Presidential address 86NS �9 Springer-Verlag 1990

Child's Nerv Syst (1990) 6:241-244

Trying to bridge a gap *

O s a m u S a t o

Department of Neurosurgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, 259-11 Japan

It is a great honor for me to have this opportunity to address you today. My chosen subject is "Trying to bridge a gap." The gap I speak of exists between the clinical understanding and research work on hydro- cephalus. Hydrocephalus is one of the major concerns of neurosurgeons - both pediatric and general neurosur- geons. Disturbances in cerebrospinal fluid (CSF) circula- tion represent one of the major pathogenetic factors in this clinico-pathological entity. At least this is the area in which I have worked.

A consideration of the growth of knowledge reveals that progress in medical treatment often stimulates inter- est in anatomical and physiological problems. It is in this way that the physiologist and clinician help one another, facilitating the growth of knowledge as a whole from the work each has contributed.

During the last quarter of a century, much valuable research has been conducted to solve the many problems of hydrocephalus. The results have provided for a clear understanding of many points. In spite of these advances, however, it is believed that in certain aspects the present concept of hydrocephalus and cerebrospinal fluid physi- ology is incomplete.

The purpose of this address is to review the historical development of' knowledge of the subject and then to describe an update of hydrocephalus research based on my personal observations.

The study of CSF may be divided into two historical periods: (1) from the time of Hippocrates to the publica- tion of Magendie's paper, which made available the observations of Cotugno; (2) from the publication of Key and Retzius on the arachinoid granulations, in 1875, to the present. These significant, though early, studies on CSF circulation have steadily increased in number and significance. We have come a long way from Hippocrates' awareness of the presence of fluid under the cranial dura and Galen's observation that there is a wa-

* Presented at the XVII Annual Meeting of the International Soci- ety for Pediatric Neurosurgery, Bombay 1989

tery substance inside the ventricles and covering the sur- face of the brain.

Unfortunately, in general, science made little progress in the Middle Ages, but it is somewhat surprising to see that writers at that time recognized and attributed dis- tinctive physiological functions to portions of the ventric- ular system: "imagination" to the anterior ventricles, "cognition" to the middle ventricle, and "memory" to the posterior ventricle!

At the beginning of anatomical dissection in the Re- naissance period, Vesalius wrote: "The entire surface of the ventricle is smooth and lubricated with a watery hu- mor and is often found to be completely filled with it. Domenico Cotugno, an Italian savant and politician, was the first to describe accurately the CSF circulation, but his description was unknown until the end of the first quarter of the nineteenth century when Magendie, com- ing upon Cotugno's work, published it in full in the orig- inal Latin in 1827. Magendie then went on to describe the existence of communications between the cavities of the brain and the subarachnoid spaces, as well as the conti- nuity of these spaces around the brain and spinal cord. On this foundation, Key and Retzius were able to struc- ture a work that culminated in the publication of their monograph of the CSF from which all modern work on this subject stems.

The greatest names in the modern history of the CSF are those of Lewis Weed and Walter Dandy. Weed's experiments on kittens, in which the fontanelle had not united, were landmark studies. In these animals, hydro- cephalus developed rapidly and the dilation of the ventri- cles and megalencephaly were quite remarkable. After a series of experiments, Dandy put forth the hypothesis that the CSF passes into the capillaries that abound in all the radicles of the subarachnoid space. Actually, he demonstrated that the CSF is in contact with the capillaries of the pia arachnoid. Later, Weed's work was re-evaluated by Hochwald and his group when the skull and dura were removed over one or both cerebral hemispheres of cats in an experiment inducing hydrocephalus. This procedure often resulted in bilat-

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era1 massive ventriculomegaly when the calvarium was removed on both sides; when removed on one side, re- markable ventriculomegaly only occurred on that side.

