0730.4g62/gZ/Ol~35-07Eo3.00/0 Copyright 0 1982 Pergamon Press Ltd COMPUTED TOMOGRAPHY AND STROKE EDEMA: CASE REPORT WITH AN ANALYSIS OF WATER IN ACUTE INFARCTION RICHARD M. TORACK Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, U.S.A. (Receioed 17 December 1980; received for publication 1 April 1981) Abstract-An index case and 13 other cases of acute ischemic cerebral infarction have been examined following the occurrence of death l-6 days postictus. Histologic studies and water content assay involved both the infarct and peri-infarct tissue. The primary site of fluid accumulation was the infarcted white matter; however, after 3 days, edema in the adjacent white matter may be significant. The reduced attenuation of CT scans is caused only by edema since necrosis of the white matter is not present. Reactive vascular changes that occur in the cortex appear to be the basis of early contrast enhancement. Three different mechanisms of edema formation have been proposed to be involved in the mass effect. Water content Stroke edema trast enhancement Reduced attenuation Vascular reaction Cell necrosis Con- INTRODUCTION Computerized tomography (CT) affords a unique opportunity to monitor the brain changes which occur following the occlusion of a major intra-cranial artery. Reduction of attenuation, presumably due to edema, has been reported within 6 hr by Inoue et al. [l] and the use of contrast enhancement can reveal an aspect of vascular permeability [2]. However, at least two reports indicate a lack of cerebral swelling, implying that the loss of attenuation is not due to edema [3, 41. The subject of contrast enhancement is even more confusing. A majority of reports indicate that contrast enhancement (CE) and/or radionuclide (RN) detection are negative for about a week [l, 5-81, yet detection and enhancement have been observed by others as early as 24 hr post-ictus [3, 9, lo]. These apparent contradictions reflect a serious deficiency in correlative tissue pathophysiology of early ischemic infarction. We do not know whether the decreased attenuation is due to increased fluid, tissue necrosis or both. We do not know whether the area of reduced density includes swelling of adjacent normal brain as well as stroke edema. We do not know how the fluid enters the infarcted area. The pathogenesis of stroke edema remains unknown despite a vast literature relating to human and experimental cerebral infarction [ll]. Progressive enlargement, uncal herniation and brainstem hemorrhage are the most common findings in cases that are fatal within the first week post-ictus [12, 131. Unfortunately, this pathological sequence has never been duplicated in an experimental model, so the cellular events which accompany fluid accumulation must be identified in post mortem material. The available autopsy studies are not helpful because they have not been designed to provide specific data relating to the nature of the abnormal fluid. The presence of edema usually is characterized by gross enlargement with softening and the presence of loosened tissue microstructure. Recent studies have indicated that water content of formalin fixed autopsy material has greater validity than these morphologic changes [14, 151. Such information would appear to be necessary for an accurate interpretation of CT in acute infarction. MATERIALS AND METHODS Case report A.C. was a 62-year old right-handed male, who had a 6 yr history of labile hypertension. One month prior to death, a BP 200/120 was discovered and treated with propanolol and hydrochlorthiazide. On the day of admission, he had a sudden onset of a left hemiparisis, with eyes deviated to 35 RICHARD M. TORACK Fig. 1. Computed tomographs of the case report. (A) Six hours after ictus, CT scan shows a normal midline with symmetrical lateral ventricles and normal radio-attenuation of the cerebral hemispheres. (B) Twelve hours after ictus, CT scan documents compression of left lateral ventricle, left to right midline shift and asymmetrically decreased radio-attenuation. This rapid development of mass effect and decreased radioattenuation implicates edema. the right. About 6 hr post-ictus, an emergency CT scan was performed and was considered to be unremarkable (Fig. 1A). He was treated with apresoline, but his BP remained at 200/100 with minor fluctuations. His level of consciousness progressively diminished, so that within 12 hr the patient was comatose with decerebrate posturing. A repeat CT scan at this time revealed massive enlargement of the right cerebral hemisphere with obliteration of the lateral ventricle and reduced attenuation of the right cerebral hemisphere compatible with massive edema (Fig. 1B). Mannitol