Paper - Meninges and cerebrospinal fluid (1938)

From Embryology

Weed LH. Meninges and cerebrospinal fluid. (1938) J Anat. 72: 181-215. PMID 17104684

Meninges and Cerebrospinal Fluid

By Lewis H. Weed

Department of Anatomy, John Hopkins University

The divorce of structure from function is particularly difficult in any anatomical study: it was only 85 years ago that the two subjects of morphology and physiology were considered to justify separate departments as academic disciplines. But with this cleavage which fortunately has not at any time been a rigid one, only certain investigations could go forward without loss of inspiration and interpretation when studied apart from the sister science; other researches were enormously hampered and could be attacked only with due regard to structure and function. So it is without apologies that I begin the presentation of the problem of the coverings of the central nervous system —coverings which encompass a characteristic body fluid. Here then is a problem of membranes serving to contain a clear, limpid liquid as a sac might hold it. Immediately many questions of biological significance are at hand: how does it happen that these structures retain fluid; where does the fluid come from; where does it go; is the fluid constantly produced or is it an inert, non-circulating medium; is the fluid under pressure above that of the atmosphere; does it move about with changes in the animal body?—but the list of problems springing into one’s mind grows too long.

Knowledge regarding these many questions has progressed since the first accounts of hydrocephalus were given by writers in the Hippocratic corpus, since discovery of the normal ventricular fluid in Galen’s time, since its meningeal existence was first uncovered by Valsalva (1911) and advanced by Cotugno (1779), since the first adequate description by Magendie (1825) 100 years ago. We know now that the ventriculo-meningeal system is not like the coelomic serous sacs which we designate as pleural, pericardial and peritoneal cavities, for in these cavities no specialized mechanisms for the production and absorption of the fluid exist. We know now that this fluid-space around the neuraxis differs from the synovial cavities, mucous bursae or tendon sheaths, all of which may possibly be grouped together in a common loose classification. We know now that the fluid-relationships about the nervous system have greatest similarity to those of the aqueous humour of the eye, with an origin from a specialized structure and a process of absorption through a differentiated structure. But let us examine the evidence for these generalizations about the meninges and the contained fluid—have we even now the right to be at all dogmatic about our knowledge of the cerebrospinal fluid and its pathways?

  • 1 This survey of the problems and investigations arising out of the cerebrospinal fluid formed the basis of lectures given in the Anatomy Department of University College by Prof, L. H, Weed at the invitation of the London University.

It is customary to speak of the pathways of the cerebrospinal fluid as being of two parts—the ventricular and meningeal. The cerebral ventricles all form part of the first pathway, communicating as they do with each other and including within them the chorioid plexuses. The ventricles are everywhere lined with a typical cuboidal or low columnar cell, the ependymal cell, which in the adult simulates closely its initial embryonic appearance. Over the vascular tufts of the chorioid plexuses of the ventricles, the ependymal cell becomes specifically differentiated into a high columnar type.

The second part of the cerebrospinal pathway is that within the meninges; of these membranes the customary anatomical description lists three. The outermost, the dura mater, is a strong, thick and dense membrane of which the cranial portion is usually depicted as being composed of two layers; these lamina split to enclose the large venous sinuses and certain other structures. In the spinal region these two layers are not in approximation, for the outer layer is taken to constitute the internal periosteum of the vertebral canal while the inner fraction becomes the true spinal dura mater. Between these two so-called layers of dura in the vertebral canal occurs the epidural space, filled in the mammals with fatty areolar tissue and thin-walled veins. Within the cranium the dura adheres closely to the inner surface of the bones forming the skull cavity, serving there as the internal periosteum.

Histologically the dura mater is composed almost exclusively of dense bands of white fibrous tissue (as shown beautifully by Key & Retzius, 1876) with but few elastic fibrils; the dense bands interlace in every direction and give no indication of a cleavage into two portions. The nuclei are sparse in number and are typical of dense fibrous membranes elsewhere in the body. The inner surface of the dura mater is covered by flattened, polygonal mesothelial cells with relatively large oval nuclei. To-day we are forced to believe that no true lymphatic vessels (those possessing an endothelial lining) exist within the dura mater.

The framework of the second, or middle, of the three meninges, the arachnoidea, is a delicate fibrous matrix composed of white fibres with an admixture of elastic elements. This framework forms a continuous sheath for the arachnoid membrane and projects inward as irregular cores for the arachnoid trabeculae. Reaching the surface of the brain, the trabecular cores blend with the subpial network. Upon this reticular base is superimposed the essential cell-element of the leptomeninges. This cell is structurally identical with that lining the inner surface of the dura, being of a flattened mesothelial type and showing characteristic functional changes in morphology (Essick, 1920; Woollard, 1924; Kubie & Schultz, 1925).

These mesothelial cells form a continuous layer over the outer surface of the arachnoidea, covering likewise the inner surface of this membrane and extending inward as a continuous cellular sheath over the arachnoidal trabeculae. As the trabeculae merge with the pia mater, these covering cells spread out over this innermost membrane. The pia mater is not, however, a continuous membrane, as is the arachnoid, for the pia is pierced by the perivascular cuffs of the entering and energent blood vessels and probably is perforated in the rhombencephalic roof areas.

Although in general the dura mater and the arachnoidea constitute definitive membranes separated by the fluid-containing subdural space, there are points of fusion between the two structures. In every case it is simplest to look upon these points of fusion as invasions of the dense dura mater by the arachnoidea, though such a description of the process is wholly arbitrary and probably incorrect embryologically.

Fig. 1.

The first of these processes of fusion are the structures known as the cranial arachnoid villi—the microscopic precursors of Pacchionian granulations, recently well studied by LeGros Clark (1920), and by Winkelman & Fay (1930). The villi are essentially continuations of the arachnoid mesh into the lateral walls of the great dural sinuses, so that the arachnoid mesothelium comes to lie directly beneath the vascular endothelium. The core of the villus may be a loose strand-like network or a reticular tissue possessing myxomatous characters. The arachnoid cells at the tip of the villi, directly beneath the vascular endothelium, are usually several layers in thickness, thus forming cellular caps over the villi. The microscopic arachnoid villus is found at all ages in man and in all mammials thus far studied, and it probably occurs throughout all orders of mammals. Essentially similar structures have been described by Elman (1923) as projecting from the arachnoid into each segmental vein throughout the spinal region.

The second type of contact between dura and arachnoidea is achieved through the so-called arachnoid cell-columns which represent prolongations of the arachnoid mesothelium into the dura in sites other than those along the dural sinuses. In this structural group, the arachnoid mesothelium is found as a solid core of cuboidal cells with large oval nuclei; this cellular core is surrounded by the fibrous tissue of the dura.

It seems unnecessary to describe at length the blood vessels of the central nervous system and meninges, as only a few characters of these vessels are involved in the questions under discussion. Most important of the anatomical features having to do with the cerebrospinal fluid is the fact that any vessel transversing the subarachnoid space is covered by arachnoid mesothelium. A second feature which is directly related to our main problem is that ultimately the venous drainage of the cranial vascular bed is through the dural sinuses, enclosed within the layers of the dura and having relatively little, if any, power of independent change of calibre.

With this brief description of the anatomical features of the ventriculomeningeal system, our discussion now passes to the problem of formation of the cerebrospinal fluid. Here the task is one of weighing evidence from many sources in biology; almost none of the specific observations is in itself conclusive proof of the site or mode of production of the fluid. Examination of these pertinent data from diverse fields leads inevitably to the view that the elaboration of the greater volume of the fluid takes place within the cerebral ventricles, and that the chorioid plexuses are the responsible structures even though final demonstration of this relationship has been lacking until recently.

The description of the glandular histological structure of the chorioid plexuses by Faivre (1853) marked the discarding of the older concept of Haller (1757) and Magendie (1825) that the cerebrospinal fluid was a product of the leptomeninges (particularly of the pia mater). Faivre made the first histological survey of these villous projections, showing that the cell-coverings were epithelial in nature and that they contained inclusions which could be interpreted as indicating secretory activity in the cells. Faivre’s observations, supported by similar microscopic studies by Luschka (1855), gave origin to the hypothesis that the chorioid plexuses of the cerebral ventricles elaborate the cerebrospinal fluid; this has remained the hypothesis upon which most of the investigations regarding the source of this peculiar body-fluid have been based.

The purely histological evidence presented in support of this hypothesis, while suggestive, lacks many elements of proof, though for many years accepted without question. During the past 30 years, renewed attempts (vide Weed, 1922; Flexner, 1934) with histological and cytological methods have been made to bridge the gap between intracellular secretion-granules (vacuoles) and the actual production of a fluid surrounding the cells. Thus there have been many descriptions of pigmented globules, of hyaline-like bodies, of osmicstaining granules, of lipoid inclusions, of glycogen plaques or particles, of Golgi apparatus, of fuchsinophilic granules, of basophilic plasmosomes, of nuclear granules, of mitochondria, etc. In all of these studies, there is no irrefutable evidence that these intracellular structures. constitute the intracellular mechanisms for the elaboration of the cerebrospinal fluid. The difficulty of final demonstration that these granules are absorbed into the fluid, or discharged into the fluid, cannot be surmounted with present-day histological methods.