More recently, a comprehensive and sophisticated ac- count of the CSF has been given by Hugh Davson, who identified the significance of ion concentration, pH, mes- senger substances with alterations in neurophysiological functions. This work opened the way to modern experi- ments on the neurophysiology of the CSF.

In 1963, Bering and Sato published a paper in which transependymal CSF absorption capacity was both con- firmed and quantitatively measured for the first time, applying the ventriculocisternal perfusion technique. In 1921, Wisloki and Putnum published a paper entitled "Absorption from the ventricles in experimentally pro- duced hydrocephalus." Following the injection of a solu- tion of potassium ferrocyanate and the ammonium ion into the ventricles, they observed that absorption occurs to some extent from the ventricles in hydrocephalic ani- mals and hypothesized that the pathway of CSF escape in the hydrocephalic is through the ependyma, into the in- tercellular spaces, and finally into the perivascular spaces. Their perspicacity should be highly valued.

Now, for hydrocephalus research: So, what took them so long? And another question: Is hydrocephalus re- search still in a shambles? My answer is definitely "No." The process is certainly slow, but we are making our way along the path, inch by inch, step by step.

The interspaces of brain tissue, compared to those of other tissues, have relatively narrow channels that are separated from the vascular components by the blood- brain barrier (BBB). Beyond the BBB, the brain inter- spaces form a maze of interconnecting and narrow patent channels that are morphologically continuous with the adjacent CSF cavities. In 1965, Brightman demonstrated that when proteins such as ferritin and horseraddish per- oxidase are injected into the CSF, these markers move with relative ease between ependymal and pial cells to distribute themselves widely throughout the extracellular spaces of the brain parenchyma. His contribution was perhaps without parallel in the recent history of hydro- cephalus research. In tissues other than CNS, net fluid shifts across the capillary wall, and interstitial fluid (ISF) drainage into the lymphatics is an important mechanism in ISF volume regulation. The situation is quite different in CNS where there is no lymphatic system and cerebral ISF in the extracellular space is separated from the blood by the BBB. In addition to this, the ependymal and pial surfaces are in contact with another extracellular fluid, namely, the CSF.

Cserr has suggested that brain ISF is produced at the BBB by the process of secretion and volume shifts be- tween the brain and surrounding CSF, and that these shifts occur via bulk flow through patent extracellular channels. Without question, this concept is a matter of particular concern with regard to the pathophysiology of hydrocephalus.

The introduction of X-ray-computed transmission to- rnography in 1972 represented a breakthough in hydro- cephalus (both clinical and laboratory) investigations. Periventricular lucency (PVL), described by Naidich and

Epstein in 1976, drew the attention of many investigators, including myself. It was truly surprising to see how quickly the ventricular system dilates when the CSF path- ways are obstructed.

The perfusion techniques previously mentioned were introduced by Pappenheimer and his group in the 1960s, permitting significant progress in CSF formation and ab- sorption studies. This protocol requires perfusion of arti- ficial CSF through the ventricular system and its removal from the cisterna magna. The tracer within the perfusate is not diffusable, but its concentration within the per- fusate is diluted by the newly formed CSF. By weighing the volume of in-flow and out-flow fluids, and computing the tracer concentration difference in the two fluids, the rate of formation and absorption can be estimated. This technique permits us to conclude that approximately 500 ml of CSF is formed in man in 24 h. It is unfortunate, however, that this method is not easily applicable in clin- ical use, but the significance of this technique in under- standing CSF physiology cannot be overemphasized.

Most recently, the introduction of magnetic nuclear resonance has given students of hydrocephalus an ex- tremely important instrument for the study of both anatomical and pathological configurations to a certain extent. CSF flow dynamics may also be studied using the flow-void phenomena, which comes from CSF move- ment synchronized with cardiac beat.

