MILIARY A N E U R Y S M S A N D "FIBRINOID" D E G E N E R A T I O N OF CEREBRAL B L O O D VESSELS William I. Rosenbhtm*
Abstract T h r e e cases o f intracerebral h e m o r r i m g e are described in which there was fibrinoid d e g e n e r a t i o n o f cerebral arteries and arterioles o r miliary aneurysms o r both. Fibrous balls are shown to be sclerosed true aneurysms. T h e s e clmx.lges o c c u r r e d in the absence o f malignant h y p e r t e n s i o n and p e r h a p s in the absence o f any hypertension. A fl~rther point o f interest was the finding o f fibrinoid at the site o f a p p a r e n t a n e u r y s m forlnation in a small a r t e r y on the cerebral surface, a location at which miliary aneurysms are not generally tlmught to form. T h e presence o f intracerebral h e n m r r l m g e in all t h r e e cases, and the r e a d y d e m o n s t r a t i o n o f similar clmnges in o t h e r cases o f intracerebral h e m o r r h a g e , suggest but do not prove that the fibrinoid d e g e n e r a t i o n o r aneurysm leads to vessel r u p t u r e and to h e m o r r h a g e itself. Also unsettled is the question o f w h e t h e r miliary a n e u r y s m s form only at sites already displaying fibrinoid cimnge. O u r data suggest tlmt pre-existing fibrinoid may not be a prerequisite f o r miliary a n e u r y s m formation.
T h e existence, cause, fate, and clinical significance o f miliary a n e u r y s m s are often assumed to be well known. Nevertheless there appears to be considerable confi~sion about these issues. For example, the last edition o f Greenfield's Neuropatholog')a still describes these miliary a n e u r y s m s as p s e u d o a n e u r y s m s while at the same time citing G r e e n z (as do Cole and Yates 3) as having described true aneurysnas. A n o t h e r text describes true a n e u r y s m s o f miliary size but at the same time uses the term "miliary a n e u r y s m " to include the organized l l e m o r r h a g e a r o u n d the r u p t u r e d aneurysm. 4 Still a n o t h e r recent text cites aneur)'snas as a cause o f cerebral h e m o r rlmge, but the impression is given that they
are a cerebral manifestation o f vascular (so-called "fibrinoid") necrosis secondary to malignant hypertension, wit!l accompanying necrosis o f renal arterioles. 5 In contrast, tile a n e u r y s m s and the fibrinoid c h a n g e o f cerebral arteries actually o c c u r in benign Iiyperteusion and even in apparently n o r m o t e n s i v e patients5 ,7 In a basic manual o f n e u r o p a t h o l o g y the aneurysms are r e f e r r e d to as a major cause o f hypertensive h e m o r r h a g e but a r e n o t described filrther, s T h e following r e p o r t describes o u r findi/'lgs after serial section o f portions o f tissue f r o m three patients, all o f w h o m were over the age o f 60 but only o n e o f whom had clinical hypertension. T h e pur-
*Professor of Pathology, Divisiou of Neuropathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 2 March 1977 pose of this report is to illustrate the sequence of changes thought to parallel aneurysm formation and "healing," to illustrate the true aneurysmal nature of the lesions, to indicate that these formations appear to be associated not only with massive hemorrhage but also with small hemorrhages of indeterminate age, and to emphasize the capacity of these lesions to occur not only in the absence of malignant hypertension but in the absence of any clinically diagnosable hypertension. S Y N O P S I S OF C L I N I C A L F E A T U R E S
T h e patients were 61,74, and 80 years old, one male and two females, respectively. The male had had a history of essential hypertension for four ),ears with blood pressures reaching 250/145. There was no history of neurologic deficit prior to the sudden onset of unconsciousness with death eight days later. T h e clinical diagnosis was intracerebral hemorrhage. T h e 74 year old woman had had no history of neurologic deficit prior to admission with mild right hemiparesis, aphasia, and right homonymous hemianopsia. Infarction of the left cerebral llemisphere was the clinical diagnosis. She improved and then was found dead on day 11. She had been seen at irregular intervals by a physician for at least the last 10 years of her life, and hypertension was never observed. In the 80 year old woman there was a sudden onset of coma with bloody cerebrospinal fluid, and she died in 24 hours. During the admission, diastolic pressure varied from 80 to 130. METHODS
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In each case an autopsy was performed, including examination of the brain, which was fixed in 20 per cent formalin for at least one week prior to sec; tioning. After coronal sectioning and tile taking of blocks for routine stud)', several blocks were taken at a distance from the areas of fresh hemorrhage and were studied by serial section. These were from the basal ganglia in case 1, the cerebral hemisphere (white matter and cortex) in
case 2, basal ganglia and thalanms in case 2, thalamus in case 3, and basis pontis in case 3. The following stains were employed on the paraffin embedded material from both brain and abdominal viscera: hematoxylin and eosin, Verhoeff-van Gieson, and azocarmine. The latter stains collagen or collagenous "hyalin" blue and fibrin red or orange. 6 Thus the stain distinguishes vessel walls that are merely sclerotic or "lwalinized" from walls that contain material that stains like fibrin and that are said to have undergone "fibrinoid" degeneration. G RESULTS General A utopsy
In cases 1 and 2 the heart weighed 750 grams and 400 grams, respectively. In both cases there was nephrosclerosis and in case 2 an adrenocortical adenoma. The heart of the third patient weighed 260 grams; this is a normal weight even for a woman of her short length (150 cm.)P In none o f the three cases was arterial or arteriolar necrosis found outside the brain.