Fortunately observations of a somewhat more conclusive nature are available through combination of histological and pharmacological methods. In this category are the descriptions of Pettit & Girard (1902), who reported an increase in volume of the chorioidal cytoplasm after injections of muscarin, pilocarpine, etc., each of which Cappelletti (1900) supposed to increase the production of cerebrospinal fluid. As these drugs are largely those which stimulate other ducted glands to secrete, Pettit & Girard’s findings (as confirmed by Meek (1907)) were considered to constitute proof that a secretory function was lodged in the chorioid plexus. Changes in these epithelial cells, in every way similar to those reported, were found by me, in a later study (1923 b), to result from the intravenous injection of large quantities of a hypotonic solution.

Certain indirect support of the relationship between the chorioid plexuses and the cerebrospinal fluid was obtained some 20 years ago in my investigation (1917) of the embryology of the meningeal spaces. It was shown that up to a stage of 14 mm. in pig embryos the growth of the cerebral ventricles kept pace with the production of the fluid within them. In slightly larger embryos a sudden expulsion of the fluid from the ventricles into the developing subarachnoid space occurred. At this stage of growth the chorioid plexuses are just beginning to become tufted; the balance between ventricular growth and production of fluid is abruptly disturbed even though the chorioidal cells are at this stage incapable of producing a cerebrospinal fluid with the physical characters of the adult fluid.

But the chorioid plexuses become more intimately related to the production of cerebrospinal fluid when one considers data from the general field of pathology. Ever since the earliest observations upon hydrocephalus, it bas been realized that the cerebrospinal fluid must, at least in part, be produced by some intraventricular structure. Attention was focused upon the chorioid plexuses by the discovery (Claisse & Levy, 1897) of a case of internal hydrocephalus associated with hypertrophy of these intraventricular structures. The experimental production of an internal hydrocephalus by Dandy & Blackfan (1914, 1917), and by Frazier & Peet (1914), gave additional support to the general contention of intraventricular production. Cushing’s (1914) observation of an exudation of a clear fluid from the chorioid plexus, exposed in exploration of a porencephalic defect, likewise added suggestive substantiation of the hypothesis, though the operative exposure of the plexus unquestionably altered pressure conditions. Dandy’s (1919) later experiment consisted of the production ofa unilateral internal hydrocephalus by obstruction of one foramen of Monro; when this plugging of the foramen was accompanied by extirpation of the chorioid plexus, no ventricular dilatation followed. These observations by Dandy cannot be looked upon as demonstrating the production of the fluid by the plexuses. The lack of histological control in his experimental animals where the chorioid plexuses were supposedly extirpated and the possibility of an intracortical escape of fluid through the operative wound vitiated many of the conclusions.

Somewhat more tangible evidence of intraventricular production of fluid may be obtained from those cases of internal hydrocephalus where an obstruction has been produced in the subarachnoid space. By subarachnoid injection of lamp black a rapidly forming internal hydrocephalus in young animals may be brought about (Weed, 1919). In these cases the chorioid plexuses apparently continue to elaborate fluid at a normal rate or at a rate which becomes slowed as the internal pressure of the ventricles increases. Histological study shows the plexuses to be quite normal even though the intraventricular pressure is approximately half again as high as in the normal controls of the same litter (Nanagas, 1921).

From the field of experimental physiology have come other data pertinent to our discussion. While working in Harvey Cushing’s laboratory I was able to record (1915) the outflow of cerebrospinal fluid from a catheter inserted into the third ventricle through the aqueduct of Sylvius and completely closing the aqueduct. Variations in rate of outflow were recorded over a period of hours, demonstrating an intraventricular source of the fluid. More recently, Flexner & Winters (1932) in the anatomical laboratory in Baltimore greatly improved the procedure and were able to measure the intraventricular production of cerebrospinal fluid under standard physiological conditions.

Flexner (1934) has developed an approach to this problem through the chemistry of the cerebrospinal fluid and is even now engaged on a study of the distribution ratio, between blood plasma and cerebrospinal fluid, of chloride, sodium and urea. Using pig embryos as sources of his blood and cerebrospinal fluid, Flexner has found that in stages up to 50 mm. the distribution of diffusible ions on the two sides of the chorioid membrane is almost exactly in agreement with the prediction of the Donnan membrane-equilibrium. At stages between 50 and 60 mm. growth, the chloride ratio of approximately 1 changes suddenly to 1-3, indicating that a new process of production of fluid. has been accomplished by some intraventricular structure. At the same time in embryonic growth, the sodium and urea ratios become characteristic of adult animals. Flexner has furthermore discovered that at this critical stage of growth the indophenol oxidase reaction abruptly becomes positive in the cells of the chorioid plexus ; quite similarly tissue oxygen uptake, as determined by the Barcroft-Warburg apparatus, shows augmentation. Flexner’s histological studies, still incomplete, have thus far yielded no evidence of cellular change in the chorioid plexuses which would account for this shift from a process of ultrafiltration between the two sides of the membrane to a process of secretion.

Table I. Chemical analyses. Fluids of pig embryos (L. B. Flexner) C.R. Distribution between C.S.F. and plasma of

c ~ cm. cl Urea Na 3-5 1-02 1-02 —_ 3-7 1-00 1-00 1-02 3-9 1-00 1-00 0-99 4-7 1-01 0-99 1-00 5-0 1-01 0-97 1-00 6-0 —_— 0-78 1:10 6-5 1:19 0-86 1-15 7-0 1-12 _— 1:10 10-0 1-20 0-63 1-09 12-0 1-30 0-78 1:12 20-0 1-25 0-80 1-16

Taking the data as a whole, whether from histological, pharmacological, pathological, or embryological standpoints, one is surely inclined to accept the intraventricular source of the fluid as established and to consider as the most likely hypothesis the production of fluid by the cells of the chorioid plexuses. Flexner’s recent observations, still under way in my laboratory, seem to me to relate the plexuses more definitely to the production of fluid than has any other single study. The shift in chloride ratio between blood and cerebrospinal fluid occurs simultaneously with the appearance of the oxidase reaction in the chorioidal epithelium—a correlation which can hardly be explained by chance. With the exception of these new findings by Flexner, it would not seem justifiable to accept the data from any one of the standpoints as conclusive for many of the observations are corroborative only ; but the weight of evidence supporting the view of chorioidal production of fluid is far in excess of that in favour of other hypothesis. Yet some workers (Hassin, 1933) in the field remain unconvinced, as may be witnessed by the interpretation of inclusions within the cells of the chorioid plexuses (particularly blood pigments) as indicating that these vascular tufts with their cylindrical epithelium are organs for the absorption rather than the production of fluid. These data seem to me to be without significance as these findings may well be looked upon as the result of phagocytosis of foreign materials in the ventricular fluid.

Accepting momentarily the hypothesis that the major portion of the cerebrospinal fluid is elaborated by an intraventricular structure, the problem of the mechanism of production of this clear liquid immediately presents itself. Since the earliest histological descriptions, repeated controversies have raged as to whether the fluid is a secretion or a filtrate. Until recently no data of permanent significance were advanced, but during the last few years many chemists and physiologists have attempted to reach a conclusion in this important question. The essence of this problem is the determination of the role played by the membranes separating blood and cerebrospinal fluid in the distribution of ionic and molecular species between the two fluids. The problem particularly concerns itself with the question as to whether the cells of the plexus, the walls of its capillaries, and the connective tissue of the stroma of the plexus perform work in the production of cerebrospinal fluid, or whether substances are distributed between blood and cerebrospinal fluids as would occur across an inert lifeless membrane. A large group of investigators, particularly Fremont-Smith and his associates (1925 a, b; 1981 a, b), has concluded that the distribution of all diffusible ions between the two fluids is in agreement with the predictions of Donnan’s law; cerebrospinal fluid by their interpretation becomes a dialysate of the blood. But this general conclusion has been contradicted by an analysis of the chemical data of the two fluids by Flexner (1984), working in my laboratory. Flexner has treated these data from a thermodynamic standpoint: he has been able to show that approximately 13 calories of energy are required for the formation of a litre of cerebrospinal fluid. A free energy change of only 0-9 of a calorie could be explained by capillary pressure. Ultrafiltration (i.e. diffusion plus hydrostatic pressure) Flexner therefore judged to be an inadequate explanation of the elaboration of the fluid. On the basis of present evidence, Flexner concluded, that the cerebrospinal fluid is to be considered a secretion, using that term to mean that the cells do work in its production. Flexner’s analysis of the problem is of utmost significance in the present stage of our knowledge of the cerebrospinal fluid.

