SUBDURAL HEMATOMA (Experimental Investigation of Membrane Formation)

by M. Gueramy, M.D.

A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfilment of the requirements for the degree of Master of Science.

Department of Neurology and Neurosurgery, McGill University, Montreal.

April 1964 TABLE OF CONTENTS Page

I. INTRODUCTION II. HISTORICAL REVIEW A. Anatomy of Dura and Subdural Space l B. Pathology and Mechanism of Chronic Subdural Hematoma 7 C. Radio-isotope Studies 13 D. Experimental Studies 17 III. EXPERIMENTAL STUDIES A. Experimental Design 24 B. Morpho1ogical Studies 28 a) Methods and Materials 28 b) Results 29 C. Radio-isotope Experiments - Cats 31 a) Methods and Materials 31 b} Results 35 D. Radio-isotope Studies - Human 40 a) Methods and Materials 40 b) Results 49 IV. DISCUSSION 53 V • SUMI'v1AR Y 59 VI. BIBLIOGRAPHY 61 VII. ACKNOWLEDGEMENTS 65 I. INTRODUCTION

Subdural haematoma was one of the first neurological lesions to be treated by man. Prehistoric man performed trepanation. Later, Hippocrates and Galen described cases with recovery after evacuation of clot which were probably subdural haematomas. As the science of medicine evolved over the centuries, investigators have argued about the etiology of this lesion. Up to now many questions have been answered. But in spite of modern knowledge of anatomy and physiology, the mechanism of chronic subdural haematoma remains obscure. This study was undertaken to add more basic knowledge to this essential question. Attempts were made to produce experimental subdural haematomas in animals. Radio-isotopes were used to trace the route of absorption of haematoma in animals and as a diagnostic aid in detecting lesions in human cases. 1.

II. HISTORICAL REVIEVJ

A. Anatomy of the Dura and Subdural Space

In 1875 Key and Retzius presented a comprehensive and thorough work on the macroscopic and microscopie structure of all three meninges, which may be summarized as follows: The dura mater of the brain consists of two layers of connective tissue fibrils with intermediate cells, most of which are filiform, lying parallel with the longitudinal direction of the fibrils, and arranged in rows in the tissue spaces between the bundles of fibrils. In the inner layer the main direction of the connective tissue fibrils on the convex side is anteromedial-posterolateral. In the outer layer the bundles are more interwoven, but their main dir ection is perpendicular on the inner layer. The two·layers are connected mutually with bundles of fibrils, crossing from one layer to another. Between these collagen fibrils, sorne elastic fibres are seen, most at the base of the skull, least on the convexity. These two membranes cannot always be separated. The blood supply of the dura is described very precisely. The outermost fibrillary layer of the dura contains arteries as well as veins; the arteries run in looping streaks, accompanied by two veins which open into 2. the superior sagittal sinus. The arteries as well as the veins form anastomoses, the vessels branching dichotomously. Fine capilleries and arteries run obliquely through the dural tissue to the inner side where a pattern of long meshed capillary net is found, the junctions of which form ampullary blood-filled dilatations; and these ampullary dilatations constitute the connecting link between the capillary and venous systems. On the outer aspect a more open capillary network is seen; and at the transition between the two capillary layers a few tiny vessels are seen. The separation between the capillary nets is most distinct in the parietal region, which also has the richest blood supply. By injection into the dural tissue, Key and Retzius succeeded in filling a rather dense-packed tubular system running parallel with the fibrils. But they found no endothelial lining of these spaces, on which account they did not regard them as lymphatics proper but merely as a system oÏ "juice channels". They further mentioned that the inside of the dura on both sides of the various sinuses, especially around the superior sagittal sinus, is equipped with a system of traveculae. In man, but not in dog or ether animal species, they demonstrated the so-called lacunae, differing in form and size, but without any parti cular lining outside the elastic membranes. In spite of repeated attempts they were only able to fill the lacunae by injections into the "juice channel nsystem and into the circulatory system. Huguenin in 1877 thought the blood supply was far more abundant in the outer leaf of the dura than in the inner, but otherwise he agreed with Key and Retzius. In 1914 Weed stated that endothelial-lined lymph ' spaces were entirely absent from the entire central nervous system, including the meninges. In 1924 Jacobi, and later Zehnder arrived at the opposite result; the dura contained lymph spaces communicating with a subdural space, the peri vascular lymph spaces and the venous ampullae. These findings have been contested by Pfeifer in 1928, who states that the vascular walls of the venous ampullae are very thin and friable, on which account he considered the demon strated communications artefact. He also denied the presence of endothelial-lined lymph spaces, whereas he recognized a ffjuice channel" system between the dural fibrils. An exhaustive description of the vascularisation of the dura was given by Pfeifer (1930) who injected the blood vessels as soon as possible after death, simultaneously with fixation of the brain and meninges in situ. The injected vascular apparatus was examined under a stereo scopie microscope, so that mistakes concerning the relative depth of the location of the vessels could be avoided. In the most superficial layer, as demonstrated previously, there is a capillary network with wide elongated meshes and vessels of fine caliber which are anastomosing with the diploic vessels but otherwise are provided with blood from the meningeal arteries, and many of them open directly into the underlying venous-capillary system. Then, at a deeper plane, come the large, markedly winding, menin geal arteries, each with two concomitant veins of quite irregular width and form, which - without any sharp border - continue in the thin-walled venous sinuses. Like several previous investigators, Pfeifer observed on the inside of the dura another, superficial, extensive capillary network, curly and necklace-like in appearance, which undoubtedly has contributed to their interpretation by earlier investigators as lymphatics (when the blood was evacuated). The thinness of the vascular wall is suggestive of great capacity for transudation and absorption on the inside of the dura, and the irregular calibre must have consequences in the circulatory regulation of the dural vessels. Erna Christensen (1941) investigated the thickness and vascularisation of the dura and her findings were similar to previous investigators. In the external layer layer of the dura, besides the larger vessels she found a polygonal capillary net in which the meshes average half a milimetre in width, and most of the capillaries measure 5u in diameter, though a lumen of lOu is encoun tered here and there. Sections from the middle of the dura present a few vessels. In the inner layer the capillaries again are numerous, forming a network with long meshes and most of the capillaries are running parallel with the fibrils with a few oblique anastomosis. The subdural space had been accepted as a potential space till Penfield in 1924 performed some experimenta in order to settle the question whether the subdural space is a truly potential space or normally contains fluid. In his experimenta anaesthetized dogs were given an injection of ten percent Formalin into the interna! carotid at a pressure of two hundred centimetres. The animals were at once placed in a refrigerator at a temperature of zero centigrade. After five to fifteen days the head was divided into frontal sections with a saw. The total bulk of the brain could then be pushed out of the sections together with the pia and arachnoid, as well as a coat of ice, clear as water in the subarachnoid space. The dura was left on the inside of the skull and on the inner 6.

surface of the dura a la of clear yellow ice was spread over both hemispheres, varying in thickness from one half to one millimetre thinnest over the There was sorne individual variation in the thickness of this layer of ice in the dogs examined. Thus it was proved that normally, at any rate in dogs, there is a smdll amount of fluid in the subdural space, and that it is not id cal with the fluid found in the subarachnoid space. e findings prove that normally there is a 1 amount of fluid in the subdural sp::J.ce, that the com position of this fluid differs from that of the cerebro spinal fluid in the subarachnoid space. B. Pathologx and Mechanism of Chronic Subdural Hematoma Early investigators agreed on the microscopie de- s ption of the subdural hematoma, but held wid di- vergent opinion r ing the iology and pathogenesis of this condition. Before 1855 the disease was regarded as resulting from hemorrhage betvJeen the meninges. 1''1organgi (1765),

