1087 Expanding Cerebellar Lacunes Due to Dilatation of the Perivascular Space Associated With Binswanger's Subcortical Arteriosclerotic Encephalopathy N. Benhaiem-Sigaux, MD, PhD, F. Gray, MD, PhD, R. Gherardi, MD, A.M. Roucayrol, MD, and J. Poirier, MD, PhD An 80-year-old hypertensive woman developed right hemiplegia and died 24 hours after admission. Neuropathologic examination revealed multiple cerebral infarcts of various ages and diffuse subcortical arteriosclerotic encephalopathy. Clusters of asymptomatic "expanding" lacunes, due to dilatation of the perivascular spaces, were found in both dentate nuclei. These cavities, which presented as space-occupying lesions, were surrounded by a single layer offlattenedcells and contained 1 or more sections of normal-looking arterioles. Such a topographic grouping of lacunes in the dentate nucleus has not been described previously. The mechanism of widening of the perivascular compartment remains unclear; its occurrence in a hypertensive patient and its association with typical Binswanger's subcortical arteriosclerotic encephalopathy and severe atherosclerosis with multiple infarcts suggest a common pathophysiologic mechanism possibly including an alteration of the blood-brain barrier. (Stroke 1987;18:1087-1092) C erebral lacunes are usually considered to be old, small, deep cerebral infarcts12 due to occlusive arterial lesions. 34 However, old hemorrhages can be a cause of lacunes and have been recently reviewed.5 Dilatations of perivascular spaces, well known since the historic paper of Marie6 and the thesis of Ferrand,7 have been reemphasized recently as a possible mechanism of genesis of cerebral lacunes. 89 To avoid the semantic confusion that surrounds the term cerebral lacune,10 a new neuropathologic classification has been proposed." 12 Lacunes due to dilatation of the perivascular space are usually asymptomatic.8 A new type of space-occupying lacune due to dilatation of the perivascular space was described as an "expanding cerebral lacune" by Poirier et al. 9 In this initial report, the thalamo-mesencephalic "expanding lacunes" were responsible for clinical symptoms. In this article, we report a new case of expanding lacune involving the cerebellum with three major points of interest: 1) the lesion was asymptomatic, presenting as an incidental autopsy finding, 2) the topographic grouping of lacunes in the dentate nuclei had never been described, and 3) the lacunes were associated with Binswanger's subcortical arteriosclerotic encephalopathy (SAE) and multiple cerebral infarcts. Such an association in a hypertensive patient suggests comFrom the D^partement d'Histologie-Embryologie-Biologic cellulaire, Faculty de M&iecine Paris-Val de Mame (N.B.-S., R.G., J.P.) and the D^partement de Pathologie (Neuropathologie), H6pital Henri Mondor (N.B.-S., F.G., R.G., A.M.R., J.P.), Creteil, France. Address for reprints: Dr. Nicole Benhaiem-Sigaux, Service d' Anatomie pathologique, Hdpital Henri Mondor, 94010 Crdteil Cedex, France. Received March 5, 1987; accepted June 22, 1987. mon pathogenetic mechanisms as the origin of these various lesions. Report of a Case An 80-year-old woman known to be hypertensive for many years had received various antihypertensive treatments. She suffered from left ventricular failure and coronary insufficiency. She was admitted to the hospital on March 8, 1983, because of dyspnea. Blood pressure was 170/100 mm Hg. She became somnolent, then comatose, and developed right hemiparesis 24 hours after admission and died within a few hours. Computed tomography (CT) scan was not obtained. Postmortem examination revealed diffuse and severe atherosclerotic lesions in the thoracic and abdominal aorta and its main branches such as the carotid, iliac, coronary, and renal arteries. An old myocardial infarct involved the posterior part of the left ventricle. The brain was sectioned after fixation for 1 month in 10% formalin. After horizontal section of the mesencephalon, the brain was cut in coronal slices and the cerebellum with the unseparated brainstem was cut in horizontal slices. Fourteen slices of the right and left cerebral hemispheres and 4 slices of the cerebellum and brainstem were embedded in celloidin. Several samples were embedded in paraffin. The sections were stained with hematoxylin and eosin, Loyez stain for myelin, Masson's trichrome, and Bodian silver impregnation combined with Luxol