If we may now accept as a fairly well-founded hypothesis the secretion of cerebrospinal fluid by the chorioid plexuses, these epithelial structures must not be considered to be the sole elaborators of the fluid even though the quantity produced by them is far in excess of that from any other source. Over 20 years ago I presented evidence (1914 5) that the perivascular spaces of the central nervous system also pour a small amount of fluid into the subarachnoid space. This conclusion was based largely upon subarachnoid injections of true solutions of foreign salts which could be precipitated in situ for subsequent histological study. None of this foreign solution was observed within the perivascular and perineuronal spaces under normal pressurerelationships; but when these pressure-relationships were altered by cerebral anaemia or by dehydration of the nervous system, the foreign solution was aspirated from the subarachnoid space into the perivascular cuffs, even into the spaces around the nerve cells. The evidence that this minimal amount of fluid passes from nerve cell to the subarachnoid space has been greatly strengthened by observations of Kubie (1928), and Kubie & Retan (1933), who have been able to wash out the cell-content of these perivascular spaces by repeated lumbar punctures or by intravenous injection of hypotonic solutions. This perivascular fluid seems to represent an addition to the ventricular cerebrospinal fluid and probably accounts for the many reported differences between subarachnoid and ventricular fluids on serological and chemical analysis. Also in any discussion of the source of the cerebrospinal fluid some note must be taken of the potentiality of the ependymal cells lining the cerebral ventricles and the central canal of the spinal cord, for these ectodermal cells may also contribute, even in the adult, a minimal addition to the intraventricular cerebrospinal fluid.

The cerebrospinal fluid is passed by the cells of the chorioid plexuses, which do work in the process (Flexner, 1934), in small amount into the neural cavities. According to observations made by Flexner & Winters (1932) in the anatomical laboratory in Baltimore, 12 c.c. of fluid are produced each day in a cat. As approximately one-tenth of the intradural volume of a mammal is represented by the cerebrospinal fluid, the secretion of 12 c.c. each day in a cat with an intradural volume of 35-40 c.c. means .a total replacement approximately every 6 hours. If we take as an average volume of cerebrospinal fluid in man the figure of 135 c.c., the formation of fluid each day in man would be between 525 and 550 c.c. This is not a rapid process but it is a process which is fairly constant over hours, though, as Flexner & Winters showed, there are periods of a few minutes’ duration when no fluid is formed.

Fig. 2.

That portion of the fluid elaborated in the lateral ventricles flows through the foramina of Monro into the third ventricle and thence by the aqueduct of Sylvius into the fourth ventricle. From the fourth ventricle, the fluid passes out into the subarachnoid space; there is no evidence that functional communications between the cerebral ventricles and the subarachnoid space exist elsewhere than in this region. The exact mode of escape of the ventricular cerebrospinal fluid from the fourth ventricle into the subarachnoid space must still be considered as uncertain. It is possible that the inferior velum of the cerebellar roof in the adult is an intact though functioning membrane as in the embryo. When studying the embryology of the subarachnoid space (1917), I ascertained that at the stage of approximately 14 mm. in the developing pig, aggregations of a precipitate from a foreign solution introduced in the cerebral ventricles and in the spinal canal system appeared in the ventricular roof; it was found that these aggregations of precipitate occurred in two areas which were differentiated histologically from the lining ependyma. At a little later stage, embryonic ventricular fluid passed through these definitive areas, as through an intact though permeable membrane; at still larger stage (approximately 26 mm.) when the subarachnoid space was completely outlined by the foreign solution, the membrane of the ventricular roof was still intact and permeable to proteins and to foreign salts. In embryos up to and including 50 mm. in the pig and man, the ventricular roof was found to be a bulging, thin membrane composed of a layer of ventricular ependymal cells and pial mesothelial cells. Whether this thin membrane breaks down to form a foramen of Magendie, as a true anatomical opening in the velum, is, in my opinion, to-day not conclusively proved, as the technical procedures available are not adequate for the purpose of demonstration. The two foramina of Luschka, connecting the lateral recesses of the fourth ventricle with the subarachnoid space, seem to have as established a basis for their existence as does the medial foramen. It is through these three foramina—or surely in the region of the inferior tela chorioidea if through an intact membrane—that the cerebrospinal fluid produced in the cerebral ventricles passes into the subarachnoid space.

From the cisternal dilatation of the subarachnoid space in the region of the medial cerebello-bulbar angle the cerebrospinal fluid very slowly seeps downward in the spinal subarachnoid space but passes more rapidly up about the base of the brain and thence more slowly over the hemispheres, thus surrounding the whole central nervous system. This movement of fluid is in large measure activated by a vis a tergo from the point of production in the cerebral ventricles. In the spinal region there may be an equivalent passage of fluid upward. The cerebrospinal fluid then circulates everywhere about the central nervous system both in the cerebral ventricles and in the tortuous meshes of the subarachnoid space. These channels are all clothed with a specialized cell, fluid-retaining so that a true circulation of fluid may be maintained; and in these channels the fluid finally comes into close relationship to the venous system through the arachnoid villi.

It is now 25 years since I embarked upon an investigation of the meninges and cerebrospinal fluid. The first problem which I undertook was that of determination of the method of return of the cerebrospinal fluid to the venous system. At that time there were several views of the anatomical pathways concerned in this progress. In the 1870’s, Key & Retzius (1876) had introduced gelatine solutions, coloured with blue, into the spinal subarachnoid space of a cadaver and had been able to trace the gelatine throughout the whole subarachnoid space and finally through the Pacchionian granulations into the great dural sinuses. Unfortunately, Key & Retzius used high pressures of injection (about 60 mm. Hg) on non-living subjects and their drawings of the Pacchionian granulations show evidence of rupture of the structures.

Key & Retzius’ view that the cerebrospinal fluid was returned to the blood stream through these arachnoid structures was accepted for many years, but the failure to discover gross Pacchionian granulations in the human infant and in the four-footed mammals had led to gradual abandonment of the hypothesis. Cushing (1902), following the rupture of a mercury balloon within the meninges, had hypothesized the occurrence of a valve-like mechanism between the subarachnoid space and the cerebral sinuses; while Mott (1910), on the basis of histological studies of brains from animals subjected to experimental cerebral anaemia, had assumed that the cerebrospinal fluid returned to the blood stream by way of the perivascular spaces into the cerebral capillaries.

At that period, there were many physiological experiments indicating a very rapid passage of foreign solutions from the subarachnoid space into the venous system. Thus Reiner & Schnitzler (1894) detected potassium ferrocyanide in the jugular blood stream 10 sec. after subarachnoid injection. Hill (1896) was able to trace methylene blue, as he described it, “‘straight into the venous sinuses”? from the cerebrospinal spaces. Ziegler (1896) and later Lewandowsky (1900) made similar observations of rapid passage of foreign true solutions into the cerebral veins after subarachnoid injection. At the same time, the evidence had become fairly strong that suspended material (carbon particles, cinnabar granules, etc.) could not pass into the venous system. Observations made with vital dyes, such as trypan blue, had not demonstrated an anatomical pathway, both because of the intraspinous toxicity of the substances and because of the affinity of certain lining cells for the dye. There were however accumulating certain data which indicated that, in addition to the major absorption of the cerebrospinal fluid into the venous system, there existed a minor pathway of absorption into the lymphatic system.

It was upon this background that I started to work upon the anatomical pathways for absorption of the cerebrospinal fluid (1914 a, b, c). It was clearly evident that morphological methods alone would not give reliable data; these methods of study had to be combined with a physiological approach to the whole problem. It was felt that a solution of foreign electrolytes which could be precipitated in situ for subsequent histological examination, offered the best chance of successful demonstration of the channels of fluid-passage. In addition, it was held that any injection into the subarachnoid space must be made at a pressure approximating that of the cerebrospinal fluid (i.e. in the neighbourhood of 125 mm. saline). As a control, certain replacement-experiments, where the spinal subarachnoid fluid was withdrawn and replaced by a foreign identifiable solution, were projected. Attempts were made with various foreign salts but almost all were discarded because of toxicity, or because of inability to form insoluble precipitates which could be subjected to the various technical procedures and still be identified in histological sections. Finally potassium ferrocyanide and iron-ammonium citrate in isotonic solution were found to be satisfactory. These foreign salts were introduced into the subarachnoid space of anesthetized mammals over periods of several hours at pressures approximating the normal. At the end of the time of injection, the animals were killed and the head of the animal quickly severed from the body and placed in an acidulated formalin solution; or in the second series, the acidulated formalin was injected into a carotid artery immediately after death. In these two ways fixation of the tissues was fairly prompt and the ferrocyanide solution was precipitated in situ as insoluble Prussian blue.

Subsequent study of the microscopic sections of the central nervous system and meninges showed that the ferrocyanide precipitate could be identified throughout the subarachnoid space. Everywhere in this space the Prussian blue granules were seen adhering to the inner surfaces of the lining mesothelial cells. In no case where fixation and precipitation were prompt was there evidence of penetration of the cell-membranes of the lining cells by the foreign solution. Most important was the finding of the precipitate in large amount in the cranial arachnoid villi, those projections of arachnoid directly beneath the endothelial walls of the dural venous channels. The foreign solution as represented by finely dispersed granules could be followed through the mesothelial cells at the cap of the villus as well as through the single-layered endothelial lining of the vessel.

No other pathway of direct absorption into the cranial blood stream was found anywhere in the material examined. No structure which could serve as a valve-like mechanism between subarachnoid space and venous sinuses was discovered. And in no case where normal pressure-relations between subarachnoid space and venous system were maintained was there evidence of passage of the foreign solution from the subarachnoid space inward along the perivascular spaces to the cerebral capillaries.

