Neonatal Case Presentation - Nature

Perinatal/Neonatal Case Presentation Segmental Arterial Mediolysis in a Preterm Frank Eifinger Jochen Fries Rainer Bald Friederike Ko¨rber Angela Kribs Bernhard Roth

We firstly report on a dystrophic preterm infant with segmental arterial mediolysis (SAM) found in arteries of placental, umbilical and cerebral tissues. These arterial lesions of unknown etiology developing in the elderly are characterized by segmental lysis of the abdominal splanchnic arteries followed by aneurysms and acute bleeding. Typically, the lesions occur in a skip pattern. We could find a small number of SAM in the spleen but much more in placental and umbilical tissues. Rarely, a vascular elastosis and splitting of individual vessels in the spleen and lung could be detected. The histological findings are similar to that of adult patients. Journal of Perinatology (2004) 24, 461–464. doi:10.1038/sj.jp.7211130

percentile1), reflecting the dystrophic aspect of the newborn. The venous hemoglobin concentration was 5.6 g/dl with 400% reticulocytes and 99 109/l platelets. Heart rate was increased (between 180 and 200 bpm) under catecholamine medication by normal blood pressure. After primary stabilization the patient died in cardiovascular collapse after 30 hours. Immediately after birth, the umbilical cord and placenta were sent to pathology for further histological investigation. Before preparation, contrast color was injected into the umbilical artery showing multiple-diameter waists in the placental arteries and extravascular hemorrhages as seen in the umbilical cord (Figure 1).

FAMILY HISTORY The mother was a 34-year-old gravida 5, para 4. The father was 36 years old. Both parents were of good health without any hereditary diseases. Two offspring died shortly after birth. The first was a male infant of 32 weeks’ gestation. Fetal anemia and oligohydramnion were also seen. The second was a female infant with 35 weeks’ gestation and hydrocephalus besides maternal polyhydramnion. Neither sibling had post-mortem examinations. Two other healthy girls were born at term.

CASE PRESENTATION The male preterm was born in the 30 67 weeks’ gestation. Prenatal diagnosis demonstrated in the 23 37 weeks’ gestation an intraventricular hemorrhage with posthemorrhagic hydrocephalus as well as a maternal polyhydramnion. Venous umbilical vessel hemoglobin concentration was extremely low with 5.8 g/dl and led to weekly intrauterine erythrocyte transfusions (altogether seven transfusions) via the venous umbilical vessel followed by rising hemoglobin values. Associated thrombopenia (58.000 109/l) was also found. Polydramnion was decompressed. In the 24 47 weeks’ gestation, a thin umbilical cord was first seen. The impossibility of punctation led to primary cesarean section in the 30 47 weeks’ gestation. The patient had an APGAR-Score of 1/4/5 and was resuscitated. Birthweight was 1250 g (15th percentile1), birthlength 38 cm (10th percentile1) and head circumference 26 cm (4th

Children’s Hospital, Department of Neonatology (F.E., A.K., B.R.), University of Cologne, Cologne, Germany; Institute of Pathology (J.F.), University of Cologne, Cologne, Germany; Department for Prenatal Medicine and Gynaecologial Sonography (R.B.), University of Cologne, Cologne, Germany; and Department of Diagnostic Radiology, Paediatric Radiology (F.K.), University of Cologne, Cologne, Germany. Address correspondence and reprint requests to Frank Eifinger, MD, Children’s Hospital, Department of Neonatology, Joseph-Stelzmann Strasse 9, Cologne 50923, Germany.

PRENATAL DIAGNOSIS Blood coagulation tests including von Willebrand factor and APCresistance were normal. No evidence of congenital infections (Parvo B19, Toxoplasmosis, Herpes Simplex Virus type I and II, Lues connata, Rubella and Cytomegalovirus) was seen. Karytotyping showed a normal 46,XY chromosome complement (FISH-analysis). Alloantiplatelet antibodies were absent. No incompatibility reactions between fetal and maternal blood were found.

PATHOLOGICAL EVALUATION OF THE PLACENTA AND THE UMBILICAL CORD For the 31st week of gestation, the placenta was 25th percentile for weight and displayed histologically a microfocally dissociated maturation besides numerous sclerosed villi. Most strikingly, vessels of the chorionic plate and the stem villi as well as the vasculature of the umbilical cord in proximity to the placental insertion site were characterized by repeated short segments of extreme luminal narrowing accompanied by a dilated vascular segment at both sides, giving the appearance of a ‘‘string of beads’’. Histologically, this narrowing corresponded in part to organized, circumscribed thrombosis with re-endothelialization of the luminal space, in part

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Figure 1. Placentography. Contrast color was injected into the umbilical artery (arrowhead) showing multiple-diameter waists in the chorionic arteries as well as in the umbilical artery. In the chorionic plate, occasional hemorrhage (upper left) could be found in the adjacent soft tissue but not in the stem villi. Hemosiderin deposits in or around the described lesions could not be observed, indicating that the occasional hemorrhage of chorionic vessels was of late and most likely post-traumatic origin and not due to vascular rupture (delivery).