fast blue. Results Multiple infarcts of various ages were found. A recent infarct involved the superficial territory of the left middle cerebral artery (MCA) and an older one the white matter of the left temporal lobe; an old infarct had destroyed the deep territory of the left MCA; watershed infarcts bilaterally involved the cerebellum at Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 1088 Stroke Vol 18, No 6, November-December 1987 B FIGURE 1. Coronal section of left hemisphere through the amygdala (A) and anterior part of the globus pallidus (B) showing spotty demyelination of the centrum ovale sparing the internal capsule and corpus callosum. Loyez stain. the junction of the territories supplied by the posterior inferior cerebellar arteries and the superior cerebellar arteries. The basilar artery showed severe atherosclerotic lesions. Diffuse, often spotty, myelin loss involved the centrum ovale (Figure 1) mainly on the left side, the white matter of the gyri, the internal and external capsules, the cerebellar white matter, and the pons; it spared the corpus callosum. Microscopic examination of the white matter showed edema, swollen oligodendroglia, spongiosis, incomplete loss of myelin, and astrocytic gliosis with Rosenthal's fibers. There were numerous dilatations of the pervivascular spaces; they occasionally contained edema fluid and/or lipid or hemosiderinladen macrophages. Some of them were large, forming macroscopic lacunes. Similar lacunes, corresponding to dilatation of the perivascular space, varying in size from 0.1 to 5 mm2, were also present bilaterally in the caudate nucleus, globus pallidus, putamen (Figure 2), and thalamus. The cortex was spared. These cavities, like those in the white matter, were round, regular, and lined by a sin- B FIGURE 2. Coronal section of cerebral hemispheres through the mamillary bodies (A) and red nuclei (B). A: Type Ilia lacunes in both lenticular nuclei. B: Type Ilia lacunes or status cribrosus (arrows) in right putamen. Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 Benhaiem-Sigaux et al Expanding Cerebellar Lacunes gle layer of epithelium-like cells (Figure 3). Each contained 1 or more sections of healthy-looking small arteries or arterioles. The surrounding parenchyma showed various degrees of edema, spongiosis, and reactive astrocytic gliosis with Rosenthai's fibers (Figure 3A). In the putamen, some of these cavities contained abnormal vessels that showed fibrosis of the wall, intimal thickening (Figure 3B), and hyalinization, which rarely narrowed the lumen. There was no amyloid angiopathy. The perforating arteries showed severe atherosclerotic lesions narrowing the lumen. Lacunes of another type, corresponding to a small, deep infarct with irregular borders surrounded by marked astrocytic gliosis and containing residual tissue fragments and lipid-laden macrophages, were present in the lentiform nuclei but not in the white matter. In the cerebellum, clusters of lacunes of various sizes due to dilatation of the perivascular space showed a characteristic grouping in the dentate nuclei (Figure 4A) involving the hilum of the left dentate nucleus in 1089 particular (Figure 5). Some of the cavities overlapped the lamina, and very few were located outside the dentate nucleus. The largest cavity was a 5 x 4 mm2 cystic lesion located in the inferior part of the hilum of the left dentate nucleus (Figure 4B), which forced back the surrounding structures but did not destroy any tissue. A well-individualized small artery crossed the cavity, which was otherwise completely empty (Figure 4B). Discussion Neuropathologic examination showed various lesions in the brain of a hypertensive patient. Diffuse atherosclerosis and multiple cerebral infarcts were present; the most recent infarct found in the territory of the left MCA probably caused the hemiparesis and subsequent death of the patient. The patient's medical history was very succinct, and no information on her previous mental status was available. However, her long history of hypertension, the macroscopic and microscopic appearance of the FIOURE 3. Microscopic appearance of the putamen. A: Type Ilia lacune (L) lined by a single-layered epithelium (E) and containing 3 sections of normal small arteries and arteriole (A). Surrounding parenchyma shows edema, spongiosis, and reactive astrocytic gliosis with Rosenthai's fibers (arrows). Hemotoxylin and eosin stain, x84. B: Type Ilia lacune (L) containing abnormal but patent artery with fibrous intimal thickening (arrows). Hematoxylin and eosin stain, x 120. C: Type Ilia lacunes (L), numerous, small, and lined by a single-layered epithelium. Hematoxylin and eosin stain, x39. Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 1090 Stroke Vol 18, No 6, November-December 1987 FIGURE 4. Horizontal sections of brainstem and cerebellum through dentate nuclei. A: Cluster of Type 111 lacunes of various sizes in dentate nuclei. B: Higher magnification of expanding lacune located in left dentate nucleus. The 5x4-mm2 cystic lesion is round, regular, and has a smooth border; it is crossed by a small artery. This expanding cavity compresses surrounding structures. cerebral white matter alterations, their association with numerous lacunes in the white matter and basal ganglia, and their sharp contrast to the almost-normal cortex were all typical of SAE. 1314 The macroscopic cavities or lacunes had different microscopic appearances and corresponded to various pathologic processes. According to the neuropathologic classification proposed by Poirieret al, 1 0 " cerebral lacunes can be divided into 3 categories: Type I lacunes correspond to old, small, deep cerebral infarcts; they are irregular anfractuous cavities, devoid of any lining epithelium, and contain macrophages and small parenchymatous fragments, usually surrounded by marked astrocytic gliosis. Type II lacunes are old, small hemorrhages that are easily recognized by the presence of hemosiderin-laden macrophages and the iron pigmentation of their walls. Type i n lacunes are due to dilatation of the perivascular space; they are round, very regular cavities and always contain 1 or 2 sections of an artery with a patent lumen and usually normal walls. The cavity is lined by a single layer of epithelial cells that correspond to the leptomeningeal cells forming the normal lining of the perivascular spaces.15 The surrounding parenchyma is usually depressed rather than destroyed. Apart from occasional Type I lacunes in the lentiform nuclei, most of the lacunes observed in our case were of Type HI. Among this group, the multiple microscopic lacunes we observed in the white matter, basal ganglia, and dentate nuclei correspond to the status cribrosus (itat cribli) described by Durand-Fardel16 as many round, small holes (criblures), always containing a patent blood vessel and located in die hemispheric white matter (Type Ula lacunes in the present classification"). Some of the lacunes seen in the lentiform nuclei can be considered lacunes de disintegration (Type nib), which were first described by Marie, 6 who claimed that they were due to perivascular dilatation destroying the adjacent brain by a specific process he named vaginalite destructive. Type IIIc lacunes8 are single subputaminal lacunes, known as solitary cavities, surrounding the lenticulostriate arteries at their entrance into the lentiform nucleus. 6 The very unusual macroscopic appearance of the cluster of cavities found at the postmortem examination of the cerebellum might have been misleading. However, cerebral porosis17 or intraparenchymal neuroepithelial cysts18 were easily eliminated on microscopic grounds. In fact, these cerebellar cavities, like the multiple cavities disseminated throughout the white matter and most of those involving the basal ganglia, satisfied the histologic criteria of Type III lacunes according to the classification of Poirier et al. " 1 2 Moreover, the cystic lesions observed in the left dentate nucleus had all the features of Type Illd or expanding lacunes: they formed round, regular cavities reaching a maximum of 5 x 4 mm2; they were delineated by a single-layered, flat epithelium and contained a small artery with a patent lumen and normal walls; they looked like space-occupying lesions that compressed and thinned the adjacent parenchyma without destroying tissue; and they caused only reactive lesions such as astrocytic gliosis, spongiosis, swollen oligodendroglia, and myelin loss with edema. Only 3 cases of similar space-occupying, "expanding," or Type Hid lacunes have been previously reported. 