Abercrombie ( 1829), and Raki tans ky ( 1844) thou~~ht the lesion was a result of hemorrha c cysts between the dura and arachnoid, whereas Bayle (1826) claimed that the hem- arase between the dura and a pseudomembrane on the de of the dura. Rokitansky scribed the lesion as a

ing spindle s~aped unila structure, localized to the parietal re on, and consisting of rust colored, vascularized membrcmes which had fused with the external of the arachnoid_and with the dura. The structure of the membrane corresponded to blood undergoing organ ization. Literature from 1817-1854 reflects the on of many authors that the membranes originated from the clot- t and organization of the accumulations of blood in the 11 arachnoid sac." In 1855 Heschl disagreed with previous viewpoints and said that blood shed into the subdural space over the convexity would sink to the base of the skull, thus could not be the cause of the usual fo~m of the chronic subdural hematom0 over the convexity of brain. In s opinion the primary factor was an inflammatory process the dura which gave se to the rmation of a strongly vascularized layer of connective ssue in parietal l of the arachnoid, in which hemorrhages might occur secondarily, varying in size from t spots to l accumul1tions of blood.

Virchow in 1g57 did not recognize the ~emorrhage as the prinary phenomenon but, took a chronic hemorrhagic inflammation in the dura as the starting point of sion, which he designated PACHYI:IENHJGITIS HAEHORRH1~GICA CI-IRONICA support of his inflammatory theory he emphasized: (l) Th the extravasates of blood were you th an membranes.

(2) That the lesion never starts with apoplectic symptoms as it would do if the ry phenou1enon were a large subdural hemorrhage. (3) t the blood then would follow the law of grav- i ta ti on and accumula te at the base, v-rhi ch is not

the case, as the lesion most often is loc ized

In 1866 Kremiansky ae;reed with the inflammatory t ory and emphasized that chronic alcoholism was one of the most common causes of the inflamma on as was evident from the frequent findings of this sion at autopsy on persans belonging to those <.lSS8S of population that used to take a great deal of alcohol, each day over a number of years. 9.

1S90 Berger stated t dividual disposition, possihly hereditary factors, a certain etiologie role and that other diseases most often paved the road the secondary inflammation. From 1885 to the end of the century most of the authors subscribed to the inflammatory theory, however

there were a few autho~s, for example, Huguenin, Wiglesworth, r , who denied the possibil y that this lesion was caused by inflarnmatory origin. They never noticed any in-

iti 1 inflammation of the dura the "endothelium" of the was ide of the dure/ intact. fore, they concluded that

the t process of this ion consisted in extens extra vas on of blood on the ner aspect of the dura. Huguenin states that he has re atedly demonstrated ruptured or degenerated varicose ve entering the superior sagitt sinus. Sorne ether authors like Heubner and have that internal hemorrhagic pachymeningitis could ar e only on a syphilitic sis. Laurent (1898) stated that rnal hemorrhagic pa tis in which the hemorrha s arise from the

rupture the capill~ries under the dura, presents no inflammation of the dura but merely the physiological efforts of an to absorb a dead fore body in its region. Therefore, fresh hemorrhagic pachymeningitis was nothing but an ensive blood clot which ly underwent or- ga ni on and became adherent to e dura. In this process the important phenomenon was proliferation of the inner capillary layer of the dura. 10.

e English literature did not p(oduce any compre hensive work on the subject before Trotter in 1914, when he presented his views and preferred to call the lesion, subdural hemorrhagic cyst. also concluded from the slowness of its course and the insidious onset of the symptoms, t:1ere could be little doubt t the b eding was of venous origin. It was nearly certain that the cerebral veins pass from the brain to the tributaries of the superior longitud sinus were t source of the blood. Leary (in 1934) on the basis of his own fifty cases, attempted to show that there was nothing mysterious about intcrnal hemorrhagic pachymeningitis and that it always ap- ared as a result of hemorrhage. The characte tic feature of the lesion turned up when the organization of the hematoma reached a certa state, as the handicap of inadequate venous drainage under which the organization took place, then became cons cuous. Munro (1938) carried out histological and chemical studies on two hundred and fifty cases with a positive his tory of trauma. He divided the chronic subdural hematorna into three groups: (l) Solid hematoma, with accumulation of blood alone in the subdural space. (2) M:ixed hematomas containing both blood and cerebro spinal fluid.

(3) Fluid hematoma with a minimal extravas~tion of

blood and a 1 amount of cerebrospinal fluid. ll.

Ifunro also correlated the age of the hematoma with the histological appearance of the membrane. Ambrosetto in 1958 reported four c,o.ses of post traumatic chronic subdural hematoma in which the clinical symptoms and the characteristic arteriographie picture regressed completely without surgical intervention. Their treatment consisted of bed rest and an ample diet fortified with a variety of vitamines, anti-hemorrhagic and vaso protective drugs, corticosteroids, and intravenous inject ions of hyp,:rtonic solution of glucose. In 1961 Ambrosetto again reported three more cases of post traumatic chronic subdural hematoma with typical clinical and angiographie picture of this lesion which were successfully managed without surgical intervention, by bed rest and sup~ortive therapy. The clinical improvernnnt was accompanied by return to normal of the previously altered electroencephalogram and angiographie demonstration of the disappearance of the lesion. Follow up studies on these cases did not show any sign of recurrence. Bender, between October 1958 and February 1960, studied nine patients with syrnptoms, sie;ns, laboratory exarnination and typical angioe;raphic pictures of subdural hematoma. All have recovered without the benefit of surg ery. The subdural collections were unilateral in eight patients and bilateral in one. The clinical syndromes con sisted of headaches, varied mental changes, clouding of 12.

consciousness, pathological reflexes and sorne, motor deficits. One ient had aphasia with a hemiparesis. Three patients gave a histo of seizures. 'lwo were in deep and two in light stupor. One shov-1ed lateral pap- illedema with hemorrhages, another had a ret al hemor rhage and a third had a homonomous eld defect. These cases were diagnosed and followed by serial angiography and improvement was accompanied with lessening of the ab normalities present on electroencephalograms. 13.

C. Radioisotope Studies During the past ten years, more than one hundred reports in the neurosurgical and nucleonic literature have indicated that radioactive isotopes can provide a useful, painless and safe method for the detection and localization of certain intracranial lesions. The reports, for exarnple, on the localization of subdural hernatomas by the isotope method will serve to indicate this variability. Using diidofluorescein, Moore found an increased concentration in one case of subdural hematoma, although the material removed at operation proved to contain very little of the radioisotope, and he suggested that the increased rate of count over the side of the subdural hern- atoma rnight be ascribahle to edema of the brain. With the same isotope Peyton and others also detected subdural hematomas, but Ashkenazy et al in eight subdural hematomas found little or no evidence of localization. The results using radioactive iodinated serum albumin (RISA) were reported highly satisfactory by Dunbar and Ray

~ho were able to localize subdural hematoma by this method in four cases. Since they found that the subdural fluid has less radioactivity than venou$ blood they assumed that was related to the radio-isotope Lei11g concentrated localization/in the brain beneath the region of the subdural clot. In one case of bilateral subd11ral hematoma, Rhody and Nowlis were unable to get any localization by RISA. 14.

