- Email: [email protected]
Unusual clinical manifestations of cystic medionecrosis—Report of a case
Case reports
Unusual
clinical
manifestations
medionecrosis-Report
of cystic
of a case
T. F. Tse, M.B. Donald Y. C. Yu, M.R.C.P.E. Hong Kong
c
ystic medionecrosis has been a distinct pathological entity since the autopsy studies of Erdheim1v2 and Rottino.3 The clinical manifestations reported have been either that of dissecting and localized aneurysms of the aorta or aortic insufficiency. Hence, diagnosis could only be made from autopsy, or from specimens of aortic aneurysms removed during operation in recent years. The purpose of this report is to present a case of cystic medionecrosis involving medium-sized arteries and arterioles resulting in unusual clinical features and to give a brief review of the literature. Case report Y. S. C., a 40-year-old Chinese dental technician, was admitted as a casualty on July 10, 1969, to the University Medical Department of Queen Mary Hospital, Hong Kong, with sudden onset of left hemiplegia for five hours. Five years prior to admission, he first noticed a pulsating cord-like structure over the left temporal region of the scalp. Similar structures were then noticed at different sites of the scalp, being most prominent over the frontal and occipital regions. Three months before admission he developed an attack of sudden transient dizziness followed an hour later by paralysis, numbness, and anesthesia over the left side of the body and face. There was slurring of speech and deviation of the angle of the mouth to the right. He recovered spontaneously six hours later without any residual weakness. Since then he had ten similar episodes each lasting from 10 minutes to 6 to 7 hours. Each attack
was unprovoked and was preceded by a short period of dizziness. All the attacks involved the left side of the face and body, except for one attack affecting the right arm alone. Throbbing frontal headache unrelated to posture or time of the day was sometimes present but never prominent. There was no loss of consciousness or disturbances of bladder and bowel. Ten days before admission he experienced dizziness and sudden blurring of vision of the left eye. This improved only very gradually and persisted up to the time of his admission. He noticed that his skin was getting coarse, dry, and progressively rough for the past three years, particularly over the front of his thighs. His past health was good and his family history was irrelevant. He had farmed in Mainland China for 10 years. Examination showed that he was of moderate body build, measuring 160 cm. in height and weighing 54 kilograms with an arm span of 160 cm. Features suggestive of Marfan’s Syndrome were absent. He was afebrile, fully conscious, and mentally clear, with no slurring of speech nor signs of meningeal irritation. The skin was generally coarse and was thickened and tight, especially over the front of both thighs. Joint laxity was absent. Two pulsatile vessels with aneurysmal dilatation were found (Fig. l), one on each side of the frontotemporal region,with two similar but nonpulsatile cordlike structures over the occipital area. No tenderness, thrill, or bruit was detected. The pulse was 80 per minute, regular, and all peripheral pulses were present. Blood pressure was 120/80 mm. Hg over both upper limbs and 130/80 mm. Hg over both lower limbs. The heart was not clinically enlarged and auscultation did not reveal any murmurs. He was found to have an upper motor neurone lesion
From the Department of Medicine, University of Hong Kong. Queen Mary Hospital. Hong Kong. Revived for publication Jan. 28, 1972. Reprint requests to: Dr. Donald Y. C. Pu. University Department of Medicine, Queen Mary Hospital.
794
American Heart Journal
December, 1972
Hong Kong.
Vol. 84, No. 6, pp. 794-800
Volume Ntcmber
84 6
affecting the left side of the body including the face. There was hypoesthesia and hypoalgesia over the left side of the body; postural and vibration senses remained intact. Right upper and lower limbs were normal. There was loss of vision in the lower half o[ the left visual field. The right optic fundus was normal: the left showed blurring of the superionasal margin of the optic disc, with narrowed arteries and veins in the upper half of the fundus, the rest of the fundus being normal. Hemorrhages or exudates were not seen. The lungs were clear and the abdomen was normal. The left pyramidal and spinothalamic tract lesions rapidly improved after admission and no residual signs were demonstrated by the next morning. He remained well during his stay in hospital, without any further attacks. His visual field gradually improved over a period of three months, and the fundal changes also disappeared at the same time. Investigations showed hemoglobin 14.5 Gm. per 100 ml.; packed cell volume 44 per cent; white blood count -12,200 with a differential count of PqELlrElnM~B”. The absolute eosinoohil count was _ ._ 2,442 per cubic mm. Erythrocyte sedimentation rate was 10 mm. the first hour. Urine examination showed no sugar, with proteinuria from 0.5 Gm. to 2.0 Gm. per 24 hours. Stool examination revealed a few rhabditiform larvae of strongyloides stercoralis. The absolute eosinophil count dropped to 400 per cubic mm. after a course of dithiazanine orally for two weeks for strongyloides infestation. Blood urea was 26 mg. per 100 ml.; creatinine was 0.8 mg. per 100 ml.; albumin/globulin ratio was 3.9/4.0; plasma protein electrophoresis showed albumin 40.8 per cent; (~1 globulin of 8.2 per cent; 012 14.3 per cent; @ 16.3 per cent; y 20.4 per cent. VDRL, Rheumatoid factor, antinuclear factor, and lupus erythematosus cells were negative. Chest x-ray was normal; electrocardiogram (ECG) was within normal limits with mean QRS vector of 0 degrees. Metacarpal index was 8.2. Barium swallow showed normal peristalsis with free flow of barium into the stomach; there was no filling defect nor other abnormalities. Trisorb resin sponge uptake of Ta was normal. Bilateral carotid cerebral angiogram was performed and revealed that the left cerebral arteries were filled from the right anterior cerebral by way of the anterior communicating artery. The vascular shadows on both hemispheres were normal in size and showed no displacement. Extracranial portion of the carotids was not visualized. Thoracic aortogram and vertebral angiogram were refused by the patient. Left temporal artery aneurysmectomy was done under local anesthesia. The aneurysm was dissected out in its entire length and resected. Postoperative period was uneventful. A similar procedure was carried out on the right temporal artery. Skin biopsy was taken over the front of the left thigh because of the peculiar thickening, and renal biopsy was done for persistent proteinuria.
Histopathology
Temporal artery aneurysm (Figs. 2 and 3). The resected blood vessel is about 1 cm. in length. At one end the vessel is thickened
Cystic medionecrosis
795
Fig. 1. Photograph showing patient’s right temporal and occipital artery aneurysms. Similar aneurysms are present on the left side.
and dilated. No dissection of vessel wall is seen. There is marked thickening of the intima and media with increase in interstitial mucin-like material stained by Alcian Blue. The elastica has been completely destroyed and no inflammatory reaction is seen. Z\Iany collaterals are present in the adventitia. Immunofluorescent staining to Ig(; and thioflavin T for amyloid are both negative. Right renal biopsy (Fig. 4). The glomeruli are essentially normal with no increase in cellularity or basement membrane thickening and immunofluorescent staining to both IgG and p,C globulins are negative. There are 2 markedly thickened arterioles near the glomerulus with markedly thickened intima and increase in Alcian Blue staining material in the media. Skin biopsy (Fig. 5). The epidermis showed features of hyperkeratosis and in the dermis a marked coarseness of the collagen bundles is noted. There is moderate increase in elastic tissue with fragmentation of the elastic fibers. Inflammatory reaction is absent and there is no increase in interstitial mucin-like material.
