The choroid plexus: A historical review

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Review Article THE CHOROID PLEXUS: A HISTORICAL REVIEW

GEORGE J. DOHRMANN Departments of Pathology and Surgery (Division of Neurosurgery), Northwestern University Medical School, Chicago, Ill. 60611 (U.S.A.)

(Accepted September 2nd, 1969)

INTRODUCTION The discovery of the choroid plexuses of the lateral ventricles is credited to Herophilus (c. 335-280 B.C.) by Galen 146. Herophilus named the structure the 'chorioid mennix', 'chorioid' taken from the outer vascular plexus of the fetus. Rufus of Ephesus (c. 100 A.D.) suggested the term 'chorioid tunic' be used to describe both the ependyma and choroid plexus 111. Vesalius reported the gross anatomy of the choroid plexus of the lateral ventricles in his De Fabrica (1543). Willis (1664) (ref. 166) described the choroid plexus of the fourth ventricle and hypothesized that the choroid plexus contained gland-like structures which produced the fluid found in the ventricles. The entire extent of the choroid plexuses was known when Ridley (1695) (ref. 133) described the choroid plexus of the third ventricle. EMBRYOLOGY The following account of the embryology of the choroid plexus refers to development in humans, except where otherwise specified. The myelencephalic and diencephalic choroid plexuses arise from an invagination of the single layered roof plate; however, the telencephalic choroid plexus is formed from a portion of the medial wall of the cerebral hemispheres, the 'area chorioidea' as named by His 77. Bailey5 divided the development of the telencephalic plexus into anterior and posterior origins. The anterior portion of the telencephalic choroid plexus arises from the invagination of the multilayered roof plate of the neural tube rather than from the thin lamina or choroidal area which gives rise to the posterior telencephalic choroid plexus. The invagination of the roof plate occurs between the paraphyseal arch and the medial wall of the hemisphere. First the myelencephalic plexus develops, followed by the telencephalic plexus and lastly by the diencephalic plexusS6, TM. Continuity is established between telencephalic and diencephalic plexuses secondarily a~. Before anlage formation can be identified, glycogen is seen to accumulate in the cells from which the choroid plexus will arise. The telencephalic plexus begins to Brain Research, 18 (1970) 197-218

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appear at 6-7 weeksS6A4~. Kappers s6 described three phases of telencephalic choroid plexus development: Phase I (6-8 weeks): the plexus has pseudostratified epithelium in which glycogen is just beginning to accumulate. Hematopoiesis appears to be the primary function of the mesenchymatous stroma during this period. Stromal cells differentiate into hemocytoblasts and angioblasts. At the 22 mm stage erythroblasts are present surrounded by a strand-like formation of angioblasts which will eventually become the vascular endothelium. Intravenous injection of methyl violet at this time causes stromal formation of histiocytes and lymphocytes. Eosinophils have also been observed under these circumstances. Surprisingly, KappersS4, s6 postulated the eosinophils may originate from dedifferentiating fibrocytes. Phase H (8-15 weeks): choroidal epithelium is rapidly becoming low columnar to cuboidal and its glycogen content is increased. Much gelatinous connective tissue forms in most animals. The choroid plexus in this phase occupies most of the lumen, but as yet has no real villi. The glycogen-laden choroidal epithelial cells have been reported to secrete a significant amount of protein into the cerebrospinal fluid161. Flexner55 described a 'presecretory' stage in the choroid plexus of the fetal pig which would be equivalent to Phase II. The cells were columnar, glycogen-filled and had a large interstitial space. Cerebrospinal fluid from these fetuses had a higher protein content than the adult and the ion concentration was typical of extracellular fluid. This has been shown to be true in humans: premature infants have a much higher protein concentration in cerebrospinal fluid than full term infants3,n6. Phase III (15-40 weeks): this last phase is slowly progressive and varies with the individual fetus. Further flattening of the epithelium occurs, resulting in low cuboidal cells, and glycogen content is much reduced in the last stages of development. As the glycogen content decreases, the position of the nuclei changes from apical or central to basaP 4~. Most of the stromal, gelatinous ground substance disappears and is replaced by fibrous connective tissue; therefore, the epithelium:stroma ratio increases. True villi appear during this phase. An alternate classification was offered by Shuangshoti and Netsky145 who divided Phase III into two sections: 17-29 weeks and 29-40 weeks on the basis of nucleus position, glycogen content and extent of villous formation. Remarkably, throughout the development of the choroid plexus, no mitoses have been observed in the choroidal epithelium while many mitoses have been described in the ependymaa6,171. After birth the stroma increases and the capillary network becomes more complex thereby producing more villi. Fine structurally the fetal choroid plexus cells (rabbit)are columnar with irregular nuclei and simple membranes. Electron microscopy shows that they contain few microvilli or cilia, and have a finely granular cytoplasm and a clumped perinuclear organelle arrangement. Interstitial spaces are wide and contain dilated capillaries and a few fibroblasts. The basal membrane is not yet infolded. Mitochondria are sparse and have few cristae 15~. Kiszelya8 observed that mitochondria were relatively absent Brain Research, 18 (1970) 197-218

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during most of fetal life but were abundant in the choroidal epithelium of infants several days old. Kiszely concluded that the fetal choroid plexus serves a resorptive function then later becomes secretory. In opposition to Kiszely, Kappers s6 stated that the choroid plexus becomes functional only after birth. The finely granular cytoplasm was proven to contain glycogen by histochemical methods and light microscopic analysis. According to Dempsey and Wislockiss, glycogen is generally associated with anaerobic conditions. They suggested that anaerobic glycolysis might provide energy for oxidative reactions in tissues which have a poor oxygen supply. In the mouse embryo, the choroid plexus accounts for 27 ~o of the total ventricular wall area 91. This is in contradistinction to human embryos in which the choroid plexus is approximately 63 % of the ventricular surface157. The lateral ventricles of the mouse embryo, including choroid plexus and ependymal lining, make up 53 % of all the ventricular surface area 91. The plexus epithelial cells lose the last of the glycogen 2 weeks after birth. Kappers s6 has demonstrated alkaline phosphatase in the choroidal stroma of mouse embryos as early as day 14.5. According to Pearse 128 alkaline phosphatase might be associated with fiber formation. MACROSCOPIC STRUCTURE