Sweet and his co-workers reported th t they were able . to detect seven out of eight subdural hematomas using arsenic 74, but that no positive scans were obtained in three sub dural hematomas using copper 64. In a chronic subdural hem atoma of about three months duration and five days following the injection of arsenic, they noticed a somewhat higher concentration in the membrane of the hematoma as compared to the clot. Planiol using IUSA and a careful technique of manual scanning with ted scans at one hour and twenty-four hours, was able to localize subdural hematoma in two cases. Feindel and others reported in 1961, three cases of subdural.hematoma which have been diagnosed by brain scans us RISA. In these cases the uptake was higher in older hematomas. He has pointed out the importance of fluid and membrane in detection and localization of the sion; he also questions the possible role of underlying edenatous brain in contributing to the increased activity. Brinkman and Kahn {1962) us photo scanning technique with Mercury203 diagnosed two cases of su':Jdural hematoma showing uniformly high uptake on an antro-posterior view over the entire single hemisphere. Rabe and Dodge in 1962 investi ed b ral subdural hematoma by means of iodinated human serum albumin ( SA) in an infant of five months. Fifteen microcuries in a volume of 1.254 cc was given intravenously and samples of blood, left subdural fluid, right subdural fluid and lumbar cerebro- spi fluid were taken and studied at regular intervals. 15.

sults showed a low concentration in the lumbar arachnoid space in comparison with subdural fluids and blood. They conclude that plasma, subdural and subarachnoid spaces were different compartments with respect to their content of al bumin, globulin, total protein, and absolute radioactivity. Radioactive albumin in subdural and subarachnoid s ces was derived from the plasma. Turnover time for albumin in the right and left subdural space and lumbar subarachnoid space was sixteen, nineteen and twenty-eight hours respectively. Mealey in 1963 produced subdural hematomas in twenty dogs. Intravenous injections of arsenic 74 were then given in thirteen animals, RISA was given intravenously in seven. The animals were sa ficed by exsanguin on. The intervals between the intravenous injection of radioisotope a~ the sac rifice of the animal were chosen to correspond more or less with intervals frequently used clinically in brain scanning. Radioautography and assay of samples were the methods used to determine and compare the uptakes of the two isotopes in these lesions and contiguous tissue. Concentration of bath isotopes were r in the subdural membrane than in the more inert contents of the hematomas or subjacent cerebral cortex. This contiguous cortex in turn contained somewhat higher activities these isotopes than did cortex from the normal hemispheres. HatJios of the concentrations in the subdural hematomas ta the underlying brain were greater with RISA than with Arsenic 74. These studies according ta Nealey 16.

indicate that it is the nature of the subdural membrane that largely detennines the extent of the uptake of Arsenic 74 or RISA in relation to the subdural hematoma. In 1962 Mealey carried out external scanning of the head after injection of RISA into seven subdural effusions in four infants. This method could demonstrate the extent of the effusion as there was not the high interference of background activity seen after intravenous injections of the isotope. He also established the time course of labelled albumin in the subdural fluid and plasma following the in jection into the subdural hematoma by sampling at regular . time intervals. Hts comparative curves show clearly that the level of isotope in blood increases very saon after sub dural injection of RISA and levels off in abo11t eighty hours and then equilibrium will be established between the plasma and the subdural fluid. · 17.

D. Exnerimental Studies In order to establish the etiology of the internal hemorrhagic pachymeningitis, now known as subdural hematoma, sorne experiments were carried out in the past. Laborde in 1865 tried to reproduce the lesion in an irnals by operations on the dog. After injection of blood in the subdural space he showed that the primary process in the lesion was hemorrhage and on autopsy, twenty-four hours later he was able to demonstrate on the inside of the

/ dura, a subdural hemorrhage surrounded by a delicate mem brane which had no connection with the arachnoid. In 1872 Sperling rroduced somewhat similar result through experiments on rabhits which were killed from four days to six weeks after operation with subdural injections of blood. He found that the injected blood underwent or ganization in the course of three weeks; this orocess started from the dura wi th the forma ti on of mernbr:::mes of the same ap pearance as those encountered in hurnans. Krerniansky (1868) brought about chronic alcohol in toxication in anirnals and on autopsy found, in a certain

nrnnber of cases, sorne changes resernbling the above findin~s, which they took to indicate that alcohol plays an important role in the occurrence of this condition. Later Ruge (1870)

and others were unable to repro~uce these experirnents. Putnarn and Putnarn (1927) carried out sorne experirnents on dogs and cats in which they injected blood in the sub dural space and on autopsy sorne of his cases did not show HL

any trace of blood or membrane. Some others showed a very thin membrane but no chronic p essive hematoma s lar to that in t human being vras ~)roduced. Zehnder in 1937 repeated these experiments but could not produce a membrane. Later 1938 he succeeded producing subdural membrane by cing an almost non-absorbable substance, Polyviol, in the subdural space. Erna Christensen ( 1941) produced experimentJ.l subdural hematoma in in several ways. ( 1) Subdural injection of citrated blood (2) ated subdural injections {3 ) Subciural injections of blood and re ted injury to the head (4) Ligation of the superior sagittal sinus ( 5 ) gation of the rior sagittal sinus and simultaneous injections of blood. Only subdural injection of the blood and simultaneous lic;ation of e superior sagitt sinus gave a h tological picture that corresponded to the findings in pati with chronic subdural hematoma. She thinks that a relatively small amount of blood injected subdurally undergoes complete re- organiz ion. Only when the ci tion is impa d at the same time does organization become defective, and id is aspirated to bal .nee the colloid-osmotic pressure. ex- a periments o failed to produce/chronic progress subdural hematoma. al studies were carried out five dogs with the injection of 0.7-2 of whole, unclotted blood from the femo vein into the subdural ST'ace by Gardner in 1932. A muscl graft was ced over the pun wound in order to se it, then bone dise was re ced and the vvound was clo~sed.. The an were killed from thre e weeks to th~ee and one half months later and there was little or no gross denee of the injected blood ath the dura.

He thought, s ce post-craniotomy subdural toma is very rare in human experience, the bony defect in these experi mental anima may favor the ssion of the lesion. In a fu~ther series of ex?eriments, Gardner passed a curved needle through a trephine hole and the substance of the brain till the tip of the lay under the dura on the opposite side. At this point 3 to 11.5 cubic centimetres of whole venous blood (autolo was inject Again, aftor two we 1 at autopsy, little gross evidence of the injected blood was found.

In a s es of eight dogs cellophane sacs, of known weight, conta ng whole blood, from the femoral vein were inserted in subdural space. The sacs with ir contents were removed later and weighed in order to note any

crease in ·weight. In five of the animals simi sacs were also placed in the rectus ath or pe tone cavity.

