Brain (1991), 114, 761-774

PERIVENTRICULAR LESIONS IN THE WHITE MATTER ON MAGNETIC RESONANCE IMAGING IN THE ELDERLY A MORPHOMETRIC CORRELATION WITH ARTERIOLOSCLEROSIS AND DILATED PERIVASCULAR SPACES by J. C. VAN SWIETEN, 1 J. H. W. VAN DEN HOUT, 3 B. A. VAN KETEL, 1 ' 2 A. HIJDRA, 4 J. H. J. WOKKE 1 and J. VAN GUN 1 (From the University Departments of Neurology, Pathology and Radiology, Utrecht, and the Department of Neurology, Academic Medical Centre, Amsterdam, The Netherlands)

SUMMARY Magnetic resonance imaging (MRI) was performed postmortem on the brains of 40 patients aged over 60 yrs who had died from causes other than brain disease. Periventricular lesions of increased signal intensity on T2-weighted images, graded as moderate or severe, were found in 10% of the patients in the age group between 60 and 69 yrs, and in 50% between 80 and 89 yrs. Macroscopic and microscopic whole-brain sections were studied in 19 brain specimens (8 with normal white matter, 4 with moderate lesions and 7 with severe lesions of the white matter on MRI). The presence or absence of periventricular lesions on MRI correlated well with the severity of demyelination and astrocytic gliosis. Demyelination was always associated with an increased ratio between wall thickness and external diameter of arterioles (up to 150 /un). A variable degree of axonal loss in Bodian-stained sections was present in the white matter of all brains with demyelination. Dilated perivascular spaces were found and studied morphometrically in 9 brain specimens; their presence correlated strongly with corrected brain weight, but incompletely with demyelination and arteriolosclerosis. Our findings suggest that arteriolosclerosis is the primary factor in the pathogenesis of diffuse white matter lesions in the elderly. This is soon followed by demyelination and loss of axons, and only later by dilatation of perivascular spaces.

INTRODUCTION

The improvement of imaging techniques of the brain in the last decade has drawn attention to the occurrence of diffuse lesions of the white matter, usually termed periventricular leukoencephalopathy (Valentine et al., 1980; Goto et al., 1981; Loizou et al., 1981). Patients with symmetrically diminished density of the white matter on computed tomography (CT) were often found to have some degree of cognitive impairment or even manifest dementia, or focal neurological signs (Steingart et al., 1987a, b; Gupta et al., 1988). Magnetic resonance imaging (MRI) has proved more sensitive than CT in detecting these white matter lesions (George et al., 1986; Erkinjuntti et al., 1987). The hypodense lesions on CT correspond with areas of increased signal intensity in T2-weighted MR images. Periventricular and focal lesions on MRI have been Correspondence to: Dr J. C. van Swieten, Department of Neurology, University Hospital, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. © Oxford University Press 1991

762

J. C. VAN SWIETEN AND OTHERS

recognized particularly in patients with stroke (Awad et al., 1986a; Gerard and Weisberg, 1986), in patients with vascular dementia (Hershey et al., 1987), and in subjects with risk factors for stroke (Awad et al., 1986a; Gerard and Weisberg, 1986; Lechner et al., 1988). The extent of the periventricular lesions may range from narrow rims to involvement of the entire white matter, with the exception of the subcortical U fibres. Focal lesions in the deep white matter may be single, multiple or confluent. Microscopic study of brains of patients with leukoencephalopathy on CT showed diffuse demyelination of the white matter, multiple infarcts in the basal ganglia and arteriolosclerosis (Caplan and Schoene, 1978; Rosenberg et al., 1979; De Reuck et al., 1980). These findings correspond with the classical description of subcortical arteriosclerotic encephalopathy or Binswanger's disease (Binswanger, 1894; Olszewski, 1962). On neuropathological study of single or few cases investigated by MRI, large periventricular lesions of increased signal intensity in T2-weighted images corresponded with extensive demyelination, cystic lacunes, and arteriolosclerosis (Kinkel et al., 1985; DeWitt et al., 1987; Revesz et al, 1989). In postmortem MRI studies of a series of brains with slight lesions of the white matter, dilatation of perivascular spaces was proposed as the microscopic correlate (Awad et al., 1986&; Kirkpatrick and Hayman, 1987), whereas others found true infarcts with necrosis, axon loss and gliosis (Braffman et al., 1988; Marshall et al., 1988). Both dilatation of perivascular spaces and lacunar infarction often occur in association with hypertension, and are frequently seen in the same brain specimens. In the neuropathological literature about Binswanger's disease, the focal abnormalities accompanying the diffuse loss of myelin have mostly been described as cystic infarcts (Olszewski, 1962; Caplan and Schoene, 1978; De Reuck et al., 1980), and only a few studies mentioned dilatation of perivascular spaces (Garcin et al., 1960). Only recently renewed attention has been paid to the distinction between these two abnormalities (Poirier and Derouesne", 1985; Benhaiem-Sigaux et al., 1987). In the present study of a series of 40 brains of patients over 60 years of age, we tried to elucidate the pathological correlates of white matter lesions on MRI, with actual measurement of arteriolar thickening and of the number and size of dilated perivascular spaces. MATERIAL AND METHODS Patients MRI examination was performed on the brains of 40 consecutive patients over the age of 60 yrs who came to autopsy. We excluded only patients in whom brain disease contributed directly to death or in whom brain surgery had been performed. Patients with dementia or epilepsy were not excluded. The cause of death was cardiovascular disease in 23 patients, infectious disease in 9, cancer in 6, and miscellaneous in 2 patients. The mean age of the patients was 76.2 (SD±8.1)yrs; 19 were female and 21 male. Thirteen patients had been cared for in psychogeriatric hospitals. One patient had been treated by ventriculoperitoneal shunting for suspected normal pressure hydrocephalus, but without subsequent improvement. MRI technique and assessment The brains had been fixed in 4% formaldehyde solution for 1—68 days. They were examined in a cylindrical container filled with formalin, with the convexity of the hemispheres lying on the bottom of the container. The brain was orientated in such a way that the optic chiasm and brainstem were exactly in the sagittal scanning plane. MRI was performed with a 1.5 T Philips gyroscan. First, a sagittal scanogram