796
Am. Heart I. Dcwmber. 1972
Tse and Y2,
Fig. 2. Right temporal artery lumen and grossly thickened (Original magnification X25.5.)
showing narrowed media and intima.
Fig. 3. Right temporal artery with cysts of mucin material in the media and intima, stained by Alcian Blue. (Alcian Blue stain. Original magnification X450.)
Discussion
WieseP in 1906 first described medial changes of blood vessels in non-syphilitic young persons dying shortly after the onset of fulminating infections. This was probably the first description of medionecrosis. Since then, various degenerative changes of the media have been reported, including cyst-like areas filled with “gelatinous materia1,“6 scattered foci of “fatty degeneration,“7 and hyaline degeneration of interlamellar connective tissue.8 However, these latter types of degenerative changes were not supported by subsequent reports. It was Erdheimls2 who described the specific lesion in the medial coat of aorta as a focal ac-
Fig. 3. Renal terioles, with (Hematoxylin X450.)
biopsy. Two markedly normal glomerulus and and eosin. Original
Fig. 5. Skin biopsy. tissue, and fragmentation the dermis. (Weigert’s x 105.)
thickened arrenal tubules. magnification
Moderate increase in elastic of elastic fibers is seen in stain. Original magnification
cumulation of basophilic homogeneous material. Thus it has been known as Erdheim’s medionecrosis or medionecrosis aortae idiopathica cystica and has been considered to be a distinct pathological entity.3 The histology in described cases consisted of intimal thickening due to proliferation of fine collagen fibers separated by pale myxomatous tissue. The elastic lamellae were very variable but were often split and fragmented, separated by irregular cystic spaces containing basophilic amorphous material staining positively for connective tissue mucin with Alcian Blue preparation.s This was believed to represent collections of acid mucopolysaccha-
ride, predominantly chondroitin sulphate B and C.‘O Manley and Kent” presented further experimental studies and suggested that it was due to chondroitin sulphate C. In addition, large accumulation of dermatan sulphate or heparitin sulphate was found in the media of the resected aortic wall.‘” There was no evidence of atheroma or syphilis and inflammatory reaction was absent. Although Gore and Seiwert? demonstrated the preponderance of elastic degeneration in young individuals in contrast to the predominantly muscular necrosis in older patients, both types appeared to be part of the same general disease process.4 Pathological
significance
Pathologically, similar accumulation of mucoid material in the media of great vessels had been observed under several circumstances. 1. In “normal” aortas. Rottino3 demonstrated deposits of mucoid material in the aorta of 92 out of 210 routine autopsy cases, occurring more commonly in the older age group. This agrees with Schultz14 and Carlson and associates15who noted a progressive increase in this material in the senescent vessel. 2. Associated with congenital anomalies. Mucoid material can be found in the media of both normal embryos from 1 to 3 months old and in adults with hypoplastic aorta. Thus Costa-Florenzr6 suggested developmental disturbance as a cause of the degenerative changes. Identical changes were also observed in patients with cardiovascular malformations with right-to-left shunts” but here the primary cause was attributed to tissue anoxia. Medial degeneration with destruction of the elastica also occurs in coarctation of the aorta,‘* bicuspid aortic valves, and calcific aortic stenosis,lg possibly as a result of hemodynamic disturbances distal to the obstruction.20 3. Pregnancy. Acid mucopolysaccharide lakes occur frequently in the aorta during pregnancy, possibly secondary to hormonal influences.21 This can perhaps explain the greater frequency of dissecting aneurysms in pregnancy than in woman of the control group, particularly towards term.22 4. .Myxoedema. Descriptions on histology of aorta in myxoedema has been few. Three
patients who developed dissecting aneurysms after total thyroidectomy were found to have mucoid degeneration of the media.23 Another case was presented where histochemical exatnination revealed presence of acid mucopolysaccharide in the aortic wall of a patient suffering from myxoedema due to chronic atrophic thyroiditis.24 5. 2Clarfan’s Syndrome. The early changes of the aorta are those of medionecrosis,2j almost indistinguishable from cystic medial necrosis originally described by Erdheim. Changes resembling the early ones in the aorta are also found in the pulmonary arteries. Specifically, peripheral arteries have shown no abnormality, but studies in these areas are distressingly few.26 6. Rheumatic fever and Hydralazine syndrome. Pappenheimer and von Glahn2’ recognized changes closely resembling idiopathic medionecrosis occurring in collagen disease states as rheumatic fever. Meyer2s considered that the primary pathologic disturbance was in the amorphous ground substance. Hydralazine (apresoline) gives rise to “hydralazine syndrome” with similar pathological damage of the medial coat. This is possibly due to its strong affinity for metallic ions, thus resulting in a trace element (probably manganese) deficiency.“g However, that the pathology of myxoedema, rheumatic fever, and hydralazine resemblescystic medionecrosis is not agreed by all pathologists. Clinical sign$icance. Although the pathological associations of cystic medionecrosis are very variable, its clinical manifestations are not many. The clinical features are always a result of weakening of the vessel wall, and thus commonly affecting the ascending aorta which is mainly exposed to the distending forces of the left ventricular stroke output.” A review of the literature reveals the following syndromes: 1. Dissecting aneurysms of the aorta13p30 and other arteries, including basilar,31 left coronary,32 splenic, and renal arteries.33 2. Local aneurysms of aorta4J2*17 and other arteries, including hepatic,34 inferior gluteal,35 and subclavian arteries.‘O 3. Aortic valvular insuficiency which might be functional due to dilatation
798
Tse and Yu