In one animal, which was killed fty-one days ter, both 20.

sacs were found to be ruptured. In remaining animals the sacs were intact when removed from three to eighteen days after implantation. Following removal, each sac was found to have ined from thirty-nine to one hundred and three percent weight. With one exception, the control sacs in the rectus sheath and peri cavity gained more in weight than did the sacs in the subdural space. He o carried out ts on the property of the inner membrane of human lesion ch was proved ta have e properties of a semi-permeable membrane. Then Gardner proposed the following hypothesis: Following a cranial trauma, hemorrhage occurs into the subdural s ce. A large amount of blood, having escaped becomes clotted, and within the course of a few days this clot is surrounded by a capsule of meso lium and connective tissue growing out from the dura. The portion of the capsule next to the becomes invaded with nutrient capillaries froô the dura and thus at,ains a greater thickness than does the avascular portion that is adjacent to the avascular arachnoid. The encapsulated clot then undergoPs p~rtial liquefaction, a resultant fluid protein content. This fluid is separated from cerebrospinal fluid, which is of low protein content, mere by the thickness of a few layers of cells constituti the inner walls of the cyst and the arachnoid membrane. Thus results an ideal setup for o~Jmotic interchange. Since the new membrane is irnperme 21.

to the protein molecules in the hemorrhagic fluid and osmotic imbalance in favor of the hemorrhagic must exist, resulting in the withdrawal of cerebros fluid into the cyst. This, of course, causes a ss- ive of the hemorrhagic cyst and eventu ly a rise in al pressure. a 1963 has reported a series of imental stud s of subdural hematoma in dogs. One:- - Subdural injection of liquid blood: A total of eight dogs had liquid blood jected subdurally. Intravenous hypertonie urea was ad- mini ered -operatively ta allow greater of blood to be ected and ta facilitate subdural rather than chnoid injections. The seven anima surviv ing inject remained clinically normal. In e do sacrificed at intervals ranging from eight to seventy- two days, no evidence of the subdural injections were noted.

seven dogs tearing of the supracortical veins was ed out. In two dogs sacrificed after eleven and ty-one days there was evidence of progressive o ization and reabsorption of the subdural hemorrhage. In two others sacrificed at thirty-three and seventy-two days, no hematoma or fibrous membrane was present. 22.

Experiment Two:- Creation of large subdural hem atoma by injection of clot. Groun A - Subdural injection of clot.

Twenty-one do~s in this group were injected with clot, and sorne evidence of the subdural injection was found in all animals at death or sacrifice. In none of the dogs did a subdural hematoma enlarge to cause dela.yed symp toms. Organization of the clots proceeded regularly and progressively, although re-absorption appeared quantitat ively slower than with liquid blood. Study of the histol- ogi cal s ections the animal sacrificed at about weekly intervals revealed that within fifteen hours after creation of the tomas, a single layer of cells had already mi grated to its external surface adjacent to the dura. The remainder of the hematoma consisted of an unorganized mass of erythrocytes. By the seventh day, phagocytosis of the red blood cells and fibroplas were pro sing in the most superficial layer of the hematoma. An outer me::1brane subjacent to the inner surface of the dura was well developed. Lying more deeply was a straturn of erythrocytes and hemoglobinous debris. An inner membrane, one cell thick \'Jas esent which together wi th the outer membrane formed a sac that enclosed the residual hematoma. two weeks of age, rnuch of the contents of these experi mental he:natornas had been cleared away. Afterwards fluid and then membrane gradually d appeared. 23.

Group B- In eight animals repeated injection of the clot or blood at weekly intervals in subdural space was carried out. In the five do3s which remained healthy and active until they were sacrificed, organization was found to be nroceeding in s te parcels. In each stratum of the hematoma which had been piled up by repeated inüections, resolution proceeded the same as others. Few other variations of the technique such as ad dition of anti-inflammatory agents, cerehrospinal fluid to the blood injected, and reduction of the intracranial pressure during the post-operative period did not affect the resolution of the experimental hematomas. 24.

• EXPERIME1JTAL STUD:IES

A. Experimental Design The cat was en as the experiment animal for this subject, mdinly cau::;e: (l) Any smaller animal would prove too difficult, technically, for this type of riment. (2) Any la animal, although more sui table, from the tive point of view was incon- venient to kcep in large numbers r chronic experiment. The animals weighed from three to four kli:lograms. They were anaesthetized with intraperitone pentobarbital,

35 mg. per kilogram of body weight as the i dose. Occa[3ionally, further, small doses were necessary in order to keep the animal anaesthetized throughout the procedtrre. A midline s Ltal incision was ca d out in the scalp: thi3 gave sufficient exposure of the skull with

r1' negligible bleed . ) . After separation the scalp by means of a self- ing retractor, the ertions of the auricular muscles were separated from the bone by a peri- osteal elevator. Then the self-retaining retractor was re-positioned in arder to retract muscles and scalp away from the bone the same time. Using a ine, a dise of bone, 2 cm in diameter \vas removed c from the parietal eminence without 25.

injury to the underlying dura mater. Acute and chronic experiments were performed and procedures for the chronic experiments were ed out under aseptic technique. Attempts were made to inject blood in the subdural space but the relatively thin dura could not be entered without injury to the even thinner arachnoid membrane im mediately beneath. Therefore, the following technique was devised to facilita the injection of fluid in the subdural space without harming the arachnoid membrane. A twenty-s gauge needle (short bevel) attached to a tuberculin syringe was put into the thickness of the dura almost parallel to the direction of the fibres with out penetrating the inner surface of the dura. Then the bevel was directed towards the deepest layers of the dura and a hubble of a was injected. This hubble of air opened the fine dural fibres immediately underneath the tip of the nee , result in the s ration of the arachnoid membrane from the dura mater and changing the potential dural ce into a true space. Autologous blood was then ected, usually to a total volume of 3 ml. The puncture site was then sealed by a small piece of muscle. (Figs. l and 2). Integrity of the arachnoid was tested by injection of two mi litres of thylene in the subdural space, followed by sampling of cerebrospinal fluid through a c ternal needle which has b0en placed in the basal cistern. It was thus found that the above-mentioned technique cil itated the injection of dye, blood and, later, radioactive 26.

albumin {RISA) into subdural spice without injury to the arachnoid membrane. 27 .

Fig . 1

Eig . 2 ').n.' J..-0.

B. Morphological Studies

Since previous investieators had i to produce a chronic subdural hematoma resembling a human sion in experimental animals, it was decided to re at the experiments with certain modifications in tee que. (a) Methods and r·:laterials Exneriment I: Subdural injection of whole blood into the suhdural space. ïen cats, of either sex, and wei 3.5 to h-5 kilograms were used in this series. The ls were prepared as d escribed in nExperiment Des 24). Venous blood, taken from the same animal was injected into the subdural space. The volume of blood injected varied from 1.5 ml. to 2.5 ml. The animals showed no clinical evidence of an expanding intracranial • They were sacrificed from one to eight we ·wi thin a few days following operation without wi th the subdural hematoma, revealed a considerab~e decrease in the amount of blood in the subdural space. Ex;)eriment II: Subdural injection of whole blood was ca ed out thirty minutes after intravenous injection of 1.5 to 2.5 gms per l·1g body weight of urea in arder to produce shrinkage of the brain and facilitate the production of a 1 r hematoma. Group A. This consisted of ten cats who received 1.5 to 29.

2.5 gms per Kilogram of body wei~ht of intravenous urea. In all cases shrinkage of the brain was satisfactory and rmitted the injection of 2 to 3.5 ml. of whole blood into the subdural s ce. The animals remained he:üthy and were sacrificed from one to eight weeks later. Group B. In ten other cats subdural hematomas were pro- duceà in the same way as Group A, but intravenous injection of urea was repeated from three to eight times every forty-eight hours. in the animal were sac ficed from one to eight we a ft er subdural injections. Experiment III: In five cats 2 ml. of whole blood were in j ected and repeated every fi're days on three occasions. The cats were sacrificed one to five weeks after the t injection. Experiment IV: In five cats one of the bridging veins along the sagittal sinus was sec oned by an angulated u cutting knife f an hour a er injection of intravenous urea. A sizeable hematoma was pronounced at this time. The animals were sacrificed from one to e weeks after operation. (b) Results: i None of the cats with experimental subdural hematoma~ showed clinical signs of a progressive e xpanding intracranial lesion. Auto9sy was performed on the cHses. The brain and its coverings, with dura intact, was remoifed and Formalin. After ten days fixation in Formalin, they vvere processed blacks of whole brain and dura were prepared. 30.

