision received August 3, 2005; accepted August 17, 2005.From the Department of Neurology (D.H., M.-G.B., H.C.), CHU Lariboisiere, Paris; 2INSERM U562 (J.-F.M., H.C.), Service Hospitalier Frederic

Joliot, Commissariat a l’Energie Atomique, Orsay; and Institut Federatif de Recherche 49 (N.M., H.C.), Service Hospitalier Frederic Joliot, Commissariata l’Energie Atomique, Orsay, France.

Correspondence to Hugues Chabriat, MD, PhD, Service de Neurologie, Hopital, Lariboisiere, 3 rue Ambroise Pare, 75010 Paris, France. [email protected]

© 2005 American Heart Association, Inc.

Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000185678.26296.38

2384 by on August 19, 2010 stroke.ahajournals.orgDownloaded from

lesions using digital imaging techniques in 10 patients with

cerebral autosomal dominant arteriolopathy with subcortical

infarcts and leucoencephalopathy (CADASIL), a genetic

disease responsible for ultrastructural changes in the wall of

arteries of diameter ,300 mm and leading to white matter

demyelination and typical lacunar infarcts.17–19

Methods

SubjectsTen symptomatic patients (mean age 4667.3 years) with character-

istic mutations in the Notch 3 gene responsible for CADASIL were

included in the present study. All had previous transient ischemic

attacks and/or completed strokes. Six had a history of attacks of

migraine with aura. Three were demented (Diagnostic and Statistical

Manual of Mental Disorders, 4th edition criteria).

MRIT1-WI were obtained on a 1.5-T MRI system (Signa General Electric

Medical Systems) equipped with gradient hardware allowing #22

mT/m. A standard quadrature head coil was used for radio frequency

transmission and reception of the magnetic resonance signal. Reduc-

tion of head motion was achieved with pillows placed on either side

of the participant’s head and a fixed strap positioned around the

forehead. High-resolution T1-WIs (inversion recovery) were ac-

quired in the axial plane with a spoiled gradient echo sequence (124

slices, 1.2-mm thick, repetition time510.3 ms, echo time52.1 ms,

and inversion time5600 ms) and 24318 cm field of view (resolution

of 0.93730.93731.2 mm).

Segmentation and 3D Analysis of Lacunar CavitiesImage postprocessing was performed using the Anatomist software

dedicated to MRI segmentation of the brain (developed by CEA).

Regions of InterestA single examiner (D.H.), who was blinded to the subject’s clinical

status, performed the selection and delineation of all of the visible

lesions using a dedicated tool. The delineation of the lesion was

based on the local threshold of the T1 signal. All of the hypointense

lesions with both a signal identical to that of cerebrospinal fluid

(CSF) and a diameter .2 mm (this diameter criterion was used to

exclude most of Virchow–Robin spaces14) were selected manually

on axial planes and thereafter delineated and filled using different

colors (automatic processing using the local threshold of the signal).

Only voxels with signal intensities as seen in the ventricles (CSF)

were included when the lesion was not uniform. The limits of each

lesion were then verified on all of the sagittal and coronal slices and

corrected manually if necessary. The k coefficient of interobserver

(D.H. and H.C.) and intraobserver (D.H.) agreement on a subset of

30 lesions was 0.76 and 0.91, respectively.

3D ReconstructionEach object was defined as a set of connected voxels and recon-

structed in 3D using the Anatomist software. To visualize the shape

of the object in 3D, the surface of this set of voxels was computed as

a mesh of triangles in 2 steps. First, the centers of the voxel facets

were linked together in order to get a high-resolution mesh. Then, to

overcome stair artifacts, an optimal decixmation algorithm reducing

the number of triangles and smoothing the mesh was applied. The

goal was to get the best trade-off between accuracy of the surface

representation and the number of triangles (Figure 1).

Volume, Shape, and Cerebral Location of the LesionsThe volume of each lesion was automatically calculated after 3D

reconstruction. The shape of each lesion was then analyzed by visual

inspection using a dedicated tool allowing the rotation of 3D objects

in all of the spatial plans (from the Anatomist software). Two

examiners (D.H. and H.C.) classified the lesions in 4 categories

according to their global aspect on visual analysis: slab, stick,

multiple components, or ovoid/spheroid (Figure 2). The category

was defined for each lesion after agreement between the 2 observers.