Discussion which concerns humans unless otherwise noted, will be limited to the choroid plexuses of the lateral ventricles as they are considered the main site of cerebrospinal fluid production 1°9. The choroid plexus appears macroscopicaUy as a tortuous vascular membrane with a definite area of enlargement at the junction of the body and posterior horn of the lateral ventricle, the glomus51. The plexus is supplied by the anterior and posterior choroidal arteries. The anterior choroidal artery arises from the internal carotid artery an,l°9 or from the middle cerebral artery ts3 and enters the choroidal fissure in the anterior portion of th~ inferior horn of the lateral ventricle. There are 4-5 pgsterior choroidal arteries which originate from the pJsterior cerebral artery, encircle th~ cerebral peduncle and enter the choroidal fissure from the tela choroidea14,1°9. One p~sterior choroidal artery commonly joins the plexus at the foramen of Monro and the most anteriorly located posterior choroidal arteries may give branches to both left and right plexuses. Connections between anterior and posterior choroidal arteries are seen in the villous area, tela choroidea and glomus10g. Generally the anterior portion of the choroid plexus is supplied by the posterior choroidal arteries and the posterior portion is supplied by the anterior choroidai artery. The arterial system is connected to the venous system by arterioles and capillaries or arteriovenous shunts. The main choroidal vein leaves the ventricle at the foramen of Monro and continues through the tela choroidea as the internal cerebral vein which joins the internal cerebral vein of the opposite side to form the vein of Galen. Millen and Woollam109 described the choroid plexus of the lateral ventricle in the rabbit. The portion of the choroid plexus in proximity to the foramen of Monro the anterior angle, shows elaborate infolding. The p3sterior plexus is relatively simple. A tongue-like process, the lingula, curves out laterally from the main portion of the Brain Research, 18 (1970) 197-21

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choroid plexus. Although the choroid plexus in the rabbit is supplied by both anterior and posterior choroidal arteries, the lingula is supplied solely by the anterior choroidal artery. A lingula is also seen in the choroid plexus of the rat. The anterior choroidal artery of the rabbit becomes quite tortuous at its junction with the posterior choroidal artery. MiUen and Woollam~09 suggested that this was a method of pressure reduction so that there would not be a large pressure gradient between the blood in the vessels of the villi and the cerebrospinal fluid. MICROSCOPIC STRUCTURE

In the human, the choroid plexuses of the lateral ventricles, third ventricle and fourth ventricle, together contain approximately 100.6 million epithelial cells, with a mean of 107 million for adult males and a mean of 96 million for adult females. The total surface area is approximately 213 sq.cm (ref. 157). Histologically the epithelium of the choroid plexus consists of a single layer of cells which are cuboidal or low columnar, measuring 15/zm in height. The epithelium was first studied by PurkinjO 30 and later by FaivrO 6, Luschka1°° and Haecke171. Nuclei are round and centrally located with one or more nucleolP 26. Separation of cytoplasm into an apical clear zone and basal granular zone was described by Pettit and Girard ~26 under normal conditions and by Weed 163 under altered physiological states. Kalwaryjskis2 claimed the separation was simply a post-mortem phenomenon. A brush border (cuticular border) was described by Kalwaryjskis2 and cilia by Studnicka150 in the choroid plexus of certain animals. Various granules have been described by many authors using different stains and staining techniques. Mitochondria were demonstrated histochemically by SundwalP 5~ and by phase contrast microscopy by Frauchinger6°. Ciaccio and Scaglioni 3° stated that fat droplets were normally found in the rabbit choroid plexus epithelium while Ma and Schaltenbrand 137 found intraepithelial fat droplets only under pathological conditions in the cat choroid plexus epithelium. The choroid plexus epithelial cells have high levels of acid phosphatase in the nuclei and nonspecific esterases and succinic acid hydrogenase in the cytoplasm169. The choroid plexus shows moderate cholinesterase activity in the epithelium and high cholinesterase activity in the stroma 6~. Cancilla, Zimmerman and Becker ~6 in their histochemical studies on the rat choroid plexus found acid phosphatase activity in epithelial cell lysosomes, thiamine pyrophosphatase activity in the Golgi apparatus of the epithelial cell and in blood vessel walls, nucleoside phosphatase activity on the ventricular surface of the epithelial cells and the blood vessels, alkaline phosphatase activity only in the blood vessels and minimal activity of diaphorase and dehydrogenases in the epithelial cell cytoplasm. The histochemical study of the human choroid plexus by Helmy and Hack 76 showed staining for plasmalogen, succinic dehydrogenase and nucleic acids in the epithelial cells. The periodic acid-Schiff reaction (PAS) for carbohydrate stained the basement membrane and intima of the blood vessels while the elastic fibers of the blood vessels and connective tissue stained for nucleic acids. In the choroid plexuses of older humans, certain intracellular pigments and inBrain Research, 18 (1970) 197-218

