Study of cerebral vascular structures in hypertensive intracerebral haemorrhage

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1 Romnin Journl of Morphology n Emryology 2005, 46(3): Stuy of ererl vsulr strutures in hypertensive intrererl hemorrhge I. E. PLEŞEA 1), A. CAMENIŢĂ 2), C. C. GEORGESCU 3), S. D. ENACHE 4), B. ZAHARIA 1), CLAUDIA VALENTINA GEORGESCU 4), MIHAELA ŢENOVICI 5) 1) Deprtment of Pthology, University of Meiine n Phrmy of Criov 2) Deprtment of Neurosurgery, University of Meiine n Phrmy of Criov 3) Deprtment of Phrmology, University of Meiine n Phrmy of Criov 4) Deprtment of Pthology, Emergeny County Hospitl, Criov 5) Deprtment of Pthology, Rilro University Hospitl, Criov Astrt Aims. The stuy ws performe in orer to ssess the ltertions of extrprenhyml n intrprenhyml vsulr strutures in 82 hypertensive ptients suspete of primry intrprenhyml hemtom, whih ie n were utopsie in orer to onfirm the ignosis. Mteril n methos. The stuie mteril onsiste of nervous tissue situte ner n istnt from the hemorrhgi lesion. The speimens of nervous tissue were proesse y the lssil histologil tehnique n stine with the usul stinings n with immunohistohemil stins for sement memrnes n enothelil ells. Results. Extrprenhyml rteries showe lssi lesions of theroslerosis. Atheromtous lesions were of ll types, even the extension towrs the mei eing enountere omplition with thromosis. At the level of the intrprenhyml loo vessels, the spetrum of the lesions ue to rteril hypertension inlue ll steps of vsulr wll egenertion, from hypertrophy of smooth musle lyer to omplete hyliniztion of rteril wll, ut with fol irregulr istriution, not relte with the proximity of hemorrhgi fous. High rteril loo pressure lso influene the pillry wlls whih showe fol or irumferentil thikening ue to the ensifition of the type IV ollgen mteril from the sement memrne struture. The CD34 immunostining showe tht enothelil ells kept their struturl integrity. Conlusions. The sequene of egenertive lesions of the ererl vsulr wll ulmintes with the hyliniztion of exessive firillr mteril form rteriolr wll or from sement memrnes. Hylin mteril is wekening the wll resistne to the stress etermine y the high vlues of loo pressure in hypertension, n, orrelte with miniml resistne of the surrouning ererl prenhym, n explin why the ererl prenhym is the only tissue in whih loo pressure vritions n eterminte vsulr rupture n ererl hemorrhge. The more equte term for esriing the vsulr wll hnges seems to e slerosis (rteriolr n even pillry) with hylinosis. Keywors: hypertensive intrererl hemorrhge, rterioloslerosis, hylinosis, immunohistohemistry. Introution Intrererl hemorrhge (ICH) is thought to e one of the most frequent iseses of nervous system, representing 3.5 5% of ll orgni iseses of this system n 5 15% of the totl numer of ererl vsulr strokes. Its iniene in ptients younger thn 40 is 0.3/ [1, 2]. IHC is the result of hemorrhge of rteril origin iretly within ererl tissue, whih involves minly the ererl prenhym ut with possile extention to ventriulr spes n osionlly to surhnoi spe [3, 4]. IHC etiology is iverse, omplex n ynmi [5 7]. Thus, IHC n e the result of mny pthologil onitions n usully ompnies other nervous system lesions [8 13]. There re two types of ererl hemorrhges: trumti n non-trumti. The lter re lso known s spontneous hemorrhges even lmost ll of them re use y lesion of rteril wll [14]. Nontrumti ICH is ivie into two min groups, epening on etiopthogenesis [4]: Primry IHC representing 78 88% of ll IHC. It is the result of spontneous rupture of smll vessels ltere either y hroni hypertension, in 80%, or y myloi eposits [15 18]. Seonry IHC representing 12 22% of IHC ptients. It is ssoite with vsulr normlities (i.e, rteriovenous mlformtions n neurisms), tumors n ogulopthies [4]. The stuy of the min use of primry intrererl hemorrhge is iffiult euse the vsulr rupture hies or t lest moifies the susistent vsulr pthology [19]. Tking into ount the ove mentione fts, we propose to evlute, in hypertensive ptients who ie from intrererl hemorrhge, the morphologil hnges of the vsulr wll t the level of the rteril strutures of ll sizes n of the pillry situte oth in the proximity of the hemorrhgi lesion n istnt from it. Mteril n methos This stuy ws performe on 82 hospitlize hypertensive ptients suspete of primry intrprenhyml hemtom, whih ie n were utopsie in orer to onfirm the ignosis. The stuie mteril onsiste of nervous tissue situte ner n istnt from the hemorrhgi lesion n it ws otine uring the utopsy rrie out t the sme hospitl.