In addition to the passage through the villi into the great venous sinuses from the cranial subarachnoid space, there was indication of a slow accessory absorption of the fluid into the lymphatic system of the body. This secondary pathway seemed to be through perineural spaces for a limited distance outward along the spinal and cranial nerves, and then an indirect passage through tissue-spaces into the adjacent lymphatic vessels. This process was especially evident around the olfactory fila in the nasal mucous membrane. It appeared, however, to be in every way an indirect, accessory mechanism of absorption for the cerebrospinal fluid.

These observations, when considered with other evidence, indicated that the cranial end of the central nervous system provided by far the greatest area of absorption. Dandy & Blackfan (1914, 1917) had previously reported an absorption of phenolsulphonphthalein from the isolated spinal subarachnoid space quantitatively as great as from both cranial and spinal spaces. Their interpretations were apparently based on the erroneous supposition that replacements of 1 c.c. of spinal subarachnoid fluid with the foreign solution could be made without increase of subarachnoid pressure or leakage into the epidural tissues about the puncture-wound. In my hands (1914 b) reversal of the experiments (i.e. injection of the same dye-stuff cephalad to the spinal ligature) showed that the cranial end of the nervous system afforded an absorptive bed so large that the exclusion of the isolated spinal subarachnoid space did not affect the quantity of the dye recovered.

While these data strongly suggested the cranium as the site of absorption of most of the cerebrospinal fluid, there was still the possibility of a pathway within the spinal subarachnoid space. This problem was attacked in my laboratory by Elman (1923), who, as mentioned previously, discovered that there were spinal arachnoid villi which projected into each of the segmental veins from the arachnoid cul-de-sac. By similar methods of ferrocyanide injections in living animals, Elman demonstrated that absorption takes place in the spinal region through these structures, just as the passage of the foreign salts into the great dural sinuses occurred. The spinal villi are however minute and the percentage of total absorption of cerebrospinal fluid going on by way of these villi can only be small.

Since the publication of these findings in 1914, there has been fairly general acceptance of the observations. In 1923 (1923 a) I restudied the question, relying on replacement-injections of the ferrocyanide solution and recording arterial and venous pressures. The findings under these conditions were essentially the same as in the experiments of 10 years previous. But the general idea of passage of cerebrospinal fluid through those specialized structures, the arachnoid villi, was questioned by Dandy (1929). His experiments consisted in freeing the brain from its connexion with the sagittal, circular and transverse sinuses, leaving the pia-arachnoid seemingly intact. As no discomfort in the experimental dogs was subsequently observed, Dandy was led to conclude that the arachnoid villi played no réle in absorption. Such a conclusion seems unwarranted as it takes no account of the fact that the animals possessed intact spinal villi; it takes no account of the possibility of regeneration or re-establishment of channels from the arachnoid membrane into the dural sinuses; it takes no account of the fact that an increased pressure of the cerebrospinal fluid may lead to the same rate of absorption with smaller absorptive surfaces. No histological findings were published by Dandy so that it is impossible to ascertain the physiological or reparative processes within the crania of the experimental animals.

At the moment we cannot regard as established any theory of drainage of cerebrospinal fiuid other than the suggested one of absorption through arachnoid villi directly into the venous system. We must, however, recognize fully the limitations of any method of demonstration of a fluid-pathway which depends upon the introduction of foreign salts. I have held it to be particularly desirable (1985 a) that some new method of investigation of this problem be devised, as both ante-mortem and post-mortem diffusion of the foreign crystalloids has always to be considered. The difficulty of post-mortem diffusion of the crystalloids now bids well to be eliminated due to the work of two medical students in my laboratory. Under Flexner’s direction, these men, Mr Ralston and Mr Scholtz, have employed a modification of the AltmannGersh technique of instantaneous freezing of the tissues in liquid air. Subarachnoid injections, under low pressures and for several hours, of an isotonic solution of sodium ferrocyanide are first made in the anaesthetized animal. While the animal is still alive, the sagittal sinus region of the head is frozen as a block of liquid air, thus preventing diffusion of the foreign salts. The block of tissue, while still frozen, is cut from the animal and dehydrated in a high vacuum at low temperature, — 30° C. The dehydrated tissue is embedded in paraffin without use of alcohol or water, and is then sectioned. The sections are treated with ferric chloride which precipitates any ferrocyanide present as an insoluble ferric ferrocyanide.

The use of this technique has given additional evidence in support of the hypothesis that the major pathway of absorption of cerebrospinal fluid is through the cranial arachnoid villi directly into the sinuses, though some diffuse staining with blue occurs about certain of the subarachnoid veins. Mr Ralston’s and Mr Scholtz’ work is still in progress, and while interpretation of the findings will necessarily depend upon additional data, it seems to eliminate one of the chief objections—post-mortem diffusion—lodged against experiments in which the foreign salts are precipitated after immersion or by arterial injection. There still remains, however, the great desirability of devising some new method of attack upon this problem—a new method which will use other foreign salts with different rates of diffusion, yet capable of precipitation in situ for subsequent microscopic study.

These attempts to determine the pathway of escape of the cerebrospinal fluid into the venous system do not of course take any account of the mechan-

Chloroform ‘| Locke's ism of absorption of the cerebrospinal ““'"* = (—— Ly Sol. fluid.

In my original study (1914a, b), |

the underlying physical forces were hardly touched upon, largely because of lack of method of attack. The problem ore could not be successfully undertaken Sol. until means were at hand to measure the absorption of small quantities of fluid from the subarachnoid space under constant pressure-relationships.

Fig. 3.

Fortunately Mortensen and I (1934) were able to devise a simple apparatus which permits the desired measurements under given conditions of pressure. The system (see fig. 3) consists of a pipette, filled with fluid and connected by a three-way stopcock both to the sub- arachnoid space of the living animal and to a small bore, open-end manometer recording pressure. On top of the fluid in the burette is superimposed a coloured oil mixture of the same specific gravity as Locke’s solution. This oil is connected through rubber tubing to a reservoir of such large volume and surface that the absorption of 10—50 c.c. of saline solution from the burette does not appreciably lower the level of the oil mixture.

The employment of this reservoir-pipette system led indirectly to an analysis of the forces concerned in the absorption of the cerebrospinal fluid (Weed, 1935 b). The early theories considered that the absorption of cerebrospinal fluid was largely a process of filtration through membranes from a point of higher to a point of lower hydrostatic pressure. These hypotheses were discarded when observations indicated an identity of pressures in torcular herophili and subarachnoid space, but the finding that the venous pressure in the superior sagittal sinus is usually lower than the pressure of the cerebrospinal fluid seemed to lend support to the general contention. Likewise, the many reports that the higher the pressure of introduction the more rapidly is an isotonic foreign solution absorbed from the subarachnoid space suggested an influence of hydrostatic pressures (Mortensen & Weed, 1934).

In considering the factors which might play a réle in the process of absorption of cerebrospinal fluid it seemed justifiable to assume that the colloid osmotic pressure of the blood and the hydrostatic pressure-difference between the subarachnoid pressure and the intracranial venous pressure should be the effective forces. The crystalloids of the blood and of the fluid are approximately the same in nature and amount, so that no effective pressures could be created by these substances. It therefore appeared feasible to attempt determination of the total effective pressures bringing about absorption of the fluid, for the osmotic pressure of the blood could be ascertained through use of appropriate celloidin membranes and the hydrostatic factor could be had by measurement of the subarachnoid pressure and of the sagittal venous pressure.

The technical procedure on the etherized dog consisted essentially in the connexion of the pipette-reservoir system to the subarachnoid space and the recording of the sagittal venous pressure by appropriate means (Weed & Hughson, 1921 c). The normal level of subarachnoid pressure of the animal was first determined and then the pressure in the subarachnoid space was raised by increments of 50 mm. until a maximum pressure of about 600 mm. of saline was attained. At each of these 50 mm. increments in subarachnoid pressure the actual absorption of Locke’s solution was determined, together with the corresponding sagittal pressure. As soon as this series of observations had been made, the actual rate of absorption in the same series of established pressures was measured for a protein-solution (gelatine, pure casein, or serum). At the end of the experiment, the colloid osmotic pressure of the blood serum and of the protein-mixture in the subarachnoid space was determined by - celloidin membranes. From these data, it became possible to calculate the total effective pressures

by adding the effective colloid osmotic value (i.e. colloid osmotic pressure of the blood minus that. of the subarachnoid fluid) to the effective hydrostatic

Total Absorption effective rate per pressure min.


saline C.c. 413 0-02 458 0-06 508 0-10 564 0-14 616 0-19 667 0-23 707 0-27 732 0-28 377 0-003 414 0-03 470 0-07 529 0-11 569 0-15 612 0-18 665 0-23

Table II Colloid Colloid Colloid C.S.F. osmotic osmotic osmotic Sagittal minus pressure pressure pressure C.S.F. venous sagittal blood modified blood minus pressure pressure pressure serum CS.F. solution Locke’s solution mm. mm. mm. mm. mm. mm. saline saline saline saline saline saline 250 149 101 312 _— 312 300 154 146 312 _ 312 350 154 196 312 _— 312 400 148 252 312 _— 312 450 146 304 312 _ 312 500 145 355 312 _— 312 550 155 395 312 — 312 600 180 420 312 — 312 Gelatin solution 300 137 163 312 98 214 350 150 200 312 98 214 400 144 256 312 98 214 450 135 315 312 98 214 500 145 355 312 98 214 550 152 398 312 98 214 600 149 451 312 98 214 Gelatin solution x { Locke’s solution 0-3] 8 & . g aa & 0-2 K x —— a g a 2 XL Se, 0-1 5 > 2 | < To? Total effective pressure in mm. saline —»

0 400

450 500 550 600 650 700 Fig. 4.