Neuropathology Apart from the vascular pathologic changes to be described later, the major findings in the three cases were as follows: Case 1 displayed fi'esh hemorrhage ill the left parieto-occipital area involving principally the white matter and sparing the diencephalon. Ill addition there was an old slit hemorrhage in each putamen and a small tmruptured vascular malformation in the cerebellum. Case 2 displayed a fi'esh hemorrhage predominantly in the white matter of the left occipital lobe. Case 3 displayed a massive fresh hemorrhage in the right cerebral hemisphere, extending into the ventricle and the subarachnoid space. In the diencephalon there were several old slit hemorrhages appreciated 0nly after microscopic examination. A fresh secondary brain stem hemorrhage was also present. The microscopic changes may be divided into three kinds. First, "fibrinoid" degeneration defined by the presence of material staining like fibrin in the,vessel
M I L I A R Y A N E U R Y S M S AND " F I B R I N O I D " DEGENERATION--RosE,~nI.uM
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Figure 1. The dark material within the vessel wall (arrows) is red "fibrinoid'" segmentally arranged in the wall of an arteriole in a sulcus. (Azocarmine stain, x 100.) Figure 2. Higher magnification of "fibrinoid'" within the wall of the vessel seen in Figure I. (x400.) Figure 3. Another vessel in the subarachnoid space displays a bulbous swelling of its wall with replacement of the normal structure by amorphous red "fibi-inoid." A narrow lumen passes from the center of the figure to the upper right hand corner. (Azocarmine stain, x400.) Figure 4. A parenchymal arteriole is shown with its wall completely replaced by amorphous "'fibrinoid," stained red either b)' hematoxyliu and eosin or by azocarmiue. The perivascular area contains loose connective tissue and hemosideriu laden macrophages. (Hematoxyliu and eosin stain, x400.) Figure 5. Two small arteries side by side in subarachnoid space. The one on the left displays wall replaced by "fibrinoid." (Azocarufine staiq, x400.) Figure 6. l'arench)'mal arteriole shows a segmental arrangement of somewhat granular "fibrinoid" material within a vessel wall, bulging to the right (arrows). The wall on the left is extremely attenuated. Similar attenuation is also illustrated at the bottom of the involved vessel in Figure 2. (Azocarmine stain, x400.)
wall: 6 T h i s m a t e r i a l was f o u n d in cases 2 a n d 3. It was o f t e n s e g m e n t a l l y a r r a n g e d so t h a t o n l y a p o r t i o n o f t h e c i r c u m f e r e n c e was i n v o l v e d in a g i v e n cross s e c t i o n (Figs. 1 to 3). T h e vessels i n v o l v e d w e r e small a r t e r i e s in t h e s u b a r a c h n o i d s p a c e (Figs. 1 to 3, 5) o r s m a l l e r a r t e r i e s a n d a r t e r i o l e s
w i t h i n tile p a r e n c h y m a . T h e s m a l l e r o f tile i n v o l v e d vessels w e r e m o s t likely to s h o w total i n v o l v e m e n t o f t h e w h o l e c i r c u m f e r e n c e (Fig. 6). T h e s e vessels h a d a " s m u d g y " e o s i n o p b i l i c wall, w h i c h s t a i n e d like f i b r i n with t h e a z o c a r m i n e stain. 6 S m u d g y art e r i o l e s w e r e n o t c o n s i d e r e d to h a v e fi-
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HUMAN P A T I t O L O G Y - V O L U M E 8, NUMBER 2 3lalrh 1977 9
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. . . . . .
Figures 7 and 8. Different levels o f same l)arenchymal vessel slmwing "parent" artery at upper right and aneurysmal dilation. "Fibrinoid" material is seen within the aueurysm wall (arrows) and slmuld not be confused with erythocytes, which also stain darkly. (Azocarmine stain, x 100.) 9 Figure 9. Aneurysmal dilation arising from parenclwmal artery on left. Elastic tissue is seen as a dark band just beneath the intima of both the parent a r t e r y a n d the aneurysm. (Verhoeff-van Gieson stain, x 100.) Figure 10. A "fibrous" ball filled with loose, blue staining connective tissue arises from an artery by a thin neck or istlmms. This structure is delineated by arrows and represents the fibrosis of an aneurysm wall and its contents (Azocarmine stain. X 100.)
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brinoid d e g e n e r a t i o n unless the azocarmine stain was positive. In several instances t h e r e were h e m o s i d e r i n laden macropimges in the perivascular zone a r o u n d such vessels (Fig. 4). Aneurysmal dilatations with patent lumens were observed arising from stnall p a r e n c h y m a l arteries in cases 2 and 3 (Figs. 7 to 9). We were not able to d e m o n s t r a t e fibrinoid in the p a r e n t branch. However, material staining like fibrin often a p p e a r e d in several loci within the walls o f the dilated aneurysmal zone (Figs. 3, 8). Altlmttgll devoid o f muscularis, tim aneurysmal walls often contained retnnants o f elastic tissue. Finally, in addition to patent aneurysms, sclerosed a n e t l r y s n l s w e r e seen. These" were f o t m d in all cases. T h e y consisted o f flask slmped collections o f collagen, j o i n e d to a small artery by a n a r r o w neck (Fig. 10). T h e V e r h o e f f elastic stain showed that tim neck, the proxitnal portion o f the a n e u r y s m p r o p e r , and i n d e e d portions o f the c i r c u m f e r e n c e opposite
the neck contained elastic tissue (Figs. 11 to 15). Scattered isolated balls o f connective tissue were seen in single sections (Fig. 16). W h e n serial sections were examined, these balls were f o u n d to r e p r e sent tim b o d y o f a sclerosed a n e u r y s m as we lmve just described it. O f t e n hemosiderin laden macrophages were f o u n d adj a c e n t to the sclerosed aneurysms.