Serial sections were carried out and were stained with Hematoxylin and Eosin and Hematoxylin Van Gieson. croscopic examination of the slides showed in tact dura and arachnoid, and normal underlying brain. In most cases sorne cell d s and hemosiderin pigment were seen in the subdural space. But, except for the occasional t cken o" the dura, no subdural nembrane "'Jas found. 31.

C. Radio-Isotope Experiments - Cats (a)Methods and terials:

4.5 kilograms, were used for this experimental se es. were prepared as described ier under

!! rimental Design" (page 24). ght cats selected at random were ven 0.1 ml. ra io-active serum albumin (instead of whole blood)

directly into the subdural space. The rema i six cats

re ce d an identical ~~ount of radio-active erial into

In all cases, the puncture hole was covered 1tlith a teased ece of muscle, then a 1 x 2 cm. 1 of cellu- co on was placed on the site to absorb ck flow of radio-active fluid. This swab was removed r a few , set aside for radio-activity ass and replaced by a second swab of cellu-cotton. This was covered a square of water-proof plastic, and a third swab in te ed between the plastic and the overlying temporal mus e to absorb serous oozing from t eut surface of the mns e. These l..:ttter tvw s11vabs \.vere removed at the time

of sac ce, usu~lly 24 hours later, and were retained

for count • One animal injected subdura was monitored ex-

ternally with detectors pl~ced over he , and over the he • 3 and 4), to correlate absorption of radio-

r' activity in the blood. Routine blood s ing was also carried out in this case. 3 2.

Radio-active cer: Com:n.ercial av ai radio-active iodinated human 1 1 serum albumin ta~ged with Iod 3 ·was used. The specifie actWity of each dose was 40 uc r 131 per 2 mgms. albumin in 0.1 mls. sterile solution. e stock solution was used within 24 hours of s pment to reduce the poss ility of increased amounts of free iodine. lccording to the manu- f cturers' specifications, the amount of unbound iodine at time of shipment was s than 1;0. Nuclear Instrumentation:

A ird-Atomic unit was used, compris type scintillation counter (5 ml. 1), pulse height analyser- amplifier, stabilized hi volta supply, precision electronic t ' and s -;:;e ed scaler. The analyser was set to an ll volt vJindow, centered 131 on the 364 KEV gamma ray of 1 {300-410 KEV). Und er these conditions, the nor .al background was 12-15 counts per min- e: ute, and the sensitivity approximately 7.0 x 10) counts r minute, per microcurie r 131 • Counting Techniques: • All blood samples were taken usi ore ously heparinized identical dispos e s s. volume was ad- justed to l ml. and the sample transferred to a plastic dis- po e co un tube. The s s were counted for 2 mins. each. s period VJaS found to be statis cally equate for blood ta ken a ft er subdural administration (counts in ex cess of 10,000) but was not equate for blood specimens 3}.

obtained after subarachnoid injection. In these Cises, "spot" samples 1.-vere selected and counted to a total of 10,000 counts to establish reliable points. In all cases, counts were corrected to the tine of injection (To). Blood samples were expressed as cts./min./ ml. SlJabs vwre counted for one minute. The actual loss of radio-activity was eatimated by comparing the swab count with a standard prepared by dispensing an extra injection dose at the time of operation, and placing solution in a l litre volumetrie flask and diluting to l litre with water. One ml. of standard solution gave a satisfactory basis for estim ation of percentage loss of initial radio-activity. External :.Ioni toring: Nuclear-Chicago surgical sèit1till tion probes viere used in conjunction with ?icker ratemeters and a 4 channel Sanborn recording unit. Two 3 mm. crystal scintillation probes, shielded with l/4" of lead, were balanced using a simul,ted iodine source, then supported over the operative site on each side of the head (Fig. 3). A 6 mm. probe, also shielded with l/4" of lead, w~s directed to the cardiac blood pool (Fig. 4). The back-ground radio-activity was recorded before and after the experiment on the recording ran~es used. The 3 mm. probe certered over the absorption area was raised whilst the RISA was injected, then replaced immediately. The ratemeters were set at full scale 100,000 c.p.m. (for the 34.

F-ig . 3

Fi g . 4 35·.

absorption area, and full scale 30,000 c.p.m., for the contralate side of the head, and for the heart detector. A tirne constant of 3 seconds was used in l cases. The 4 channel chart paper was started before the actual injection, and was allowed to run at 0.25 mm per second for the 24 hour pcriod. The times at which blood samples 'Nere t were a o marked on the continuous recording.

(b) Resul>ts Subdural Injection: Four cases showed rapid appearance of radio-activity in the blood amount to a maximum value of 4.6-6.7% of the dose given at 7-12 hours after injection (Fig. 5). In one case which was externally monitored, the shape the curve of appearance of raàio-activity in the blood as obtained from serial samples was alrnost identical to that obta ed by the external cardiac probe recoràing ( g. 6). 'l'he other three cats s:towed mu ch lower uptake, maximum lo5-2o3% at 14-18 hours. e are represented on a separate graph ( • 7) as it is lt that this is an arte fact due to technical difficulties. Considerable del of about four hours was sent between time of exposure the dura and time of injection of RISA. It was noticed that the dura had dried and had a parchment-like texture. Great care was taken to keep the exposed membrane moist in subsequent cases, and this uptake pattern was then avoided. was also 36.

noted that in this group two out of three cats did not sur vive for the 24 hour experimental period - death intervened at 12 and 16 hours and was assumed to be due to anaesthesia. All the factors contrjbuting to this group would have to he studied further before any real conclusion could be drawn. fubarachnoid Injection:

Six cats all showe~ a slow appearance of low concen tration of radio-activity in the blood - the amount recorded ranged from 0.06-0.25% of the ,total dose injected at 12-16 ho1.1rs. All results are seen graphically in (Fig. 5) and are plotted with counts ner minute per ml. of blood on a 3 cycle logarithmic ordinate against time in hours along the linear abscissa. As can be seen, there is a clearly marked division into two separate groups, corresponding to subdural and sub arachnoid administration of RISA. There is a considerable variation with each group, although the essential pattern remains constant. 37.

100,000 SUB-DURAL RIS A

Activity of peripheral blood "tl 0 0 a:l ...... SUB-ARACHNOID E a. RIS A ....

1000

-x: ~x-x

2 4 6 8 10 12 14 16 18 20 22 24 26 28 Hours After Injection

Fig. 5 38.

External Gamma Detector Over Head

lnjected Side

Normal Side

0 External Gamma Detector Over Heart SK ...., ..... -- ...... ,,.,. ~ ~ ...... __ "" --- ...... É 1 1 --.. ci- 2.SK 1 ... 1 1 ' o.______

0 Gamma Activity of Blood Samples .,.,,. .... ---+------.,._ __ _ ,. ------...... ,.~ -~------~ ... / ... / 1 1 •Q. 1. E 1 li .;

0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Injection

Fig. 6 39.

-100,000 SUBDURAL RIS A

10,000

"U 0 0 Cil '..ù Activity of peripheral blood '

1000

2 4 6 8 10 12 14 16 18 20 22 24

Hours After Injection

Fig. 7 40.

D. Radio-Isotope Studies - Human a) Methods and Materia1s: 20 In 1962, Neohydrin 1abe11ed with Mercury 3 replaced the use of RISA as a scanning agent.