In addition, the presence or absence of a tail extension was assessed

for each lesion (evidence of a main component among the 4 previous

categories associated with a filiform extension).

The exact lesion location was also defined as being either in the

white matter (internal capsule, external capsule, periventricular white

matter, pons, or centrum semiovale) or in the subcortical gray matter

(thalamus, caudate nucleus, putamen, or pallidum).

Statistical AnalysisA descriptive analysis of parameters derived from all of the 3D

reconstructed objects was first obtained (volume, shape, and loca-

tion). Then, relationships between the shape of lacunar infarcts and

their volume and/or location were analyzed using ANOVA or x2

tests. Statistical analysis was performed with the SAS package

(Abacus Concepts Inc.) using a level of significance ,0.05.

Results

Descriptive Analysis of MRI Segmented Lesions

VolumeWe segmented 102 lacunar infarcts. The number of lesions

ranged from 1 to 16 for each patient. The volume of segmented

lesions ranged from 10 to 1146 mm (median, 104; mean,

188622). Figure 3 illustrates the number of lesions according

to their size in the whole sample of patients. A total of 93%

Figure 1. Illustration of the mesh of tri-angles obtained by the software used forsegmentation of lacunar infarcts before(A: no color; B: with color) and aftersmoothing (C and D: final object ana-lyzed by the observer).

Figure 2. The shape of the lesions wascategorized in 4 types illustrated on thisfigure: slab, stick, multiple components,or ovoid/spheroid. The classification wasmade after agreement between 2 exam-iners who were blinded to the originalMRI data.

Herve et al Shape and Volume of Lacunar Infarcts in CADASIL 2385


of lacunar infarcts had a volume ,500 mm, and more than

half of them were ,100 mm.

Shape and Tail ExtensionAmong the segmented lesions, most of lacunar infarcts

(83.3%) were ovoid or spheroid. Three lesions were shaped

as sticks (2.9%), 9 were shaped as slabs (8.8%), and the last

5 had multiple components (4.9%).

Figure 4 illustrates the discrepancy between the shape of

lesions as detected on 2D imaging and that observed on 3D

imaging; it also shows the different shapes of lacunar infarcts,

which can be detected in a single subject. Among the 102

segmented lesions, 13 presented with a tail extension. In an

illustrative case (Figure 5), the tail extension of a segmented

cavity followed the direction of axonal tracts within the white

matter.

Volume and Number of Lesions: RelationshipsWith Location and ShapeIn the present series, 62 lesions were detected in the white

matter and 40 in the gray matter. The volume of lacunar

infarcts was larger in the white matter than in the gray matter

(2276260 versus 110691 mm3, respectively; P50.008).

ANOVA showed a significant interaction between the shape

and the volume of ischemic lesions. Lacunes with complex

shape (multiple components; 5286239 mm3) appeared much

larger than ovoid/spheroid lesions (167620 mm3), slab lesions

(239660 mm3), or stick lesions (50614 mm3; P,0.01).

However, the frequency of the different shapes did not

significantly differ between the white matter and gray matter

(P50.47). In addition, the number of cavities with a tail

extension did not significantly differ in the white matter and

the gray matter (17% versus 6%, probability not significant).

Patients with multiple components lesions had more ischemic

lesions (mean, 1266) than patients without such complex

lesions (mean, 866), although this difference did not reach

statistical significance (P50.2).

Figure 3. Frequency of ischemic lesions according to their vol-ume in the sample of 10 CADASIL patients. Note that 93% ofischemic lesions were ,500 mm and that more than half ofthem were ,100 mm.

Figure 4. 3D and 2D presentation of 6lacunar cavities analyzed in the samepatient. Each 3D segmented cavity ispresented in different visual angles.

2386 Stroke November 2005


DiscussionThis is the first study showing that 3D segmentation of small

infarctions is possible and that it allows a detailed in vivo

analysis of the shape and volume of lacunar cavities in the

brain. Using this technique, in 10 CADASIL patients, we

found the following: (1) most lacunar infarctions in this

disorder had a volume far ,500 mm3; (2) nearly 1 of 5 of

these lesions did not have an ovoid or spheroid shape; and (3)

wallerian degeneration was probably involved in the cavita-

tion of some of these ischemic lesions in the white matter.