DISCUSSION
Tile present study does not bear directly u p o n tile frequency o f fibrinoid necrosis o r miliary aneurysms in cerebral h e m o r r l m g e nor does it p r o v e a causative relationship between these vascttlar changes and the h e m o r r h a g e . Nevertheless it is o f interest that one o r both changes were f o u n d so readily ill these t h r e e cases. In fact, in a series o f seven cases o f hemisplmric or p r i m a r y pontine h e m o r r h a g e s , one or both o f these changes
MILIARY ANEURYSMS AND " F I B R I N O I D " DEGENERATION-RosE,xaLO,Xt w e r e f o n l l d in five, e v e n t h o u g l l s e r i a l s e c t i o n s w e r e o b t a i n e d in f e w e r t l m n six b l o c k s p e r case. T h e s e cases w e r e r a n d o m l y s e l e c t e d a f t e r e l i m i n a t i n g cases o f h e m o r r l m g e d u e to c o n g e n i t a l " b e r r y " aneurysm, lenkemia, and aplastic anemia. The fi'equency of these findings, even after modest search, suggests that either t h e n e c r o t i c vessel o r t h e a n e u r y s m m a y r u p t n r e to i n i t i a t e a m a s s i v e h e m o r r h a g e , e i t h e r d i r e c t l y o r i n d i r e c t l y . ~~ H o w e v e r ,
in at l e a s t o n e p t t b l i s h e d i n s t a n c e s e r i a l s e c t i o n s f a i l e d to r e v e a l e i t h e r m i l i a r y a n e u r y s m s o r f i b r i n o i d a t t h e sites o f r e c e n t vessel r u p t u r e , a l t h o u g h t h e a t t t h o r c o u l d 1tot r u l e o u t t h e possibility t h a t m i n u t e foci o f f i b r i n o i d h a d b e e n d e s t r o y e d b y t h e r u p t u r e at t h e s e s i t e s ? ~ T h e presence of many sclerosed aneurysms indicates that "healing" may occur presumably by organization of thrombus within t h e a n e n r y s m a l sac, a n d t h a t b l e e d i n g o f
Figures 11 and 12. Black elastic lamellae are found both at tile origin of a fibrous ball (Fig. 1 1) and at distal portions of its circumference (Fig. 12), thus iqdicating its derivation from all arterial aneur)snL (Verhoeffvan (;ieson stain, x !00.) Figures 13 and" 14. Figure 14 shows another fibrous ball with black elastica at its origin and at several points arotmd its circunfference. Figttre 13 is a higher magnification, showing the origin of the ball from a small parenchymal artery, which displays well developed elastic tissue. (Verhoeff-van (;ieson staiq. Fig. 13, x400. Fig. 14, • 100.) Figures 15 and 16. An apparently isolated fibrous ball is seen in Figure 16. The identity of such structures with "'sclerotic" aneurysms and their derivation from smaller arteries are not recognized unless sections are obtained that show their origin from small vessels or tlmt indicate the presence of arterial structures, such as elastic tissue, within the ball. Wavy black elastic lamellae around the circumference were readily demonstrable as indicated b}" the higher magnification in Figure i 5. (Verhoeff-van Gieson stain. Fig. ! 5, x 800. Fig. 16, • 100.)
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HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 2 March 1977 massive proportions need not occur as part o f the natural history o f miliary aneurysms. On the o t h e r hand, the presence o f hemosiderin laden macroplmges, in the vicinity o f sclerosed aneurysms and adj a c e n t to vessels u n d e r g o i n g fibrinoid necrosis, suggests that m i n o r leakage o f red cells is c o m m o n . T h e presence o f clearl); identified wall r e m n a n t s in the f o r m o f elastic tissue in the walls o f the sclerosed aneurysms, as well as in the walls o f patent aneurysms, strongly indicates that these are " t r u e " aneurysms. This is particularly i m p o r t a n t in the case o f the sclerosed aneurysms, since it indicates that these are not merely o r g a n i z e d extravasations o f blood outside o r adjacent to r u p t u r e d vessels. O t h e r workers have also recognized fibrous balls as sclerosed miliary aneurysms. T M Coles and Yates 3 have shown how a n t u n b e r o f the aneurysxns described by others may well be false aneurysms and suggest that this may be the case with some a n e u r y s m s illustrated by Charcot and B o u c h a r d . TM H o w e v e r , t h e r e is no d o u b t f r o m the description o f Charcot and B o u c h a r d that they in addition did describe true miliary aneurysms, to which their names are sometimes given as an e p o n y m . Ross-Russell, 7 who d e m o n s t r a t e d large n u m b e r s o f t r u e aneurysms by injection m e t h o d s and histologic studies, dismisses the question o f p s e u d o a n e u r y s m s versus true a n e u r y s m s as a s e n l a n t i c o n e , deriving from an a r g u m e n t as to w h e t h e r the adventitia o f a p a r e n c h y m a l blood vessel is derived f r o m the blood vessel p r o p e r o r f r o m the pia. According to Ross-Russell, some workers have c o n s i d e r e d these aneurysnls to be p s e u d o a n e u r y s m s merely because they believed the aneurysmal adventitial wall to be derived from pia r a t h e r than the vessel p r o p e r . G r e e n 2 raises this question, and this may account for the impression that he was describing a p s e u d o a n e u r y s m . 1 Cole and Yates 3 on the o t h e r hand clearly indicate that pseudoa n e u r y s m s are extravascular extravasations o f blood and fibrin a n d o u g h t not to be confused with the aneurysms described by Green. As already noted, the aneurysms described in o u r own material are true a n e u r y s m s confined by the blood vessel wall. T h e relationship o f the fibrinoid #
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c h a n g e to the formation o f the microa n e u r y s m s has not been established. In fact, the present study has shown that aneurysmal dilation can occur with only focal or absent fibrinoid. T h e presence o f fibrinoid in the walls o f miliary aneurysms has been illustrated by Ross-RusselF and probably by Green, 2 a m o n g others. Alt h o u g h it seems reasonable to assume that the fibrinoid change represents vessel weakness a n d that dilation may follow that weakness, there is fairly conclusive evidence f r o m studies of renal arterioles that fibrinoid d e g e n e r a t i o n may follow r a t h e r than p r e c e d e dilation. 13 O n e o f o u r cases suggests tlmt fibrinoid necrosis may occur simultaneously with but i n d e p e n d e n t o f a n e u r y s m formation, since in this case (Figs. 1 to 3) fibrinoid was n o t e d in surface arteries, a site at which miliary aneurysms have not been r e p o r t e d (e.g., ref. 12). On the o t h e r hand, the same case seems to display a surface vessel that does show an a n e u r y s m a l dilation with fibrinoid completely replacing the a n e u r y s m wall (Fig. 3). With respect to the fibrinoid change itself, we must point out that inflammatory cells, o f either the chronic o r the acute variety, were rarely if ever seen within o r adjacent to the diseased vessels we have studied. T h i s is in keeping with the descriptions o f Fisher, ~~ G r e e n , 2 and others, although Feigen and Prose 6 describe such i n f l a m m a t o r y clmnges. Because o f the freq u e n t absence o f a cellular infiltrate, we believe that the term "arteritis" is a ntisn o m e r if applied to the fibrinoid changes described here. In addition, the t e r m "fibrinoid" should not be taken to m e a n that only fibrin is present in the affected arterial wall. R a t h e r the term merely denotes material staining like fibrin, which may contain not only fibrin but o t h e r substances that may require more sophisticated tests for identification. Finally, the relationship o f fibrinoid change a n d miliary aneurysms to h y p e r tension should be discussed. Ross-Russell 7 has stated that the aneurysms occur in o l d e r normotensive individuals and that their fi'equency is increased and the age o f onset is accelerated by hypertension. U n f o r t u n a t e l y in his extensive and valuable study, hypertension was defil~ed as including those patients with a difistolic
