The Blood-Brain Barrier: An Expression of the Absence of Interstitial Spaces in Ectodermal Tissue?

THE BLOOD-BRAIN BARRIER: AN EXPRESSION OF THE ABSENCE OF INTERSTITIAL SPACES IN ECTODERMAL TISSUE? tV. JAMES GARDNER, M.D.* Some years ago, it came to my attention that a small tumor in the subarachnoid space may so elevate the protein content ofspinal fluid that its mechanical interference with fluid removal will increase intracranial pressure . Leakage ofplasma from vessels in the tumor causes the high protein content and represents a breakdown of the blood-cerebrospinal fluid barrier (i). Tumors buried within the brain or cord are less apt to increase cerebrospinal fluid protein but do tend to become cystic. I suspected that this retained protein-rich fluid did not result from liquefaction necrosis but from leakage of blood plasma, i.e., a breakdown ofthe blood-brain barrier. Preliminary studies showed that the Tiselius pattern ofcyst fluid resembled that of the patient's serum, offering support to the leakage theory (2). This investigation ofcyst fluids initiated a review ofthe subject of the blood-brain barrier, which proved so interesting that it has sidetracked the original problem. I. The Barrier—Prior to 1957 Paul Ehrlich (3) was among the first to show that vital staining affects all organs except the brain. However, the origin ofthe concept ofa barrier to the passage ofsubstances from blood into brain is attributed (4) to the systematic experiments of Goldmann (5). He used trypan blue, an acid colloid dye of relatively small molecular size, subsequently proven the most suitable dye for studying barrier permeability. When he injected the * Department ofNçurological Surgery, The Cleveland Clinic Foundation, and The Frank E. Bunts Educational Institute, Cleveland, Ohio. This paper is from a lecture given September 19, 1959. to the staff ofthe Cleveland Clinic. 169 dye intravenously in large quantities, it stained all organs but the brain, which remained uncolored except for its choroid plexus. No toxic symptoms resulted. However, when he injected a small amount ofdye into the cerebrospinal fluid, animals died in convulsions and the brain was colored deep blue. Goldmann concluded that there must be a barrier to the passage of toxic substances between blood and brain not present in other organs nor between cerebrospinal fluid and brain. Because at that time cerebrospinal fluid was considered important in nourishing the brain, he placed the site ofthe barrier in the choroid plexus. It perhaps is merely a curious coincidence that this same trypan blue, injected into pregnant rats, produces hydrocephalus and spina bifida in the offspring (6). Numerous researchers, employing various substances, have confirmed the presence ofa barrier between blood and brain, but even despite the recent aid afforded by radioactive tracers, the exact location and nature of this barrier have continued to puzzle investigators. Since 1956 may well be considered by future historians an important milestone in our understanding ofthe blood-brain barrier, I shall briefly summarize the high points ofBakay's (4) survey ofthat date. The morphologiclocus ofthe blood-brain barrier then was considered to lie somewhere between the intravascular and the interstitial fluid compartments, and it was believed that the latter constituted from 20 to 30 per cent of total brain volume. Intravenous vital dye studies had shown that the barrier exists in lower vertebrates, is present in fetal life, and persists for from one to three hours after death; that in vitally stained organs the dye may or may not be present in parenchyma but is always found in stroma; and that when dye is introduced into cerebrospinal fluid, the brain absorbs it after the manner of an amorphous colloidal mass containing no free fluid. It was known that alterations in permeability ofthe blood-brain barrier can hardly be obtained by physiologic means but that the barrier does break down in pathologic states such as injury, infection, infarct, and tumor. It was known that malignant gliomas exhibit a higher uptake ofradioactive isotopes, including radioactive iodinated serum albumin, than do benign gliomas; that the highest uptake occurs in metastatic carcinomas, sarcomas , and some meningiomas; these tumors, significantly, arise from tissues that do not possess a barrier. It was recognized that shrinkage ofthe brain resulting from intravenous injection of hypertonic solutions is an 170 W. James Gardner · Blood-Brain Barrier Perspectives in Biology and Medicine · Winter...