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

763

was produced. Then images were acquired in the axial plane with a slice thickness of 7 mm and a slice increment of 1.4 mm in all brains. Multiple slice spin-echo (SE) sequences were performed with a repetition time (TR) of 2000 ms and an echo time (TE) of 50 and 100 ms, producing a T2-weighted image. Identically orientated slices in the axial plane were acquired with an inversion recovery (IR) sequence, in 37 of the 40 brains. A TR of 1500 ms, inversion time (TT) of 575 ms and a TE of 30 ms were used, producing a heavily T,-weighted image. In this fashion, exact comparison of T, and T2-weighted images was possible. Coronal MRI slices of severe lesions were made in a few cases to localize these lesions more accurately. Two investigators judged the MRI scans for the presence and degree of periventricular lesions in the white matter, as evident from increased signal intensity in T2-weighted images or a low signal-intensity in the heavily Tj-weighted images. The MRI scans were classified in 3 groups: normal white matter, moderate periventricular lesions or severe periventricular lesions. A hyperintense rim around the tip of the frontal horns was present in all brains, and was not considered abnormal. Moderate periventricular lesions involved only part of the anterior or posterior white matter. Lesions were regarded as severe if these extended from the frontal or occipital horns to the corticomedullary junction, involving all or most of the anterior or posterior white matter. In addition, the signal intensities of white and grey matter were compared in the T r weighted images, and were correlated with the duration of formalin fixation. Macroscopic observations and light microscopy Two of the 40 brains were excluded from further analysis. In 1 case with a history of trauma there were lesions in the frontobasal white matter on MRI which corresponded with areas of myelin loss on microscopic study. In 1 other case, with severe white matter lesions on MRI, there was diffuse involvement of the white matter by a non-Hodgkin lymphoma. From the remaining 38 brains, we selected 19 brain specimens for further neuropathological and quantitative investigation. All specimens with severe periventricular lesions were selected. Brain specimens with normal white matter or with moderate lesions were selected to correspond with the age of the patients with severe periventricular lesions. Consecutive whole-brain, paraffin-embedded slices of 15 tun thickness were cut through the anterior part of the frontal horns and through the occipital horns, and were stained with haematoxylin-eosin, with Weil's stain and Luxol fast blue for myelin, with phosphotungstic acid haematoxylin (PTAH) for gliosis, with periodic acid-Schiff (PAS) for senile plaques, with elastica van Gieson for arteriolosclerosis, and with Congo red for amyloid. White matter specimens of 1 cm XI cm were taken from the region anterolateral to the frontal horns, up to the subcortical region, and were stained for axons with Bodian. The white matter on Weil-stained sections was assessed by 2 experts in neuropathology, independently of each other and without knowledge of the MRI findings. Three groups were distinguished: normal white matter (group A), moderate demyelination (group B), and severe demyelination (group C). Demyelination in frontal or posterior coronal sections was judged as moderate if the pallor on Weil staining involved only part of the white matter, and as severe if the pallor extended as far as to the subcortical U fibres. An enlarged perivascular space is defined as a round regular cavity, the wall consisting of gliosis, and with a patent arteriole. Such spaces can be reliably distinguished from an artefactual space, caused by postmortem retraction of brain parenchyma from the adventitia of the arteriole. A lacunar infarct is recognized as an irregular cavity with dense astrocytic gliosis in the wall; it is caused by occlusion of a small penetrating artery (Fisher, 1965; Kappelle and van Gijn, 1986). Senile plaques in the cerebral cortex were counted in 30 low power microscopic fields taken from the frontal, temporal and parietal lobes. Amyloid angiopathy was rated as absent or present. Quantitative analysis of arteriolosclerosis Arteriolosclerosis consists in proliferation of the intima, degeneration of the internal elastic lamina, and hypertrophy with hyalinization of the tunica media, together resulting in thickening of the wall and narrowing of the lumen (Woollam and Millen, 1968). Camera lucida drawings at magnification X40 were made of samples of arterioles, up to 150 /un, in the white matter of frontal and parietal sections, after elastica van Gieson staining (mean sample 45 arterioles, range 11 — 107 arterioles). After having coded the samples to avoid bias, we measured from these drawings the diameter of the cross-sectioned arterioles and their wall thickness, by means of an IBM-PC with graphic tablet. In case of obliquely sectioned arterioles, the smallest diameter and wall thickness were measured. For each brain specimen, the mean ratio between