of the aortic ring or with direct medionecrosis of the aortic valve.36 4. Rupture of the aorta due to thinning.37 To the above, we would like to add five other clinical features as illustrated by the patient here presented; i.e., 1. Multiple aneurysms of the extracranial arteries. Aneurysms of the temporal artery are rare. Non-traumatic aneurysms of the occipital artery must be exceedingly rare as 90 per cent of cases of temporal artery aneurysms were traumatic in origin. The others were considered arteriosclerotic, unclassified, and doubtfuL3* Guidaand Moore3g were able to find only 111 reported cases of aneurysms of the temporal artery in the literature up to 1968. Hagstrom and colleagues40 subsequently reported five more cases and considered that there were only 130 cases up to that time. It was unfortunate that the histological descriptions were usually not given in greater detail. The present case assumes significance not only because of its rarity but also because, to the best of our knowledge, this is the first reported case of temporal artery and occipital artery, and in fact, multiple extracranial artery aneurysms due to cystic medionecrosis. 2. Trartsient cerebral ischemia. The repeated attacks of transient hemiplegia and facial paralysis with spontaneous complete recovery within a few hours suggest a vascular lesion. Judging from the marked distensibility and smoothness of the vessel wall when the resected temporal artery was examined, it is not surprising that the vessels should appear normal in angiograms even when mucoid degeneration was present. However, since the origin of the common carotid and vertebral-basilar arteries were not visualized in the cerebral angiogram, a lesion in the extracranial portion of the carotid or vertebral-basilar artery which could also account for the transient ischemic episodes cannot be entirely ruled out. 3. Renal involvement. The persistent proteinuria which varied from ‘01.5 to 2
Am. Heart J. December, 1972
Gm. per day prompted us to do a renal biopsy. That vessels as small as the arterioles could be involved was a surprising finding. This could only mean that possibly all the vessels in the body, from the aorta to the arteriole, took part in the degenerative process, in contrast to the results of Milne and associates4’ who found that in their case the degenerative process did not extend into the branches of the aorta. 4. Retinal involvement. The retina changes are possibly due to thrombosis or emboli of a branch of retinal artery. Although unlike the renal changes, histological proof of involvement of the retinal vessels is lacking, it may be assumed that they were involved in a manner similar to the renal arterioles, unless embolization from extracranial arteries is again incriminated. This again suggests that medial degeneration is a generalized process rather than being limited to the aorta. 5. Skin Aanges. Skin changes associated with idiopathic cystic medionecrosis have never been described. However, skin changes occurring in filarfan’s Syndrome had been reported occasionally. These include scanty subcutaneous fat, laxity of ligaments, scaly areas of the feet, and hyperkeratosis of the toes, elastoma-like lesions, and acrosclerosis.42 The histopathology of the skin biopsy in this patient is most peculiar in that there is presence of coarse collagen bundles and fragmentation of the elastic fibers. Histologically this would suggest Ehlers-Danlos Syndrome, although clinical support from hyperelasticity of the skin is lacking. A recent clinical and histological study of the skin of 10 patients with Marfan’s Syndrome by Moretti and co-workers43 revealed changes very similar to, or identical with those in Ehlers-Danlos Syndrome, but with less marked hyperelasticity in the former group of patients. Hence, the skin changes in this patient need not be exclusive of Ehlers-Danlos Syndrome, but form part of the clinical picture of a gen-
Volume Numbev
84 6
Cystic medi0nrc.rosi.s
eralized mesenchymal disorder. In fact, Goodman and colleagues44 reported a case of combined EhlerDanlos and Marfan’s Syndromes. Erdheim’s medionecrosis or Marfan’s Syndrome. That this patient had medionecrosis of blood vessels was established by biopsies. Medionecrosis can be associated with many conditions (Marfan’s Syndrome, myxoedema, pregnancy, etc., see above) and has been produced in experimental animals by a number of techniques, including lathyrism,45-47 pyridoxine deficiency,48 and copper deficiency. 49 The mucoid component of the degenerative process merely represents one aspect of the body reaction.50 Whether this patient has Marfan’s Syndrome is highly debatable. Clinically there ere none of the stigmata characteristic of this syndrome and family studies are impossible because the other members of his family are living in Mainland China. However, this can still be Marfan’s Syndrome, for there are undoubtedly cases where aortic medionecrosis occurs without skeletal and ocular cllanges.26 Together with the skin changes observed in this patient, we believe that this is a formes frustes of Marfan’s Syndrome rather than Erdheim’s medionecrosis alone. It is also believed that many cases of Erdheim’s medionecrosis may be an incomplete form of Alarfan’s Syndrome.31-53 Summary
Although cystic medionecrosis of great vessels has been a well-known pathological entity, the diagnosis is usually made at autopsy. The clinical manifestations are often limited to the aorta, resulting in aneurysms and aortic insufficiency. Report is given of a case where the degenerative process involves medium-sized arteries and arterioles, giving rise to multiple aneurysms of the extracranial arteries, transient cerebral ischemia, persistent proteinuria and retinal involvement, associated with skin changes. Different pathological conditions where medionecrosis occur are reviewed. The relationship between Erdheim’s idiopathic cystic medionecrosis and Marfan’s Syndrome is briefly discussed. We wish to thank Dr. W. C. Chan, of Pathology, Queen Mary Hospital, for histological studies.
Department Hong Kong,
799
REFERENCES 1. Erdheim, J.: Medionecrosis aortae idiopathica, Virchows Arch. IPathol. Anat. 273:454. 1929. 2. Erdheim, J.: Medionecrosis aortae idiopathica cystic, Virchows Arch. [Pathol. Anat.] 276:187, 1930. 3. Rottino, A.: Medial degeneration of the aortnA study of 210 routine-autopsy specimens by a serial block method. Arch. Pathol. 28:377. 1939. 4. Bahnson, H. T., and Nelson, A. R.: Cystic medial necrosis as a cause of Iocalised aortic aneurysms amenable to surgical treatment, Ann. Surg. 144:519, 1956. 5. Wiesel, J.: Die Erkrankungen arteriellen pefaesse in Verlaufe akuter Infectionen, Z. Heilkd. 27:262, 1906. 6. Freedman, A.: Cyst of the wall of the carotid artery, Montreal Med. J. 38:.583, 1909. 7. Moriani, G.: Ueber einen Fall von Aneurysma dissecans aortae mit besonderer Berucksichtigung frischer Rupturen der Aortemedia, \‘irchows Arch. [Pathol. Anat.] 202:283, 1910. 8. Sailor, S.: Dissecting aneurysm of the aorta, Arch. Pathol. 33:704. 1942. 9. Persaud, I:.: Subclavian artery aneurysm and idiopathic cystic medionecrosis, Br. Heart J. 30:436, 1968. 10. Meyer, K., and Rapport, M. M.: Mucopolysaccharides of ground substance of connective tissue, Science 113:596, 1951. 