MILIARY ANEURYSMS AND "FIBRINOID" DEGENERATION-RosE,~nLU.Xt pressure over 1 10 mm. Hg, a n d tiros tim normotensive g r o u p may well have included patients who were hypertensive by m a n y s t a n d a r d criteria. In fact, nine o f Iris normotensive patients had large hearts, often a sign o f hypertension. O f tim three cases described in tim present report, one had n o r m a l blood pressure but an enlarged heart. Anotlter had a n o r m a l size heart, but diastolic pressures were occasionally hypertensive d u r i n g the terminal admission. Tiros, we do not feel that o u r studies o r tim best available literature really decides the issue o f a necessary o r causal relationslfip between h y p e r t e n s i o n and either nfiliary aneurysms o r fibrinoid change. We can say that h y p e r t e n s i o n often accontpanies the latter. Wlmt is clear, in addition, is tlmt malignant h y p e r t e n s i o n or accelerated h y p e r t e n s i o n is definitely not a prerequisite for the cerebrovascular clmnges we have been discussing. Tiffs is true w h e t h e r o n e uses blood pressure levels or fibrinoid c h a n g e o f renal and o t h e r visceral arteries or arterioles as the criterion for calling the h y p e r t e n s i o n malignant o r accelerated. T h u s , at least two o f o u r patients failed to show any criteria o f malignant hypertension. O t h e r s lmve had sintilar experience3 Since the fibrinoid change in cerebral vessels d u r i n g benign hypertension (or n o r m o t e n s i o n ) is indistinguislmble histologically from the clmnges o c c u r r i n g in visceral vessels during malignant hypertension, it may be that cerebral vessels are m o r e sensitive than extracerebral vessels to some c o m m o n factor(s) p r o d u c i n g the fibrinoid change, and tlmt these factor(s) can o p e r a t e even in the absense o f clinically manifest h y p e r t e n sion.
SUMMARY T h r e e cases are described with fibrinoid d e g e n e r a t i o n o f cerebral arteries and arterioles o r miliary aneurvsnts. Fibrous balls are shown to be scleros'ed'true aneurysnts. T h e s e clmnges o c c u r r e d in the absence o f malignant h y p e r t e n s i o n attd perlmps in tim absence o f an)" h y p e r t e n sion. A t i m b e r point o f interest was tim finding o f fibrinoid at tim site o f a p p a r e n t a n e u r y s m f o r m a t i o n in a small artery on the cerebral surface, a location at which miliary a n e u r y s m s are not generally
thougilt to form. T h e presence o f intracerebral h e m o r r h a g e in all three cases a n d the r e a d y d e m o n s t r a t i o n o f silnilar changes in o t h e r cases o f intracerebrai h e m o r r h a g e suggest but do not p r o v e that tim fibrinoid d e g e n e r a t i o n or a n e u rysm leads to vessel r u p t u r e and the h e m o r r l m g e itself. Also unsettled is tim qnestion o f w h e t h e r tim miliary a n e u r y s m forms only at sites already displaying fibrinoid clmnge. O n tiffs point o u r data tend to s u g g e s t tlmt pre-existing fibrinoid may n o t be a prerequisite for miliary a n e u r y s m formation.
REFERENCES 1. Blackwood,W., Mc,Meneme)', W. H., Me)er, A., Norman, R. M., and Russell, D. S.: Greenfield's Neuropathology. London, Edward Arnold, 1969, p. 1. 2. Green, F. H. K.: Miliary aneurysms in the brain. J. Path. Bact.,33:71-77, 1930. 3. Cole, F. M., and Yates, P.: Intracerebral microaneurisms and small cerebrovascular lesions. Brain, 90:759-768, 1967. 4. Adams, R. D., and Sidman, R. C.: Introduction to Neuropathology. New York, McGraw-Hill Book Company, 1968. 5. Schlager, U. T.: Basic Neuropathology. Baltimore, The Williams & Wilkins Co., 1970. 6. Feigen, I., and Prose, P.: Hypertensive fibrinoid arteritis of the brain and gross cerebral hemorrhage. A form of "hyaliuosis." Arch. Neurol., 1:98-110, 1959. 7. Ross-Russell, R. W.: Observations on intracerebral aneurysms. Brain, 86:425-443, 1963. 8. Esconrolle, R., and Poirier, J..: Manual of Basic Neuropathology. Philadelphia, W. B. Saunders Company, 1973. 9. Zeek, P. M.: The weight of the normal human heart. Arch. Path., 34:820-832, 1942. I0. Fisher, C. M.: Pathologicalobservations in hypertensive cerebral helnorrhage. J. Neuropath. Exp. Neurol.,30:536-550, 1971. 11. Goto, I., Kimoto, K., Katsuki, S., Minmtsu, T., and Ikui, H.: Pathological studies on the intracerebral and retinal arteries in cerebrovascular and noncerebrovascular diseases. Stroke, 6:263-269, 1975. 12. Charcot, J. M., and Bouchard, C.: Nouvelles recherches sur la pathog6ne de l'hemorrhagie cdrdbale. Arch. Physiol., I:110-227, 643-665, 725-755, 1868. 13. Hill, G. S., and tleptinstall, R. H.: Steroid induced hypertension in the rat. A microangiographic and histologic study on the pathogenesis of hypertensive vascular and glomerular lesions. Am.J. Path., 52:1-40, 1968. Division of Nenropathology Medical College of Virginia Box 17, MCV Station Richmond. Virginia 23298
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Abstract T h r e e cases o f intracerebral h e m o r r i m g e are described in which there was fibrinoid d e g e n e r a t i o n o f cerebral arteries and arterioles o r miliary aneurysms o r both. Fibrous balls are shown to be sclerosed true aneurysms. T h e s e clmx.lges o c c u r r e d in the absence o f malignant h y p e r t e n s i o n and p e r h a p s in the absence o f any hypertension. A fl~rther point o f interest was the finding o f fibrinoid at the site o f a p p a r e n t a n e u r y s m forlnation in a small a r t e r y on the cerebral surface, a location at which miliary aneurysms are not generally tlmught to form. T h e presence o f intracerebral h e n m r r l m g e in all t h r e e cases, and the r e a d y d e m o n s t r a t i o n o f similar clmnges in o t h e r cases o f intracerebral h e m o r r h a g e , suggest but do not prove that the fibrinoid d e g e n e r a t i o n o r aneurysm leads to vessel r u p t u r e and to h e m o r r h a g e itself. Also unsettled is the question o f w h e t h e r miliary a n e u r y s m s form only at sites already displaying fibrinoid cimnge. O u r data suggest tlmt pre-existing fibrinoid may not be a prerequisite f o r miliary a n e u r y s m formation.