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clusions were discovered6AS,19,66,17L Von Volkmann lss divided the pigments into three types: large granular form, vesicular form and thread-like form. Ring-shaped inclusions were described by Biondi 19 and Bargmann 6 in human choroidal epithelium. These inclusions consisted of non-homogeneous filaments, 15 nm in diameter 7. A basement membrane consisting of a lamellar structure between the base of the epithelial cells and the plexus stroma was described by Askanazy4 and Franceschini5s. Goldmann67-69 believed this lamella to function as the blood-cerebrospinal fluid barrier. Leonhardt96, 97, from his films of cell cultures, believed that there were protoplasmic bridges from the epithelial cells to the capillaries. Such protoplasmic bridges were dismissed as artifacts by Schaltenbrand taT. In the area of the glomus in the human choroid plexus, the vessels have a peculiar structure and are regarded as modified veins by most authorsZl,1°8,149. Vessels with lumina of large diameter are seen to anastomose with vessels having very small lumina. Their histological structure varies from veins elsewhere in the body in that their walls have no muscular layer. The tortuous venous-like vessels consist of endothelium and connective tissue which is inseparable from stromal connective tissue. Therefore, these venous structures all share the same connective tissue, making them large endothelial channels embedded in a connective tissue stroma. Capillaries in the choroid plexus possess a large diameter (approximately 15 #m) in comparison with other capillaries (approximately 3 #m) throughout the body 157. Connective tissue consisting of fibroblasts and collagen fibrils is located between the choroid plexus epithelium and the capillaries. Histochemical studies show alkaline phosphatase in the connective tissue and the blood vessel walls 169. Mast cells have been reported in the connective tissue of bovine choroid plexus 151 and choroid plexus of Ambystoma 87. Benedikt15 was the first to demonstrate nerve fibers in the choroid plexus. Later a number of authors described nerve fibers in the choroid plexuses of various animalsa~,a°,slAag,149. Although both myelinated and unmyelinated fibers are found, the majority of fibers in the choroid plexus are unmyelinated. Voetmann 157 regarded the myelinated fibers as sensory and the unmyelinated fibers as vasomotor. The nerves generally follow the vasculature and originate from the glossopharyngeal nerve 14a, the vagus nerve 15 and the sympathetics of the anterior and posterior choroidal arteries. St6hr 149 described interepithelial nerve fibers which he had interpreted to be pressure receptors. Clark a2 also demonstrated interepithelial nerve fibers in the choroid plexus of the neonatal kitten. The presence of pericapillary nerve cells in the choroid plexus villi was reported by AndiaL FINE STRUCTURE Since 1955 the electron microscope has been used to study the choroid plexuses of many species (caO0~; chick20; dog144,168; frog102,12s; guinea pig2a; lamprey94; lizard112; man7; monkey168; mouse42; opossuml68; rabbitZ02,108,121,15~,168,170; rat la'2e'ag'1°~'154,les; salamander2s; toad la6; woodchucklaS). Electron microscopic studies have also been done on the ependyma of the rat 22-24.

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Fig. 1. Diagram of a mammalian choroidal villus in cross section drawn to scale. The cuboidal epithelial cells have numerous microvilli on the apical membrane as well as tufts of cilia. Lateral and basal cell membranes are infolded. A basement membrane (not drawn) lies beneath the epithelium. Intervening between the central capillary containing erythrocytes and the epithelial basement membrane is the interstitium consisting of a pial cell, pial cell processes and collagen fibrils. Approximate magnification x 3200.

Each c h o r o i d a l villus is c o m p o s e d o f a single layer o f c u b o i d a l cells resting on a b a s e m e n t m e m b r a n e , a layer o f i n t e r p o s e d connective tissue elements a n d a b l o o d vessel b e n e a t h (Fig. 1). I n the villi at the distal p o r t i o n o f the c h o r o i d plexus, the b l o o d vessels are m a i n l y capillaries while arterioles a n d small arteries p r e d o m i n a t e at the base. Connective tissue elements are n o t a b l y m o r e n u m e r o u s in the b a s a l a r e a o f the c h o r o i d plexus. A p i c a l b r u s h borders, c o m p o s e d o f microvilli, are p r e s e n t o n the epithelial cells o f all v e r t e b r a t e c h o r o i d plexuses so far e x a m i n e d with the exception o f the lizard, Gecko japonicus ii2. Microvilli are finger-like, m e m b r a n e - b o u n d , c y t o p l a s m i c p r o t r u -

Brain Research, 18 (1970) 197-218

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sions which vary in diameter and uniformity of structure from slender symmetrical projections to apical bleb formations depending upon the fixation procedure. A theory of apocrine secretion based on electron microscopic observations of apical bleb formation and apparent discharge into the ventricle has been advanced by Wislocki and Ladman 16s. Millen and Rogers l°s stated that these blebs were due to unfoldings and distention of the microvilli. Tennyson and Pappas 152 explained the bleb production as cell injury and fixation artifact. Pinocytotic vesicles are particularly numerous and are located in the proximity of the apical, basal and lateral membranes. Cilia have been reported in many species and measure 160-200 nm in diameter. Clusters of cilia are observed in groups protruding from the apical surface of the cell. The actual number of cilia varies in different species: 3-4 per cell in the rabbit l°a; 4-8 per cell in the rat and opossumlSS; 11-16 per cell in the monkey16S; up to 50 per cell in the salamander 2s. The fine structure of cilia in the vertebrate choroid plexus epithelial cells conforms to that first described by Fawcett and Porter 5° in molluscs, amphibia, mouse and man, with nine pairs of peripherally arranged filaments and two centrally located filaments. Lateral cell membranes are closely approximated and desmosomes are noted near the ventricular surface. The basal plasma membrane, which rests on the basement membrane, is infolded. Basal extracellular space may occasionally be seen. The nucleus of the choroid plexus epithelial cell, which is a spherical structure located in a central or basal position, has up to three nucleolil°s and is enclosed by a double membrane, the nuclear envelope. Nuclear pores are readily demonstrable. Dohrmann and Herdson 42 described lobated nuclei in the choroidal epithelium of young mice but not in aging mice. They suggested that the lobated nuclei, in conjunction with the high concentration of rough endoplasmic reticulum and polyribosomes in the interlobar cytoplasm, were reflections of greater nucleocytoplasmic interaction in the choroidal epithelial cells of young mice. Mitochondria are present, measuring 400-600 nm in length and 200-300 nm in width. They have a typical fine structure, including a double membrane, with the inner membrane infolded to form the cristae. Numerous mitochondria are dispersed throughout the cytoplasm of the cell and are often seen in close approximation with rough endoplasmic reticulum. Many vesicles of rough endoplasmic reticulum, measuring 300-350 nm in diameter, are seen throughout the cytoplasm. Rough endoplasmic reticulum is also present as parallel stacks of double membranes, which occur alone, or in apparent continuity with the nuclear envelope, or in close proximity to mitochondria. The Golgi apparatus is located in a paranuclear position and consists of elliptical vesicles lined by a smooth membrane. In the choroidal epithelium of the dog and rabbit, vesicles containing ferritin-like material have been described by Wislocki and Ladman lss and in the guinea pig by Case2L This is in accordance with the finding of a high hemosiderin concentration in the choroid plexus epithelium by Flather s3. Polyribosomes are present throughout the cytoplasm of all choroidal epithelial cells, and lipid bodies, lysosomes, multivesicular bodies and focal areas of cytoplasmic degradation are noted in some. Brain Research, 18 (1970) 197-2!8