11. Manley, G., and Kent, P. W.: Aortic mucopolysaccharides and metachromasia in dissecting aneurvsm, Br. J. Exp. Pathol. 44:635, 1963. 12. Sy%bas, -P. N., Baldwin, B. J., Silverman, M. E.. and Galambos. Svndrome -I. T.: Marfan’s with aneurysm of ascending aorta and aortic regurgitation, Am. J. Cardiol. 25:483, 1970. 13. Gore, I., and Seiwert, 1’. J.: Dissecting aneurysm of the aorta-pathological aspects: An analysis of eighty-five fatal cases, Arc?i. Pathol. 53:121, 19.57. 14. Schultz, A.: Ueber die chromotropie des Gefaessbindegewebes in ihrer physiologischen und pathologischen Bedeutune, insbesondere ihre Beziehungen zur Arteriosklerose, Vii-chows Arch. [Pathol. Annt.] 239:415, 1922. 1 j. Carlson, R. G., Lillehei, C. M’., and Edwards, J. E.: Cystic medial necrosis of the axending aorta in relation to age and hypertension, Am, I. Cardiol. 25:411, 1970. 16. Costa-Florenz, A. von: Normale and patholoeische Anatomie. Z. Kreislaufforsrh. 23:715. 1931. 17. Lopes de Faria, J.: Medionecrosis of the aorta with secondary arteriosclerosis in congenital cyanotic cardiac defects, Beitr. Pathol. Anat. 125:129, 1961. 18. Reifenstein, G. H., Levine, 5. A., and Gross, R. E.: Coarctation of the aorta. A review of 104 autopsied cases of the “adult” type two years of age or older. AM. HEART 1. 33:146. 1947. 19. McKusick, V. A., Logue, Ii. B., and Bahnson, H. T.: Association of aortic valvular disease and cystic medial necrosis of the ascending aorta, Circulation 16:188, 1957. 20. Heath, D., Edwards, J. E.. and Smith, C. A.:
Am. Heart J. December, 1972
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
The rheologic significance of medionecrosis and dissecting aneurysm of the ascending aorta in association with calcific aortic stenosis, Mayo Clin. Proc. 33:228, 1958. Merendino. K. A.. Winterscheid. L. C.. and billard, D.’ H.: Cystic medial necrosis with and without Marfan’s Syndrome, Surg. Clin. North Am. 47:1403, 1967. Becker, H., Hausler, H., and Maurer, H.: Aortenruptur und Graviditat, Geburtschilfe. Frauenheilkd. 26:944, 1966. Kountz, W. B., and Hempelmann, L. H.: Chromatotrophic degeneration and rupture of aorta following thyroidectomy in cases of hypertension, AY. H&ART J. 20:599, 1940. Baradnav. , , G. Y.: The oatholoav of idiopathic medionecrosis of the aorta, with special -reference to the histochemical factors, Morph. Igazs. Orv. Szemle 1:86, 1961. Becker, H.: Der typische supravalvulare aortenabriss bei Marfan Syndrome, Z. Kreislaufforsch. 56:658, 1967. McKusick, V. A.: Hereditable disorders of connective tissue 111. The Marfan Syndrome, J. Chronic Dis. 2:609, 1955. Pappenheimer, A. M., and von Glahn, W. C.: Contributions on lesions of the aorta associated with acute rheumatic fever and with chronic cardiac disease of rheumatic origin, J. Med. Res. 4*:%!, 1922. Meyer, K.: Rheumatic diseases, Philadelphia and London, 1952, W. B. Saunders Company. Comens, P.: Manganese depletion as an etiological factor in hydmlaline disease, Proceedinqs of the Tenth Annual Meeting of the Southern Society for Clinical Research, 1956 (abstract). Talermnn, A., Hayes, J. A., and Lindo, V.: Aortic aneurysms in lamlica, Trans. R. Sot. Trop. Med. Hyg. 62:52, 1968. Hvlnnd. H. H.: Thrombosis of intracranial respecarteries; Report of 3 cases involving, tively, anterior cerebral, basilar and internal carotid arteries, Arch. Neurol. Psychiatr. 30:342, 1933. Lovitt, W. V., Jr., and Corzine, W. J., Jr.: Dissectins intramural haemorrhage of anterior descending branch of left coronary artery, Arch. Pat.hol. 5%:458, 1952. Watson, A. J.:. Dissecting aneurysm of arteries other than the aorta. -1. Pathol. Bact. 72:439, 1956. Zeppa, R., and Womack, N. A.: Medial degeneration and aneurysm of the hepatic artery, Arch. Surg. 86:252, 1963. Harrison, T. S.: Some principles in the management of peripheral artery aneurysms, Surg. Gynecol. Obstet. 117:156, 1963. Ferlic. R. M., Goott, B., Edwards, J. E., and Lillehei, C. W.: Aortic valvular insufficiency associated with cystic medial necrosis: Surgical and pathological considerations, Ann. Surg. 165:1, 1967.
37.
38.
39.
40.
41.
42.
43.
44.
4.5.
46.
47.
48.
49.
50. 51.
52.
53.
Hayes, J. A., and Woo-Ming, M. 0.: Diffuse cystic medionecrosis and aortic thinning: Rupt&e at operation in a young man with a patent ductus arteriorus. Dis. Chest 48:645. 1965. Winslow, N., a& Edwards, M.: Aneurysm of temporal artery, Bull. School Med. Univ. Md. 19:119, 1935. Guida, P. M., and Moore, S. W.: Aneurysms and arteriovenous fistulas of the temporal artery, Am. J. Surg. 115:825, 1968. Hagstrom, W. J., Vanecko, R. M., Yao, J., Beers, M.D., and Stuteville. 0. H.: Suoerficial tempdral artery aneurysm; Plast. Rkconstr. Surg. 44:190, 1969. Milne, J. H., Graham, J. G., and Simpson, J.: Cystic mucoid degeneration of aortic media with spontaneous rupture of aorta, Glasgow Med. J. 31:206, 1950. Loveman, A. B., Gordon, A. M., and Fliegelman, M. T.: Marfan’s Syndrome, some cutaneous aspects, Arch. Dermatol. 87:428, 1936. Moretti, G., Le Coulant, P., Staeffen, J., et al.: La peau dans le syndrome de marfan: Interest diagnostique, Presse MCd. 72:2985, 1964. Goodman, R. M., Baba, N., and Wooley, C. F.: Observations on the heart in a case of combined Ehlers-Danlos and Marfan Syndromes, Am. J. Cardiol. 24:734, 1969. Yamakawa, K., Kitanura, K., Ohta, H., and Noda, Y.: Experimental studies on medionecrosis of the aorta-Discussion on the underlyin4 factors of lathyrism, Ehlers-Danlos and Marfan’s Syndrome.Jap. Heart J. 1:408, 1960. Ponseti. I. V.. and Baird. I,.: Scoliosis and dissecting ‘anellr$sm of the aorta in rats fed with lathyrus odoratus seeds, Am. J. Pathol. 28:1059, 1952. Hosada, Y., and Iri, H.: Angiolathyrism II Elastin, collagen and hexosamine content of the lathvritic rat aorta, Angiology 18:616, 1967. Rinehart, J. F., and Greenberg, I.. D.: Vitamin Bg deliciencv of the Rhesus monkev with oarticulnr reference to the occurrenceof athkrosclerosis, dental caries and hepatic cirrhosis, Am. J. Clin. Nutr. 4:318, 1956. Shields, G. S., Coulson, W. F., Kimball, D. A., Carnes, W. H , Cartwright, G. E., and Wintrobe. M. M.: Studies on copper metabolism 32. Cardiovascular lesions in copper deficiency swine, Am. J. Pathol. 41:602, 1962. Gore, I.: Pithogenesis of dissecting aneurysm of the aorta. Arch. Pathol. 53:142. 1952. Golden, R. ‘L., and Lakin, H.: ‘The formes frustes in Marfan’s Syndrome, N. Engl. J. Med. 260:797, 1959. Tuna, N., and Thal, A. P.: Some unusual features of the Marfan Syndrome. Report of four cases, Circulation 24:1154. 1961. Bartda, F., and Papilian, b. V.: Considerations on dissecting aneurysm of the aorta in idiopathic cystic medionecrosis and Marfan’s Syndrome, Morfol. Norm. Patol. 11:165, 1966.