The volume of 500 mm3 corresponds with less than one

third of the volume of a sphere of 15-mm diameter, the upper

limit usually chosen for the definition of a lacunar infarct on

2D imaging (4/3 pR351767 mm3). In the present study, the

largest cavity corresponded to only two thirds of this refer-

ence volume. This is in line with postmortem results obtained

by Fisher11 who reported that most infarctions secondary to

diseases of perforating arteries had a diameter ,4 mm (and,

therefore, a maximal volume of 267 mm3) and with a recent

microanatomic study of lenticulostriate arteries showing that

the maximal volume irrigated by perforator arteries with a

diameter ,350 mm was 508 mm3.20 Such data suggest that

the classical limit of 15 mm in diameter for the definition of

lacunar cavity on 2D imaging is overestimated and that

ischemic cavities .500 to 1000 mm may have a different

origin or involve arteries with larger trunks.

In the present study, we found that the shape of lacunar

cavities was most often ovoid or spheroid. However, 17% of

lesions presented with a different morphology. The visual

analysis of different lesions performed in 1 typical case

demonstrated that the 2D analysis can lead to misinterpreta-

tion of the actual shape and size of these lesions. Elsewhere,

we found a significant relationship between the shape and

volume of the segmented lacunes. Cavities with complex

shapes (multiple components) appeared much larger than

ovoid/spheroid, slab, or stick lesions. The trend toward more

ischemic lesions associated with complex cavities suggests

that the latter may result from the confluence of multiple

Figure 5. On 2D imaging (A), 2 lesionsare detected. One lesion is round (whitearrow), the other is oblong (yellow arrow)and observed within the corpus callo-sum. The 3D reconstruction (B) enablesthe visualization of the right hemisphere,the corpus callosum (yellow), and thereconstructed cavity (orange). Note thatthe lesions appearing separated on 2Dimaging are in continuity on 3D imaging.The ovoid lesion actually had a tailextension through the corpus callosumparallel to axonal tracts at this level.

Herve et al Shape and Volume of Lacunar Infarcts in CADASIL 2387


ischemic cavities. Alternatively, the involvement of perforat-

ing arteries with larger trunks and more branches may also be

responsible for larger and irregular tissue necrosis.

We detected the presence of a tail extension in 13% of

the segmented lacunar cavities, whatever their basic shape.

The observation of a typical ischemic lacunar lesion with a

long tail extension crossing the corpus callosum in an

illustrative case suggests that secondary degeneration of

axonal bundles originating from the lesion may be sometimes

involved in the morphogenesis of lacunes. This may also

explain the larger volume of cavities detected in the white

matter compared with those located in gray matter. Secondary

wallerian degeneration has been repeatedly observed on

T2-weighted MRI in the corticospinal pathway remote from

ischemic lesions,21–23 and recent diffusion tensor imaging

studies revealed that this phenomenon can result in more

or less severe microstructural tissue loss.24,25 These tissue

changes might be involved in the cavitation of ischemic

lesions particularly in the white matter, as already observed in

the development of cavities in syringomyelia.26

There are several limitations in the present study: (1) the

imaging analysis was performed only in a small number of

CADASIL patients; (2) we chose to analyze only areas with

an magnetic resonance signal identical to that of CSF on

T1-weighted images, which may cause an underestimation of

the exact size of ischemic lesions: lacunar infarctions are

most often observed as focal areas of complete tissue necrosis

with secondary cavitation (type 1a of lacune)27 but can also

correspond with lesions with incomplete tissue loss and

limited or absent cavitation (type 1b or incomplete small

infarct)28,29; and (3) because the resolution was '1 mm, we

cannot exclude partial volume effects altering the estimation

of the shape and exact volume of the ischemic lesions.

However, despite of these limitations, we think that the

present results are promising. In vivo 3D imaging of lacunar

infarcts may be helpful in future for the following uses: (1)

additional categorization of small artery diseases; (2) to

evaluate the importance of secondary degenerative processes

associated with small deep infarcts; and (3) to refine the

classical 2D criteria used in clinical practice for the definition

of lacunar infarctions.

AcknowledgmentsWe acknowledge Drs Christian Stapf and Christophe Tzourio fortheir helpful comments concerning this manuscript.

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Dominant Arteriopathy With Subcortical Infarcts and