Segmental Arterial Mediolysis in Preterm

Figure 2. Arterial vessel of umbilical cord. At left, elastic van Gieson stain showing lamina elastica interna characteristic for arterial vessels. Sector-like mediolysis with preservation of circumscribed medial segment. At right, smooth muscle actin staining of deeper levels of artery. Note changes in segment of wall with mediolysis. 1, normal arterial media; 2, complete loss of media; 3, mediolysis without inflammation.

to focal myofibroblastic proliferation. A pre-/ and poststenotic vascular dilatation of the afflicted vessel was observed also in part due to aneurysmatic dilatations. The obvious cause of the thrombosis appeared as a vascular segment with massive loss of myocytes in the medial layer without accompanying inflammatory response, as could be seen in occasional vascular lesions with thrombosis in the umbilical cord artery (Figure 4). Only complete vessel disintegration with thrombosis (Figure 5) in stem villi resulted in loss of stainable media (Figure 4). Immunohistologically, the lack of myocytes in the arterial vessels was confirmed by the segmental loss of smooth muscle actin staining (Figures 2 and 3). Figure 3. Stem villus with vascular medial damage (smooth muscle actin staining). Left: mediolysis of muscular wall. Right: vessel from different villus with preserved wall.

PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM In nearly all large caliber arteries of the cerebral base (Circulus arteriosus Wilisii) and many large intracerebral arteries, a disseminated vacuolar degeneration of myocytes of the media could be observed, again without any inflammatory response. Some angiodysplastic arteries displayed a tortuous course and an arrangement reminiscent of a capillary hemangioma. In the cerebral hemisphere, numerous parenchymal bleedings could be observed. This necrotic tissue showed a lack of staining for glial acidic fibrillary protein (GFAP) and smooth muscle antigen (SMA). Inflammatory demarcation and clearing of cerebral tissue was 462

found showing numerous CD68-positive macrophages. The infarcted areas were of different ages as indicated by erythrocyte phagocytation, revealed by a positive Berliner Blau staining reaction.

PATHOLOGY OF THE INNER ORGANS Fetopsy findings showed regularly located and constructed inner organs (liver, spleen, gastrointestinal tract, lung, heart, Journal of Perinatology 2004; 24:461–464


Figure 4. Arterial vessel of umbilical cord with intimal fibrous cap at vascular bend, possible organized thrombus. Left: elastic van Gieson stain, Right: smooth muscle actin stain. Arrowhead shows intact lamina elastica interna characteristic for arterial vessels. 1, muscular media; 2, intimal cap.

Figure 5. Re-endothelialized, thrombosed vessel in stem villus with loss of media (only single cell smooth muscle actin staining, left); organization of thrombus (elastic van Gieson, right).

urinogenital tract) with age-appropriate maturation. Rarely, a vascular elastosis and splitting of individual vessels in the spleen and lung could be detected.

DISCUSSION In 1976, Slavin and Gonzalez-Vitale2 described three adult patients with distinct lesions in large splenic and hepatic muscular arteries causing partial or total mediolysis of these vessels. The author named this pathology ‘‘Segmental Mediolytic Arteriitis’’. In 1989 Slavin et al.3 turned the entity to ‘‘Segmental Arterial Mediolysis’’. Journal of Perinatology 2004; 24:461–464

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He demonstrated that characteristic inflammatory processes combined with the lack of an inflammatory response are missed. In 1949 Gruenwald4 reported on necrotic coronary arteries in stillborn and newborn infants. Later on in 1979, de Sa5 described a detailed study of the coronary arterial tree and myocardial abnormalities in more than 250 stillbirths and infants. Segmental arterial mediolysis (SAM) is a nonatherosclerotic, noninflammatory vascular disease of unknown origin. Typically, the lesions occur in a skip pattern of the major arteries arising from the abdominal aorta (abdominal splanchnic arteries). Transmural mediolysis causes gaps in the arterial wall following dissected aneurysms and spontaneous ruptures. SAM is suspected to be caused by vasospasm in neonates, infants and adults as a result of high levels of catecholamines and other pressor substances.6,7 In asphyxiated infants and stillborns Gruenwald4 found mediolytic necrosis in the outer part of the coronary arteries. It was suggested that these coronary and myocardial lesions were caused by hypoxia. However, it is absolutely unclear whether similar lesions of coronary arteries of newborns and stillborns represent the same disease as SAM in adults. Leu et al.8 described conditions in young adults involving the cerebral arteries. Tashima et al.9 could demonstrate migration disorders of neurons and typical histological changes in cerebral cortex, for example, disappearance of the stratified structure in ischemia-hypoxia-induced intrauterine growth retardation. However, the cortex of our patient showed a normal neurohistological structure, and cerebral vascular lesions are similar to those of adult patients. Complications like intracerebral bleeding occur even in the unborn. Anemia was one of the major prenatal clinical signs that led to multiple intrauterine transfusions. Repeated cordocentesis may contribute to irregularities in size and structure of the umbilical cord.10 However, complications like bleeding or other adverse outcomes during cordocentesis are rare and well restricted.11 Our histological and macropathological examinations of umbilical and placental tissues showed extravascular blood clots, thrombosis, stenosis and extravascular erythrocytes. Baergen et al. investigated placental and umbilical tissues in uncomplicated pregnancies. He demonstrated that vascular thrombi and infarcts can often be found without any fetal complications by normal neonatal outcomes.12–14 Pathological coagulation status and congenital infections were excluded and the bone marrow was of normal structure. The immunohistochemistry of affected arteries showed numerous vacuolizations of myocytes in the outer media. It seems that this process is of a lytic nature accompanied by little or no inflammatory reaction. We found focal localized media defects by intact endothelial wall structure. These findings are in agreement with histological examinations of Slavin and Gonzalez-Vitale, where significant inflammatory reactions were conspicuously absent in acute lesions. The same author observed vacuolization 463