Unusual
clinical
manifestations
medionecrosis-Report
of cystic
of a case
T. F. Tse, M.B. Donald Y. C. Yu, M.R.C.P.E. Hong Kong
c
ystic medionecrosis has been a distinct pathological entity since the autopsy studies of Erdheim1v2 and Rottino.3 The clinical manifestations reported have been either that of dissecting and localized aneurysms of the aorta or aortic insufficiency. Hence, diagnosis could only be made from autopsy, or from specimens of aortic aneurysms removed during operation in recent years. The purpose of this report is to present a case of cystic medionecrosis involving medium-sized arteries and arterioles resulting in unusual clinical features and to give a brief review of the literature. Case report Y. S. C., a 40-year-old Chinese dental technician, was admitted as a casualty on July 10, 1969, to the University Medical Department of Queen Mary Hospital, Hong Kong, with sudden onset of left hemiplegia for five hours. Five years prior to admission, he first noticed a pulsating cord-like structure over the left temporal region of the scalp. Similar structures were then noticed at different sites of the scalp, being most prominent over the frontal and occipital regions. Three months before admission he developed an attack of sudden transient dizziness followed an hour later by paralysis, numbness, and anesthesia over the left side of the body and face. There was slurring of speech and deviation of the angle of the mouth to the right. He recovered spontaneously six hours later without any residual weakness. Since then he had ten similar episodes each lasting from 10 minutes to 6 to 7 hours. Each attack
was unprovoked and was preceded by a short period of dizziness. All the attacks involved the left side of the face and body, except for one attack affecting the right arm alone. Throbbing frontal headache unrelated to posture or time of the day was sometimes present but never prominent. There was no loss of consciousness or disturbances of bladder and bowel. Ten days before admission he experienced dizziness and sudden blurring of vision of the left eye. This improved only very gradually and persisted up to the time of his admission. He noticed that his skin was getting coarse, dry, and progressively rough for the past three years, particularly over the front of his thighs. His past health was good and his family history was irrelevant. He had farmed in Mainland China for 10 years. Examination showed that he was of moderate body build, measuring 160 cm. in height and weighing 54 kilograms with an arm span of 160 cm. Features suggestive of Marfan’s Syndrome were absent. He was afebrile, fully conscious, and mentally clear, with no slurring of speech nor signs of meningeal irritation. The skin was generally coarse and was thickened and tight, especially over the front of both thighs. Joint laxity was absent. Two pulsatile vessels with aneurysmal dilatation were found (Fig. l), one on each side of the frontotemporal region,with two similar but nonpulsatile cordlike structures over the occipital area. No tenderness, thrill, or bruit was detected. The pulse was 80 per minute, regular, and all peripheral pulses were present. Blood pressure was 120/80 mm. Hg over both upper limbs and 130/80 mm. Hg over both lower limbs. The heart was not clinically enlarged and auscultation did not reveal any murmurs. He was found to have an upper motor neurone lesion
From the Department of Medicine, University of Hong Kong. Queen Mary Hospital. Hong Kong. Revived for publication Jan. 28, 1972. Reprint requests to: Dr. Donald Y. C. Pu. University Department of Medicine, Queen Mary Hospital.
794
American Heart Journal
December, 1972
Hong Kong.
Vol. 84, No. 6, pp. 794-800
Volume Ntcmber
84 6
affecting the left side of the body including the face. There was hypoesthesia and hypoalgesia over the left side of the body; postural and vibration senses remained intact. Right upper and lower limbs were normal. There was loss of vision in the lower half o[ the left visual field. The right optic fundus was normal: the left showed blurring of the superionasal margin of the optic disc, with narrowed arteries and veins in the upper half of the fundus, the rest of the fundus being normal. Hemorrhages or exudates were not seen. The lungs were clear and the abdomen was normal. The left pyramidal and spinothalamic tract lesions rapidly improved after admission and no residual signs were demonstrated by the next morning. He remained well during his stay in hospital, without any further attacks. His visual field gradually improved over a period of three months, and the fundal changes also disappeared at the same time. Investigations showed hemoglobin 14.5 Gm. per 100 ml.; packed cell volume 44 per cent; white blood count -12,200 with a differential count of PqELlrElnM~B”. The absolute eosinoohil count was _ ._ 2,442 per cubic mm. Erythrocyte sedimentation rate was 10 mm. the first hour. Urine examination showed no sugar, with proteinuria from 0.5 Gm. to 2.0 Gm. per 24 hours. Stool examination revealed a few rhabditiform larvae of strongyloides stercoralis. The absolute eosinophil count dropped to 400 per cubic mm. after a course of dithiazanine orally for two weeks for strongyloides infestation. Blood urea was 26 mg. per 100 ml.; creatinine was 0.8 mg. per 100 ml.; albumin/globulin ratio was 3.9/4.0; plasma protein electrophoresis showed albumin 40.8 per cent; (~1 globulin of 8.2 per cent; 012 14.3 per cent; @ 16.3 per cent; y 20.4 per cent. VDRL, Rheumatoid factor, antinuclear factor, and lupus erythematosus cells were negative. Chest x-ray was normal; electrocardiogram (ECG) was within normal limits with mean QRS vector of 0 degrees. Metacarpal index was 8.2. Barium swallow showed normal peristalsis with free flow of barium into the stomach; there was no filling defect nor other abnormalities. Trisorb resin sponge uptake of Ta was normal. Bilateral carotid cerebral angiogram was performed and revealed that the left cerebral arteries were filled from the right anterior cerebral by way of the anterior communicating artery. The vascular shadows on both hemispheres were normal in size and showed no displacement. Extracranial portion of the carotids was not visualized. Thoracic aortogram and vertebral angiogram were refused by the patient. Left temporal artery aneurysmectomy was done under local anesthesia. The aneurysm was dissected out in its entire length and resected. Postoperative period was uneventful. A similar procedure was carried out on the right temporal artery. Skin biopsy was taken over the front of the left thigh because of the peculiar thickening, and renal biopsy was done for persistent proteinuria.
Histopathology
Temporal artery aneurysm (Figs. 2 and 3). The resected blood vessel is about 1 cm. in length. At one end the vessel is thickened
Cystic medionecrosis
795
Fig. 1. Photograph showing patient’s right temporal and occipital artery aneurysms. Similar aneurysms are present on the left side.
and dilated. No dissection of vessel wall is seen. There is marked thickening of the intima and media with increase in interstitial mucin-like material stained by Alcian Blue. The elastica has been completely destroyed and no inflammatory reaction is seen. Z\Iany collaterals are present in the adventitia. Immunofluorescent staining to Ig(; and thioflavin T for amyloid are both negative. Right renal biopsy (Fig. 4). The glomeruli are essentially normal with no increase in cellularity or basement membrane thickening and immunofluorescent staining to both IgG and p,C globulins are negative. There are 2 markedly thickened arterioles near the glomerulus with markedly thickened intima and increase in Alcian Blue staining material in the media. Skin biopsy (Fig. 5). The epidermis showed features of hyperkeratosis and in the dermis a marked coarseness of the collagen bundles is noted. There is moderate increase in elastic tissue with fragmentation of the elastic fibers. Inflammatory reaction is absent and there is no increase in interstitial mucin-like material.