and Decadron were given to control the edema; however, the patient made no significant response and died approx 24 hr after the onset of the illness. Autopsy jndings The brain was perfused with 10% phosphate buffered formalin, pH 7.0, following removal from the intracranial cavity and immersed in this type of formalin for one week prior to examination. The right cerebral hemisphere appeared to be enlarged with flattened gyri and narrowed sulci. There was a large area of palpable softening that corresponded to the distribution of the right middle cerebral artery. The right cingulate gyrus and the right uncus were herniated. Numerous focal hemorrhages occurred in the midbrain and rostra1 pons. There was a fresh thrombus which occluded the right middle and anterior cerebral arteries. The cerebrum was sectioned in a tangential plane that was intended to correspond to the plane of the CT scan. This was not completely successful but a good correlation was noted in Fig. 2. The right hemisphere was noted to be enlarged and the right lateral ventricle was compressed. The area of palpable softening was devoid of hemorrhage except for some petechiae in the watershed areas at the periphery of the infarct. The cortex and white matter had a normal coloration. Blocks of tissue were obtained from the center of the infarct (A), from the firm area immediately adjacent to the softening (B), from the occipital pole (C) and from a comparable site in the distribution of the left cerebral artery (D). One slice of this block was embedded in paraffin, sectioned at 7 Stroke edema 37 Fig. 2. A gross photograph of a tangential section of the brain in the case report. Enlargement of the right cerebral hemisphere is present and the right lateral ventricle is almost completely occluded. Area A is in the center of softening, B is the area of borderline firmness, C is completely firm, D is the normal corresponding site. micra and stained by means of the H & E and LFB/PAS techniques. A second slice was used to provide 10 micra frozen sections that were stained with the oil red 0 technique for free fatty acids. The remainder of the block was separated into gray and white matter, weighed in a drying bottle with a microbalance, dried in a 100°C oven for a minimum of 72 hr and reweighed. This dry wt was used to compute water content. The results of the morphologic and water assays have been summarized in Table 1. The area of greatest water increase was the infarcted white matter; however, all sites in the right cerebral hemisphere had increased water content including the non-infarcted occipital pole (C). The most advanced morphological changes were noted in the cortex at A including free fat and a reactive vascular change (Fig. 3). These findings did not occur at B; instead the neurons appeared pyknotic and were compatible with more recent extension of the original infarct. The tissue from D was normal. Table 1. Autopsy data of case report Site A B C D Microscopic changes Oil red-0 H and E (1) Eosinophilic neurons (2) Reactive blood vessels Pyknotic neurons Normal neurons Normal neurons “/;,Water increase Cortex White matter + 9.3 15.0 0 0 0 2.5 6.0 0.0 5.2 10.3 0.0 RICHARD Fig. 3. A light M. TORACK photomicrograph of a reactive venule in the infarcted droplets of free fatty acids are present in the perivascular cortex of the case report. area. Oil red 0. x 50. Numerous Water analysis of acute ischemic cerebral infarction A series of 13 other cases of acute cerebral infarction dying within 1 week was collected from the past autopsy material (Table 2). Blocks of tissue, taken from the infarct, from the adjacent normal brain, and from the opposite hemisphere were studied exactly as those of the case report. The results of the water assays are presented in Figs 4 and 5. The mean percent increase in water content at all sites was 4.9”/; which was used to differentiate lesser and greater degrees of edema. In each case, the greatest increase in water content occurred in infarcted white matter (Fig. 4). Infarcted cortex generally had less water and fewer percent increases greater than 4.9%. The water content of the adjacent normal white matter exceeded a 4.99: increase Table 2. Characteristics of fatal Age Sex Post-ictal duration (days) (1) 78 Female Female 1 2 Male Male Male Male Male Female Male Female Female Female Female 2 2 3 3 4 4 5 5 5 6 6 (2) 62 (3) 68 (4) 84 (5) 66 (6) 76 (7) 69 (8) 80 (9) 72 (10) 73 (11) 76 (12) 82 (13) 75 ischemic Location Brainstem hemorrhage Infarct Occlusion RMC LAC LMC RMC RMC LMC RMC LMC LMC RMC RMC LMC LMC LAC LMC RIC LIC 0 + RMC 0 0 + 0 0 0 0 + 0 + + Ahhret~iutions: RAC, LAC---right, RMC, LMC-right, RIG, LIC---right, infarction left anterior cerebral artery. left middle cerebral artery. left internal carotid artery. LMC RIG LMC LIC RMC RMC LMC LMC LlC Stroke edema E t IIg IOig 36 39 00 A *- 6- t7 8 6 _ E 5- .