764

J. C. VAN SWIETEN AND OTHERS

the thickness of the wall and the total diameter of the arteriole was used as a measure for the severity of arteriolosclerosis. This ratio cannot exceed the value of 0.5, in which case the lumen is occluded. The accuracy of the sampling method was determined by measuring all visible arterioles in frontal and parietooccipital sections of 2 brains (80 and 96 arterioles) and by subsequently comparing the results with those of previous samples from the same specimen (63 and 70 arterioles, respectively). No marked differences were found between the mean ratios (0.23 vs 0.22, and 0.27 vs 0.25). Dilatation of perivascular spaces (DPS) was measured in the same manner: the calculated areas of all DPS were added together and expressed in mm2 per cm2 white matter. RESULTS

Frequency of MRI lesions in relation to clinical features Of the 38 MRI scans, the periventricular white matter had a normal signal intensity of T2-weighted images (fig. 1A) in 25 brain specimens (mean age 73.8 yrs±7.2 SD).

FIG. 1. Postmortem in vitro T2-weighted MRI scan of formalin-fixed brain specimens with normal white matter (A), periventricular lesions of increased signal intensity involving only part of the white matter (B), and severe periventricular lesions extending to the subcortical region (c) (TR = 2 s, TE = 5OX1CT3 s).

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

765

Moderate lesions around the frontal and/or occipital horns (fig. 1B) were present in 6 cases (mean age 80.0 yrs ± 6.6 SD), and severe periventricular lesions (fig. lc) were seen in 7 brain specimens (mean age 82.4 yrs ± 8.5 SD). Focal lesions in the basal ganglia and deep white matter or in the cortex were found equally often in these three groups. A reversal of grey and white matter signal intensities occurred on T,-weighted images between 24 and 48 h of formalin fixation. A good correlation was found for the severity of lesions between the axial and the coronal plane. The frequency of white matter lesions in different age groups is shown in Table 1. In the group aged between 60 and 69 yrs, normal white matter was found in 9 of 10 patients (90%), whereas only 6 of 12 patients (50%) aged between 80 and 89 yrs showed normal white matter on MRI. Dementia had been diagnosed in 3 of the 25 patients with normal white matter, 1 of the 6 patients with moderate lesions, and 5 of the 7 patients with severe lesions. A history of hypertension was equally frequent in the three groups. TABLE 1.FREQUENCY OF PERIVENTRICULAR LESIONS WITH INCREASED SIGNAL INTENSITY IN T,-WEIGHTED MR IMAGES IN DIFFERENT AGE GROUPS ?90

No. 10 13 12 3

Moderate lesions 0 3 2 1

Severe lesions 1 1 4 1

Percentage with lesions 10 31 50 67

Total

38

6

7

34

Macroscopic appearance Of the 19 brain specimens selected for further neuropathological investigation, 9 had normal white matter at MR imaging, 3 had moderate lesions, and all 7 brains with severe periventricular lesions were included {see Methods). All necrotic lesions that were found on macroscopic study of one or both hemispheres had already been identified by MR imaging. Also, 2 lacunar infarcts in the pons had been well visualized by MRI. Three groups were distinguished according to the staining for myelin. Group A were 8 cases with white matter of normal appearance (fig. 2A); group B were 4 brains with moderate demyelination (fig. 2B); group C were 7 cases with severe demyelination on one or both sections, in the frontal and in the posterior region (fig. 2c). The extent of periventricular lesions on MRI correlated well with the severity of demyelination on Weil sections. Demyelination on Weil-stained sections was graded as 1 deg more severe than MRI lesions in 2 brains, and 1 deg less severe than MRI lesions in 1 brain. Microscopic findings A small zone of demyelination with astrocytic gliosis adjacent to the ventricle was found in all brains. This zone corresponded to the rim of high signal intensity around the ventricle on the MRI scans. Moderate or severe demyelination on Weil sections was microscopically diffuse and sometimes patchy, with astrocytic gliosis. In all brains with severe demyeUnation, axonal swelling and axonal loss was present in variable degree

766

J. C. VAN S W I E T E N AND O T H E R S

Fw. 2. Corona] whole brain sections through the frontal horns with normal white matter (A), periventricular myelin pallor involving only part of the white matter (B), and periventricular myelin pallor extending to the subcortical U fibres (Weil stain) (c).