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Kidney proximal tubule cells ~24 possess a fine structure very similar to the epithelial cells of the choroid plexus. Microvilli are present in both, though they are thin and uniform in the proximal tubule cell, but are polypoid and non-uniform in the choroid plexus epithelial cell. Other cells also noted for water transport, such as salivary duct cells and ciliary epithelial cells, have infolded basal membranes. Lateral and basal membranes of the striated salivary duct cell are infolded while only the lateral membranes of the ciliary epithelial cell are so arranged 119,1z5A43. The epithelial cells rest on a thin, regular, mildly osmiophilic basement membrane. It has been suggested by Dempsey and Wislocki z9 and Wislocki and Ladman 16v that the basement membrane acts as a part of the hematoencephalic barrier. On the other side of the epithelial basement membrane are the connective tissue elements, consisting of collagen fibrils and various cells, which according to Maxwell and PeasO 02 belong to the leptomeningeal system. They identified the cells and their processes as pial cells. A great flattening of the pial cells is noted and their thin fingerlike extensions may constitute a partial barrier. Maxwell and PeasO 02 estimated the pial barrier to be 85 ~o continuous and suggested that it might pose a baffle for slowing diffusion since it is not a definite barrier. Unmyelinated nerve fibers in association with arterioles are present. Macrophages, fibroblasts and several leukocytes have been seen by Wislocki and Ladman 16s. Melanophores and mast cells have been demonstrated in the connective tissue spaces of Necturus 2s. Capillaries with attenuated, fenestrated endothelium and a thin basement membrane are present on the proximal side of the connective tissue space. The capillary diameter is large, measuring up to 6 or more erythrocytes in width ~0z. The pores measure 30-50 nm in diameter. It is interesting to note that capillaries in several different areas of active fluid transport have a similar structure. Thus, the capillaries of intestinal villi HT, renal proximal tubule t24, ciliary body of the eye a2° and choroid plexus 10~ are all structurally similar, and would be classified 'A-2-u' by the system of Bennett, Luft and Hampton 16. Arterioles are more numerous close to the base of the choroid plexus. They have flattened endothelial cells and an amorphous matrix which extends from the endothelial cells to encircle the surrounding smooth muscle cells 49. Small bundles of collagen fibrils are scattered throughout the amorphous matrix. FUNCTION

Various functions have been attributed to the choroid plexus including secretion, dialysis, absorption, purification, and endocrine activity. Of these, the theory of choroid plexus secretion has received the most attention in the literature. Following Willis' hypothesis 166 that the choroid plexus contained gland-like structures which produced the cerebrospinal fluid, FaivrO 6 and Luschka 1°° suggested that the entire choroid plexus functioned in a secretory capacity. The choroid plexus was further implicated in cerebrospinal fluid production by Claisse and Levi 31 in a report of hydrocephalus resulting from hypertrophy of the plexuses. Luschka 1°°, Galeotti 65, Findlay 51 and Studnicka 15° described secretory globules both within the choroid Brain Research, 18 (1970) 197-218