2 250 I. E. Pleşe et l. The frgments were otine using the following lgorithm: frgment whih inlue the periphery of the hemorrhgi lesion, frgment situte t istne of 2 3 m from the periphery of the hemorrhgi lesion n nother frgment situte in the ontrolterl hemisphere. The speimens of nervous tissue were proesse y the lssil histologil tehnique (fixe in 10% neutrl uffere formlin n emee in prffin) n stine with the usul stining Hemtoxylin & Eosin n with speifi stins for ifferent omponents of the mesenhyml strutures (vn Gieson n Golner stins) in the Pthology Lortories of the Emergeny County Hospitl n of the Rilro University Hospitl in Criov, s well s with immunohistohemil stins using LSAB/HRP tehnique n ntioies ginst vsulr sement memrnes n enothelil ells (i.e., Colgen IV n CD 34) in the Histopthologil n Immunohistohemil Lortory of the Criov University of Meiine n Phrmy Pthology Deprtment. Results n isussions Chnges of extrprenhyml lrge rteries wll Extrprenhyml lrge rteries showe, efore entering the ererl prenhym, only lssil lesions of theroslerosis. The theromtous lesions were foun in most of the ptients. The severity n extention of therosleroti lesions presente wie iniviul n interiniviul vritions n were not orrelte with the ptients ge. The key morphologi hnges in theroslerosis re: fol thikening of intim n lipi umultion, prouing the hrteristi theromtous plques. On gross speimens, the therosleroti lesions usully involve the rteril wll only prtilly long its irumferene (eentri lesions) (Figures 1 n 2), h non-uniform istriution n ifferent sizes. They h the spet of whitish-yellow enoluminl outgrowths whih sometimes were onfluent, generting lrger lesions. On ross setion, the re situte towrs the vsulr lumen (firous p), tene to e more firm n white. The eeper soft yellow re, foun espeilly in the enter of the lrger plques, ontine yellowish visous eris, lle therom (Figure 1, n ). Mirosopilly, the theromtous plques ontine ll three min omponents: ells, onnetive tissue extrellulr mtrix n intrellulr n extrellulr lipi umultions their mounts vrying in ifferent plques, n thus, resulting in wie spetrum of lesions. We foun usully enough, ol lesions, with superfiil firous p onsisting of smooth musle ells, reltively ense onnetive tissue n few leukoytes. The plques h lrge mount of ollgen fires in the sl n entrl res with only smll mount of theromtous mteril elow the superfiil firous p (Figures 2 n 3). There ws ellulr re elow n roun the firous p eges, onsisting of mixture of mrophges, smooth musle ells n lymphoytes in extrellulr mtrix elements suh s ollgen, elsti fires n proteoglyns. We foun lso plques where ellulr n vsulr omponents of the grnultion tissue were present roun the nhoring zone n the sl regions of the lesions. They were inving the plque n orgnizing it (Figures 2 n 3). In some of the more vne lesions, the progressive firosis trnsforme the ftty therom into firous sr. Typil theromtous plques were ommon, with neroti ore, ple eeply in the vsulr wll, onsisting of n morphous mss n reltively unnt quntity of lipi mteril (minly represente y holesterol rystls), ellulr eris n firin. Chrteristi omponents of this neroti ore were the swollen lipi-len mrophges, with smll nulei frequently in n eentri position n retiulr ytoplsm, known s fomy ells (Figures 2 n 3). In mny ses, the inner elsti ws intt (Figures 3 n ), the theromtous lesion eing still situte t the intiml level, ut with n importnt extension towrs the vsulr lumen, whih eme signifintly nrrowe. However, lthough theroslerosis is initilly restrite to the intim, in some ses, espeilly in lrge extrprenhiml vessels, the theromtous lesion eme severe n involve the mei, prouing the estrution of the inner elsti n the erese of the mile lyer thikness, these ltertions eing visile espeilly on Golner stine speimens (Figures 2 n 3). The trophy of the mile lyer resulte in signifint loosening n susequent neurisml spinle-shpe ilttions in ertin extrererl rteril segments. Thromosis, the most fere omplition, usully ours on fissure or ulerte lesions. In some ses, we foun in the lumen of lrge rteries thromi whih prtilly olue it (Figure 4 n ). Some of these thromi were inorporte within the intiml plque y orgniztion. Chnges of penetrting rteries n intrprenhyml rterioles The lesions spetrum moifie in the next vsulr level: the intrprenhyml rteril segments. From this level, no theromtous lesion ws oserve foun in ny of the ses. We oserve inste, in ll the mirosopilly exmine ses ifferent stges of evolution of the vsulr wll egenertive proess etermine y the hypertensive isese. The first stge onsiste in the hypertrophy, in ifferent egrees, of the penetrting rteries wll (Figure 5, n ). One hrteristi feture of this step of the vsulr retive proess inue y high pressure vlues ws the thikening n foling of the inner elsti, phenomenon est seen on Golner stine smples (Figure 5, ).