/

in Bodian-stained sections. A lacunar infarct (fig. 3A) or a cortical infarct was found in 3 of the 6 brains with severe demyelination, and 5 of the 7 brains with normal white matter. Senile plaques, more than 1 per microscopic field, were found in 8 brain specimens, 3 of which also had severe demyelination of the white matter. Amyloid angiopathy, found in 5 cases, was strongly associated with senile plaques. There was no relation between the number of senile plaques and amyloid angiopathy and the severity of demyelination (Table 2). Of the 5 brains of patients with severe demyelination and dementia, 4 showed no cortical infarcts, and 2 of these showed no or only a few senile plaques. Quantitative analysis We measured the wall thickness of nearly 1000 arterioles (less than 150 /un in diameter) in the white matter in the frontal and parietal sections (fig. 3B). The mean diameter of the arterioles in group A was 45.2 /tin ±3.8 SD, in group B 49.8 /*m±6.0 SD, and in group C 55.5 /tm±3.5 SD. All 8 brain specimens with normal white matter had mean arteriolar thickness ratios below 0.20 and all 11 specimens with moderate or severe demyelination had ratios above 0.20 (Table 2, fig. 4). The difference in ratios between the three groups, calculated by means of the Kruskall-Wallis test was statistically significant (P < 0.01). This difference is mainly due to a difference between groups A and B.

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

FIG. 3. A, small lacunar infarct with irregular borders and surrounding gliosis, an occluded artenole, and lipidloaded macrophages (PTAH-stain). B, fibrohyaline thickening of aneriolar walls (elastica van Gieson-stain). c, dilated perivascular space whhregularborders without gliosis, a patent artenole with thickening of its wall (PTAH-stain). Bars = 200 jim.

768

J. C. VAN SWIETEN AND OTHERS TABLE 2. MORPHOMETRIC ANALYSIS OF ARTERIOLES IN THE WHITE MATTER IN RELATION TO DEMENTIA, DEMYELINATION OF WHITE MATTER AND PRESENCE OF INFARCTS, DILATED PERIVASCULAR SPACES, SENILE PLAQUES AND AMYLOID ANGIOPATHY No. Dementia Ratio SD DPS Normal white matter on Weil-stained sections 1 0.17 0.04 2 0.18 0.05 3 0.15 0.05 4 0.17 0.04 5 0.16 0.04 6 0.17 0.05 7 + 0.19 0.06 8 0.18 0.05 Moderate demyelination of the white matter 9 + 0.25 0.06 + 10 0.25 0.05 + 11 0.22 0.06 12 + 0.27 0.07

Infarcts

Plaques

Amyloid

c LL L C

L L LL

Severe demyelination of the white matter

13 14 15 16 17 18 19

0.26 0.29 0.26 0.24 0.23 0.25 0.24

0.06 0.06 0.06 0.06 0.05 0.06 0.06

LL L+C C

DPS = dilatation of perivascular spaces; L =• lacunar infarct; C = cortical infarct.

Dilated perivascular spaces (DPS, fig. 3c) were present in 6 of the 7 brain specimens with severe demyelination and arteriolosclerosis, in 2 of the 4 brains with moderate demyelination and arteriolosclerosis, and in 1 brain specimen with normal white matter and normal arterioles (Table 2). The number of DPS and sum of their measured areas per cm2 varied widely, with an extremely high number of DPS in 2 brain specimens (fig. 5). The presence and degree of DPS in the total group correlated well (r = 0.63, P < 0.01) with lower relative brain weight, which is the actual brain weight divided by the reference brain weight according to age and sex (Dekaban and Sadowsky, 1978).

DISCUSSION

We found a strong correlation between lesions of increased signal intensity in the white matter on T2-weighted images on MRI and the presence of demyelination and gliosis in 19 brain specimens. Demyelination of the white matter was always accompanied by arteriolosclerosis, whereas normal arterioles were always found in brains with normal white matter. Dilatation of perivascular spaces (DPS) was strongly but incompletely correlated with demyelination and arteriolosclerosis. The presence of amyloid angiopathy and senile plaques in the grey matter was not related to demyelination of the white matter.

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

769

0.30cd

isi u t! c

cd

•g"5 °- 2 0 .2 T3 CO

a: O.1O-L Normal white matter (n=8)

Severe Moderate demyelination demyelination (n=7) (n=4)

FIG. 4. Correlation of degree of arteriolosclerosis, expressed as the ratio of wall thickness to external vessel diameter of arterioles, with the presence and severity of demyelination in Weil-stained sections in 19 brain specimens.

110 —

100c

8 90-

0.2 0.4 0.6 0.8 Area of DPS/area of WM

FIG. 5. Sum area of dilated perivascular spaces (DPS) in mm2 per unit white matter (WM) area in cm2 correlated with relative brain weight (actual brain weight as a percentage of reference brain weight according to sex and age (Delcaban and Sadowsky, 1978). This correlation was statistically significant. Normal white matter (O); moderate demyelination (A); severe demyelination ( • ) .