91920 The first publication9 gave a precise description of expanding lacunes and reported the case of a 59-year-old nonhypertensive woman who developed progressive thalamic dementia. CT scan showed hydrocephalus and lacunar low densities in the mesencephalon and both thalami. Neuropathologic examination revealed space-occupying lacunes bulging into the third ventricle, squeezing the aqueduct, protruding Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 Benhafem-Sigaux et al Expanding Cerebellar Lacunes into the fourth ventricle, and situated in the territory of the paramedian mesencephalo-thalamic arterial pedicle. The cavities were round and regular and varied in size from 1 to 10 mm in diameter. Each cavity was lined by a single layer of epithelial-like cells. There 1091 was no gliosis around the cavities except in the left thalamus. In almost all cavities, a normal small artery or arteriole was present. The vascular lumen was empty. Rare macrophages and lymphocytes were observed in the cavities. Multiple very small cavities of the same FIGURE 5. Microscopic appearance of dentate nucleus. A, B: Cluster of Type III lacunes (L) of various sizes involving mainly the hilum of the dentate nuclei. Some cavities overlap the lamina (La) and very few lie outside the dentate nucleus. The largest cavities displace surrounding structures, causing thinning of the lamina. Loyez stain, x27. C: Type III lacune (L) lined by single-layered epithelium (E) containing sections of arteriole (A), edema fluid, and macrophages (m). Surrounding parenchyma showed edema and spongiosis. Masson's trichrome stain, x 130. Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 1092 Stroke type were also found in the left pallidum. The patient was not hypertensive, but a paramedian mesencephalic artery showed severe lesions of segmental necrotizing angiitis of unknown etiology. The authors9 found a rather similar case" in the literature; a 70-year-old normotensive patient had developed a progressive psycho-organic syndrome and strokes. Neuropathologic examination snowed "massive cavities" in the basal ganglia of both cerebral hemispheres, bulging into the lateral ventricle. Macroscopic and microscopic appearances of these cavities looked quite similar to those of the present case despite the absence of mention by the author of any epithelium around the cavities. Pilleri19 termed the condition "status cavernosus," which he attributed to an as yet unrecognized vascular process. Two almost symmetrical "expanding cerebral lacunes" bulging into the lateral ventricles with characteristic macroscopic and microscopic features were also described20 in a 66-year-old hypertensive patient who had been treated for normal pressure hydrocephalus and who died from a thalamic hemorrhage. One of these lacunes was demonstrated on CT scan. These lesions were associated with various types of cerebral lacunes. In our case, as in the case reported by Derouesne" et al,20 the patient's medical history was very poor, and because of the multiplicity of lesions, no clinical signs could be precisely related to the expanding lacunes. The particular topographic grouping of the lacunes in the cerebellar dentate nucleus in our case is very unusual and has not been previously reported; however, some similarity may exist between Type IIIc giant lacunes, which develop around the perforating arteries of the basal ganglia, and the cluster of cerebellar lacunes, which developed around small perforating arteries of the dentate nucleus, seen in our case. The mechanisms involved in the formation of the Type m lacunes are not clearly understood and are probably multiple. Dilatation of perivascular spaces is observed in cerebral atrophy as a result of shrinking of brain parenchyma. In elderly hypertensive patients, it has been suggested that dilatation of perivascular spaces could result from the mechanical stress caused by high blood pressure on brain arterioles.21 The usual association, in the literature1314 as well as in our case, of SAE with Type III lacunes suggests that a common pathophysiologic mechanism can explain the development of both lesions. Subarachnoid hemorrhage is generally believed to be caused by a disruption of the blood-brain barrier due to episodes of high blood pressure causing focal vasogenic brain edema and/or chronic hypoxia related to arteriolar arteriosclerotic changes.14 An abnormality of arterial wall permeability may also explain the dilatation of the perivascular space forming Type HI lacunes.9 The presence of segmental necrotizing angiitis of the artery supplying the involved territory in the case of Poirier et al9 and of severe arteriosclerotic