plque in posterior ererl rtery (Pitres setion

Atheromtous plque (vn Gieson stin, o. 10, o.

3 Stuy of ererl vsulr strutures in hypertensive intrererl hemorrhge 251 Figure 1 Atheromtous plque in posterior ererl rtery (Pitres setion on neropti smple fixe in formlin) Figure 2 Atheromtous plque (vn Gieson stin, o. 10, o. 4; o. 20) Figure 3 Atheromtous plque (Golner stin, o. 10, o. 4; o. 20) Figure 4 Atheromtous plque. Reent re thromus (vn Gieson n Golner stins, o. 10, o. 4)

252 I. E. Pleºe et l. Figure 5 Intrprenhyml rtery.

stin; () vn Gieson stin; () Golner stin (o. 10, o.

Complete slerosis of the vsulr wll: () HE stin; () vn Gieson stin; (),

4 252 I. E. Pleºe et l. Figure 5 Intrprenhyml rtery. Smooth musle hypertrophy; thikening n foling of inner elsti: (), () HE stin; () vn Gieson stin; () Golner stin (o. 10, o. 65) Figure 6 Intrprenhyml rtery. Complete slerosis of the vsulr wll: () HE stin; () vn Gieson stin; (), () Golner stin (o. 10, o. 65) Figure 7 Smooth musle trophy. Meio-ventitil firosis. Inipient hylinosis: (), () HE stin; () vn Gieson stin; () Golner stin (o. 10, o. 65) Figure 8 Complete hylinistion of vsulr wll: () HE stin; () vn Gieson stin; () Golner stin; () CD34 stin (o. 10, o. 100)

Stuy of ererl vsulr strutures in hypertensive intrererl hemorrhge

() Golner stin; (), (), () Collgen IV stin (o. 10, o.

memrne thikening: (), () Golner stin; () Vn Gieson stin (o. 10, o.

memrne thikening (Collgen IV stin, o. 10, o.