The acquisition of detailed knowledge of blood circu- lation in the hydrocephalic brain remains of paramount importance both from the pathophysiological point of view and the continued development of treatment meth- ods for hydrocephalus. Periventricular hypodensity is of- ten observed in hydrocephalic brains. The reduced atten- uation coefficient observed in the periventricular white matter on CT scan may indicate reduced conductance to CSF outflow. Regarding the pathophysiology of PVL, it has been suggested that areas of hypodensity represent the passage of CSF from the ventricle through the ependymal lining. Assuming that morphological and physiological changes in relation to cerebral blood circu- lation in hydrocephalus are substantial, we focused on microcirculatory alterations or changes in microvascula- ture in the areas of periventricular hypodensity. Small electrodes, used for hydrogen clearance studies, rendered an attractive way to determine regional CBF in different areas of experimental animals, demonstrating that it is substantially reduced in white matter, particularly in the areas of PVL.

Concurrent with the functional changes observed in hydrogen clearance studies, derangement in the anatomi- cal characteristics of the microvasculature was docu- mented when the brain was perfused with a microbarium suspension. Specifically, groups of animals were studied with microbarium suspension at varying time intervals after kaolin injection into the cisterna magna. In the chronic stage, the study disclosed two types of changes. In one group, in spite of striking ventriculomegaly, mi- crovasculature changes were not prominent, but there was another group in which ischemic changes were prominent with rather minimal or moderate ventricular enlargement.

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Normal brain perfused with carbon black demon- strated distinctive demarcation between the white matter and the gray matter, in which the capillary network is extremely rich. On the other hand, when the hydro- cephalic brain is perfused with carbon black suspension 2 weeks after kaolin injection, discoloration of the brain parenchyma with carbon particles is unremarkable and not homogeneous. This observation is most evident in the region of the supralateral angle of the lateral ventricle. Areas of PVL seen on CT scan correlated well with non- homogeneous perfusion by carbon black.

The derangement in the microvasculature docu- mented in both colloidal carbon and microbarium perfu- sion experiments would account for the regional CBF reduction measured in the periventricular region. This series of experiments indicated that microcirculatory im- pairment cannot be the sole explanation and that circula- tory disturbances represent one of the significant factors to be implicated in the pathophysiology of hydro- cephalus.

With the evidence obtained in our laboratory that regional blood flow is reduced in experimental hydro- cephalus and the information reported from other insti- tutions that there is a reduction in CBF values in patients with NPH, measurement of regional CBF and 2 values in NPH patients were carried out utilizing the stable xenon CT CBF method. Each subject was positioned in the Hitachi 1000 scanner and the desired levels for scanning were selected. These selected levels were in the horizontal plane parallel to the orbitomeatal line. Xenon contrast scans were obtained after 40% xenon gas inhalation for ] 6 min, and optimal information was collected in ten re- gions of interest, including cortical gray matter, deep white substance, basal ganglia, thalamus, internal capsle and the areas of PVL. In patients who showed significant clinical improvement after shunting, post-shunt xenon CT studies revealed a substantial increase in the regional CBF, particularly in the region of PVL. Regional CBF increase was noticed only in the temporal white matter in patients without significant clinical improvement follow- ing shunt surgery. It was interesting to note that there were significant regional CBF increases following glyc- erol administration before surgery in patients who were good responders to shunt surgery. The increase of re- gional CBF in the particular region in these patients was more than 50% when compared to preoperative values. It was assumed that after glycerol, minute pressure differ- ences between the ventricular CSF and surrounding brain tissue are corrected and that microcirculatory dis- orders of the brain tissue are somewhat stabilized.

The technical advance, phosphorous 31 magnetic res- onance spectroscopy, provided us with in vitro dynamic analysis of organic phosphates in hydrocephalic rat brain. In vivo energy metabolism in these animals was also evaluated, measuring the activity of lactate dehydro- genese and its isozyme patterns. Hydrocephalus was in- troduced by means of kaolin suspension injection into the cisterna magna, revealing chronological changes in ven- tricular size in these animals. For MR spectroscopy stud- ies in this investigation, 4.7 tesla BEM-]40/200 with a double-turn surface coil of 15 mm in diameter was used.