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plexus epithelial cells and frequently on the free surface of the epithelium, and from these observations concluded that it had a secretory function. The concept of secretory globules came to be known as the 'vesicular theory' of secretion l°a. Pettit and Girard 127 cast doubt on this theory by demonstrating that the number of globules increased with the time the choroid plexus remained unfixed. Furthermore, Meek l°a reported an increase in globules with mechanical trauma to fresh choroid plexus. Several workers including Cappelletti 27, Pettit and Girard lz6,127 and Meek 1°8 investigated the effects of ether anesthesia and intravenous administration of pilocarpine, atropine and muscarine on the production of cerebrospinal fluid in dogs, rabbits, guinea pigs and rats. They found that the production of cerebrospinal fluid greatly increased with ether anesthesia and doubled with pilocarpine injection while secretion was diminished with atropine and muscarine. Pettit and Girard 126,127 and Meek 1°3 removed the choroid plexuses following these experiments and found histological changes in the choroidal epithelium of stimulated animals including an increase in cell height and a separation of cytoplasmic contents producing a clear area at the apex of the cell and a granular area at the base of the cell. Langley95 stimulated the rabbit parotid gland by intravenous pilocarpine injection or feeding and recorded the formation of a basal clear zone and an apical granular zone in alveolar cells. As stimulation persisted the basal clear zone of the cells became larger while the number of granules in the apical zone of the cells decreased pari passu. These findings are in striking contradistinction to the morphology of active choroid plexus epithelium, because the parotid gland secretes enzymatically active proteins. Increased cerebrospinal fluid production in dogs was also observed following intravenous administration of extract of the posterior lobe of the pituitary164, pilocarpine hydrochloride41 and epinephrine s. However, histological studies were not attempted on the choroid plexuses of these experimental animals. Histological studies, the results of which supported the theory of secretion were reported by numerous authors including Galeotti 6~, Loeper 99, Schl/ipfer 140, Francini 59, Meek x°a, Enge145, Hworostuchin80, Grynfeltt and Euzi~re 7°, Weed 16z and Cushing3a. These authors reported increased numbers of mitochondria, together with the presence of intracellular granules and vacuolation of the choroid plexus epithelial ceils, and concluded that these morphological appearances were compatible with secretory activity. The work of Dandy and Blackfan35, who obstructed the aqueduct of Sylvius in dogs and thereby produced hydrocephalus, showed that at least in this species, cerebrospinal fluid is produced predominantly in the ventricles. Later Dandy 34 proved that most of the cerebrospinal fluid is produced by the choroid plexuses. He showed that occlusion of one foramen of Monro resulted in ipsilateral hydrocephalus, but if the choroid plexus was first removed, occlusion resulted in a collapsed ventricle. Cushing~3 studied the human choroid plexus in vivo and noted droplets of serous material exuding from the epithelial cells into the ventricular fluid. After placement of a silver clip on one of the choroidal arteries, the plexus blanched and the exudation stopped. Further evidence for the secretory function of the choroid plexus is derived from the fact that a defective cerebrum with only the choroid plexus in existence produces a cerebrospinal fluid-filled sac, hydranencephalya37. Brain Research, 18 (1970) 197-218

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Flexner54 compared the composition of plasma with the composition of cerebrospinal fluid and discovered that the cerebrospinal fluid contained higher concentrations of chloride and magnesium ions and lower concentrations of proteins, glucose, amino acids, uric acid, phosphate, calcium and potassium ions than plasma. From his calculations of the energy necessary for cerebrospinal fluid formation, he concluded that the fluid could not be formed merely as a dialysate. Flexner clarified his position by stating: 'The fluid, on the basis of present evidence, is to be considered a secretion with the understanding that the term secretion means that cells must do work in formation of the cerebrospinal fluid.' Metabolic studies of the choroid plexus by Krebs and Rosenhagen 93 using the Warburg method revealed a metabolism comparable to that of liver and kidney. A later biochemical analysis of the choroid plexus was undertaken by Fischer and Copenhaver 52, who studied enzyme systems active in basic cellular metabolism including anaerobic glycolysis, succinic dehydrogenase and cytochrome oxidase. Enzyme activity of alkaline phosphatase, carbonic anhydrase, cholinesterase and fl-glucuronidase, all of which may play a role in active transport, were also studied. The authors concluded that 'biochemical analysis of the choroid plexus indicates that general metabolic activity is one-third to one-half the value of the kidney.' Kral, Stary and Winternitz92 took serum and cerebrospinal fluid from the same patient and dialyzed them against each other using a collodion membrane. Post-dialysis alterations were noted, thereby casting doubt on the concept that cerebrospinal fluid is produced as a dialysate. Recent studies comparing ion concentrations in the ventricular and cisternal cerebrospinal fluid with a plasma ultrafiltrate were undertaken by Ames, Sakanoue and Endo 1. The ventricular cerebrospinal fluid contained a higher sodium and magnesium concentration and a lower calcium concentration than the plasma ultrafiltrate while the cisternal cerebrospinal fluid contained a higher concentration of chloride, sodium and magnesium and a lower concentration of potassium and calcium than the plasma ultrafiltrate. The authors suggested that ion concentrations in the cerebrospinal fluid are maintained homeostatically by active transport. Measurements of electrical potential across the choroidal epithelium by Welch and Sadler a~5 showed that in formation of cerebrospinal fluid sodium must ascend a steep electrochemical gradient. Studies of the choroid plexus in tissue culture by Cameron 25 revealed definite secretion. Threshold values exist below which certain substances present in the blood do not appear in the cerebrospinal fluid. Such substances include nitrates, iodides, bile pigments and salicylates 33,37,a59,16°. However, not all substances have a defined threshold value. In experiments with rats given silver nitrate in their drinking water, silver particles were seen within the choroid plexus basement membrane and infrequently within the choroidal epithelial cells39A67. A report by Van Breemen, Reger and Cooper a55 stated that under such circumstances silver passes from the blood in ionic form, into the basement membrane within which it is precipitated by combining with sulfhydryl groups. Electron microscopic studies of selective transport across the choroidal capillaBrain Research, 18 (1970) 197-2t8