750 800

pressure which was derived by substracting the sagittal venous pressure from the established subarachnoid pressure. When the comparative absorption rates of the Locke’s solution and of the foreign protein-solution were plotted against the total effective pressures, a linear relationship for both the Locke’s and the protein-solutions was apparent. Meninges and Cerebrospinal Fluid 197

These findings, that the rates of subarachnoid absorption of an isotonic crystalloid solution and a protein-containing solution when plotted against total effective pressures are described by the same straight line, would indicate that the factors assumed to make up the “total effective pressure” are actually the ones responsible for the process of absorption of the cerebrospinal fluid. In spite of all the difficulties and shortcomings of the methods for the determination of colloid osmotic pressures the data when accepted as an average seem adequate. While certain observers have found that during anaesthesia the colloid osmotic pressure of the blood changes, control observations under the same conditions as these experiments have given no indication that this osmotic pressure changes to any appreciable extent during the period of etherization. The data were clear-cut in demonstrating that the rate of absorption of a protein-solution from the subarachnoid space is slower than that of an isotonic crystalloid solution. The effective colloid osmotic pressure of the blood is diminished by the amount of colloid osmotic pressure of the mixture of cerebrospinal fluid and protein-solution: the passage of the fluid (water plus crystalloids) through the absorbing membranes is therefore retarded. It would seem reasonable to assume that protein does not leave the subarachnoid space in appreciable quantity during the short period of introduction of the foreign solution. The regularity of the experimental data indicates that there is no material change of protein concentration in the subarachnoid space during the period of measurement. This constancy seems to be a function of the total quantity of the protein-solution in that space (relatively large at high pressures apparently) and of the amount of water abstracted from the protein-solution by absorption. The experiments were apparently executed rapidly enough for the amount of absorption of water to make no detectable difference in the protein concentration.

Further experiments with hypertonic and hypotonic solutions of crystalloids have indicated a rate of subarachnoid absorption exactly that of the isotonic solution. A linear relationship between absorption rate and effective pressure was apparent. The explanation for these extraordinary results with distilled water and Locke’s solution of double salt concentration is not clear: “it may be that such solutions within the subarachnoid space are quickly rendered isotonic. Recently further extensions of these experiments have been made using sucrose solutions for comparison with the isotonic solutions in their absorption rate. With 5 % solution of this sugar in Locke’s solution, the rate of absorption from the subarachnoid space was found to be much slower than was the case with the normal Locke’s solution. When plotted against total effective pressure its rate of absorption formed a straight-line relationship but at a far lower level than with the Locke’s solution. Here the large molecule of sucrose apparently exercised an osmotic pull against the colloid osmotic pressure of the blood, decreasing the effective pressure over the short period of the experiment (30 min.).

From an analysis of the data in this series of experiments it seems fair to conclude that the total effective force actuating the normal process of absorption of the cerebrospinal fluid is compounded of the colloid osmotic pressure of the blood plus a hydrostatic factor derived from the difference in subarachnoid pressure and intracranial venous pressure.

Hitherto it has been necessary to refer to pressure conditions within the cranium, and possibly some confusion has arisen because of reference to the pressure of the cerebrospinal fluid and of the intracranial venous system without more detailed discussion. The idea of equality of pressures between the cerebrospinal fluid and the cerebral veins as advanced by Hill (1896) was abandoned following upon the work of Dixon & Halliburton (1914).

Fig. 5.

Since that time current conceptions have acknowledged an independence of the two pressures. In the horizontal position, four-footed mammals (especially the common experimental animals, cat and dog) exhibit a pressure of the cerebrospinal fluid which is customarily slightly higher than that in the superior sagittal sinus. An average value of the cerebrospinal fluid pressure in the cat and dog is 125 mm. of saline, while the sagittal pressure usually ranges 15-50 mm. below this level.

The fluid’s pressure is momentarily affected by rapid changes in the cerebral arterial pressure but not by slowly effected alterations. Changes in the pressure of the cerebral veins are generally held to alter the pressure of the cerebrospinal fluid, always in the same direction and to a lesser extent. Conversely, alteration of the pressure of the cerebrospinal fluid has been assumed by many workers to be reflected in the pressure of the cerebral veins, but conflicting reports of this possible effect are found in the literature. These generalizations imply that a condition of pressure-equilibrium exists between the two fluids (cerebral venous blood and cerebrospinal fluid) which are separated by a membrane comprised of vascular and meningeal tissues and that this equilibrium can be shifted by change in either of these pressures. Such alteration of either pressure would in this interpretation lead to a new equilibrium, characterized by change in the same direction of the other pressure and by a shift in position of the membrane separating the two fluids.

In an investigation of this general pressure-relationship carried out by Weed & Flexner (1933), it was quickly found that even profound alterations of the subarachnoid pressure have no effect upon the pressure in the cerebral veins. This observation was a confirmation and extension of the results obtained by Becht (1920). This lack of effect of subarachnoid pressure upon the cerebral venous pressure held for all animals in the series during the first 2 hours of etherization ; but after this period of prolonged anaesthesia occasional animals showed a slight change in intracranial venous pressure from alteration in subarachnoid pressure. Such reactions were of small extent—10-15 mm. venous pressure-change on subarachnoid pressure-change of 150 mm.—and were interpreted as being due to general fatigue of the animal, particularly of its vasomotor system.

The converse of this physiological phenomenon was found by Flexner and myself to be of a positive nature. Increase in cerebral venous pressure, as effected by obstruction upon the veins of the neck of the animal, results in a quick rise of the pressure of the cerebrospinal fluid, but always to a lesser extent. This

Table III. Positional pressure-changes in cerebrospinal fluid and superior sagittal sinus, together with volume-changes of the fluid

Head down Tail down rc A > c > Pressure- Pressure Volume Pressure- Pressure- Volume Mano- change charge dislocated change change dislocated Condition meter CS.F. sagittal C.S.F. C.S.F. sagittal CS.F.

of animal bore mm. mm. mm. c.c. mm. mm, c.c. Living dog, 1 185 237 0-321 126 204 0-219 E99 4 102 230 1-163 64 204 0-736 6 62 229 1-779 33 204 0-947 8+ 33-5 234 2-258 15-5 201 1-045 10- 30-5 233 2-173 14-5 200 1-033 12 20-5 235 2-337 9-0 199 1-026 1* 185 235 0-321 110 198 0-191 Dog, imme- 1 243 325 0-422 234 299 0-406 diately after 4 208 328 2-392 . 141 304 1-622 death, E 68 6 145 327 4-162 79 298 2-267 8+ 73 329 4-920 32 295 2°167 10- 68 325 4-845 33 296 2-350 12 43 328 4-902 20 297 2-280

1 mm. manometer replaced after other manometers were used in series. 13—2 200 Lewis H. Weed

reaction is well known experimentally and is employed clinically in the Queckenstedt test. Eleven experiments in our series yielded an average increase of 276 mm. in cerebral venous pressure and 176 mm. in the cerebrospinal fluid pressure, indicating that 65 % of the venous pressure-increase is reflected in the pressure of the fluid. Flexner and I extended our studies to tilting experiments to ascertain the influence of different pressure-changes in the cerebrospinal fluid upon the pressure-changes in the superior sagittal sinus. Data were obtained which indicated that, as in the horizontal position, pressure-changes in the cerebrospinal fluid have no effect upon pressure-changes in the sagittal sinus. In addition, by means of the use of different sized manometers a very definite relationship of pressure-change to volume-change in the cerebrospinal fluid was obtained. At a given point in the individual animal a maximum volume-dislocation of the cerebrospinal fluid is obtained; the employment of larger manometers, permitting outflow of greater amounts of fluid under lower pressure-conditions did not result in displacement of larger quantities of fluid from the animal.

These findings permit an interpretation of the kind of pressure-equilibrium which exists between the cerebrospinal fluid and the cerebral veins. Any intracranial venous pressure-change results in change of the cerebrospinal fluid pressure, about six-tenths of the venous pressure-change being effective in the fluid when the fiuid-dislocation is minimal. With the experimental increase of cerebrospinal fluid pressure brought about by the introduction of fluid into the subarachnoid space, a certain diminution of intradural venous volume must follow; but the pressure in these cerebral veins remains unaltered. Conversely, when the pressure of the cerebrospinal fluid is reduced mechanically, or by tilting, the cerebral venous bed reciprocally compensates by dilatation, the veins expanding and permitting an increase of intradural venous volume though maintaining in these expanded channels the same pressure. Under both these conditions the venous walls come to rest (i.e. to equilibrium) at a point determined by the new subarachnoid pressure. There is, however, a distinct limitation of this process—the limitation of volume-dislocation which has been shown experimentally both in the dead and living animal. When this limit of volume-adjustment of the venous bed is reached the venous walls must remain in a “‘steady state”, irrespective of the further alteration of the pressure on the outer sides.