These findings are in favour of the notion that extensive demyelination and/or gliosis is the pathological correlate of periventricular white matter lesions seen on MRI, and they also suggest that arteriolosclerosis precedes and probably causes the demyelination and loss of axons, and that dilatation of perivascular spaces is a secondary event. The presence of areas of hyperintensity on MRI did not completely correspond with the degree of demyelination in Weil-stained sections of 3 brains. The most probable explanation is that MR images were mostly made in the axial plane, whereas the Weilsection were made in the coronal plane; nevertheless, in a few other cases lesions in the coronal MRI plane corresponded well with similar lesions in the axial plane. Some other limitations of the present study have to be pointed out. First, the frequency of white matter lesions in our study is not representative for the general population, because

770

J. C. VAN SWIETEN AND OTHERS

a large number, namely 13, of brains were obtained from psychogeriatic hospitals. The frequency of the lesions differed also from that in other studies (George et al., 1986; Gerard and Weisberg, 1986), because only large lesions were considered suitable for comparison with slices in the frontal plane. Secondly, the calculated ratios for wall thickness of arterioles should not be considered as absolute values, since contraction by fixation changed the real proportions. In other studies, a correction for calculating the true thickness of the tunica media was carried out (Okeda, 1973), or injection of barium sulphate under high pressure into the cerebral vessels was performed (Ross Russell, 1963; Cook and Yates, 1972). Nevertheless, the mean ratios of the arterioles in these 19 brains could be compared with each other, which resulted in a sharp cut-off point with regard to arteriolar size between brains with or without demyelination. The same limitation applies to the summed area of dilated perivascular spaces. Although these spaces could be histologically well differentiated from artefactual spaces as a result of retraction (Woollam and Millen, 1968), they were probably of smaller size in vivo. We found lesions with increased signal intensity of the white matter on the T2-weighted images in nearly every brain with demyelination and gliosis. The origin of the changes in signal intensity, i.e., in T, and T2 relaxation times and proton density, cannot be attributed to 'demyelination' per se. Astrocytic gliosis has proven to result in a prolongation of the relaxation time T, and a minor change in T2 (Barnes et al., 1988), and it has been argued that MRI changes seen in multiple sclerosis and Binswanger's disease are caused by increased extracellular water content as well as astrocytic gliosis. In accordance with ReV6sz et al. (1989), we consider that the MRI lesions in our formalin-fixed brains are the result of increase of extracellular space due to demyelination, together with gliosis. CT scanning has proved less sensitive than MRI in demonstrating white matter lesions in series in which it was compared with postmortem studies of white matter (Lotz et al., 1986; Rezek et al., 1987; Janota et al., 1989). Other studies in which MRI scanning in a series of brains of elderly patients was compared with neuropathological investigation resulted in conclusions different from ours. In some of these studies periventricular or focal lesions in the white matter were attributed to DPS or lacunar infarcts (Awad et al., 1986£>; Braffman et al., 1988), and not primarily to demyelination. But others, like ourselves, explained even punctate lesions around the frontal horns in all investigated brains as demyelination (Sze et al., 1986). Another finding we could not confirm is a putative concurrence of Alzheimer changes or amyloid angiopathy with demyelination (Gray et al., 1985; Brun and Englund, 1986). In our study, we found infarcts in some but not all patients with demyelination and arteriolosclerosis. Binswanger originally described white matter atrophy without focal lesions in 8 patients with slowly progressive dementia followed by focal neurological deficits. He considered this to be a clinical and pathological entity (Binswanger, 1894). According to Binswanger, the disease should be differentiated from the so-called 'arteriosklerotische Hirndegeneration', multi-infarct dementia in present terms, by the absence of focal lesions. However, this distinction became less clear by Alzheimer's description of focal lesions in similar cases of diffuse demyelination (Alzheimer, 1898). In more recent studies (Caplan and Schoene, 1978; Babikian and Ropper, 1987), the occurrence of minor strokes became even a conditional element in the diagnosis of Binswanger's disease. In that view, Binswanger's disease and the lacunar state frequently