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ries lend further support to the theory of choroid plexus secretion. Pappas and Tennyson TM injected a variety of electron dense colloidal particles intravenously, including thorotrast, gold sol and saccharated iron oxide, but did not find any of these particles in the choroidal capillary pores or the basement membrane of the choroidal capillaries. In thicker walled capillaries and arterioles, they did note electron dense particles in endothelial pinocytotic vesicles and in the intercellular spaces. Later Becker, Novikoff and Zimmerman12 injected peroxidase intravenously and noted its uptake by the rat choroid plexus epithelial cells. Peroxidase traversed the capillaries and was seen in the extracellular space and in pinocytotic vesicles within the choroid plexus epithelial cells. All peroxidase in the cells was present in membrane bound vesicles within 15 min following injection. In direct contrast the passage of ferritin through the pores of endothelial cells has been demonstrated in glomerular capillaries by Farquha# 7 and Farquhar, Wissig and Palade 4s. Such a phenomenon has not been demonstrated in the capillaries of the choroid plexus. Other investigators favored the theory of dialysis as the mechanism for cerebrospinal fluid formation. Diametrically opposed to the concept of secretion were the views of MestrezaO 05, Becht and Matill 1°, Becht and Gunnar 9, Mestrezat and LedebO °6,t°7, Foley56 and Forbes, Fremont-Smith and Wolff57, all of whom claimed that cerebrospinal fluid was a dialysate formed by the choroid plexus. MestrezaO °5, using freezing point depression, observed that the total osmotic pressure of the plasma and the cerebrospinal fluid is the same. Becht and Matill 1° and Becht and Gunnar 9 demonstrated increased cerebrospinal fluid production with a rise in either arterial or venous pressure; however, the increased cerebrospinal fluid production was correlated most closely with the increased venous pressure. Mestrezat and Ledebt1°6A°7 placed collodion sacs with 5 ~ NaC1 into containers of horse serum or into the peritoneal cavity and allowed equilibration to occur. Sac contents were approximately the same as the cerebrospinal fluid constituents. Foley56 showed a reversal of flow through the choroid plexus by demonstrating an uptake of fluid from the ventricles when the choroid plexus was infused in vivo with a hypertonic NaCI solution. He placed a solution of potassium ferrocyanide and ferric ammonium citrate, which was isotonic with the cerebrospinal fluid, in the ventricles. The. choroid plexus was removed, fixed in HCl-formalin and uptake of the iron salt was indicated by its presence in the plexus epithelial cells as Prussian blue. Forbes, Fremont-Smith and Wolff57 repeated the experiment of Foley and reported identical observations. However, a similar experiment by Nanagas 113 did not show any Prussian blue in the choroid plexus but did show Prussian blue in the ependymal cells. Lending further support to the theory of dialysis as the mechanism for cerebrospinal fluid production were the experiments of Schaltenbrand and Putnam tas and Putnam and Ask-Upmark TM. After intravenous injection of fluorescein, Schaltenbrand and Putnam t3s, using a binocular microscope, watched fluorescein leaving the choroid plexus of live cats. Putnam and Ask-Upmark TM, in a similar experiment, noted fluorescein exuding from both the living choroid plexus and white matter as well. Fremont-Smith61 also believed in the concept of cerebrospinal fluid formation by dialysis. He found that there is a relationship between the concentration of plasma Brain Research, 18 (1970) 197-218

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proteins and the distribution of chloride ions: the greater the protein content of the plasma, the greater the chloride ion content of the cerebrospinal fluid. From these observations he concluded that the Donnan membrane equilibrium plays an important role in the distribution of chloride across the choroid plexus and, thereby, is a significant factor in cerebrospinal fluid production. With regard to the choroid plexus as an absorptive organ, a variety of authors have stated that absorption is either the sole function or one of several functions of the choroid plexus. Askanazy4 observed hemosiderin deposits within the choroidal epithelial cells of patients with intraventricular hemorrhage. He suggested that the choroid plexus may act in absorption as well as secretion. Becht8 stated that in the pharmacologically stimulated choroid plexus epithelial cells, a granular basal zone and a clear apical zone were seen, while in the secreting acinar cells of the parotid gland, a clear basal zone and a granular apical zone were observedgL From these observations, Becht surprisingly concluded that the choroid plexus may act in absorption since it shows morphological changes exactly opposite to the changes in the secreting cells of the parotid gland. Becht's statement lacks logical development in that the parotid gland secretes enzymatically active proteins while the choroid plexus does not. Hassin 7z suggested that the cerebrospinal fluid was formed by the brain, while the choroid plexuses acted in removal of waste from the cerebrospinal fluid. Hassin73,74 theorized that the choroid plexus absorbed specific wastes from the cerebrospinal fluid and thereby functioned as a purifying apparatus for the cerebrospinal fluid. Remaining a dissenter, Hassin 75 stated the cerebrospinal fluid was formed in the perivascular spaces, a 'lymph of the central nervous system', and absorbed by the perineural spaces after elimination of noxious substances by the choroid plexus. More evidence for absorption was added by Flather 53, Tennyson and Pappas 152, Pappenheimer, Heisey and Jordan 122, Smith et al. 147, Klatzo et al. 9o, Robinson et al. 135, and Brightman23. Tissue culture of the choroid plexus by Flather 53 showed transport of indicator solution through the epithelium and accumulation in the connective tissue space. Tennyson and Pappas 152 described pinocytotic uptake of thorotrast by the choroid plexus epithelium following intravenous injection. Pappenheimer, Heisey and Jordan 122 studied the choroid plexus of the fourth ventricle in goats following the intraventricular administration of Diodrast and phenolsulfonphthalein. They reported active transport of both substances from cerebrospinal fluid to blood. Diodrast and phenolsulfonphthalein are organic acids which are secreted by the proximal tubules of the kidney. The authors state: 'The close qualitative resemblance of the transport process (in the choroid plexus) to that in the kidney suggests that we are dealing with a homeostatic mechanism regulating the special composition of cerebral fluids . . . . It is possible that choroidal epithelium of the lateral ventricles loses its capacity to transfer Diodrast, etc. in the adult, whereas the embryonic absorptive capacity is retained by the choroidal epithelium of the 4th ventricle. The separate embryological development of the telencephalic choroid plexuses may be of importance in this connection.' After inhibiting Diodrast transport by means of the intraventricular administration of p-aminohippurate or phenolsulfonphthalein, the authors observed a passive component of Diodrast transfer from cerebrospinal fluid Brain Research, 18 (1970) 197-218