With this surface coil, the detectable area was limited to the supratentorial region. From the sequential changes in the MR spectrum in hydrocephalic rat brain, it appears that each component decreases in its intensity as time passes after kaolin introduction; however, the difference is not statistically significant. The ratio of phosphocre- atine and phosphomonoesterase plus inorganic phos- phate showed a decrease in phospocreatine content in hydrocephalic rats. In hydrocephalic animals there was also a decrease in beta-ATP fraction when the beta-ATP and inorganic-phosphate plus phosphomonoesterase ra- tio was computed. Following in vivo MR spectroscopy studies, the rats were killed and the brains quickly re- moved and homogenized. Activity of lactate hydroge- nese, which catabolizes lactate formation from pyruvate, is an index of anaerobic metabolism. The lactate hydro- genese activity in hydrocephalic rat brain was found to be 1.5 times higher than that in the control animals. Thirty- one phosphorous magnetic resonance spectroscopy thus provides us a noninvasive, in vitro investigation in high energy phosphorous compound metabolism. From the series of MR spectroscopy studies it was demonstrated that there is a decrease in beta-ATP, phosphocreatine, and intercellular pH in kaolin-induced hydrocephalic rat brain, while both lactate dehydrogenase activity and LDH-5 fraction are increased in acute kaolin hydro- cephalus.

Single photon emission computed tomography (SPECT) is now widely used to evaluate cerebral blood flow. Because of its possible radiation hazard, however, well-documented SPECT studies in children are rather rare, so we have done only a few SPECT CBF measure- ment studies in childhood hydrocephalus and its related diseases. After being treated with compound iodine-glyc- erin 24 h prior to the study, 0.5 to 1.0 gCi of 123I-IMP was administered intravenously, and this was followed by scanning. Images were obtained 20 min and 4 h after the injection of the radioactive substance. Preliminary evalu- ation indicates that the hydrocephalus patients whose SPECT studies demonstrate less early radioactivity in the periventricular areas and more late activity in the same area are good candidates for shunt surgery.

Disturbances in the CSF circulation are the most in- formative parameters concerning the changes in ventricu- lar size, but the physical properties of the cerebral par- enchyma are also important in determining ventricular size. Unfortunately, we still do not know the biological principles that determine ventricular size.

At this time in my life, 30 years since I first began to study hydrocephalus in the laboratory and truly an equal amount of time studying clincial manifestations and treating surgically hydrocephalic children, I find myself always building bridges between the laboratory and the operating theater. I do not think the laboratory condi- tions, controlled and on animals to be sure, are totally different and nontransferable to clinical situations. They are different only in that we still do not understand the pathogenesis of hydrocephalus. My inability here to transfer laboratory conclusions successfully to clinical medicine continue to make me humble, but they also continue to inspire me!

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Before I close my talk, I shall quote the last several lines of Walt W h i t m a n ' s masterpiece "Passage to Ind ia" :

Passage, immediate passage! the blood burns in my veins!

Away O soul! Hoist instantly the anchor! Cut the hawsers - haul out every sail! Have we not stood here like trees in the ground long enough? Have we not grovel'd here long enough, eating and drinking like mere brutes? Have we not darken'd and dazed ourselves with books long enough?

Sail forth - steer for the deep waters only, Reckless, O soul, exploring, I with thee, and thou with me. For we

are bound where mariner has not yet dared to go, And we will risk the ship, ourselves and all.

0 my brave soul! 0 father, father sail! 0 daring joy, but safe! Are they not all the seas of God? 0 father, father, father, sail!

T h a n k you, indeed, for your a t ten t ion , a nd please accept my grat i tude for hav ing chosen me to serve as your pres- ident. In this, as in my life with hydrocephalus , I am humble and excited.