796
Am. Heart I. Dcwmber. 1972
Tse and Y2,
Fig. 2. Right temporal artery lumen and grossly thickened (Original magnification X25.5.)
showing narrowed media and intima.
Fig. 3. Right temporal artery with cysts of mucin material in the media and intima, stained by Alcian Blue. (Alcian Blue stain. Original magnification X450.)
Discussion
WieseP in 1906 first described medial changes of blood vessels in non-syphilitic young persons dying shortly after the onset of fulminating infections. This was probably the first description of medionecrosis. Since then, various degenerative changes of the media have been reported, including cyst-like areas filled with “gelatinous materia1,“6 scattered foci of “fatty degeneration,“7 and hyaline degeneration of interlamellar connective tissue.8 However, these latter types of degenerative changes were not supported by subsequent reports. It was Erdheimls2 who described the specific lesion in the medial coat of aorta as a focal ac-
Fig. 3. Renal terioles, with (Hematoxylin X450.)
biopsy. Two markedly normal glomerulus and and eosin. Original
Fig. 5. Skin biopsy. tissue, and fragmentation the dermis. (Weigert’s x 105.)
thickened arrenal tubules. magnification
Moderate increase in elastic of elastic fibers is seen in stain. Original magnification
cumulation of basophilic homogeneous material. Thus it has been known as Erdheim’s medionecrosis or medionecrosis aortae idiopathica cystica and has been considered to be a distinct pathological entity.3 The histology in described cases consisted of intimal thickening due to proliferation of fine collagen fibers separated by pale myxomatous tissue. The elastic lamellae were very variable but were often split and fragmented, separated by irregular cystic spaces containing basophilic amorphous material staining positively for connective tissue mucin with Alcian Blue preparation.s This was believed to represent collections of acid mucopolysaccha-
ride, predominantly chondroitin sulphate B and C.‘O Manley and Kent” presented further experimental studies and suggested that it was due to chondroitin sulphate C. In addition, large accumulation of dermatan sulphate or heparitin sulphate was found in the media of the resected aortic wall.‘” There was no evidence of atheroma or syphilis and inflammatory reaction was absent. Although Gore and Seiwert? demonstrated the preponderance of elastic degeneration in young individuals in contrast to the predominantly muscular necrosis in older patients, both types appeared to be part of the same general disease process.4 Pathological
significance
Pathologically, similar accumulation of mucoid material in the media of great vessels had been observed under several circumstances. 1. In “normal” aortas. Rottino3 demonstrated deposits of mucoid material in the aorta of 92 out of 210 routine autopsy cases, occurring more commonly in the older age group. This agrees with Schultz14 and Carlson and associates15who noted a progressive increase in this material in the senescent vessel. 2. Associated with congenital anomalies. Mucoid material can be found in the media of both normal embryos from 1 to 3 months old and in adults with hypoplastic aorta. Thus Costa-Florenzr6 suggested developmental disturbance as a cause of the degenerative changes. Identical changes were also observed in patients with cardiovascular malformations with right-to-left shunts” but here the primary cause was attributed to tissue anoxia. Medial degeneration with destruction of the elastica also occurs in coarctation of the aorta,‘* bicuspid aortic valves, and calcific aortic stenosis,lg possibly as a result of hemodynamic disturbances distal to the obstruction.20 3. Pregnancy. Acid mucopolysaccharide lakes occur frequently in the aorta during pregnancy, possibly secondary to hormonal influences.21 This can perhaps explain the greater frequency of dissecting aneurysms in pregnancy than in woman of the control group, particularly towards term.22 4. .Myxoedema. Descriptions on histology of aorta in myxoedema has been few. Three
patients who developed dissecting aneurysms after total thyroidectomy were found to have mucoid degeneration of the media.23 Another case was presented where histochemical exatnination revealed presence of acid mucopolysaccharide in the aortic wall of a patient suffering from myxoedema due to chronic atrophic thyroiditis.24 5. 2Clarfan’s Syndrome. The early changes of the aorta are those of medionecrosis,2j almost indistinguishable from cystic medial necrosis originally described by Erdheim. Changes resembling the early ones in the aorta are also found in the pulmonary arteries. Specifically, peripheral arteries have shown no abnormality, but studies in these areas are distressingly few.26 6. Rheumatic fever and Hydralazine syndrome. Pappenheimer and von Glahn2’ recognized changes closely resembling idiopathic medionecrosis occurring in collagen disease states as rheumatic fever. Meyer2s considered that the primary pathologic disturbance was in the amorphous ground substance. Hydralazine (apresoline) gives rise to “hydralazine syndrome” with similar pathological damage of the medial coat. This is possibly due to its strong affinity for metallic ions, thus resulting in a trace element (probably manganese) deficiency.“g However, that the pathology of myxoedema, rheumatic fever, and hydralazine resemblescystic medionecrosis is not agreed by all pathologists. Clinical sign$icance. Although the pathological associations of cystic medionecrosis are very variable, its clinical manifestations are not many. The clinical features are always a result of weakening of the vessel wall, and thus commonly affecting the ascending aorta which is mainly exposed to the distending forces of the left ventricular stroke output.” A review of the literature reveals the following syndromes: 1. Dissecting aneurysms of the aorta13p30 and other arteries, including basilar,31 left coronary,32 splenic, and renal arteries.33 2. Local aneurysms of aorta4J2*17 and other arteries, including hepatic,34 inferior gluteal,35 and subclavian arteries.‘O 3. Aortic valvular insuficiency which might be functional due to dilatation
798
Tse and Yu
of the aortic ring or with direct medionecrosis of the aortic valve.36 4. Rupture of the aorta due to thinning.37 To the above, we would like to add five other clinical features as illustrated by the patient here presented; i.e., 1. Multiple aneurysms of the extracranial arteries. Aneurysms of the temporal artery are rare. Non-traumatic aneurysms of the occipital artery must be exceedingly rare as 90 per cent of cases of temporal artery aneurysms were traumatic in origin. The others were considered arteriosclerotic, unclassified, and doubtfuL3* Guidaand Moore3g were able to find only 111 reported cases of aneurysms of the temporal artery in the literature up to 1968. Hagstrom and colleagues40 subsequently reported five more cases and considered that there were only 130 cases up to that time. It was unfortunate that the histological descriptions were usually not given in greater detail. The present case assumes significance not only because of its rarity but also because, to the best of our knowledge, this is the first reported case of temporal artery and occipital artery, and in fact, multiple extracranial artery aneurysms due to cystic medionecrosis. 2. Trartsient cerebral ischemia. The repeated attacks of transient hemiplegia and facial paralysis with spontaneous complete recovery within a few hours suggest a vascular lesion. Judging from the marked distensibility and smoothness of the vessel wall when the resected temporal artery was examined, it is not surprising that the vessels should appear normal in angiograms even when mucoid degeneration was present. However, since the origin of the common carotid and vertebral-basilar arteries were not visualized in the cerebral angiogram, a lesion in the extracranial portion of the carotid or vertebral-basilar artery which could also account for the transient ischemic episodes cannot be entirely ruled out. 3. Renal involvement. The persistent proteinuria which varied from ‘01.5 to 2