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

771

coexist and in their pure forms they represent only the two extremes of a pathophysiological continuum. It might also be argued, however, that in Binswanger's disease, whether fully developed or not, the brunt of the disease is borne by small arterioles, below 150 /xm in size, whereas lacunar infarcts are usually caused by occlusion of larger penetrating arteries, between 400 fim and 1 mm. Our method of measuring relative wall thickness correlated exactly with the presence or absence of demyelination. The sharp distinction in arteriolar size between brains with and without demyelination suggests that arteriolosclerosis is soon followed by demyelination; otherwise one would expect to find some brains with arteriolosclerosis but without demyelination. Thickening of walls of cerebral arteries with diminution in lumen has been found with increasing age and hypertension (Ross Russell, 1963; Cook and Yates, 1972). In all postmortem cases of Binswanger's disease, arteriolosclerosis, that is, thickening of arteriolar walls with hyalinosis of the tunica media, has been found (Olszewski, 1962; Caplan and Schoene, 1978). In two studies a semiquantitative correlation was found between arteriolosclerosis and demyelination (Goto et al., 1981; Lotz et al., 1986), which is in accordance with our results. Does demyelination precede loss of axons or do nerve fibres disappear as a whole? R6vesz et al. (1989) emphasized that in fully developed Binswanger's disease there is a more or less equal loss of axons and myelin, and that the term demyelination is therefore inappropriate. But we found a variable degree of axonal swelling and axon loss within the group with severe demyelination, which suggests that demyelination may indeed be the primary process. We found that the presence and severity of DPS were strongly correlated with arteriolosclerosis and with loss of brain weight after correction for age. Dilatation of perivascular spaces, together with loss in brain weight, was already mentioned in studies of'arteriosklerotische Hirndegeneration' (Binswanger, 1894; Alzheimer, 1898). Other authors described these spaces in cases of Binswanger's disease (Nissl, 1920; Garcin et al., 1960). Although DPS should be distinguished from lacunar infarcts (Marie, 1901), they have frequently been found in brains of hypertensive patients (Cole and Yates, 1967). The pathogenesis of these spaces is disputed. The hypothesis of unfolding of small arteries and high pressure pulsation as a cause of DPS, as proposed by Hughes (1965), is supported by the coexistence of arteriolosclerosis in many patients (Cole and Yates, 1967). Ball (1989) defended the view that cortical atrophy was the primary factor, followed by loss of axons and myelin, and finally by formation of DPS 'ex vacuo'. He did not count arteriolosclerosis as a factor. But in contrast to Ball's hypothesis, we found demyelination and arteriolosclerosis in 8 of 9 brains with DPS, whereas senile plaques and amyloid angiopathy were found as often in brains with DPS as in those without. We therefore suggest that demyelination, and not cortical cell loss, precedes the development of DPS. The loss of nerve fibres is most probably the result of arteriolosclerosis with chronic ischaemia (De Reuck et al., 1980). The wide range of severity of DPS indicates a gradual process of demyelination and subsequent cerebral atrophy, which might explain that moderate demyelination in 3 brains and severe demyelination in 1 brain had not yet resulted in significant cerebral atrophy and development of DPS. This explanation does not exclude a more direct role of arterioles in the development of dilated perivascular spaces by pulsatile forces. Do the findings in our series represent Binswanger's disease, or degrees of it? Diffuse

772

J. C. VAN SWIETEN AND OTHERS

white matter involvement in an elderly patient can be associated with other pathological conditions, such as a diffuse non-Hodgkin lymphoma which was found in one of the present cases (Hochberg and Miller, 1988). Moreover, diffuse white matter lesions in a demented patient do not exclude Alzheimer's disease. Finally, dementia in a patient with periventricular lesions and enlarged ventricles is sometimes, but not always, caused by a normal pressure hydrocephalus (Caplan and Schoene, 1978; Thomsen et al., 1986). Two patients in our series had dementia and severe white matter lesions on postmortem MRI but no infarcts or Alzheimer changes in the cortex, and can be considered as 'pure' examples of Binswanger's disease. Our results therefore confirm previous reports that diffuse demyelination can be the only cause of dementia.

ACKNOWLEDGEMENTS We are grateful to Dr R. Ravid, of the Netherlands Brain Bank Amsterdam, for providing us with a number of brain specimens, to Mr H. Sakkers for neuropathological staining of brain specimens, to Mr H. Veltman for his help with quantitative investigation of blood vessels, to Dr J. C. van Latum and Dr P. R. Bar for advice on statistics and other comments, and to Dr E. F. M. Wijdicks for reviewing the manuscript. This investigation has been supported by the N. W. O. Council for Medical Research (grant no. 716.006).

REFERENCES ALZHEIMER A (1898) Neuere Arbeiten fiber die Dementia senilis und die auf atheromatoser Gefasserkrankung basierenden Gehirnerkrankungen. Monatschrifi fUr Psychiatrie und Neurologie, 3, 101 — 115. AWAD IA, SPETZLER RF, HODAK JA, AWAD CA, CAREY R (1986a) Incidental subcortical lesions identified

on magnetic resonance imaging in the elderly. 1. Correlation with age and cerebrovascular risk factors. Stroke, 17, 1084-1089. AWAD IA, JOHNSON PC, SPETZLER RF, HODAK JA (1986b) Incidental subcortical lesions identified on

magnetic resonance imaging in the elderly. U. Postmortem pathological correlations. Stroke, 17, 1090-1097. BABIKIAN V, ROPPER AH (1987) Binswanger's disease: a review. Stroke, 18, 2 - 1 2 . BALL MJ (1989) 'Leukoaraiosis' explained. Lancet, i, 612-613. BARNES D, MCDONALD WI, LANDON DN, JOHNSON G (1988) The characterization of experimental gliosis