T h e existence, cause, fate, and clinical significance o f miliary a n e u r y s m s are often assumed to be well known. Nevertheless there appears to be considerable confi~sion about these issues. For example, the last edition o f Greenfield's Neuropatholog')a still describes these miliary a n e u r y s m s as p s e u d o a n e u r y s m s while at the same time citing G r e e n z (as do Cole and Yates 3) as having described true aneurysnas. A n o t h e r text describes true a n e u r y s m s o f miliary size but at the same time uses the term "miliary a n e u r y s m " to include the organized l l e m o r r h a g e a r o u n d the r u p t u r e d aneurysm. 4 Still a n o t h e r recent text cites aneur)'snas as a cause o f cerebral h e m o r rlmge, but the impression is given that they
are a cerebral manifestation o f vascular (so-called "fibrinoid") necrosis secondary to malignant hypertension, wit!l accompanying necrosis o f renal arterioles. 5 In contrast, tile a n e u r y s m s and the fibrinoid c h a n g e o f cerebral arteries actually o c c u r in benign Iiyperteusion and even in apparently n o r m o t e n s i v e patients5 ,7 In a basic manual o f n e u r o p a t h o l o g y the aneurysms are r e f e r r e d to as a major cause o f hypertensive h e m o r r h a g e but a r e n o t described filrther, s T h e following r e p o r t describes o u r findi/'lgs after serial section o f portions o f tissue f r o m three patients, all o f w h o m were over the age o f 60 but only o n e o f whom had clinical hypertension. T h e pur-
*Professor of Pathology, Divisiou of Neuropathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia.
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HUMAN PATHOLOGY--VOLUME 8, NUMBER 2 March 1977 pose of this report is to illustrate the sequence of changes thought to parallel aneurysm formation and "healing," to illustrate the true aneurysmal nature of the lesions, to indicate that these formations appear to be associated not only with massive hemorrhage but also with small hemorrhages of indeterminate age, and to emphasize the capacity of these lesions to occur not only in the absence of malignant hypertension but in the absence of any clinically diagnosable hypertension. S Y N O P S I S OF C L I N I C A L F E A T U R E S
T h e patients were 61,74, and 80 years old, one male and two females, respectively. The male had had a history of essential hypertension for four ),ears with blood pressures reaching 250/145. There was no history of neurologic deficit prior to the sudden onset of unconsciousness with death eight days later. T h e clinical diagnosis was intracerebral hemorrhage. T h e 74 year old woman had had no history of neurologic deficit prior to admission with mild right hemiparesis, aphasia, and right homonymous hemianopsia. Infarction of the left cerebral llemisphere was the clinical diagnosis. She improved and then was found dead on day 11. She had been seen at irregular intervals by a physician for at least the last 10 years of her life, and hypertension was never observed. In the 80 year old woman there was a sudden onset of coma with bloody cerebrospinal fluid, and she died in 24 hours. During the admission, diastolic pressure varied from 80 to 130. METHODS
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In each case an autopsy was performed, including examination of the brain, which was fixed in 20 per cent formalin for at least one week prior to sec; tioning. After coronal sectioning and tile taking of blocks for routine stud)', several blocks were taken at a distance from the areas of fresh hemorrhage and were studied by serial section. These were from the basal ganglia in case 1, the cerebral hemisphere (white matter and cortex) in
case 2, basal ganglia and thalanms in case 2, thalamus in case 3, and basis pontis in case 3. The following stains were employed on the paraffin embedded material from both brain and abdominal viscera: hematoxylin and eosin, Verhoeff-van Gieson, and azocarmine. The latter stains collagen or collagenous "hyalin" blue and fibrin red or orange. 6 Thus the stain distinguishes vessel walls that are merely sclerotic or "lwalinized" from walls that contain material that stains like fibrin and that are said to have undergone "fibrinoid" degeneration. G RESULTS General A utopsy
In cases 1 and 2 the heart weighed 750 grams and 400 grams, respectively. In both cases there was nephrosclerosis and in case 2 an adrenocortical adenoma. The heart of the third patient weighed 260 grams; this is a normal weight even for a woman of her short length (150 cm.)P In none o f the three cases was arterial or arteriolar necrosis found outside the brain.