5 Stuy of ererl vsulr strutures in hypertensive intrererl hemorrhge 253 Figure 9 Cpillires with fol thikening of the sement memrne: () Golner stin; (), (), () Collgen IV stin (o. 10, o. 65) Figure 10 Cpillires with inresing n extention of sement memrne thikening: (), () Golner stin; () Vn Gieson stin (o. 10, o. 65) Figure 11 Cpillires with inresing n extention of sement memrne thikening (Collgen IV stin, o. 10, o. 65) Figure 12 Hylinistion of the outer lyers of the thikene sement memrne (Collgen IV stin, o. 10, o. 65)

100) Figure 15 Arteriole with hylinise wlls

6 254 I. E. Pleºe et l. Figure 13 Intrprenhyml rteriole with ontinuous enothelil lyer ( CD34 stin, o. 10, o. 65) Figure 14 Intrprenhyml pillries with ontinuous enothelil lyer ( CD34 stin, o. 10, o. 100) Figure 15 Arteriole with hylinise wlls entering mirohemorrhgi foi (), (), () HE stin; () Golner stin (o. 10, o. 65) Figure 16 The onset of hemorrhge y efrtion of hylinise vsulr wll (HE stin, o. 10, o. 65)

7 Stuy of ererl vsulr strutures in hypertensive intrererl hemorrhge 255 A seon signifint spet ws the hypertrophy of the mile lyer smooth musle ells (Figure 5, n ). The thir importnt phenomenon ws the eginning of firosis, initilly insie the vsulr ventiti, leing to its thikening n thinning of the outer elsti (Figure 5, n ). The seon stge of the egenertive proess onsiste in the progressive trophy of smooth musle ell n their replement y multilyere ollgen network with onentri rrngement proue y firolsts. Thus, the vsulr wll ws trnsforme into firous sleeve extening from the suenothelil spe to the externl ventiil lyer (Figure 6, ). The III r stge is hrterize y the onset n the extension of the hyline egenertion of the ollgen fiers whih reple the mile vsulr lyer n re in exess in the ventitil lyer. Thus, the smooth musle lyer is progressively issoite n reue onomitntly with meio-ventitil firosis (Figure 7). Figure 7, n shows the ispperne of the outer elsti, extensive firosis n hyline egenertion of ollgen fiers, espeilly of those outlying the vsulr wll. The finl stge of the egenertive proess is represente y the omplete hyline trnsformtion of the vsulr wll (Figure 8, ). Unlike ollgen firillry strutures, the morphous hyline hs low resistne to mehnil stress inue y high pressure vritions tht re no longer orrete y the musulr sleeve. Thus, hyline mteril represents the sight of possile vsulr rupture. Cpillry hnges By extening the morphologil nlysis to pillrytype vsulr strutures we hve oserve some interesting spets we i not fin to e esrie in the literture. The first oservtion, even on usul stins, is the fol thikening of the sement memrne (BM) of ererl pillries whih ppers to e more ovious t the rnhing sites n not to exten to the entire irumferene of the pillry (Figure 9, ). Anti-ollgen IV immunostining showe tht the fol n/or irumferentil thikening ws the result of the ensifition of the ollgen mteril present in the BM of the pillry wlls (Figure 9, ). The seon stge of this proess seems to e the inrese of the