Since May, 1963, Hg197 has been used in place of Hg203 for label1ing Neohydrin and, as yet, can be obtained only on a research basis. The biological behaviour of Neohydrin is the same in both instances, but the physica1 properties of Hgl97 make it a safer radio-isotope to use routinely.

Using Hg203 Neohydrin: Renal function was taken into account - the advisability of using this agent was contra-indicated if the B.U.N. was greater than 50. A dose of 2 mls. of non-radioactive mercurohydrin was given intra~-muscularly 24 hours before injection and scanning was carried out at 0 (immediate), 3 and 6 hour intervals after the administration of the radio-isotope.

Using Hg197 Neohydrin: No blocking dose was considered necessary when using this radio-isotope. Five microcuries per kilogram were given intravenously, and scan ning carried out as for Hg203 Neohydrin. 41.

b) Brain Scanning: The patient was placed on a stretcher, and the head immobilized as far as possible in a nylon sling. Great care was taken to ensure that the patient's head was correct ly positioned within the scanning path, and measurements were made in all planes. Each scan takes approximately 30 minutes. c) Nuclear Instrumentation: The "Automatic Contour Scanner" comprises twin balanced scintillation detection systems. Each detecter has a thallium activated sodium iodide crystal, 1~" in diameter and l" thick. Each collimator consists of a l" thick lead shield, and has a straight opening, l" in diameter and 2-3/4" deep.

The scanning path followed by the twin detectors is significantly different from that seen in conventional rectilinear scanning, but has advantages in its specifie adaptation to the shape of the head. The detectors simultaneously scan symmetrical areas over both sides of the head, from front to back, in a series of nine concentric parasaggital arcs. In addition the central axis of each scanner is directed to a point on the opposite side of the mid-line, thus producing a crossing effect which lends a three dimensional aspect to the scanning pattern. This enables the interpreter to distinguish a deep from a super ficial lesion. 42.

The radioactivity of the area scanned is plotted on a semi-circular sheet of paper. The pulses from each detector pass through conventional amplifiers, pulse height analysers, and scalers. A mechanical printing circuit is activated and prints a dot for a present number of counts - routinely one dot represents lOO counts from one detector. In addition, a subtraction circuit is employed so that the difference in the counts recorded by the detectors can also be plotted out through a second set of stampers acting on the same paper. Routinely, these stampers are set to make a symbol every time the difference between the detectors amounts to 40 counts. Separate marks are used for right and left increased count rates.

Thus, for one scan sheet produced, it is possible to see at a glanee any area of increased uptake of radio-active material and to see which side it is on. In addition, the total count over this area can be determined and compared with the background count recorded over a corresponding region of the normal side of the head.

The pulse height analysers are set to include the main energy emitted by each particular isotope, e.g.: Hg~~~ 210 - 380 KEV (Main peak at 279 KEV) Hg+ 45 - lOO KEV (Usable photon range from complex emission spectrum) 43.

The success of this type of scanning depends on the identical responses of each detecter system to a given source of radio-activity. The "balance" of the twin detecter system is thus checked before and after every scan. The maximum deviation allowed when both detectors are centered equidistant from a given source, is 800 counts in an accumulated 80,000 counts.

Biopsy Sampling: As soon as surgical removal of the lesion was started, a venous blood sample was withdrawn using a heparinized syringe. All surgical samples were placed in a dry dish, identified, and about l gram removed and placed in a previously weighed counting tube. After re-weighing to obtain an accurate sample weight, the tube was then sealed. One ml. of venous blood, and one ml. of sub-dural fluid, when available, was measured separately into pre-weighed counting tubes.

Nuclear Instrumentation: A Baird-Atomic unit was used, comprising a well-type scintillation counter (5 ml. well), pulse height analyser/ amplifier, stabilized high voltage supply, precision electronic timer, and high speed scaler.

The analyser was set to an 11 volt window, centered on the 279 KEV gamma peak of Hg 203 (210-320 KEV). Under these conditions, the normal background count was 15-20 c.p.m. 44.

Counting Technigues: At all times, variation due to geometrical factors was eliminated as far as possible by using similar size samples. Tissue samples less than 0.5 gms. were not included. All samples were counted to a present count of lOK. No correction was made for physical decay unless there was a delay of more than 5 days between surgery and counting dates. No decay correction was required as long as all samples were counted at the same time.

Counts were calculated as counts per minute per gram and expressed in relation to blood activity taken as lOO%. 45.

Example Case Report: This 69 year old male (A.P.) wakened with rather dense right-sided hemiparesis on the morning of November 1, 1963. He started to improve gradually until his first admission to the M.N.I. on December 2, 1963. On examination, he was found to have sorne memory impairment, especially for recent events, slight weakness of the right arm and leg, increased reflexes bilaterally but with flexor plantar response bilaterally.

Skull x-rays showed displacement of the pineal gland about 6 mm. to the right and EEG was within normal limits. He refused further investigation and was discharged.

The patient was seen in the Out-Patient Department on January 6, 1964 and showed no significant change in his status.

He was readmitted on January 20, 1964, since his condition was worsening. There was a two-week history of right-sided weakness (more pronounced) and two days of left frontal headache. On examination, he was noted to have slight confusion, expressive dysphasia, early papilloedema, moderate spastic right-sided hemiparesis (more pronounced distally). The reflexes were increased on the right.

Skull x-rays showed the pineal gland displaced 10 mm. to the right. A left carotid angiogram revealed a lens shaped subdural haematoma measuring about 4.0 cm. in maximum thickness. 46.

Echo-encephalogram showed a shift of the midline about 8 mm. to the right and in addition it was possible to get a large reproducable echo high in the parietal region, approximately 3.5 cm. from the surface. It was felt that it could probably be an echo from the subdural brain intersurface.

EEG showed continuous moderate voltage, irregular 1~ to 2~ cycle per second slow waves over the left hemisphere from the frontal to occipital regions, maximal over the left parietal region.

The patient was operated upon on January 22, 1964 and was found to have a subdural collection with well-formed ouber and inner membranes about 3 mm. in thickness.

The first brain scan was carried out on December 4, 1963, using 350 Mercuryl97_Neohydrin. Scan at 3~ hours and

5~ hours after injection showed a diffuse wide uptake, 47% and 64% respectively, over the left fronto-temporo-parietal region.

Brain scanning was repeated during his second admission on January 21, 1964. A scan immediately after the injection showed 17% over the left fronto-parieto-occipital region, and this increased to 76% at 7 hours. (Fig. 8 and Fig. 9). 47o

...... Scan 64-29C Jan.21/64 ,. 350 pc Neohydrin ...... Hg-197 ...... " .. : .. ...: . . Pt. A.P. . ..,., • • • • If·. . • • • • ._ ..• ,;,- ÂÂ ;.,; ;.,; ,..·. • llf. • • ~ • • .. "., • • : • •• • '~Jif •• ·· ·~r:o j..AI\AM" • ·:""4..r"• ., •• ..... • • • .... A A..,..,- • • ,_,., •• • .. • • ..• •• .. • 0 • •• • • • ...,. 1.f • 1,•• ., •• ., •• o. • • • •• • i.f. AA~~A.f· .• ..; .,. ., •• • • • ·..... • : .. ""' • • : • •• • • ~ • ..... -.; • ., •• 7• •. • l' •. : ~ t. A A A :, : • ..,.,•• • ~: ...,. • •• .•• .. •. • • .. • • • • ~~...... ,• • •#f_.7..,·· • .,..,• .....,. ., .. 7" • • • • • • • .. 111111 • • • • • llo A JI • •. ".y • -, • • .., • ..,. ... • ••• .. 0 • • ,....,... •• ..,.• .,7• • ....,. •• ,.,..• . : .... : ..,.. . ., . . ... • 0 •. ·t'• ,...... , .• •..• 7 •• ,.. - ...,...... • • .,•• 7•· 7 • . , . ,·· .,.. . • ... •• ..,.•• ,.:. -· •• >. .. '>"• . , •• 7.. -.• •• . .. .. 7 HOURS SUBDURAL HEMATOMA, LEFT TOT AL COUNTS: Differentiai Uptake =67% L. 24574 R. 18092

Fig. 8 48.