Neuropathology Apart from the vascular pathologic changes to be described later, the major findings in the three cases were as follows: Case 1 displayed fi'esh hemorrhage ill the left parieto-occipital area involving principally the white matter and sparing the diencephalon. Ill addition there was an old slit hemorrhage in each putamen and a small tmruptured vascular malformation in the cerebellum. Case 2 displayed a fi'esh hemorrhage predominantly in the white matter of the left occipital lobe. Case 3 displayed a massive fresh hemorrhage in the right cerebral hemisphere, extending into the ventricle and the subarachnoid space. In the diencephalon there were several old slit hemorrhages appreciated 0nly after microscopic examination. A fresh secondary brain stem hemorrhage was also present. The microscopic changes may be divided into three kinds. First, "fibrinoid" degeneration defined by the presence of material staining like fibrin in the,vessel
M I L I A R Y A N E U R Y S M S AND " F I B R I N O I D " DEGENERATION--RosE,~nI.uM
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Figure 1. The dark material within the vessel wall (arrows) is red "fibrinoid'" segmentally arranged in the wall of an arteriole in a sulcus. (Azocarmine stain, x 100.) Figure 2. Higher magnification of "fibrinoid'" within the wall of the vessel seen in Figure I. (x400.) Figure 3. Another vessel in the subarachnoid space displays a bulbous swelling of its wall with replacement of the normal structure by amorphous red "fibi-inoid." A narrow lumen passes from the center of the figure to the upper right hand corner. (Azocarmine stain, x400.) Figure 4. A parenchymal arteriole is shown with its wall completely replaced by amorphous "'fibrinoid," stained red either b)' hematoxyliu and eosin or by azocarmiue. The perivascular area contains loose connective tissue and hemosideriu laden macrophages. (Hematoxyliu and eosin stain, x400.) Figure 5. Two small arteries side by side in subarachnoid space. The one on the left displays wall replaced by "fibrinoid." (Azocarufine staiq, x400.) Figure 6. l'arench)'mal arteriole shows a segmental arrangement of somewhat granular "fibrinoid" material within a vessel wall, bulging to the right (arrows). The wall on the left is extremely attenuated. Similar attenuation is also illustrated at the bottom of the involved vessel in Figure 2. (Azocarmine stain, x400.)
wall: 6 T h i s m a t e r i a l was f o u n d in cases 2 a n d 3. It was o f t e n s e g m e n t a l l y a r r a n g e d so t h a t o n l y a p o r t i o n o f t h e c i r c u m f e r e n c e was i n v o l v e d in a g i v e n cross s e c t i o n (Figs. 1 to 3). T h e vessels i n v o l v e d w e r e small a r t e r i e s in t h e s u b a r a c h n o i d s p a c e (Figs. 1 to 3, 5) o r s m a l l e r a r t e r i e s a n d a r t e r i o l e s
w i t h i n tile p a r e n c h y m a . T h e s m a l l e r o f tile i n v o l v e d vessels w e r e m o s t likely to s h o w total i n v o l v e m e n t o f t h e w h o l e c i r c u m f e r e n c e (Fig. 6). T h e s e vessels h a d a " s m u d g y " e o s i n o p b i l i c wall, w h i c h s t a i n e d like f i b r i n with t h e a z o c a r m i n e stain. 6 S m u d g y art e r i o l e s w e r e n o t c o n s i d e r e d to h a v e fi-
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HUMAN P A T I t O L O G Y - V O L U M E 8, NUMBER 2 3lalrh 1977 9
-
- ' ~
. . . . . .
Figures 7 and 8. Different levels o f same l)arenchymal vessel slmwing "parent" artery at upper right and aneurysmal dilation. "Fibrinoid" material is seen within the aueurysm wall (arrows) and slmuld not be confused with erythocytes, which also stain darkly. (Azocarmine stain, x 100.) 9 Figure 9. Aneurysmal dilation arising from parenclwmal artery on left. Elastic tissue is seen as a dark band just beneath the intima of both the parent a r t e r y a n d the aneurysm. (Verhoeff-van Gieson stain, x 100.) Figure 10. A "fibrous" ball filled with loose, blue staining connective tissue arises from an artery by a thin neck or istlmms. This structure is delineated by arrows and represents the fibrosis of an aneurysm wall and its contents (Azocarmine stain. X 100.)
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brinoid d e g e n e r a t i o n unless the azocarmine stain was positive. In several instances t h e r e were h e m o s i d e r i n laden macropimges in the perivascular zone a r o u n d such vessels (Fig. 4). Aneurysmal dilatations with patent lumens were observed arising from stnall p a r e n c h y m a l arteries in cases 2 and 3 (Figs. 7 to 9). We were not able to d e m o n s t r a t e fibrinoid in the p a r e n t branch. However, material staining like fibrin often a p p e a r e d in several loci within the walls o f the dilated aneurysmal zone (Figs. 3, 8). Altlmttgll devoid o f muscularis, tim aneurysmal walls often contained retnnants o f elastic tissue. Finally, in addition to patent aneurysms, sclerosed a n e t l r y s n l s w e r e seen. These" were f o t m d in all cases. T h e y consisted o f flask slmped collections o f collagen, j o i n e d to a small artery by a n a r r o w neck (Fig. 10). T h e V e r h o e f f elastic stain showed that tim neck, the proxitnal portion o f the a n e u r y s m p r o p e r , and i n d e e d portions o f the c i r c u m f e r e n c e opposite
the neck contained elastic tissue (Figs. 11 to 15). Scattered isolated balls o f connective tissue were seen in single sections (Fig. 16). W h e n serial sections were examined, these balls were f o u n d to r e p r e sent tim b o d y o f a sclerosed a n e u r y s m as we lmve just described it. O f t e n hemosiderin laden macrophages were f o u n d adj a c e n t to the sclerosed aneurysms.