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to blood by the choroid plexus of the fourth ventricle. Smith et al. 147, using the isolated chick choroid plexus, demonstrated transchoroidal transport of fluorescent-labeled albumin from the incubation medium. Labeled albumin was noted in the choroidal epithelial cells and the stroma. No active transport of fluorescent-labeled globulin was observed by the authors. Studies by Klatzo et al. 9° strongly suggested that in cats there is active uptake of fluorescein-labeled albumin by the choroid plexus and the ependyma, following its injection into the cisterna. In vitro studies of the choroid plexus by Robinson et al. la5 have demonstrated uptake of sulfate, thiosulfate and iodide from the artificial cerebrospinal fluid medium. Brightman23 reported intercellular diffusion and pinocytotic uptake by the ependymal cells following injection of ferritin into the ventricles of rats. The choroid plexus was used clinically as an organ of excretion by Fulcher6~ and Fulcher and Parrish s4. Nine patients were used in the study. Two had normal renal function and were used as controls, one had arteriosclerosis and bromide poisoning, one had hypertension, and four had arteriosclerosis and high concentrations of blood-urea nitrogen. With continuous lumbar drainage of the cerebrospinal fluid in these patients, the cerebrospinal fluid samples had a higher concentration of NaC1, the same concentrations of urea nitrogen and bile pigment (in slight jaundice) and lower concentrations of potassium and creatine, than those of the serum. The patient with bromide poisoning was treated by this method and the concentration of the bromide in the cerebrospinal fluid increased as that of the serum diminished. The authors stated that the procedure would be effective in the treatment of bromide poisoning and would be of some benefit to patients in temporary renal failure in combating generalized edema. The authors noted the treatment would be of no value to patients with chronic renal disease. An endocrine function was attributed to the choroid plexus by Holl~inder and Spiegel 79 and Papadato and Sapkowa 11s. Holl/inder and Spiegel 79prepared extracts of bovine choroid plexus which with intravenous administration produced a transient fall in the blood pressure of cats but not rabbits. Papadato and Sapkowa 11s described the choroid plexuses as endocrine glands but offered no proof of this theory. Dixon and Halliburton4° prepared extracts of human, ox and sheep choroid plexuses. Intravenous administration of these extracts caused increased formation of cerebrospinal fluid in dogs; however, the authors did not directly attribute endocrine function to the choroid plexus. Bering17 stated that, among other functions, the choroid plexus acts as a cerebrospinal fluid pump. He noted that each pulse of the choroid plexus creates a pressure gradient which forces cerebrospinal fluid out of the ventricles and, therefore, theorized that the pump-like action is important in embryonic development of the subarachnoid pathways. PATHOLOGY

In the present discussion, the following pathological conditions involving the choroid plexus will be reviewed: non-specific reactions to injury; regressive changes Brain Research, 18 (1970) 197-218

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with increasing age; morphological alterations in psychiatric patients; correlation between experimentally induced renal disease and choroid plexus injury; light and electron microscopic observations of the choroid plexus in experimental hydrocephalus; and primary choroid plexus neoplasms. Non-specific reactions of the choroid plexus to various types of irritations have been described by Ma, Schaltenbrand and Cheng 101 who found epithelial and stromal changes following intraventricular injections of trypan blue, washed erythrocytes or air. Approximately 24 h after injection, the choroidal epithelial cells appeared swollen, the cytoplasm turbid, the number of mitochondria increased, the Golgi apparatus larger, and free fat was identified within the cytoplasm. Several days later the nuclei stained with less intensity and cytoplasmic vacuolation was noted. Stromal changes consisted of dilated blood vessels and an edematous, glassy connective tissue. Complete restoration of the normal histology was seen 10-12 days following the injection. Regressive changes in the choroid plexus related to age were described by Dunn and Kernohan 44. In a comprehensive study of 324 brains, from autopsies on humans ranging in age from neonates to 1013years, the authors ob3erved regressive changes in the choroid plexuses of the lateral ventricles with increasing age. They noted a flattening of the epithelial cells and an increase in vacuolation and lipoid pigment. Connective tissue proliferation and calcified and non-calcified hyaline plaques within the stroma of the villi were seen. At the base of the plexus, cellular proliferation, hyaline degeneration and fatty degeneration were described. Psammoma bodies and cysts were present in the stroma also near the base of the choroid plexus. Arteries and arterioles showed intimal thickening and medial fibrosis. All these changes increased with age but were not limited to or correlated with any specific age. The choroid plexuses of the lateral ventricles from psychiatric patients were examined by Findlay51. He found concentric hyaline bodies (psammoma bodies) in the stroma, which he believed to be hyalinized arterioles and venules. Staining of the choroid plexuses with osmic acid revealed fatty areas in the concentric bodies. The author theorized that concentric bodies underwent a fatty change followed by calcification to produce the concretions seen with increased frequency in senile patients. Mulberry bodies lz4, aggregations of hyalinized endothelial cells, were noted, particularly in the region of the glomus. Findlay51 described these mulberry bodies as nonspecific pathological changes. Connective tissue hyperplasia and hyaline degeneration with occasional osteoid plate formation were observed in the stroma. Hyaline degeneration commonly involving the adventitia, media and intima was present in small arteries and arterioles. Examination of the choroid plexuses from schizophrenics, non-schizophrenic psychotics and normal individuals revealed a sclerosis and atrophy of large groups of choroidal epithelial cells in both psychiatric groupsSL Purjesz, Dancz and Horvath 129 hypothesized that the choroid plexus might function in a similar manner as the kidney and, if so, might show histological changes under conditions producing pathologic renal histology. Following an approach based on the work of Schlayer and Hedinger141, who had intravenously injected chromium, HgCIz, cantharidin, arsenic and diphtheria toxin into rabbits and discovered that Brain Research, 18 (1970) 197-218