E'ig. 9 49.

(b) Results: In this series, 11 cases of proven subdural hematoma were studied by external o-ray detection after injection of Neohydrin-labelled with Mercury 203, (5 patients) or with Mercury 197 (6 cases).

All cases showed almost immediate concentration of radio-activity in the region of the subdural hematoma when compared with the contra-lateral side of the head. The differentiai uptake was seen to increase progressively in scan studies made at intervals after the injection of radio active Neohydrin. However, there was a considerable variation in the degree and in the rate of uptake (FigJD,page 51). The possible causes for these effects will be discussed later.

In 7 cases coming to operation the amount of radio activity was assayed in samples of membrane, fluid and clot. The activity was related to the amount present in lee of blood at that time. No correlation was found between the relative uptake Mercury 203 when considered in terms of duration of the lesion or interval from injection to sample time (Fig.ll,page 52). However, there was generally a higher amount of radio-activity in the membrane than in the fluid, and solid clot showed very low uptake.

When the relationship between clinical history, operative findings, brain scanning results and radio-assay of surgical samples was studied, it was seen that: 50.

a) Where the brain scan result showed less than 2o% differential uptake over six hours, the hematoma was either very thin, or was composed mainly of clot with little fluid, and sorne membrane formation. This agrees with the low amount of radio-activity present in the clot sample measured separately.

b) Where the differentiai uptake in the brain scan was higher (up to 75% in 6 hours) the hematoma consisted mainly of fluid with membrane formation and virtually no solid clot. Sample studies at operation again confirm the higher uptake of radio-activity by fluid and membrane.

Although sampling techniques indicate a greater concentration of radio-activity per gm of membrane than per gm of fluid, each of these elements do not necessarily contribute equally to the total external count during scan ning. Clearly, the larger the hematoma, the greater the amount of fluid and solid clot as compared to membrane. External uptake is therefore dependant on the proportion of these three elements in a particular lesion. 51.

Uptake Difference on Brain Scons Uptake Difference on Brain Scans

100 Mercury - 203 Neohydrin Mercury - 197 Neohydrin

70 ....• .!! Q. 60 :::1 ] c •:ii ::: i5 t;e __ , ,. M ...... ------· S-L ______.. 0 ..------.. ------...... ------

2 3 4 s 6 8 0 2 J 4 s 6 7 8 Hours Aher Injection Hours After lnjec lion

Fig. 10 52.

Du ration Case no. of lesion Percentage uptake compared with blood Sample time in weeks in hours 0 25

8 4

2 5 6

3 4 22

2 10

5 5 5

7 6 11 5

7 2 72

li clot ~Fiuid . Membrane & Clot

Fig. ll 53.

IV. DISCUSSION

Interest in experimental production of subdural haematomas started as early as 1865. Many investigators tried to produce subdural haematomas in different ways, but mainly by the injection of whole blood into the sub dural space. The majority of the experimenta showed organization and rapid clearance of blood within a few weeks. Since their techniques of the introduction of blood into the subdural space were not clearly described, there was unsatisfactory proof that the arachnoid membrane remained intact during the procedures. For these reasons, it was decided to repeat these experimenta with suitable modifications.

It was considered that more recent information regarding the control of the volume of the brain with urea could be applied in the experimental production of subdural haematomas. A technique was developed of in troducing blood into the subdural space without injury to the arachnoid. This was essential in order that injected blood would not be absorbed by draining into the subarachnoid space.

In one group of experimenta blood only was injected into the subdural space. Since the main interest was to determine if a progressive lesion could be produced, the cats were sacrificed at intervals after the first week.

Re-opening in sorne of them, without interference ~ith the 54.

haematoma, was carried out merely for observation. It was shown in all cases that clearance of the blood occurred with the animal showing-no clinical evidence of an expanding intracranial lesion during that period. Within a few minutes of injection, it was obvious that a solid clot had been formed under the dura (page 27). Re-openings in a few days revealed an obvious reduction in the thickness of the haematoma and disintegration of clot into fluid. Histo logical examination showed normal dura, arachnoid and under lying brain. In most instances cellular debris and haemosiderin were seen in the subdural space on the side of the injection. There was also granulation tissue on the outside of the dura in the region of the craniectomy. No subdural membrane was observed. Urea did not change the results whatsoever when given either as one initial dose to allow more blood into the subdural space or in repeated doses to shrink the brain for a longer period of time. Nor did interruption of the bridging veins with or without urea produce any progressive lesion.

The outcome of all these experiments was compatible with the results given by previous investigators. It seemed evident that blood is absorbed from the subdural space in animals regardless of the variations of technique or the amount of blood injected.

After the formation of clot, disintegration and liquefaction take place within a few days, followed by 55.

rapid absorption of the fluid. To explain this, two theories can be postulated:

l) The process can be brought about by diffusion of protein molecules through the arachnoid into the subarachnoid space. This is unlikely for two reasons: a) Since the arachnoid is a semi-permeable membrane it would not allow the passage of the protein molecules into the subarachnoid space.

b} High osmotic pressure from proteins within the haematoma would attract the cerebrospinal fluid from the subarachnoid space and increase rather than decrease the volume of the haematoma.

2) The existence of an active draining system can remove the high protein content fluid so rapidly that there would be no significant increase in volume even though high osmotic pressure may attract sorne cerebrospinal fluid through the arachnoid. Fluid might be removed by way of the meshwork of capillaries over the inner surface of the dura (see Anatomy of Dura, page 1) or by "juice" channels (described by Key and Retzius, page 2) into the venous system. The lymphatic system may have a role in this process since the subdural space ex tends extracranially around the cranial nerves and spreading of the fluid in this area can thus be removed by lymphatic system. 56.

In order to examine these possible routes of absorption, radio-active iodine-labelled albumin was introduced into the subdural space and the tracer was detected in the blood and cerebrospinal fluid was checked for radio-activity. Tracer appeared rapidly in the blood, as detected by serial samples, but cerebrospinal fluid in the basal cistern, taken simultaneously with each blood sample, showed virtually no evidence of radio-activity. However, absence of the tracer in the cisternal fluid did not exclude the possibility of the appearance of radio active albumin in the subarachnoid space over the convexity and its absorption into the blood through the pacchionian granulations along the sagittal sinus. To clarify this, RISA was injected in the subarachnoid space in one group of animals and in the subdural space in another group. In animals with the subdural injection, radio-activity appeared rapidly in the blood and gave a high count. In comparison, those receivtng a subarachnoid injection showed slow appearance and a low count rate. The comparison of these two curves (Fig. 5) clearly shows that the subdural RISA has been drained into the blood through a different route than the cerebrospinal fluid. These experiments indicate the existence of an-active draining system through the inner surface of the dura, lymphatic system or both. It appears probable that blood injected into the subdural space in animals is absorbed rapidly via this route. 57.

In patients with subdural haematomas, a radio active tracer given intravenously concentrates rapidly in the haematoma (Fig. 10). Mealy (1962) carried out a "reversed study" by injecting RISA directly into a subdural haematoma. He reported that activity soon appeared in the peripheral blood and that equilibrium between these two compartments was established.