by quantitative nuclear magnetic resonance imaging. Brain, 111, 83-94. BENHAIEM-SIGAUX N, GRAY F, GHERARDI R, ROUCAYROL AM, POIRIER J (1987) Expanding cerebellar

lacunes due to dilatation of the perivascular space associated with Binswanger's subcortical arteriosclerotic encephalopathy. Stroke, 18, 1087-1092. BINSWANGER O (1894) Die Abgrenzung der allgemeinen progressiven Paralyse. Berliner Klinische Wochenschrift, 49, 1103-1105; 50, 1137-1139; 52, 1180-1186. BRAFFMAN BH, ZIMMERMAN RA, TROJANOWSKI, JQ, GONATAS NK, HICKEY WF, SCHLAEPFER WW (1988)

Brain MR: pathologic correlation with gross and histopathology. 1. Lacunar infarction and VirchowRobin spaces. American Journal of Neuroradiology, 9, 621—628. BRUN A, ENGLUND E (1986) A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Annals of Neurology, 91, 253-262. CAPLAN LR., SCHOENE WC (1978) Clinical features of subcortical arteriosclerotic encephalopathy (Binswanger disease). Neurology, New York, 28, 1206-1215. COLE FM, YATES P (1967) Intracerebral microaneurysms and small cerebrovascular lesions. Brain, 90, 759-768. COOK TA, YATES PO (1972) A histometric study of cerebral and renal arteries in normotensives and chronic hypertensives. Journal of Pathology, 108, 129-135.

PERIVENTRICULAR WHITE MATTER LESIONS ON MRI

773

DEKABAN AS, SADOWSKY D (1978) Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Annals of Neurology, 4, 345—356. DE REUCK J, CREVITS L, DE COSTER W, SIEBEN G, VANDER EECKEN H (1980) Pathogenesis of Binswanger

chronic progressive subcortical encephalopathy. Neurology, New York, 30, 920—928. DEWITT LD, KISTLER JP, MILLER DC, RICHARDSON EP, BUONANNO FS (1987) NMR-neuropathologic

correlation in stroke. Stroke, 18, 342-351. ERKINJUNTTI T, KETONEN L, SULKAVA R, SIPPONEN J, VUORIALHO M, IIVANAINEN M (1987) Do white

matter changes on MRI and CT differentiate vascular dementia for Alzheimer's disease? Journal of Neurology, Neurosurgery and Psychiatry, 50, 37—42. FISHER CM (1965) Lacunes: small, deep cerebral infarcts. Neurology, Minneapolis, 15, 774—784. GARCIN R, LAPRESLEL J, LYON G (1960) Encephalopathie sous-corticale chronique de Binswanger: &ude anatomo-clinique de trois observations. Revue Neurologique, 102, 423—440. GEORGE AE, DE LEON MJ, KALNIN A, ROSNER L, GOODGOLD A, CHASE N (1986) Leukoencephalopathy

in normal and pathologic aging. 2. MRI of brain lucencies. American Journal of Ncuroradiology, 7, 567-570. GERARD G, WEISBERG LA (1986) MRI periventricular lesions in adults. Neurology, Cleveland, 36, 998-1001. GOTO K, ISHII N, FUKASAWA H (1981) Diffuse white-matter disease in the geriatric population: a clinical, neuropathological, and CT study. Radiology, 141, 687-695. GRAY F, DUBAS F, ROULLET E, ESCOUROLLE R (1985) Leukoencephalopathy in diffuse hemorrhagic cerebral

amyloid angiopathy. Annals of Neurology, 18, 54—59. GUPTA SR, NAHEEDY MH, YOUNG JC, GHOBRIAL M, RUBINO FA, HINDO W (1988) Periventricular white

matter changes and dementia: clinical, neuropsychological, radiological, and pathological correlation. Archives of Neurology, Chicago, 45, 637-641. HERSHEY LA, MODIC MT, GREENOUGH PG, JAFFE DF (1987) Magnetic resonance imaging in vascular

dementia. Neurology, Cleveland, 37, 2 9 - 3 6 . HOCHBERG FH, MILLER DC (1988) Primary central nervous system lymphoma. Journal of Neurosurgery, 68, 835-853. HUGHES W (1965) Origin of lacunes. Lancet, ii, 1 9 - 2 1 . JANOTA I. MIRSEN, TR, HACHINSKI VC, LEE DG, MERSKEY H (1989) Neuropathologic correlates of leuko-

araiosis. Archives of Neurology, Chicago, 46, 1124 — 1128. KAPPELLE LJ, VAN GUN J (1986) Lacunar infarcts. Clinical Neurology and Neurosurgery, 88, 3-17. KINKEL WR, JACOBS L, POLACHINI I, BATES V, HEFFNER RR (1985) Subcortical