DISCUSSION
Tile present study does not bear directly u p o n tile frequency o f fibrinoid necrosis o r miliary aneurysms in cerebral h e m o r r l m g e nor does it p r o v e a causative relationship between these vascttlar changes and the h e m o r r h a g e . Nevertheless it is o f interest that one o r both changes were f o u n d so readily ill these t h r e e cases. In fact, in a series o f seven cases o f hemisplmric or p r i m a r y pontine h e m o r r h a g e s , one or both o f these changes
MILIARY ANEURYSMS AND " F I B R I N O I D " DEGENERATION-RosE,xaLO,Xt w e r e f o n l l d in five, e v e n t h o u g l l s e r i a l s e c t i o n s w e r e o b t a i n e d in f e w e r t l m n six b l o c k s p e r case. T h e s e cases w e r e r a n d o m l y s e l e c t e d a f t e r e l i m i n a t i n g cases o f h e m o r r l m g e d u e to c o n g e n i t a l " b e r r y " aneurysm, lenkemia, and aplastic anemia. The fi'equency of these findings, even after modest search, suggests that either t h e n e c r o t i c vessel o r t h e a n e u r y s m m a y r u p t n r e to i n i t i a t e a m a s s i v e h e m o r r h a g e , e i t h e r d i r e c t l y o r i n d i r e c t l y . ~~ H o w e v e r ,
in at l e a s t o n e p t t b l i s h e d i n s t a n c e s e r i a l s e c t i o n s f a i l e d to r e v e a l e i t h e r m i l i a r y a n e u r y s m s o r f i b r i n o i d a t t h e sites o f r e c e n t vessel r u p t u r e , a l t h o u g h t h e a t t t h o r c o u l d 1tot r u l e o u t t h e possibility t h a t m i n u t e foci o f f i b r i n o i d h a d b e e n d e s t r o y e d b y t h e r u p t u r e at t h e s e s i t e s ? ~ T h e presence of many sclerosed aneurysms indicates that "healing" may occur presumably by organization of thrombus within t h e a n e n r y s m a l sac, a n d t h a t b l e e d i n g o f
Figures 11 and 12. Black elastic lamellae are found both at tile origin of a fibrous ball (Fig. 1 1) and at distal portions of its circumference (Fig. 12), thus iqdicating its derivation from all arterial aneur)snL (Verhoeffvan (;ieson stain, x !00.) Figures 13 and" 14. Figure 14 shows another fibrous ball with black elastica at its origin and at several points arotmd its circunfference. Figttre 13 is a higher magnification, showing the origin of the ball from a small parenchymal artery, which displays well developed elastic tissue. (Verhoeff-van (;ieson staiq. Fig. 13, x400. Fig. 14, • 100.) Figures 15 and 16. An apparently isolated fibrous ball is seen in Figure 16. The identity of such structures with "'sclerotic" aneurysms and their derivation from smaller arteries are not recognized unless sections are obtained that show their origin from small vessels or tlmt indicate the presence of arterial structures, such as elastic tissue, within the ball. Wavy black elastic lamellae around the circumference were readily demonstrable as indicated b}" the higher magnification in Figure i 5. (Verhoeff-van Gieson stain. Fig. ! 5, x 800. Fig. 16, • 100.)
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HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 2 March 1977 massive proportions need not occur as part o f the natural history o f miliary aneurysms. On the o t h e r hand, the presence o f hemosiderin laden macroplmges, in the vicinity o f sclerosed aneurysms and adj a c e n t to vessels u n d e r g o i n g fibrinoid necrosis, suggests that m i n o r leakage o f red cells is c o m m o n . T h e presence o f clearl); identified wall r e m n a n t s in the f o r m o f elastic tissue in the walls o f the sclerosed aneurysms, as well as in the walls o f patent aneurysms, strongly indicates that these are " t r u e " aneurysms. This is particularly i m p o r t a n t in the case o f the sclerosed aneurysms, since it indicates that these are not merely o r g a n i z e d extravasations o f blood outside o r adjacent to r u p t u r e d vessels. O t h e r workers have also recognized fibrous balls as sclerosed miliary aneurysms. T M Coles and Yates 3 have shown how a n t u n b e r o f the aneurysxns described by others may well be false aneurysms and suggest that this may be the case with some a n e u r y s m s illustrated by Charcot and B o u c h a r d . TM H o w e v e r , t h e r e is no d o u b t f r o m the description o f Charcot and B o u c h a r d that they in addition did describe true miliary aneurysms, to which their names are sometimes given as an e p o n y m . Ross-Russell, 7 who d e m o n s t r a t e d large n u m b e r s o f t r u e aneurysms by injection m e t h o d s and histologic studies, dismisses the question o f p s e u d o a n e u r y s m s versus true a n e u r y s m s as a s e n l a n t i c o n e , deriving from an a r g u m e n t as to w h e t h e r the adventitia o f a p a r e n c h y m a l blood vessel is derived f r o m the blood vessel p r o p e r o r f r o m the pia. According to Ross-Russell, some workers have c o n s i d e r e d these aneurysnls to be p s e u d o a n e u r y s m s merely because they believed the aneurysmal adventitial wall to be derived from pia r a t h e r than the vessel p r o p e r . G r e e n 2 raises this question, and this may account for the impression that he was describing a p s e u d o a n e u r y s m . 1 Cole and Yates 3 on the o t h e r hand clearly indicate that pseudoa n e u r y s m s are extravascular extravasations o f blood and fibrin a n d o u g h t not to be confused with the aneurysms described by Green. As already noted, the aneurysms described in o u r own material are true a n e u r y s m s confined by the blood vessel wall. T h e relationship o f the fibrinoid #