For a century and a half the hypothesis that the skull and bony coverings of the vertebral canal form a rigid container for the central nervous system has occupied the attention of anatomists, physiologists, and neurologists. That a professor of anatomy at Edinburgh, Alexander Monro II, should have originated a doctrine of such basic significance in intracranial physiology should arouse the pride of every British anatomist. Monro (1783) ventured the hypothesis that the quantity of the blood circulating within the cranium must at all times be constant ‘‘as the substance of the brain, like that of the other solids of our body, is nearly incompressible” and as the brain "is enclosed in a case of bone”. Having no knowledge of the cerebrospinal fluid in its meningeal bed, though the publications of Haller (1757) and Cotugno (1779) preceded by a few years his own, Monro assumed a constant intracranial volume in which alterations in arterial volume were compensated for by reciprocal changes in the venous volume. Monro’s original hypothesis was further developed by Kellie (1824), whose stimulating report is given in the first volume of the Transactions of the Medical and Chirurgical Society of Edinburgh, 1824. Kellie attempted experimental and pathological verification of the views advanced by Monro. Kellie’s conclusions, based on observations in animals and in persons frozen to death, were that a state of bloodlessness did not exist in the brains of animals killed by bleeding, that the amount of blood in the cerebral veins was not affected by posture or by gravity, that congestion of these vessels was not found in those conditions in which it might well be expected, and that compensatory readjustments between the arterial and venous sides maintained a constant intracranial vascular volume. Kellie wrote “‘that in the ordinary state of these parts we can not lessen, to any extent, the quantity of blood within the cranium, by arteriotomy or venesection; whereas if the skull of an animal be trephined then hemorrhage will leave very little blood in the brain”. With Kellie’s apparent verification of Monro’s hypothesis other workers applied the doctrine to pathological conditions in man, particularly in cases of apoplexy. In these studies an attempt was made to determine whether the cerebral haemorrhage was compensated for by decrease in the volume of the intracranial arterial and venous bloods. The thesis, which quite properly became known as the Monro-Kellie doctrine, was widely accepted and interest in it became profound.

The doctrine was necessarily modified when increasing knowledge of the cerebrospinal fiuid developed from Magendie’s first adequate description (1825) and his second comprehensive monograph (1842). Shortly after this second publication, Burrows (1846) questioned the accuracy of the hypothesis of fixed intracranial blood volume and introduced into the concept a third element—the cerebrospinal fluid. Burrows repeated many of Kellie’s supposedly critical experiments relating to the effect of posture on the quantity of intracranial blood, and in his coloured plates is shown an apparent difference in these volumes in animals suspended post-mortem by the head or by the tail. Burrows placed great importance on the.cerebrospinal fluid as the means of replacing blood lost through systematic haemorrhage, for he felt that exsanguination unquestionably diminished the quantity of intracranial blood. He was unable to decide whether “‘ the space vacated under such conditions was filled with serum” (cerebrospinal fluid?) or was eliminated by “resiliency of the cerebral substances under decreased pressure”; but in this second phrase is contained the first suggestion that the volume of the brain may be altered by physiologic conditions. Summing up Burrows’ contentions, it is clear that he was in general accord with the major thesis that the intracranial volume is at all times fairly constant—a thesis which accepts the view that the bony containers of the central nervous system are rigid, preventing alteration in the total volume of the tissues and fluids within them.

Originally restricted to the cranium, the doctrine of a rigid container for the central nervous system with a fixed and constant capacity was necessarily extended to include the vertebral portion of the system. This modification was essential when it became generally appreciated that the cerebrospinal fluid of the spinal subarachnoid. space communicated freely with that of the cerebral ventricles and cranial subarachnoid space (Key & Retzius, 1876). The vertebral arches were then looked upon as affording the requisite rigidity for firm suspension of the spinal dural sac. The Monro-Kellie doctrine thus came to be interpreted as the concept which viewed the entire central nervous system as being enclosed within a bony container (cranium and vertebral canal) of sufficient rigidity to secure constancy in volume of the intradural contents. Such an idea involved appreciation of the anatomical relationships within the whole cranio-vertebral system and was intimately related to the integrity of the skull and of the vertebral column whose relative rigidity was held to modify in an essential way the spinal dural component. In this modified form the Monro-Kellie doctrine of a rigid container of fixed volume has really afforded the basic hypothesis for all studies on the pressure and volume relationships about the nervous system.

As such a thesis necessarily affected all ideas of postural change in the pressures of the cerebrospinal fluid and of intracranial blood vessels, it is not surprising to find that shortly after Burrow’s publication attempts were made to ascertain the truth of the important hypothesis by experimental methods. Many workers (Donders, 1851; Kussmaul & Tenner, 1859; and others) essayed by direct observations through a cranial window to secure evidence regarding the constancy or variability of the intracranial vascular volume; their methods, more reliable than observations on dead animals, did not permit control of all of the factors. The data presented by these workers hardly justified the conclusion of a variable intracranial blood volume, yet certain of these observations have bearing on the present consideration of the problem. Thus Ecker (1848) recorded in a trephined animal a marked diminution of the cerebral volume on division of the carotid arteries, thereby recalling attention to the function of the cranial vault in protecting the nervous system from the direct application of atmospheric pressure.

Many years later, Hill (1896), introducing more rigid methods of physiological control, concluded that ‘‘the volume of the blood in the brain is in all physiological conditions but slightly variable”. Again here in London, Dixon & Halliburton (1914) studied the general problem of the Monro-Kellie doctrine by methods but slightly different from those employed by Hill. Basing their conclusions on the apparently great variations in intracranial pressures, particularly in the relation of the pressure of the cerebrospinal fluid to that in the torcular herophili, they asserted that "the cranial contents cannot any longer be regarded as a fixed quantity without the power of expanding or contracting in volume". Such an assertion necessarily involved extreme modification of the doctrine, if not definite renunciation. The observations of Dixon & Halliburton indicated that unquestionably, within the physiologic limits established, variations in the pressures of the cerebrospinal fluid and of the cerebral venous blood could be affected without the exact correspondence reported by Hill.

My interest in this doctrine had been aroused many years before my work led me into direct contact with the hypothesis. During the course of an investigation to determine what agents, if any, would affect the volume of the brain, Weed & McKibben (1919 a, b) ascertained that the intravenous injection of solutions, the osmotic pressure of which differed from that of the blood, caused in the living animal outspoken alterations in the volume of the brain. It was shown by us that hypotonic solutions given intravenously markedly raised the pressure of the cerebrospinal fluid and increased the volume of the brain, while hypertonic solutions on similar administration caused lowering of the pressure of the cerebrospinal fluid and a corresponding diminution of the volume of the brain. With strongly hypertonic solutions, the pressure of the cerebrospinal fluid was frequently reduced to negative values (i.e. below atmospheric pressure), so that occasionally negative records of as great a magnitude as the previous positive readings were obtained.

It was apparent that these alterations in the cerebral volume and in the pressure of the cerebrospinal fluid, effected by the intravenous injection of solutions of various concentrations, were dependent upon the interchange of water and salts between blood and the nervous system with its cerebrospinal fluid. The negative pressures in the cerebrospinal fluid involved even more the consideration of the accuracy of the Monro-Kellie thesis. The experimental production of a pressure below atmospheric in the cerebrospinal fluid could be brought about only if the elasticity of the elements contained within the cranium and vertebral canal were exceeded, only if the elastic limits of the system were surpassed by the magnitude of the forces applied. Thus the great withdrawal of fluid from the nervous system, due to the strongly hypertonic solutions within the blood stream, apparently exceeded the elastic limit of the craniovertebral contents. Under these circumstances, the bony containers of the central nervous system came to serve as a rigid system, preventing the direct application of atmospheric pressure to the intradural contents.

This work on the effect of solutions of different concentrations was continued with the co-operation of Hughson (1921 a, b, c). Our first undertaking was the determination of the general systemic and intracranial effects of these solutions when given intravenously, and a second problem dealt with the Monro-Kellie hypothesis directly. We were able to show that the intactness of the cranial vault is essential for the production of negative pressures in the cerebrospinal fluid, following the intravenous injection of hypertonic solutions. With the cranial duramater exposed directly totheatmosphere, negative pressures could not be obtained, even though marked shrinkage of the brain occurred.

Fig. 6. Intravenous injection of 150 c.c. Ringer’s solution.

Fig. 7. Intravenous injection of 150 c.c. distilled water.

Fig. 8. Intravenous injection of 30 c.c. 30% NaCl.

It was realized that these methods of demonstration were drastic in nature and that the means employed were such as to bring out maximum variations rather than the minute effects which might theoretically play a réle in the normal physiological use of the bony containers of the nervous system. Our own findings bore a very definite relationship to the original observation of Kellie on the difference in intracranial blood volume in intact and trephined skulls on alteration of the animal’s posture, and it was but a logical step to shift investigative interests to the problem of pressure-alterations about the nervous system as effected by changes in the position of the experimental animal.