Am. Heart J. December, 1972
Gm. per day prompted us to do a renal biopsy. That vessels as small as the arterioles could be involved was a surprising finding. This could only mean that possibly all the vessels in the body, from the aorta to the arteriole, took part in the degenerative process, in contrast to the results of Milne and associates4’ who found that in their case the degenerative process did not extend into the branches of the aorta. 4. Retinal involvement. The retina changes are possibly due to thrombosis or emboli of a branch of retinal artery. Although unlike the renal changes, histological proof of involvement of the retinal vessels is lacking, it may be assumed that they were involved in a manner similar to the renal arterioles, unless embolization from extracranial arteries is again incriminated. This again suggests that medial degeneration is a generalized process rather than being limited to the aorta. 5. Skin Aanges. Skin changes associated with idiopathic cystic medionecrosis have never been described. However, skin changes occurring in filarfan’s Syndrome had been reported occasionally. These include scanty subcutaneous fat, laxity of ligaments, scaly areas of the feet, and hyperkeratosis of the toes, elastoma-like lesions, and acrosclerosis.42 The histopathology of the skin biopsy in this patient is most peculiar in that there is presence of coarse collagen bundles and fragmentation of the elastic fibers. Histologically this would suggest Ehlers-Danlos Syndrome, although clinical support from hyperelasticity of the skin is lacking. A recent clinical and histological study of the skin of 10 patients with Marfan’s Syndrome by Moretti and co-workers43 revealed changes very similar to, or identical with those in Ehlers-Danlos Syndrome, but with less marked hyperelasticity in the former group of patients. Hence, the skin changes in this patient need not be exclusive of Ehlers-Danlos Syndrome, but form part of the clinical picture of a gen-
Volume Numbev
84 6
Cystic medi0nrc.rosi.s
eralized mesenchymal disorder. In fact, Goodman and colleagues44 reported a case of combined EhlerDanlos and Marfan’s Syndromes. Erdheim’s medionecrosis or Marfan’s Syndrome. That this patient had medionecrosis of blood vessels was established by biopsies. Medionecrosis can be associated with many conditions (Marfan’s Syndrome, myxoedema, pregnancy, etc., see above) and has been produced in experimental animals by a number of techniques, including lathyrism,45-47 pyridoxine deficiency,48 and copper deficiency. 49 The mucoid component of the degenerative process merely represents one aspect of the body reaction.50 Whether this patient has Marfan’s Syndrome is highly debatable. Clinically there ere none of the stigmata characteristic of this syndrome and family studies are impossible because the other members of his family are living in Mainland China. However, this can still be Marfan’s Syndrome, for there are undoubtedly cases where aortic medionecrosis occurs without skeletal and ocular cllanges.26 Together with the skin changes observed in this patient, we believe that this is a formes frustes of Marfan’s Syndrome rather than Erdheim’s medionecrosis alone. It is also believed that many cases of Erdheim’s medionecrosis may be an incomplete form of Alarfan’s Syndrome.31-53 Summary
Although cystic medionecrosis of great vessels has been a well-known pathological entity, the diagnosis is usually made at autopsy. The clinical manifestations are often limited to the aorta, resulting in aneurysms and aortic insufficiency. Report is given of a case where the degenerative process involves medium-sized arteries and arterioles, giving rise to multiple aneurysms of the extracranial arteries, transient cerebral ischemia, persistent proteinuria and retinal involvement, associated with skin changes. Different pathological conditions where medionecrosis occur are reviewed. The relationship between Erdheim’s idiopathic cystic medionecrosis and Marfan’s Syndrome is briefly discussed. We wish to thank Dr. W. C. Chan, of Pathology, Queen Mary Hospital, for histological studies.
Department Hong Kong,
799
REFERENCES 1. Erdheim, J.: Medionecrosis aortae idiopathica, Virchows Arch. IPathol. Anat. 273:454. 1929. 2. Erdheim, J.: Medionecrosis aortae idiopathica cystic, Virchows Arch. [Pathol. Anat.] 276:187, 1930. 3. Rottino, A.: Medial degeneration of the aortnA study of 210 routine-autopsy specimens by a serial block method. Arch. Pathol. 28:377. 1939. 4. Bahnson, H. T., and Nelson, A. R.: Cystic medial necrosis as a cause of Iocalised aortic aneurysms amenable to surgical treatment, Ann. Surg. 144:519, 1956. 5. Wiesel, J.: Die Erkrankungen arteriellen pefaesse in Verlaufe akuter Infectionen, Z. Heilkd. 27:262, 1906. 6. Freedman, A.: Cyst of the wall of the carotid artery, Montreal Med. J. 38:.583, 1909. 7. Moriani, G.: Ueber einen Fall von Aneurysma dissecans aortae mit besonderer Berucksichtigung frischer Rupturen der Aortemedia, \‘irchows Arch. [Pathol. Anat.] 202:283, 1910. 8. Sailor, S.: Dissecting aneurysm of the aorta, Arch. Pathol. 33:704. 1942. 9. Persaud, I:.: Subclavian artery aneurysm and idiopathic cystic medionecrosis, Br. Heart J. 30:436, 1968. 10. Meyer, K., and Rapport, M. M.: Mucopolysaccharides of ground substance of connective tissue, Science 113:596, 1951. 11. Manley, G., and Kent, P. W.: Aortic mucopolysaccharides and metachromasia in dissecting aneurvsm, Br. J. Exp. Pathol. 44:635, 1963. 12. Sy%bas, -P. N., Baldwin, B. J., Silverman, M. E.. and Galambos. Svndrome -I. T.: Marfan’s with aneurysm of ascending aorta and aortic regurgitation, Am. J. Cardiol. 25:483, 1970. 13. Gore, I., and Seiwert, 1’. J.: Dissecting aneurysm of the aorta-pathological aspects: An analysis of eighty-five fatal cases, Arc?i. Pathol. 53:121, 19.57. 14. Schultz, A.: Ueber die chromotropie des Gefaessbindegewebes in ihrer physiologischen und pathologischen Bedeutune, insbesondere ihre Beziehungen zur Arteriosklerose, Vii-chows Arch. [Pathol. Annt.] 239:415, 1922. 1 j. Carlson, R. G., Lillehei, C. M’., and Edwards, J. E.: Cystic medial necrosis of the axending aorta in relation to age and hypertension, Am, I. Cardiol. 25:411, 1970. 16. Costa-Florenz, A. von: Normale and patholoeische Anatomie. Z. Kreislaufforsrh. 23:715. 1931. 17. Lopes de Faria, J.: Medionecrosis of the aorta with secondary arteriosclerosis in congenital cyanotic cardiac defects, Beitr. Pathol. Anat. 125:129, 1961. 18. Reifenstein, G. H., Levine, 5. A., and Gross, R. E.: Coarctation of the aorta. A review of 104 autopsied cases of the “adult” type two years of age or older. AM. HEART 1. 33:146. 1947. 19. McKusick, V. A., Logue, Ii. B., and Bahnson, H. T.: Association of aortic valvular disease and cystic medial necrosis of the ascending aorta, Circulation 16:188, 1957. 20. Heath, D., Edwards, J. E.. and Smith, C. A.:
Am. Heart J. December, 1972
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
34.