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c h a n g e to the formation o f the microa n e u r y s m s has not been established. In fact, the present study has shown that aneurysmal dilation can occur with only focal or absent fibrinoid. T h e presence o f fibrinoid in the walls o f miliary aneurysms has been illustrated by Ross-RusselF and probably by Green, 2 a m o n g others. Alt h o u g h it seems reasonable to assume that the fibrinoid change represents vessel weakness a n d that dilation may follow that weakness, there is fairly conclusive evidence f r o m studies of renal arterioles that fibrinoid d e g e n e r a t i o n may follow r a t h e r than p r e c e d e dilation. 13 O n e o f o u r cases suggests tlmt fibrinoid necrosis may occur simultaneously with but i n d e p e n d e n t o f a n e u r y s m formation, since in this case (Figs. 1 to 3) fibrinoid was n o t e d in surface arteries, a site at which miliary aneurysms have not been r e p o r t e d (e.g., ref. 12). On the o t h e r hand, the same case seems to display a surface vessel that does show an a n e u r y s m a l dilation with fibrinoid completely replacing the a n e u r y s m wall (Fig. 3). With respect to the fibrinoid change itself, we must point out that inflammatory cells, o f either the chronic o r the acute variety, were rarely if ever seen within o r adjacent to the diseased vessels we have studied. T h i s is in keeping with the descriptions o f Fisher, ~~ G r e e n , 2 and others, although Feigen and Prose 6 describe such i n f l a m m a t o r y clmnges. Because o f the freq u e n t absence o f a cellular infiltrate, we believe that the term "arteritis" is a ntisn o m e r if applied to the fibrinoid changes described here. In addition, the t e r m "fibrinoid" should not be taken to m e a n that only fibrin is present in the affected arterial wall. R a t h e r the term merely denotes material staining like fibrin, which may contain not only fibrin but o t h e r substances that may require more sophisticated tests for identification. Finally, the relationship o f fibrinoid change a n d miliary aneurysms to h y p e r tension should be discussed. Ross-Russell 7 has stated that the aneurysms occur in o l d e r normotensive individuals and that their fi'equency is increased and the age o f onset is accelerated by hypertension. U n f o r t u n a t e l y in his extensive and valuable study, hypertension was defil~ed as including those patients with a difistolic
MILIARY ANEURYSMS AND "FIBRINOID" DEGENERATION-RosE,~nLU.Xt pressure over 1 10 mm. Hg, a n d tiros tim normotensive g r o u p may well have included patients who were hypertensive by m a n y s t a n d a r d criteria. In fact, nine o f Iris normotensive patients had large hearts, often a sign o f hypertension. O f tim three cases described in tim present report, one had n o r m a l blood pressure but an enlarged heart. Anotlter had a n o r m a l size heart, but diastolic pressures were occasionally hypertensive d u r i n g the terminal admission. Tiros, we do not feel that o u r studies o r tim best available literature really decides the issue o f a necessary o r causal relationslfip between h y p e r t e n s i o n and either nfiliary aneurysms o r fibrinoid change. We can say that h y p e r t e n s i o n often accontpanies the latter. Wlmt is clear, in addition, is tlmt malignant h y p e r t e n s i o n or accelerated h y p e r t e n s i o n is definitely not a prerequisite for the cerebrovascular clmnges we have been discussing. Tiffs is true w h e t h e r o n e uses blood pressure levels or fibrinoid c h a n g e o f renal and o t h e r visceral arteries or arterioles as the criterion for calling the h y p e r t e n s i o n malignant o r accelerated. T h u s , at least two o f o u r patients failed to show any criteria o f malignant hypertension. O t h e r s lmve had sintilar experience3 Since the fibrinoid change in cerebral vessels d u r i n g benign hypertension (or n o r m o t e n s i o n ) is indistinguislmble histologically from the clmnges o c c u r r i n g in visceral vessels during malignant hypertension, it may be that cerebral vessels are m o r e sensitive than extracerebral vessels to some c o m m o n factor(s) p r o d u c i n g the fibrinoid change, and tlmt these factor(s) can o p e r a t e even in the absense o f clinically manifest h y p e r t e n sion.
SUMMARY T h r e e cases are described with fibrinoid d e g e n e r a t i o n o f cerebral arteries and arterioles o r miliary aneurvsnts. Fibrous balls are shown to be scleros'ed'true aneurysnts. T h e s e clmnges o c c u r r e d in the absence o f malignant h y p e r t e n s i o n attd perlmps in tim absence o f an)" h y p e r t e n sion. A t i m b e r point o f interest was tim finding o f fibrinoid at tim site o f a p p a r e n t a n e u r y s m f o r m a t i o n in a small artery on the cerebral surface, a location at which miliary a n e u r y s m s are not generally
thougilt to form. T h e presence o f intracerebral h e m o r r h a g e in all three cases a n d the r e a d y d e m o n s t r a t i o n o f silnilar changes in o t h e r cases o f intracerebrai h e m o r r h a g e suggest but do not p r o v e that tim fibrinoid d e g e n e r a t i o n or a n e u rysm leads to vessel r u p t u r e and the h e m o r r l m g e itself. Also unsettled is tim qnestion o f w h e t h e r tim miliary a n e u r y s m forms only at sites already displaying fibrinoid clmnge. O n tiffs point o u r data tend to s u g g e s t tlmt pre-existing fibrinoid may n o t be a prerequisite for miliary a n e u r y s m formation.
REFERENCES 1. Blackwood,W., Mc,Meneme)', W. H., Me)er, A., Norman, R. M., and Russell, D. S.: Greenfield's Neuropathology. London, Edward Arnold, 1969, p. 1. 2. Green, F. H. K.: Miliary aneurysms in the brain. J. Path. Bact.,33:71-77, 1930. 3. Cole, F. M., and Yates, P.: Intracerebral microaneurisms and small cerebrovascular lesions. Brain, 90:759-768, 1967. 4. Adams, R. D., and Sidman, R. C.: Introduction to Neuropathology. New York, McGraw-Hill Book Company, 1968. 5. Schlager, U. T.: Basic Neuropathology. Baltimore, The Williams & Wilkins Co., 1970. 6. Feigen, I., and Prose, P.: Hypertensive fibrinoid arteritis of the brain and gross cerebral hemorrhage. A form of "hyaliuosis." Arch. Neurol., 1:98-110, 1959. 7. Ross-Russell, R. W.: Observations on intracerebral aneurysms. Brain, 86:425-443, 1963. 8. Esconrolle, R., and Poirier, J..: Manual of Basic Neuropathology. Philadelphia, W. B. Saunders Company, 1973. 9. Zeek, P. M.: The weight of the normal human heart. Arch. Path., 34:820-832, 1942. I0. Fisher, C. M.: Pathologicalobservations in hypertensive cerebral helnorrhage. J. Neuropath. Exp. Neurol.,30:536-550, 1971. 11. Goto, I., Kimoto, K., Katsuki, S., Minmtsu, T., and Ikui, H.: Pathological studies on the intracerebral and retinal arteries in cerebrovascular and noncerebrovascular diseases. Stroke, 6:263-269, 1975. 12. Charcot, J. M., and Bouchard, C.: Nouvelles recherches sur la pathog6ne de l'hemorrhagie cdrdbale. Arch. Physiol., I:110-227, 643-665, 725-755, 1868. 13. Hill, G. S., and tleptinstall, R. H.: Steroid induced hypertension in the rat. A microangiographic and histologic study on the pathogenesis of hypertensive vascular and glomerular lesions. Am.J. Path., 52:1-40, 1968. Division of Nenropathology Medical College of Virginia Box 17, MCV Station Richmond. Virginia 23298
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