arteriosclerotic

encephalopathy (Binswanger's disease): computed tomographic, nuclear magnetic resonance, and clinical correlations. Archives of Neurology, Chicago, 42, 951—959. KIRKPATRICK JB, HAYMAN LA (1987) White-matter lesions in MR imaging of clinically healthy brains of elderly subjects: possible pathologic basis. Radiology, 162, 509—511. LECHNER H, SCHMIDT R, BERTHA, G, JUSTICH E, OFFENBACHER H, SCHNEIDER G (1988) Nuclear magnetic

resonance image white matter lesions and risk factors for stroke in normal individuals. Stroke, 19, 263-265. Loizou LA, KENDALL BE, MARSHALL J (1981) Subcortical arteriosclerotic encephalopathy. A clinical and radiological investigation. Journal of Neurology, Neurosurgery and Psychiatry, 44, 294-304. LOTZ PR, BALLJNGER WE, QUISLING RG (1986) Subcortical arteriosclerotic encephalopathy: CT spectrum and pathologic correlation. American Journal of Neuroradiology, 7, 817 — 822. MARJE P (1901) Des foyers lacunaires de disintegration et de diffe'rents autres &ats cavitaires du cerveau. Revue de Midecine, 21, 281 - 2 9 8 . MARSHALL VG, BRADLEY WG, MARSHALL CE, BHOOPAT T, RHODES RH (1988) Deep white matter

infarction: correlation of MR imaging and histopathologic findings. Radiology, 167, 517—522. NISSL F (1920) Zur Kasuistik der arterioslderotischen Demenz (Ein Fall von sog. 'Encephalitis subcorticalis'). Zeitschrift fllr die Gesamten Neurologic und Psychiatrie, 19, 438—443. OKEDA R (1973) Morphometrische Vergleichsuntersuchungen an Hirnarterien bei Binswangerscher Encephalopathi und Hochdruckencephalopathie. Ada Neuropathologica, Berlin, 16, 2 3 - 4 3 . OLSZEWSKJ J (1962) Subcortical arteriosclerotic encephalopathy: review of the literature on the so-called Binswanger's disease and presentation of two cases. World Neurology, 3, 359-374.

774

J. C. VAN SWIETEN AND OTHERS

POIRIER J, DEROUESNJ* C (1985) Le concept de lacune cir€brale de 1838 a nos jours. Revue Neurologique, 141, 3 - 1 7 . REVESZ T. HAWKINS CP, DU BOULAY EPGH, BARNARD RO, MCDONALD WI (1989) Pathological findings

correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger's disease). Journal of Neurology, Neurosurgery and Psychiatry, 52, 1337-1344. REZEK DL, MORRIS JC, FULLING KH, GADO MH (1987) Periventricular white matter lucencies in senile dementia of the Alzheimer type and in normal aging. Neurology, Cleveland, 37, 1365 — 1368. ROSENBERG GA, KORNFELD M, STOVRING J, BICKNELL JM (1979) Subcortical arteriosclerotic

encephalopathy (Binswanger): computerized tomography. Neurology, New York, 29, 1102-1106. Ross RUSSELL RW (1963) Observations on intracerebral aneurysms. Brain, 86, 424—442. STEINGART A, HACHINSKI VC, LAU C, FOX AJ, FOX H, LEE D et al. (1987a) Cognitive neurologic findings in demented patients with diffuse white matter lucencies on computed tomographic scan (leuko-araiosis). Archives of Neurology, Chicago, 44, 36-39. STEINGART A, HACHINSKI VC, LAU C, FOX AJ, DIAZ, F, CAPE R et al. (19876) Cognitive and neurologic

findings in subjects with diffuse white matter lucencies on computed tomographic scan (leuko-araiosis). Archives of Neurology, Chicago, 44, 32—35. SZE G, D E ARMOND SJ, BRANT-ZAWADSKI M, DAVIS RL, NORMAN D, NEWTON TH (1986) Foci of MRI

signal (pseudo lesions) anterior to the frontal horns: histologic correlations of a normal finding. AJR: American Journal of Roentgenology, 147, 331—337. THOMSEN AM, B0RGESEN SE, BRUHN P, GJERRIS F (1986) Prognosis of dementia in normal-pressure

hydrocephalus after a shunt operation. Annals of Neurology, 20, 304—310. VALENTINE AR, MOSELEY IF, KENDALL BE (1980) White matter abnormality in cerebral atrophy: clinicoradiological correlations. Journal of Neurology, Neurosurgery and Psychiatry, 43, 139—142. WOOLLAM DHM, MILLEN JW (1968) Vascular tissues in the central nervous system. In: Pathology of the Nervous System, Volume 1. Edited by J. Minckler. New York and London: McGraw-Hill, pp. 486-498. (Received February 6, 1990. Revised April 24, 1990. Accepted May 2, 1990)

Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces.

Magnetic resonance imaging (MRI) was performed postmortem on the brains of 40 patients aged over 60 yrs who had died from causes other than brain dise...
3MB Sizes 0 Downloads 0 Views