lesions in our case and that of Derouesn6 et al20 support this hypothesis. Our patient was hypertensive for a long time and had a severe and Vol 18, No 6, November-December 1987 diffuse atherosclerotic disease causing a myocardial infarct and multiple cerebral infarcts. These degenerative arteriolar changes secondary to severe hypertensive disease (arteriolar segmental degeneration or lipohyalinosclerosis) are also responsible for lacunar infarcts (or Type I lacunes)' that are usually associated with SAE and Type III lacunes.14 Acknowledgments We are grateful to Martine Favolini for her excellent technical assistance, to Sylvie Daude" and Aurore Feyfant for their secretarial help, and to Marie-Claude Lescs, Sylvie Mousky, and Pascal Miele for the photographic work. References 1. Escourolle R, Poirier J: Manual of Basic Neuropalhology. Philadelphia, WB Saunders Company, 1978 2. Fisher CM: Lacunes: Small, deep cerebral infarcts. Neurology 1965;15:774-784 3. Benhaiem-Sigaux N, Gherardi R, Salama J, Gray F, Amouroux J, Poirier J: Thrombosis of a saccular microaneurysm causing cerebral (pontine) lacunae. Ada Neuropathol 1986;69: 332-336 4. Fisher CM: The arterial lesions underlying lacunes. Acta Neuropathol 1969;12:1-15 5. Mori E, Tabuchi M, Yamadori A: Lacunar syndrome due to intracerebral hemorrhage. Stroke^ 1985;16:454-459 6. Marie P: Des foyers lacunaires de disintegration et de diffe'rents &ats cavitaires du cerveau. Rev Mid 1901;21:281-298 7. Ferrand J: Essai sur V Himipligie des Vieillards. Les Lacunes de Disintigration Ciribrale. Paris, Jules Rousset, 1902 8. Poirier J: Giant cerebral lacuna due to dilatation of the perivascular space: A case report. Clin Neuropathol 1983;2:138—140 9. Poirier J, Barbizet J, Gaston A, Meyrignac C: D6mence thalamique, lacunes expansives du territoire thalamo-me'sence'phalique paramedian, hydrocephalie par stenose de l'acqueduc de Sylvius. Rev Neurol 1983;139:349-358 10. Poirier J, Derouesn6C: Le concept de lacune ce're'brale de 1938 anosjours. Rev Neurol 1985;141:l-37 11. Poirier J, Derouesnd C: Cerebral lacunae. A proposed new classification (letter). Clin Neuropathol 1984;3:266 12. Poirier J, Gray F, Gherardi R, Derouesnd C: Cerebral lacunae. A new neuropathological classification (abstract). J Neuropathol Exp Neurol 1985;44:312 13. Olszewski J: Subcortical arteriosclerotic encephalopathy. World Neurol 1962;3:359-375 14. Dubas F, Gray F, Roullet E, Escourolle R: Leucoencephalopathies arteriopathiques. Rev Neurol 1985;141:93-108 15. Fleury J, Gherardi R, Poirier J: Les espaces peri vasculaires du systeme nerveux central. Donntes histophysiologiques. Ann Pathol 1984;4:245-247 16. Durand-Fardel M: M^moire sur une alteration particuliere de la substance ce're'brale. Gaz Med Paris 1842; 10:23-26, 33-38 17. Gherardi R, Gray F, Fagot A, Razavi F, Poirier J: Les £tats cavitaires du cerveau et la porose ce're'brale. J Med Ltg Droit Med 1985;28:219-224 18. Gherardi R, Lacombe MJ, Poirier J, Roucayrol AM, Wechsler J: Asymptomatic encephalic intraparenchymatous neuroepithelial cysts. Acta Neuropathol 1984;63:264-268 19. Pilleri G: Ueber eine besondere normotone intracerebrale gefasserkrankung "status cavemosus" mit schwerpunkt im oberen himstamm. Psychiatr Neurolog 1965;150:358-382 20. Derouesne C, Gray F, Escourolle R, Castaigne P: "Expanding cerebral lacunae" in a hypertensive patient with normal pressure hydrocephalus. J Neuropathol Appl Neurobiol (in press) 21. Hughes W: Origin of lacunae. Lancet 1965;2:19-21 KEY WORDS • cerebral lacunes • blood-brain barrier multiple cerebral infarcts • perivascular space dilatation Binswanger's subcortical arteriosclerotic encephalopathy Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016 Expanding cerebellar lacunes due to dilatation of the perivascular space associated with Binswanger's subcortical arteriosclerotic encephalopathy. N Benhaïem-Sigaux, F Gray, R Gherardi, A M Roucayrol and J Poirier Stroke. 1987;18:1087-1092 doi: 10.1161/01.STR.18.6.1087 Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1987 American Heart Association, Inc. All rights reserved. Print ISSN: 0039-2499. Online ISSN: 1524-4628 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://stroke.ahajournals.org/content/18/6/1087 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Stroke is online at: http://stroke.ahajournals.org//subscriptions/ Downloaded from http://stroke.ahajournals.org/ by guest on June 29, 2016