\” 432I - . I 2 3 4 5 6 Days Fig. 4. Percentage increase in water content of infarcted cortex (0) and in infarcted white matter (0) in patients dying within 6 days. The solid line connects the mean daily values of cortical water and the broken line connects similar values for the white matter. in only 3 cases and all of these occurred between days 4-6 (Fig. 5). Adjacent normal cortex never had a degree of water increase greater than 4.9%. DISCUSSION The case report represents an unusual example of acute massive infarction complicated by widespread hemispheral edema. The brain change was recognized within 12 hr by means of a CT scan which revealed a mass effect with decreased attenuation throughout the hemisphere. In this case, the decreased density including both infarcted and non-infarcted brain and the tissue analysis indicated that edema occurred in both areas. This case was unique in its early development of tissue necrosis, in having the greatest amount of water in the infarcted white matter and in a water increase in adjacent normal cortex greater than 4.9%. The latter is most impressive since in no other case did Days Fig. 5. Percentage increase in water content of adjacent cerebral swelling cortex is designated by (0) and white matter by (0). The solid and broken lines connect mean daily values for cortex and white matter respectively. RICHARD 40 M. TORACK normal cortical water increase more than 2.5%. These findings suggest a hemispheral loss of autoregulation that probably was triggered by the massive infarct and the malignant hypertension [16, 17). The most consistent finding in both the case report and the other cases is the identification of the infarcted white matter as the primary site of edema. Severe edema can develop within 24 hr and is present at about the same level throughout the 6 day interval. None of these cases had any evidence of necrosis in the white matter so that the decreased attenuation of the CT scan is apparently entirely a result of the excess fluid. In contrast to infarcted white matter, the cortex can become necrotic as early as 24 hr, but usually not until the 4th day. This degeneration results in neuron loss, free fat and a change in the microvasculature that has been correlated with increased permeability. This is probably the basis for contrast enhancement and its variability would account for the diversity of the CT experience [3, 9, lo]. The occurrence of significant edema in adjacent normal white matter complicates the interpretation of decreased density in the CT scan. The distinction between infarct and normal brain is only possible microscopically and even palpable softening is not completely accurate. However, in this study the edema of the adjacent normal brain usually occurred after the 3rd day. As a result reduced attenuation occurring within the initial 3 day interval may be chiefly an infarct effect whereas at a later time it probably includes adjacent edema. The mechanism of fluid accumulation is only partly explained by the experimental data. The cortical neuronal changes and the less severe transient edema appear to be quite comparable to the animal models of cytotoxic edema [18, 191. In this situation, the edema is believed to be intracellular, involving the injured neurons. Another form of edema is indicated by the swelling of the adjacent normal white matter. The experimental correlate to this situation would appear to be perifocal edema in which fluid is derived from the vasculature at the reactive interface between brain and a destructive lesion [ZO]. The edema in infarcted white matter is not explained by cytotoxic or perifocal edema and appears to represent another mechanism. The only other experimental form of edema is that associated with certain types of chemical intoxication, in which the fluid is located within myelin clefts [21, 221. Similar clefts occur as a part of post mortem autolysis and cannot be proven in autopsy material. SUMMARY CT brain scans represent a most reliable method by which to evaluate the fluid abnormalities which occur in the first week following an ischemic cerebral infarction. The earliest and most consistent change is edema of infarcted white matter. Edema can also involve the adjacent noninfarcted brain, but this usually occurs after the third day. A correct interpretation of diminished density is dependent upon the postictal interval and perhaps by the presence of certain clinical findings such as hypertension. The occurrence of contrast enhancement would appear to be due to the reactive vascular change that evolves in the cortex secondary to neuron death. Usually this occurs somewhat later and more variably than the diminished density. Correlative autopsy water analysis appears to be a practical and valid method to evaluate the changes in CT scans. Acknowledgement-The and in the preparation author wishes to thank of this manuscript. Thomas Naidich, M.D. for his assistance in the interpretation of the CT scan REFERENCES 1. Y. moue, K. Takemoto, T. Miyamoto, N. Yoshikawa, S. Taniguchi, S. Saiwai, Y. Nishimura and T. Komatsu, Sequential computed tomography scans in acute cerebral infarction, Radiology 135, 655-662 (1980). 