Our unpublished data regarding the appearance of radio-activity in the cerebrospinal fluid after intravenous injection of RISA showed that at no time did activity of CSF per ml. exceed 1% of activity per ml. of blood.

These results indicate that there is a continuous exchange between blood plasma and subdural fluid. They also tend to contradict Gardner's hypothesis that cerebrospinal fluid is absorbed by the subdural haematoma.

If recent available facts are considered, the following mechanism can be postulated:

Minor injury may rupture one of the bridging veins, producing an accumulation of blood within the subdural space. The actual volume of blood collected may depend on a number of factors, including venous pressure, clotting time, extent of damage to the ruptured vessel, the volume of brain tissue relative to the cranial capacity. After the blood forms a solid clot, the dura starts to react by fibroblastic proliferation and early coagulation. 58.

If the haematoma is relatively thin, complete organ ization may result in its disappearance. Alternatively, as the clot starts to disintegrate the drainage system actively removes protein, so reducing osmotic pressure within the lesion and preventing further absorption of fluid.

If the haematoma is large, the dura will be unable to effect complete organization, and proliferation will tend to encapsulate the lesion. In ·addition, the drainage system may be initially inadequate to cope with such a lesion and will be further hindered by membrane formation isolating the area. These factors thus lead to an encapsulated collection of fluid of high osmotic pressure within the subdural space. This fluid is separated from the circulating blood only by the walls of numerous newly-formed blood vessels of the surrounding membrane. Hence, fluid, minerals, and protein can be exchanged between the subdural fluid and circulating blood.

The behaviour of the haematoma would depend on many factors, particularly those affecting the osmotic balance between these two compartments. The fluctuating clinical picture would appear to be a direct reflection on these changes. A sudden alteration could be attributed to a secondary haemorrhage of the fragile vessels of the membrane, or brain oedema adding to intracranial pressure. 59.

V. SUMMARY

1) This study was undertaken to determine sorne of the mechanisms underlying the formation and evolution of subdural haematomas.

2) Various techniques were tried to produce an experimental lesion in cats. It was not possible to obtain a chronic subdural haematoma comparable with that found in man.

3} Direct surgical observations and histological examinations were carried out to follow the organization and resolution of experimental lesions. Radio-active serum albumin placed in the subdural space was found to pass into the circùlating blood and did not appear to involve the cerebro-spinal fluid system.

4) The clinical investigations and pathological findings in a series of patients with chronic subdural haematomas has been included. One complete sample case history is cited.

5) The experimental evidence of these studies suggests that a small subdural haematoma can be organized and absorbed into the blood stream. However, a larger haematoma tends to become encapsulated by membrane formation. This walled blood vessels in the newly formed membrane then allow an exchange of fluid, protein, salts and other materials between blood plasma and the contents of the haematoma, thus setting up a fluctuating osmotic balance. 60.

6) Primates should be used in future research on chronic subdural haematomas in order to produce an experimental lesion which may be more comparable with those found in man. 61.

VI. BIBLIOGRAPHY

ABERCROMBIE, S.: Path. und prakt. Untersuchungen ubern die Krankheiten des Gehirns und Rllckenmarks. Brenen, 1829. (Cited byE. Christensen, 1944). AMBROSETTO, C.: Osservazioni sul trattamento del1'ematoma subdurale cronico post-traumatico. Sist. Nerv. 10: 435, 1958. AMBROSETTO, 0.: Post-traumatic subdural hematoma. Arch. Neurol. (Chicago) 6: 287-292, 1962. ASHKENAZY, M., DAVIS, L. and MARTIN, J.: An evaluation of the technique and results of the radioactive di-iodofluo rescein test for the localization of intracranial lesions. J. Neurosurg. 8: 300-314, 1951. BAGNALL, H.J., BREND, P., BROWNELL, G.L. and SWEET, W.H.: Position-Scanning with Copper-64 in the diagnosis of intracranial Lesions. J. Neurosurg. 15: 411-426, 1958. BAYLE, A.L.J.: Traité-Des Maladies Du Cerveau Et De Ses Membranes. Paris, Gabon, 1926. 250 p. BENDER, M.B.: Resolution of subdural hematoma. Trans. Amer. Neurol. Ass. 192-194, 1960. BERGER, H.: Zur Atiologie und Pathogenese der Pachymeningitis interna chronica. Erlangen, Junge and Sohn, 1890. 40 p. BRINKMAN, C.A., and KAHN, E.A.: Brain scanning with mercury 203 labeled Neohydrin. J. Neurosurg. 19: 644-651, 1962. CHRISTENSEN, E.: Studies on chronic subdural hematoma. Acta Psychiat. Neurol. 19: 69-148, 1944. DUNBAR, H.S. and RAY, B.S.: Localization of brain tumors and other intracranial lesions with radioactive iodinated human serum albumin. Surg. Gynec. Obstet. 98: 433-436, 1954. FEINDEL, W., ROVIT, R.L. and STEPHENS-NEWSHAM, 1.: Localization of intracrania1 vascu1ar lesions by radio active isotopes and an automatic contour brain scanner. J. Neurosurg. 18: 811-821, 1961. 62.

GARDNER, W.J.: Traumatic subdural hematoma with particular reference to the latent interval. Arch. Neur. Psychiat. (Chicago) 27: 847-858, 1932. HESCHL, R.: Kompendium der allgemeinen und speciellen pathologischen Anatomie. Vienna, W. Braumllller, 1855. 291 p. HEUBNER, 0.: Pachymeningitis haemorrhagica bei hereditHrer Syphilis. Virchow Arch. Path. Anat. 84: 267-274,1881. HUGUENIN, 0.: Inflammation of the dura mater. In: Cyclopedia of the Practice of Medicine. New York, William Wood, 1877. V.l2, p.386-426. JACOBI, W.: Das Saftspaltsystem der Dura. Arch. Psychiat. Nervenkr. 70: 268-285, 1924. KEY, A. und RETZIUS, G.: Studien in der Anatomie des Nervensystems und des Bindegewebes. Stockhofrm, Lamson und Wallin, 1875, p.68. KREMIANSKY, J.: Ueber die Pachymeningitis interna haemoiThagica bei Menschen und·Hunden. Virchow Arch. Path. Anat. 42: 129-161, 321-351, 1868. LABORDE, J.: Contribution a l'étude des conditions patho géniques des kystes sanguins de l'arachnoide; recherches expérimentales sur les animaux. C.R. Soc. Biol.(Paris), 1864. 70 p.

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Thanks are due to the many individuals whose gener- osity and cooperation made this work possible. The author is deeply indebted to Dr. Theodore Rasmussen for his constant encouragement and understanding throughout this investigation. The suggestions offered by Dr. William Feindel, Dr. Gilles Bertrand and Dr. Gordon Mathieson have been of great hel p.

For their technical assistance in the experimental phase of this endeavor, the author wishes to thank Miss Mary Roach, R.N. and staff; special thanks are due to Mrs. J. Zannelli, whose work in the Isotope experiments was in valuable. Mr. John Gilbert and Miss Barbara Nuttal assisted with histological preparation.

The final shaping of this work in print has been accomplished by the efforts of Mr. Charles Hodge and his staff who prepared the graphes and illustrations, of Miss Gladys Davidson and Miss Pamela Bottomley who typed the preliminary manuscrip, and of Mrs. Marjorie Blanchard and Miss M. Provencher who completed the final draft.