First of all, it seemed obvious that the degree of rigidity of the bony cranium and of the vertebral column would determine in some measure such alterations of the pressure of the cerebrospinal fluid. Were the spinal dural tube so suspended within the epidural space that it could not collapse inward, were its fibrous architecture of such small elasticity that outward distensibility were hardly measurable, were the cranium with its adhering dura a rigid box-like container, and were the vascular regulatory mechanisms of the intradural contents so effective that no volume-change or dislocation of blood would occur?—if these suppositions were correct, no cerebrospinal fluid would be extruded from the needle on puncture in the horizontal position. Likewise if these suppositions were correct, the measurable pressures of the cerebrospinal fluid in the horizontal position would be reproduced in the vertical condition of a mammal, for this assumed rigidity of the containers of the nervous system would then be such as to prevent a dislocation of fluid from the uppermost portions of the system to the lowest. Such potential dislocations of the cerebrospinal fluid would be necessary for measurable alterations in pressure, even though in such positional change, increase in height of the vertical column of molecules imposed upon the lowermost portion would undoubtedly effect a pressure-change within the fluid itself.

The problem of the cerebrospinal fluid in relation to change in posture is related primarily to the potential pressure-changes as may be effected by the fluid-column in the subarachnoid space. Anatomically and physiologically this column of fluid is continuous, even in the meshes of the subarachnoid space. The first question necessarily is whether such a potential column exerts its full hydrostatic effect when the animal is abruptly tilted from the horizontal to the vertical position or whether the elasticity of the cranio-vertebral system is such as to prevent the action of the full column of fluid. The answer to this question would give some hint of the degree of protection of the nervous system from the effects of atmospheric pressure and some suggestion of possible physiological adjustments which might have taken place when man assumed the erect posture.

The need for an analysis of these potentialities in relation to the MonroKellie thesis has been met by a series of experiments involving tilting anaesthetized animals, from the horizontal to the vertical head-down and tail-down positions (Weed, 1929). Most of these observations were carried out on dogs of uniform size and the findings in this animal may be considered to be typical, as the reactions in the cat, dog, and macaque are essentially similar. In these dogs the distance from the occipital protuberance to the last lumbar spine was in the neighbourhood of 400 mm.; this measurement may be taken to be that of the height of the column of fluid which might exert a hydrostatic effect in the two vertical positions. The tiltings from the horizontal to the head-down position caused increases in the pressure of the occipital cerebrospinal fluid which averaged 105 mm. of normal saline solution. In the contrariwise tiltings, from the horizontal to the vertical tail-down position, an average decrease of 74 mm. was recorded in the pressure of the cerebrospinal fluid, as measured in the occipital region. Changes in the carotid pressure (reflecting intracranial arterial pressure) were not of great significance during such positional alterations, but the head-down tiltings caused an average increase of 184 mm. in the pressure of the superior sagittal sinus, and the opposite positional change, an average decrease of 80 mm.—in each case changes of greater magnitude than in the cerebrospinal fluid itself. In the fluid itself, only one-third to one-fourth . of the potential hydrostatic column was effective.

Another type of experiment having significance in our discussion had also been carried out (Weed & Flexner, 1932 b). In this the pressure of the cerebrospinal fluid was recorded in the occipital region and by lumbar puncture measurement was made in the lower spinal region. In the horizontal position the pressures in both manometers were the same, but when the dog was tilted to the vertical head-down position the fluid in the lumbar manometer ran in the animal’s subarachnoid space, to be followed by air. Under these circumstances atmospheric pressure was directly applied to the cerebrospinal fluid throughout the lower spinal segment; the pressure-increase measured in the occipital manometer became approximately 185 mm. instead of the customary 105 mm. in the intact preparation.

These observations were followed by further experiments (Weed & Flexner, 1932 b; Weed, 1933 a, b) in which the cranial vault was largely removed, or in which laminectomy was performed throughout the lumbar and thoracic regions. With the pressure of the cerebrospinal fluid measured by an occipital manometer, both of these preparations exhibited normal pressures of the cerebrospinal fluid in the horizontal position. In those dogs in which the cranial dura mater was widely exposed to the atmosphere, the head-down tiltings gave pressure increases of the cerebrospinal fluid of the same extent as in the intact animal; but on tilting from the horizontal to the tail-down position, the pressure of the fluid decreased only 56 mm. on the average (74 mm. in the intact dog). On the other hand, the laminectomized animal showed, on the taildown tiltings, a pressure-decrease of the same magnitude as in the intact dog; but on vertical head-down tilting the pressure of the occipital cerebrospinal fluid increased on the average 185 mm., as compared to 105 mm. in the intact dog. Of particular significance was the fact that in the laminectomized and lumbar-punctured animals the increases of pressure on vertical head-down tiltings were identical with the pressure-increases in the superior sagittal sinus; the full effect of atmospheric pressure was operative through the lumbar needle and upon the exposed spinal dura mater. The increase in intracranial venous pressure was taken to be a reflection likewise of hydrostatic pressures exerted through the soft parts of the body.

The data from these experiments may be interpreted as demonstrating that the vertebral arches and cranium have a definite physiologic function in removing the central nervous system from the full effects of atmospheric pressure. They lead also to the assumption that within these bony coverings there are elements which lack rigidity, as an obvious dislocation of fluid occurs within the dural sac during such positional tiltings. To speak of such a lack of rigidity within the bony coverings is really another way of saying that the system possesses elasticity—an elasticity which allows a dislocation of fluid from one part of the subarachnoid space to another—not the maximal but a fractional dislocation, permitted by dilatatién and compression of the intradural vascular bed, by inward collapse of the spinal sac with stretching of the epidural fibres and dilatation of the epidural venous plexus. The stretching of the spinal dura mater itself has been found to be so small as to afford a negligible expansibility.

Some of these questions had been advanced by Grashey (1892) in a monographic presentation of the hydrostatics of the cerebrospinal fluid. As a hypothetical exposition of certain phases of the problem of the potential modification of hydrostatic effects through the elasticity of the vascular components, Grashey’s contribution has been of great value. A far simpler, purely physical representation of the theoretical relationships of the cerebrospinal fluid and its containing membranes was presented by Weed & Flexner (1985 b). The system was likened to a rigid tube, enclosed by elastic membranes at both ends and completely filled with fluid at atmospheric pressure. Such a model, in the vertical position, will have the level of atmospheric pressure midway between the two sagging membranes, if these membranes are of equal elasticity. In this vertical position a decrease in the elasticity of one of the membranes will shift the level of atmospheric pressure toward the more elastic membrane. Or again, the physics of the problem may perhaps be even more clearly illustrated by a single system consisting of a rigid central bar to which are attached two rigid discs; the walls of the system are formed by elastic membranes sealed to the outer edges of the discs. When filled with fluid at atmospheric pressure and placed in a vertical position, inward collapse of the membrane occurs in the upper half of the system and outward bulging in the lower.

Study of the pressure-reactions in such a physical system with the inward collapse and outward bulge of its membranes, and consideration of the data from the experimental animals lead to the conclusion that the explanation for the phenomena of positional pressure-changes in the cerebrospinal fluid unquestionably rests on the dislocation of fluid coincident with change of the hydrostatic column. But the measurement of the fluid’s pressure with an open-end manometer of small bore in the customary experiment permits an external dislocation of fluid—an obvious change in volume either into the manometer from the animal’s subarachnoid space or from the manometer into the subarachnoid space. The influence of this factor of fluid-dislocation has been studied (Weed et al. 1932) in tilting experiments with measure of the pressure of the cerebrospinal fluid by the bubble manometer (recording pressure without external dislocation of fluid), and by manometers of various bores. The pressure-alterations in the cerebrospinal fluid, as recorded by the bubble manometer, were slightly greater than those in the open-end 1 mm. manometer ; and as manometers of larger and larger bore were used the pressure changes became smaller and smaller in both positional tiltings. Determination of the fluid dislocated into or from these open-end manometers showed that a larger and larger dislocation of fluid occurred in the larger and larger manometers, though there was an obvious limit to the volume displaced.

Fig. 9. Pressure-changes in cerebrospinal fluid in head up-tail down and head downtail up positions, using manometer of larger and larger bore. (See text.)

This dislocation of fluid on tilting from the horizontal to the vertical position has led to the uncovering of a definite relationship between the pressure-differences and the volume-differences recorded in the cerebrospinal fluid (Weed e¢ al. 1982; Weed & Flexner, 1982 a; Flexner e¢ al. 1982; Flexner & Weed, 1933 b). This ratio, expressed in the term dV/dP, was found to be amazingly constant in the four mammals studied—dog, cat, macaque and a single chimpanzee. Its magnitude, approximately 0-17 in adult animals, is considerably smaller in immature animals and larger in the old; there is therefore a definite age-difference in the relationship. The ratio dV/dP is the same on determination from data obtained on head-down or tail-down tiltings—a fact of great significance in any discussion of the assumption of erect posture.