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each of these substances could produce a toxic nephritis, Purjesz et aL injected dogs subcutaneously, intravenously and intra-arterially with HgCI2, K2CrO4, uranyl nitrate and cantharidin. The kidneys showed degeneration of the tubules and hyperemia with frequent hemorrhage and glomerulonephritis. Choroid plexus alterations included epithelial degeneration, hyperemia, hemorrhage, serosal inflammation, exudation and cellular infiltration of the connective tissue. HgCI2, KzCrO4 and uranyl nitrate which chiefly affect the renal proximal tubules, caused the greatest damage to the choroidal epithelium. Surprisingly, they concluded that since the renal tubular cells (particularly the proximal tubule cells) of the kidney and the choroid plexus epithelial cells both showed injury under the same conditions, the cerebrospinal fluid is probably produced by the choroid plexus in a similar manner as urine is formed by the kidneys. With regard to experimental hydrocephalus, vitamin Blz deficiency has been demonstrated to cause non-communicating hydrocephalus in rats114,115. In offspring from vitamin B12-deficient mothers, a stenosis of the cerebral aqueduct was observed. Histologic examination revealed a frequent absence of tall columnar epithelium usually present in the roof of the third ventricle and cerebral aqueduct while the choroid plexus epithelium exhibited vacuolation, pyknotic nuclei and fat inclusions. In non-hydrocephalic litter mates the same choroid plexus changes were described but were much less marked. Experimental hydrocephalus was also produced by Mellanby TM who first described the increased cerebrospinal fluid pressure and hydrocephalus resulting in offspring from vitamin A-deficient dogs. Millen and Woolam 110 described the production of hydrocephalus in rabbits born of a mother deficient in vitamin A. They found no obstruction to cerebrospinal fluid outflow and suggested that the mechanism of hydrocephalus was hypersecretion. Tennyson and Pappas TM studied the same experimental model and noted both obstructive and non-obstructive hydrocephalus. However, electron microscopic observations show similar fine structural changes in the choroidal epithelium of both types, including multiple infoldings of the nuclear envelope, clumping of nuclear chromatin, randomly arranged rough endoplasmic reticulum cisternae, myelin figures and abundant, large pleomorphic mitochondria. Uptake of thorium dioxide injected into the lateral ventricle was greatly decreased in hydrocephalic offspring relative to normal offspring 152. Witzel and Hunt 170 also studied the fine structure of the choroid plexus in the hydrocephalic progeny of vitamin A-deficient rabbits. They found enlarged endothelial cell junctions, manyintracapillary platelet thrombi, free erythrocytes and leukocytes in the subarachnoid space, increased numbers of whorled endoplasmic reticulum formations within the choroidal epithelial cells and enlarged cisternae between the plasma membranes of the epithelial cells. The effects of hypervitaminosis A on the rat choroid plexus were studied by Becker and Sutton 13. In weanling rats the fine structural alterations included an increased number of lysosomes and a reduction of the Golgi apparatus in the choroidal epithelial cells. However, in adult rats the fine structure of the choroid plexus was normal. Using intravenously injected peroxidase as a tracer, the authors noted a vascular to ventricular transport of peroxidase which was increased in weanling rats by excess vitamin A. Brain Research, 18 (1970) 197-218

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The hypertrophied choroid plexus in a case of non-obstructive hydrocephalus was studied histologically by Davis 36. The villi were larger and more numerous than normal and exhibited an increased branching. Choroidal epithelium was comprised of normal cuboidal cells arranged in a single layer. The stroma contained mere blood vessels than normally present; however, the stroma was otherwise within normal limits. Neoplasms arising from the epithelium of the choroid plexus are rare, comprising 0.5-0.6 ~o of all intracranial tumors 173. Van Wagenen156, in a review of the literature, found that in cases of primary choroid plexus neoplasms, 50 ~ were located in the fourth ventricle, 34.7 ~o in the lateral ventricles and 17.3 ~ in the third ventricle. 93 ~ of the choroidal neoplasms occurring in the lateral ventricles were noted in the left lateral ventricle. Primary choroid plexus carcinoma has been recently reviewed by Lewis 9s. To date, the only study of the choroid plexus in systemic disease has been reported by Dohrmann and Herdson 43. They used NZB/NZW hybrid mice, a strain which develops a disease resembling human systemic lupus erythematosus. Fine structural examination of the choroid plexus revealed an irregular, homogeneous thickening of the capillary basement membranes. Other miscellaneous reports on the pathology of the choroid plexus include Hoff 78, Rand and Courville13~, Divry21 and Steiner and Shanklin~4s. Hoff78 reported on increased permeability of the choroid plexus in experimental head injury. In a survey of 62 cases of fatal cerebral trauma, Rand and Courville 132 noted edema of the stroma and vacuolation of the epithelial cells of the choroid plexus. The presence of amyloid in the choroid plexus of elderly brains was described by Divry21. Amyloid was present within the choroidal epithelium, confined to the free margins of the cells. Steiner and Shanklin14s studied the choroid plexus in hyaline membrane disease and noted histological changes consisting of an edematous interstitium and swollen epithelial cells. SUMMARY

The embryology, macroscopic structure, microscopic structure, fine structure, function and pathology of the choroid plexus were reviewed. Conflicting opinions have been noted and selected critical comments expressed. ACKNOWLEDGEMENTS

The preparation of this review article was supported in part by Grant No. 5-TI-GM-I 31 from the National Institutes of Health and by Neurosurgical Training Grant No. 5408 from the National Institute of Neurological Diseases and Stroke. I thank Peter B. Herdson for helpful comments throughout the preparation of the manuscript.

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