2. R. A. Kramer, G. P. Janetos and G. Perlstein, An approach to contrast enhancement in computed tomography of the brain, Radiology 116, 641-647 (1975). 3. M. H. Gado, E. Coleman, A. L. Merlis, P. 0. Alderson and K. S. Lee, Comparison of computerized tomography and radionuclide imaging in “stroke,” Stroke 7, 109-l 13 (1976). 4. D. 0. Davis and B. D. Pressman, Computerized tomography of the brain, Radial. Clin. North. Am. 12, 297-313 (1974). 5. D. H. Yock and W. H. Marshall Jr, Recent ischemic brain infarcts at computed tomography: Appearances pre- and post contrast infusion, Radiology 117, 599-608 (1975). 6. S. D. Wing, D. Norman, J. A. Pollock and T. H. Newton, Contrast enhancement of cerebral infarcts in computed tomography, Radiology 121, 89-92 (1976). 7. G. Di Chiro, E. L. Timmis, A. E. Jones, G. S. Johnston, M. K. Hammock and S. J. Swann, Radionuclide scanning and microangiopathy of evolving and completed brain infarction, Neurology, New York 24, 418-423 (1974). . Stroke edema 41 8. W. M. Blahd, Nuclear Medicine, 2nd Edn, pp. 262-265. McGraw-Hill, New York (1971). 9. G. A. Norton, P. R. S. Kishore and J. Lin, CT contrast enhancement in cerebral infarction, Am. J. RoentgenoL 131, 881-885 (1978). 10. J. K. Campbell, 0. W. Houser, J. C. Stevens, H. W. Wahner, H. L. Baker and W. N. Folger, Computed tomography and radionuclide imaging in the evaluation of ischemic stroke, Radiology 126, 695-702 (1978). 11. R. Katzman, R. Clasen, I. Klatzo, J. S. Meyer, H. M. Pappius and A. G. Waltz, Brain edema in stroke, Stroke 8, 512-540 (1977). 12. C. M. Shaw, E. C. Alvord Jr and R. G. Berry, Swelling of the brain following ischemic infarction, Archs Neural. 1, 161-177 (1959). 13. L. K. Y. Ng and J. Nimmannitya, Massive cerebral infarction with severe swelling, Stroke 1, 158-163 (1970). 14. R. M. Torack, H. Alcala, M. Gado and R. Burton, Correlative assay of computerized cranial tomography (CTT), water content and specific gravity in normal and pathological post mortem brain, J. Neuropathol. exp. Neural. 35, 385-392 (1976). 15. A. J. Yates, W. Thelmo and H. M. Pappius, Post mortem changes in the chemistry and histology of normal and edematous brains, Am. J. Pathol. 79, 555-564 (1975). 16. N. A. Lassen, The luxury perfusion syndrome and its possible relation to acute metabolic acidosis localized within the brain, Lancet 11, 111331115 (1966). 17. H. A. Hansson, B. Johansson and C. Blomstrand, Ultrastructural studies on cerebrovascular permeability in acute hypertension, Acta neuropathol32, 187-198 (1975). 18. M. D. O’Brien, A. G. Waltz and M. M. Jordan, Ischemic cerebral edema. Distribution of water in brains of cats after occlusion of the middle cerebral artery, Archs Neuroi 30, 45W60 (1974). 19. S. Shibata, C. P. Hedge and H. M. Pappius, Effect of experimental ischemia on cerebral water and electrolytes, .I. __ Neurosurg. 41, 146159(1974). 20. I. Klatzo, Neuropathological aspects of brain edema. Presidential Address, J. Neuropathol. exp. Neural. 26, 1-14 (1967). 21. F. P. Aleu. R. Katzman and R. D. Terrv. Fine structure and electrolvte analvsis of cerebral edema induced bv- alkvltin . intoxication, J. NeuropathoL exp. Neuro? 22, 403414 (1963). . _ 326333 (1973). 22. P. Lampert, J. O’Brien and R. Garrett, Hexachlorophene encephalopathy, Acta neuropathol23, About the h&o-RICHARD M. TORACK is a Georgetown Medical School graduate, Class of 1952. Following a pathology residency at Montefiore Hospital, Bronx, NYC, and a special fellowship at Yale University School of Medicine, he became an Assistant-Associate Professor of Pathology at Cornell University Medical School 1962-1968. In 1968, he became an Associate Professor and in 1970 a Professor of Pathology at Washington University School of Medicine in St. Louis, Missouri. His research background in brain edema has chiefly involved electron microscopic studies that have been reported since 1959. His interest in brain CT scans was initiated in 1975 in order to enhance the interpretation of anatomic changes as well as of CT images.