BM ensifition, ssoite with ifferent egrees of irumferentil n longituinl extension (Figure 10, ). Collgen IV immunostining offere etter view of irumferentil sl memrne ensifition (Figure 11, ). It is interesting to notie tht even this BM speifi ollgen mteril unerwent n initil proess of ensifition, followe y hylinistion phenomenon (Figure 12, ). Enothelil hnges Two mehnisms were esrie in the genesis of the intrprenhiml snguine extrvstion: vsulr wll rupture n erythroipeesis. The seon mehnism requires the presene of n ltertion t the level of the vsulr enothelium. One of our ojets ws to nlyze the sttus of the vsulr enothelium in ll types of intrprenhyml vessels using nti CD34 ntioy. We oserve tht rteries n rterioles i not show ny ltertions with isontinuities in the vsulr enothelium (Figure 13, ). The sme integrity of enothelil strutures ws lso seen in intrprenhyml pillries (Figure 14, ). Genesis of the hemorrhgi fous We present, in the en, some suggestive imges showing vsulr strutures of rteril type within the hemorrhgi fous or in its proximity tht presente some of the ove mentione hnges n espeilly hyline egenertion, n lso their involvement in intrprenhyml overflow. Figure 15,, shows rteriolr-type vessels with ifferent egrees of hylinistion surroune y erythroyti overflows in the proximity of mssive hemorrhgi foi. Figure 16,, presents ler imges with the efrtion of the ompletely hylinise rteriolr wll, mssive erythroyte outflow in the perivsulr re n susequent flooing of the surrouning ererl prenhym. The sme phenomenon oul lso e oserve in pillries exept tht the wll rupture implie oth norml pillries n pillries with the ove mentione hnges. The mirosopi stuy involve only the ptients eese efore the ompletion of investigting proeures, usully in the first 24 hours of hospitliztion. On the other hn, hypertensive isese ws, in most ses, either mjor risk ftor or etermining ftor. Thus, t lest in the ses where we performe neropti exmintion we foun no eviene of vsulr mlformtion to explin the rmti intrprenhyml hemorrhge. Arteril n rteriolr egenertive hnges i not suggest the presene of norml eposits of fol morphous mteril tht woul le to possile ignosis of myloi ngiopthy n thus requesting the ompletion of the morphologil investigtion lgorithm y performing speil stin for myloi (Congo re). Thus, vsulr lesions tht were enountere n nlyze were interprete s eing the result of the hrmful effet of hroni hypertension on intrprenhyml vsulr strutures. We lso i not fin ny signs of firinoi nerosis in helthy vsulr wll. Finlly, we hve to mention tht the lesions we esrie, in ifferent stges, were enountere oth in vsulr strutures in the proximity of the hemorrhge, in the sme hemisphere, s well s in its ounterprt. Conlusions In onlusion, the vsulr wll hnges re ifferent epening on vessel histologil struture n funtion. We propose the following evolution sequenes for the egenertive lesions involving rteril n pillry-type intrprenhyml vsulr strutures uner the influene of hypertensive isese:

8 256 I. E. Pleşe et l. Penetrting rteries n rterioles Smooth musle egenertion / firinoi nerosis. Sustitutive progressive slerosis in of the mei n lter on of the entire wll. Hylinistion of the sustituting ollgen fier network. Spinle-shpe ilttions. Rupture of impire vsulr wll in hyliniztion res. Cpillries Thikening of the sl memrne Hylinistion of ollgen fiers insie the thikene sl memrne. Rupture of norml pillry wll / impire pillry wll in hylinistion res. Spinle-shpe ilttions. Rupture of impire vsulr wll in res with hyliniztion. Hylin mteril res in the vsulr wll re points of low resistne n therefore, possile site of wll rupture in se of rupt inresing of loo pressure. The sequene of evolutive lesions ulminting with vsulr wll hyliniztion, renering it vulnerle to high pressure wves ssoite with minimum resistne of the surrouning prenhym whih oesn t llow the vessel to withstn lrge pressure vritions or onstntly inrese vlues n explin why the ererl prenhym is the only prenhym in whih vritions in loo pressure n le to intrprenhyml hemorrhge susequent to vsulr wll rupture. The term lipohylinosis ws first introue y Fisher C. M. (1969) n onsiere to e hele vsulr wll lesion [20]. It is hrterize y omplex struturl isorgniztion with or without neurisml ilttions n is more n more often sujet to ontroversy [19, 21]. Thus, we propose to e use no longer in morphologil esription of ererl vsulr strutures lesions generting ICH. In turn, we reommen the lrey knowlege term of rterioloslerosis with hylinosis whih esries more urtely one of the stges of the vsulr wll egenertion whih n le to vsulr wll rupture with susequent intrprenhyml leeing. Referenes [1] ALPERS J. B., MANCALL L. E., Clinil Neurology, F. A. Dvis Compny, Philelphi, 1971, 189. [2] GEORGESCU C. C., Cirumstnţe e priţie suferinţelor ererle ute. În:: GEORGESCU C. C., Controlul frmologi l tulurărilor irultorii şi metolie in suferinţele ererle ute, E. Meilă Universitră, Criov, 2004, [3] FRANKOWSKI R. F., Epiemiology of stroke n intrererl hemorrhge. In: KAUFMAN H. H. (e), Intrererl hemtoms, Rven Press, New York, 1992, [4] QURESHI A. I., TUHRIM S., BRODERICK J. P. et l., Spontneous intrererl hemorrhge, N Engl J Me, 2001, 344(19): [5] KASE C. S., MOHR J. P., Generl fetures of intrererl hemorrhge. In: BARNETT H. J. M., STERN B. M., MOHR J. P., YATSU F. M. (es), Stroke: pthophysiology, ignosis n mngement, volume III, Churhill Livingstone, New York, 1986, [6] MILLIKAN C. H,. MCDOWELL F., EASTON J. D., Stroke, Le & Feiger, Philelphi, [7] ADAMS H. P., BILLER J., Hemorrhgi intrrnil vsulr isese. In: JOYNT R. J. (e), Clinil Neurology, volume 2, J. B. Lippinott Compny, Philelphi, 1988, [8] MCCORMICK W. F., ROSENFIELD D. B., Mssive rin hemorrhge: review of 144 ses n n exmintion of their uses, Stroke, 1973, 4: [9] MCCORMICK W. F., Vsulr iseses. In: ROSENBERG R. N., GROSSMAN R. G., SCOCHET S. S. JR. et l. (es), The linil neurosienes: neurology, neurosurgery, neuropthology, neuroriology, neuroiology, volume 3, Churhill Livingstone, New York, 1983, [10] BROTT T., THALINGER K., HERTZBERG V., Hypertension s risk ftor for spontneous intrererl hemorrhge, Stroke, 1986, 17: [11] BAHEMUKA M., Primry intrererl hemorrhge n hert weight: liniopthologi se ontrol review of 248 ptients, Stroke, 1987, 18: [12] MCKEEVER P. E., The rin, spinl or, n meninges. In: STERNBERG S. S. (e), Dignosti Surgil Pthology, 3 r eition, volume 1, Lippinott Willims n Wilkins, Philelphi, 1999, [13] BĂJENARU O., TIU C., PANEA C., Hemorgi ererlă etioptogenie, ignosti, prinipii terpeutie, Revist Română e Stroke, 2001, IV(1): [14] VOGEL F. S., FULLER G. N., BOULDIN T. W., The nervous system. In: RUBIN E., FARBER J. L. (es), Pthology, 3 r eition, Lippinott Rven, Philelphi New York, 1999, [15] FOULKES M. A., WOLF P. A., PRICE T. R. et l., The Stroke Dt Bnk: esign, methos, n seline hrteristis, Stroke, 1988, 19: [16] MCCORMICK W. F., Pthology n pthogenesis of intrrnil sulr neurysms, Semin Neurol, 1984, 4: [17] DE GIROLAMI U., FROSCH M. P., ANTHONY D. C., The entrl nervous system. In: COTRAN R. S., KUMAR V., ROBBINS S. L. (es), Pthologi sis of isese, 5 th eition, W. B. Suners Compny, Philelphi, 1994, [18] ARIESEN M. J., CLAUS S. P., RINKEL G. J. E., ALGRA A., Risk ftors for intrererl hemorrhge in the generl popultion. A systemti review, Stroke, 2003, 34:2060. [19] LAMMIE G. A., LINDLEY R., KEIR S. et l., Stress-relte primry intrererl hemorrhge utopsy lues to unerlying mehnism, Stroke, 2000, 31: [20] FISHER C. M., The rteril lesions unerlying lunes, At Neuropthol, 1969, 12:1 15. [21] VINTER H. V., WANG Z., Non-CAA ngiopthies n their possile intertions with ererl myloi ngiopthy, Amyloi, 2001, 8(Suppl 1):2 9. Miling ress Inu Emil Pleşe, Assistnt Professor, M. D., Ph. D., Deprtment of Pthology, University of Meiine n Phrmy, Street Petru Rreş no. 2 4, Criov, Romni; Phone: (2), E-mil: emp@umfv.ro, pthology@umfv.ro Reeive: 10 Novemer 2005 Aepte: 14 Deemer 2005

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