35.
36.
The rheologic significance of medionecrosis and dissecting aneurysm of the ascending aorta in association with calcific aortic stenosis, Mayo Clin. Proc. 33:228, 1958. Merendino. K. A.. Winterscheid. L. C.. and billard, D.’ H.: Cystic medial necrosis with and without Marfan’s Syndrome, Surg. Clin. North Am. 47:1403, 1967. Becker, H., Hausler, H., and Maurer, H.: Aortenruptur und Graviditat, Geburtschilfe. Frauenheilkd. 26:944, 1966. Kountz, W. B., and Hempelmann, L. H.: Chromatotrophic degeneration and rupture of aorta following thyroidectomy in cases of hypertension, AY. H&ART J. 20:599, 1940. Baradnav. , , G. Y.: The oatholoav of idiopathic medionecrosis of the aorta, with special -reference to the histochemical factors, Morph. Igazs. Orv. Szemle 1:86, 1961. Becker, H.: Der typische supravalvulare aortenabriss bei Marfan Syndrome, Z. Kreislaufforsch. 56:658, 1967. McKusick, V. A.: Hereditable disorders of connective tissue 111. The Marfan Syndrome, J. Chronic Dis. 2:609, 1955. Pappenheimer, A. M., and von Glahn, W. C.: Contributions on lesions of the aorta associated with acute rheumatic fever and with chronic cardiac disease of rheumatic origin, J. Med. Res. 4*:%!, 1922. Meyer, K.: Rheumatic diseases, Philadelphia and London, 1952, W. B. Saunders Company. Comens, P.: Manganese depletion as an etiological factor in hydmlaline disease, Proceedinqs of the Tenth Annual Meeting of the Southern Society for Clinical Research, 1956 (abstract). Talermnn, A., Hayes, J. A., and Lindo, V.: Aortic aneurysms in lamlica, Trans. R. Sot. Trop. Med. Hyg. 62:52, 1968. Hvlnnd. H. H.: Thrombosis of intracranial respecarteries; Report of 3 cases involving, tively, anterior cerebral, basilar and internal carotid arteries, Arch. Neurol. Psychiatr. 30:342, 1933. Lovitt, W. V., Jr., and Corzine, W. J., Jr.: Dissectins intramural haemorrhage of anterior descending branch of left coronary artery, Arch. Pat.hol. 5%:458, 1952. Watson, A. J.:. Dissecting aneurysm of arteries other than the aorta. -1. Pathol. Bact. 72:439, 1956. Zeppa, R., and Womack, N. A.: Medial degeneration and aneurysm of the hepatic artery, Arch. Surg. 86:252, 1963. Harrison, T. S.: Some principles in the management of peripheral artery aneurysms, Surg. Gynecol. Obstet. 117:156, 1963. Ferlic. R. M., Goott, B., Edwards, J. E., and Lillehei, C. W.: Aortic valvular insufficiency associated with cystic medial necrosis: Surgical and pathological considerations, Ann. Surg. 165:1, 1967.
37.
38.
39.
40.
41.
42.
43.
44.
4.5.
46.
47.
48.
49.
50. 51.
52.
53.
Hayes, J. A., and Woo-Ming, M. 0.: Diffuse cystic medionecrosis and aortic thinning: Rupt&e at operation in a young man with a patent ductus arteriorus. Dis. Chest 48:645. 1965. Winslow, N., a& Edwards, M.: Aneurysm of temporal artery, Bull. School Med. Univ. Md. 19:119, 1935. Guida, P. M., and Moore, S. W.: Aneurysms and arteriovenous fistulas of the temporal artery, Am. J. Surg. 115:825, 1968. Hagstrom, W. J., Vanecko, R. M., Yao, J., Beers, M.D., and Stuteville. 0. H.: Suoerficial tempdral artery aneurysm; Plast. Rkconstr. Surg. 44:190, 1969. Milne, J. H., Graham, J. G., and Simpson, J.: Cystic mucoid degeneration of aortic media with spontaneous rupture of aorta, Glasgow Med. J. 31:206, 1950. Loveman, A. B., Gordon, A. M., and Fliegelman, M. T.: Marfan’s Syndrome, some cutaneous aspects, Arch. Dermatol. 87:428, 1936. Moretti, G., Le Coulant, P., Staeffen, J., et al.: La peau dans le syndrome de marfan: Interest diagnostique, Presse MCd. 72:2985, 1964. Goodman, R. M., Baba, N., and Wooley, C. F.: Observations on the heart in a case of combined Ehlers-Danlos and Marfan Syndromes, Am. J. Cardiol. 24:734, 1969. Yamakawa, K., Kitanura, K., Ohta, H., and Noda, Y.: Experimental studies on medionecrosis of the aorta-Discussion on the underlyin4 factors of lathyrism, Ehlers-Danlos and Marfan’s Syndrome.Jap. Heart J. 1:408, 1960. Ponseti. I. V.. and Baird. I,.: Scoliosis and dissecting ‘anellr$sm of the aorta in rats fed with lathyrus odoratus seeds, Am. J. Pathol. 28:1059, 1952. Hosada, Y., and Iri, H.: Angiolathyrism II Elastin, collagen and hexosamine content of the lathvritic rat aorta, Angiology 18:616, 1967. Rinehart, J. F., and Greenberg, I.. D.: Vitamin Bg deliciencv of the Rhesus monkev with oarticulnr reference to the occurrenceof athkrosclerosis, dental caries and hepatic cirrhosis, Am. J. Clin. Nutr. 4:318, 1956. Shields, G. S., Coulson, W. F., Kimball, D. A., Carnes, W. H , Cartwright, G. E., and Wintrobe. M. M.: Studies on copper metabolism 32. Cardiovascular lesions in copper deficiency swine, Am. J. Pathol. 41:602, 1962. Gore, I.: Pithogenesis of dissecting aneurysm of the aorta. Arch. Pathol. 53:142. 1952. Golden, R. ‘L., and Lakin, H.: ‘The formes frustes in Marfan’s Syndrome, N. Engl. J. Med. 260:797, 1959. Tuna, N., and Thal, A. P.: Some unusual features of the Marfan Syndrome. Report of four cases, Circulation 24:1154. 1961. Bartda, F., and Papilian, b. V.: Considerations on dissecting aneurysm of the aorta in idiopathic cystic medionecrosis and Marfan’s Syndrome, Morfol. Norm. Patol. 11:165, 1966.