Table IV. Derivation of dV/dP and E for macaque C 30

Head down Tail down A A. Differ- Diffr- | Differ. Differ. Pres- ence in ence in Pres- ence in ence in sure- pres- Volume volume sure- pres- Volume volume Mano- change, sure- dis- dis- change, sure- dis- dismeter C.S.F. change located located dV/dP C.S.F. change located located dV/dP mm. cm. cm. c.c. C.c. cm. cm. c.c. c.c. 1 14-5 —_— 0-252 — _ 8-0 _— 0-139 _— _— 4 10-8 3-7 1-048 0-796 0-215 6-0 2-0 0-582 0-443 90-221 6 71 14 1-874 1-622 0-219 40 40 1-056 0-917 0-229 8 4:7 9-8 2-397 2145 0-219 26 5-4 1-326 1-187 0-219 10 3-6 10-9 2-565 2-313 0-212 2-0 6-0 1-425 1-286 0-214 Average 0-216 0-221

This ratio dV/dP is of course found in the usual physical formula for determining elasticity where elasticity is considered to be the stress divided by the strain—i.e. E=dP/(dV/V). Using this formula, as had been done in a somewhat different way by Ayala (1928, 1925), and taking as the volume V the intradural contents, it was found that the elasticity of the intradural contents was of approximately the same magnitude in the four mammals tested. While the employment of this physical formula for determination of elasticity has been recently questioned (Pollock & Boshes, 1936), doubt as to the suitability of the formula has existed in the minds of my co-workers and myself for several years. The question essentially relates to the employment of any value within the nervous system as the total volume, or V, in the formula for the modulus. It is obvious that taking the intradural contents as V, figures of constant value are obtained, but it is doubtful whether the elasticity of the system can be determined with accuracy in terms of dynes.

The existence of such physiological elasticities within the cranio-vertebral system leads at once to consideration of the normal employment of these elasticities in life. The cranium and vertebral arches constitute a rigid container for the nervous system only when these elasticities are exceeded, yet they contain within their walls approximately the same total contents at all times. This relatively fixed volume is made up of brain, blood and cerebrospinal fluid. The volume of brain has been shown to be capable of experimental change; the volume of cerebrospinal fluid can be increased or diminished; and the volume of blood can surely vary. So with three variable elements comprising a relative fixed total volume, the idea of a reciprocal relationship, as first suggested by Monro and then by Kellie, becomes most logical. These workers did not restrict the reciprocal relationship to a diminution of cerebral bloodvolume in cases of intracranial effusion of fluid, but applied it to the relationship between arterial and venous volumes within the cranium. The first comprehensive appreciation of the problem should be attributed to Burrows in his discussion of the Monro-Kellie doctrine; his portrayal of reciprocal volumechanges between blood and cerebrospinal fluid has remained accepted without essential modification. Recent investigations, based on observations through an intracranial window (Kubie & Hetler, 1928) or on chemical analyses (Weil et al. 1981), have demonstrated an increased intracranial blood volume after shrinking of the nervous system by intravenous hypertonic solutions—a reciprocal volume-adjustment by the blood for withdrawal of intradural fluid.

These reciprocal volume-adjustments apparently take place constantly in the normal life of the organism. They are probably of small amount in the quiet state, dependent here upon minor vascular adjustments or small changes in the osmotic pressures of the blood; but when positions of the vertebrate are changed by posture, the reciprocal adjustments are of considerable magnitude. In four-footed mammals, on abrupt tilting from the horizontal to the vertical positions, a demonstrable dislocation of cerebrospinal fluid occurs from the uppermost to the lowermost portions of the nervous system. This dislocation of cerebrospinal fluid is permitted and accompanied by local reciprocal volumeadjustments—the venous bed in the uppermost portion of the nervous system becomes dilated while that in the lowermost portion becomes compressed. The mechanism of adjustment in local volumes is apparently prompt and effective.

In the four-footed mammals studies (Weed et al. 1982; Weed & Flexner, 1982 a; Flexner et al. 1982; Flexner & Weed, 1983 b)—cat, dog, macaque and chimpanzee—the relationship between volume-change and pressure-change in the cerebrospinal fluid is the same when determined from data derived from head-down and tail-down tiltings. Two of these animals—the macaque and the chimpanzee—spend almost as great a portion of their lives in the erect posture as does man, and in these as in the other four-footed mammals there is no indication of the development of any physiological protection against the dislocation of cerebrospinal fluid on positional change of the body. If this deduction be correct, our inquiry shifts logically to the problems presented by the giraffe with its head held high above his spinal cord and by the bat which hangs suspended head-down. But no data from these highly specialized mammalian forms are as yet available, and we are therefore forced to proceed directly to comparable positional alterations in the pressures about the nervous system in man.

Many important reports, particularly by Zylberlast-Zand (1921), Pfaundler (1899), Ayer (1926), and Barré & Schrapf (1921), on differences in lumbar pressure of the cerebrospinal fluid in man in the prone and in the erect position, indicate that a comparable dislocation of fluid occurs in man as in the fourfooted mammal on positional change. Ayer’s finding of a small negative pressure on cistern puncture in man in the sitting position and Walter’s (1929) deduction that in erect man the point of atmospheric pressure is in the midthoracic region, permit one to hypothesize that in this erect position man has a negative pressure of not less than —400 mm. saline at the calvarium. And recent direct observations (Masserman, 1934, 1935) of lumbar pressures on tilting patients lead also to the conclusion that dislocation of cerebrospinal fluid from the uppermost to the lowermost parts of the nervous system occurs on positional change. The physiological mechanism in man seems therefore to be essentially the same as in the four-footed mammal: there was apparently no development of a special protective mechanism when man stood erect.

But has not our story of the cerebrospinal fluid given one suggestion of a protective mechanism within this rigid cranio-vertebral system? It was shown previously that alterations in the pressure of the cerebrospinal fluid have no effect on the pressure in the cerebral veins, even though the cerebral venous volume changes rapidly in compensatory fashion. The operation of this mechanism is apparently such that in the assumption of the erect position for instance, a marked lowering of the pressure of the cerebrospinal fluid in the cranium occurs, the cerebral venous volume there increases, but the cerebral venous pressure is unaffected by the decrease in cerebrospinal fluid pressure. Any decrease in the cerebral venous pressure under these conditions is the reflexion of change in the systemic venous pressure, effected by change in the hydrostatic columns of venous blood. Thus there exist local reciprocal volume-adjustments within the cranio-vertebral system on change in posture—not reciprocal pressure-adjustments. This physiological arrangement may possibly be the saving mechanism which allowed the four-footed horizontal mammal to become a vertical, erect organism, for in spite of an apparent dislocation of a long column of cerebrospinal fluid, with its accompanying pressure-changes about the nervous system, the intracranial venous system retains an effective pressure capable of returning blood to the systemic circulation. But was not there a great physiological hazard when the first vertebrate, with a horizontal nervous system, developed mobility of neck and head, so that the head could be raised above the rest of the nervous system, thus occasioning a dislocation of cerebrospinal fluid from the head-end of the organism and altering so markedly the pressure and volume-relationships about the neural axis? Fortunately nature saw to it that a rigid skull and vertebral column were provided: even to-day we should be thankful that we stand erect under the protection and aegis of a Monro-Kellie doctrine.

But these speculations and deductions could be continued almost indefinitely regarding this clear limpid fluid surrounding the nervous system. In a way I have attempted to give a somewhat connected story of the cerebrospinal fluid from its origin in the cerebral ventricles to its final pathway of absorption into the venous system. And in addition I have tried to touch upon some of the problems which arise in the fluid from the assumption of the erect posture by man. The story has not been in any sense a complete one but it has followed the rambles of one’s research interests into various aspects of the problem for 20 years. It has been the tale of a certain opportunism in research, but the tale is probably the more interesting because of the side-paths followed rather than the continued pursuit of a logical plan of investigation.

Over 20 years ago I asked myself this question: What actually does the cerebrospinal fluid do around the nervous system? Why is that fluid there and what function does it fulfill? Halliburton (1916) had asked himself the question and had concluded that it was ‘‘an ideal physiological saline solution”. With that general statement no one working on the fluid can possibly disagree, but does it get us very much farther along the pathway of knowledge? We know that such a fluid-bed may protect the nervous system from certain shocks and traumata; we have evidence that the fluid carries off certain waste-products from the central nervous system, as is done by endothelial-lined lymphatic vessels in other parts of the body. We understand also that the fluid may serve a nutritive function for the delicate arachnoidea which is almost entirely devoid of a capillary network. We are aware, furthermore, that the cerebrospinal fluid may afford certain advantages for the animal organism in permitting partial floating or suspension of the nervous tissues in a fluid-bed. On the other hand, we have come to realize that the cerebrospinal fluid is capable of dislocation as the vertebrate changes posture, and for this dislocation there is no apparent compensation in the physiological mechanism. Is not this fluid disadvantageous as a water column when man stands erect? Or is not its chief function one of providing means of prompt reciprocal volumeadjustment when there occur changes in volume of one or another of the two remaining elements within this rigid container of the nervous system? Here perhaps is one of the real functions of the cerebrospinal fluid—a means of reciprocal volume-adjustment within a container which is largely protected from atmospheric pressure. But all of these speculations must remain as pure speculations and to-day we know so little more of the essential function of the fluid than we knew a quarter of a century ago. Yet we have become somewhat more certain as to how and where the fluid is produced, somewhat more certain as to how and where the fluid is returned to the venous system, somewhat more certain as to how and where the nervous system is protected by the three membranes and craniovertebral container. But there is still much to be learned about the meninges and cerebrospinal fluid—the problem must still be followed with equal regard for structure and function.


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