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and mediolysis in arteries of resected uteri with placenta accreta after administration of potent vasopressors.3 This effect might play an important role in inducing mediolysis. During birth, vasoactive substances lead to compressions of umbilical arteries presumably to minimize fetal blood loss.15 Ullberg et al.16 investigated anastomosis between umbilical arteries in 64 placentas from singleton pregnancies with small for gestational age. She found no extensive macroscopical lesions, and angiograms showed arteries of normal structure without stenosis or diameter waists. This would hardly explain defects in placental as well as in umbilical vessels. Two preterm siblings of the same family died within the first few hours after birth without having post-mortem examination. We therefore cannot exclude a possible hereditary transmission. We found a small number of SAM in spleen but much more in placental tissue and brain. The visceral vascular pathology was not examined; however, macroscopically no aneurysms could be found. However, SAM seems not only to be limited to adults but can also be found in preterms. Locations other than abdominal vessels are possible. Alongside pressor substances other unknown influential factors might exist. It is possible that our patient had a premature and distinct form of SAM with life-limiting complications that might be developing into SAM later in life.

References 1. Voigt M, Schneider KT, Jahrig K. Analysis of a 1992 birth sample in Germany. 1: New percentile values of the body weight of newborn infants. Geburtshilfe Frauenheilkd 1996;56:550–8. 2. Slavin RE, Gonzalez-Vitale JC. Segmental mediolytic arteritis: a clinical pathologic study. Lab Invest 1976;35:23–9. 3. Slavin RE, Cafferty L, Cartwright Jr. J. Segmental mediolytic arteritis. A clinicopathologic and ultrastructural study of two cases. Am J Surg Pathol 1989;13:558–68.

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4. Gruenwald P. Necrosis in the coronary arteries of newborn infants. Am Heart J 1949;38:889–97. 5. de Sa DJ. Coronary arterial lesions and myocardial necrosis in stillbirths and infants. Arch Dis Child 1979;54:918–30. 6. Joris I, Majno G. Endothelial changes induced by arterial spasm. Am J Pathol 1981;102:346–58. 7. Slavin RE, Saeki K, Bhagavan B, Maas AE. Segmental arterial mediolysis: a precursor to fibromuscular dysplasia? Mod Pathol 1995;8:287–94. 8. Leu HJ. Cerebrovascular accidents resulting from segmental mediolytic arteriopathy of the cerebral arteries in young adults. Cardiovasc Surg 1994;2:350–3. 9. Tashima L, Nakata M, Anno K, Sugino N, Kato H. Prenatal influence of ischemia-hypoxia-induced intrauterine growth retardation on brain development and behavioral activity in rats. Biol Neonate 2001;80: 81–7. 10. Tongsong T, Wanapirak C, Kunavikatikul C, et al. Cordocentesis at 16-24 weeks of gestation: experience of 1,320 cases. Prenat Diagn 2000;20:224–8. 11. Ghidini A, Sepulveda W, Lockwood CJ, Romero R. Complications of fetal blood sampling. Am J Obstet Gynecol 1993;168:1339–44. 12. Baergen RN, Malicki D, Behling C, Benirschke K. Morbidity, mortality, and placental pathology in excessively long umbilical cords: retrospective study. Pediatr Dev Pathol 2001;4:144–53. 13. Zhang P, Benirschke K. Placental pathology casebook. Serpentine aneurysms of the placenta with fetal consequences. J Perinatol 2000;20:63–5. 14. Castellucci M, Kosanke G, Verdenelli F, Huppertz B, Kaufmann P. Villous sprouting: fundamental mechanisms of human placental development. Hum Reprod Update 2000;6:485–94. 15. Tsukahara H, et al. Vasoactive and natriuretic mediators in umbilical cord blood: a report of our observation and review of the literature. Early Hum Dev 2002;69:57–64. 16. Ullberg U, Lingman G, Ekman-Ordeberg G, Sandstedt B. Hyrtl’s anastomosis is normally developed in placentas from small for gestational age infants. Acta Obstet Gynecol Scand 2003;82:716–21.

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