EXPERIMENTAL

The

NEUROLOGY

Possibility after ELTZABETH

55,

1-42 (1977)

of Structural Spinal Cord PUCHALA

and Functional Restitution Injury. A Review1

AKD

WILLIAM

F.

WINDLE?

CONTENTS PAGE

1 4 6 10

Introduction .......................................... The transected human spinal cord ...................... Immaturity in relation to regeneration ................... Factors influencing regeneration in mature mammals ...... Terminal axon sprouting .......................... Collateral axon sprotuing .......................... Relation of sex to regeneration ..................... Barriers to regeneration ........................... Enhancement of central regeneration .................... Pyrogens and hormones ........................... Millipore filter membrane .......................... Immunity ........................................ Nerve growth factor .............................. Enzymes ........................................ Other agents .....................................

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11 12 12 14 15 17 17 17 17 19

1 Review articles (57, 146, 277, 285) in 1929, 1942, 1956, and 1964 dealt broadly with regeneration in the nervous system. The present review concerns mainly the spinal cord because of the gravity of traumatic spinal injuries and expanding efforts to find solutions of the paraplegia problem. 2 Library facilities used for this review were those at Case Western Reserve University, Ohio State University, and the University of California at Los Angeles. Research by the authors was supported by Grant NS-11507 from The National Institutes of Health. The bibliography compiled by Veraa (261) was helpful. The present address of Elizabeth Puchala is Science Library, University of Georgia, Athens, Georgia 30602. The authors acknowledge support from Help Them Walk -Again Fo~n?ation, Las Vegas, Nevada, 89108, from whom reprints may be obtained. 1 Copyright All rights

0 1977 by Academic Press, of reproduction in any form

Inc. reserved.

ISSN

0014-4886

PUCHALA

AND

WINDLE

Concussion and contusion of the spinal cord .............. Closed impact injury .............................. Open impact injury ............................... Myelotomy after impact injury ..................... Therapy with chemical agents ...................... Treatment with hypothermia ....................... Reconstruction of the traumatized cord .................. Bridging with peripheral nerves .................... Nerve grafts ..................................... Conclusion ........................................... References ...........................................

20 20 20 21 22 23 24 24 24 26 27

INTRODUCTION Man has known from early times that the integrity of the spinal cord is essential for voluntary locomtion and that a broken neck, if not fatal, can render an individual helpless. Today he is becoming increasingly aware of vulnerability of the spinal cord, The annual incidence for traumatic damage of the spinal cord ranges regionally from 1.3 to 3.3 per 100,000 population and has been increasing steadily. The epidemiology was discussed recently by Kirtzke (143). The earliest description of human paraplegia and quadriplegia are found in The Edwin-Smith Surgical Papyrus (35). Egyptian physicians nearly 4000 years before the present recorded remarkably clear accounts of these conditions. Symptoms were accurately described, instructions for examining the patient were given, and the dire prognosis indicated. No records of animal experiments on spinal cord function are known earlier than the second century when Galen (213) described his findings in young pigs, goats, and monkeys. That pioneer in experimental neurology exposed the spinal cord and incised it at various levels. After making a longitudinal incision through its entire length, he found that an animal continued to breathe and was able to move its limbs, but when he transected the cord, paralysis ensued caudal to the site of the cut. He observed that diaphragmatic function was spared by a cervical transection that paralyzed all extremities. Galen died in the year 199 A.D., and more than 16 centuries were to elapse before experiments on the spinal cord were resumed. If the possibility of healing a damaged spinal cord occurred to anyone during the Dark Ages, the thought was dismissed. Not until the second half of the nineteenth century do we know of efforts again being made to create in animals the conditions leading to paraplegia in man. Severing the spinal cord was the most direct way to produce paraplegia, and investigators at first confined their efforts to that method; for many years

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the prevalent research centered on the question of regeneration of axons in the transected spinal cord. Experiments of Brown-Sequard (38-40) from 1849 to 1851 were the first combining physiological and histological methods to investigate the phenomenon. He used mainly adult pigeons, cutting the cord just caudal to the wings. One bird, surviving for more than 14 months, gave evidence of having fully recovered motor and sensory functions. Histological examination was said to have revealed nerve fibers traversing the scar at the site of the lesion, but the techniques available at that time to identify them left much to be desired. Perhaps without further evidence, we should not dismiss his findings as errors of judgment but, instead, question whether conditions for regeneration in the avian spinal cord are the same as in the mammal. They are known to be different in the reptilian cord (81). Moreover, it has been demonstrated (196) that fibers of the severed olfactory nerve of pigeons do regenerate and establish functional connections in the olfactory bulb, some as early as 18 days after their transection. Brown-Sbquard’s experiments in pigeons have not been repeated. Other investigators (88, 235) performed short-term studies on birds that were inadequate to reveal regenerating fibers, if any were present. Interest in central nervous system regeneration developed slowly. Two decades later, investigators began to explore the phenomenon in mammals. In 1873 Denton (68) declared that he had observed motor function in the hind limbs of puppies only a week after severing the spinal cord. He believed he saw regenerated nerve fibers 6 months later when the region of the transection was examined histologically. Spinal reflex stepping was not understood and there can be little doubt that he misinterpreted his observation of the animals’ movements. Reports by other experimenters appeared from time to time but few of them provided noteworthy information. The older literature has been reviewed repeatedly (146, 170, 215, 224, 244, 270). In 1894 Stroebe (243) described the invasion of nerve fibers into the tissue between the ends of the severed spinal cord of rabbits but not crossing the lesion site, a finding that was later confirmed with silver staining methods by several investigators including Bielschowsky (29) and Ram& y Cajal (217). The latter used kittens and puppies, transecting their spinal cord and applying his refined histological techniques to a study of subsequent events at the lesion site. The findings of Stroebe (243) and earlier investigators were mentioned by de Quervain (215) at an international surgical congress in Brussels and were referred to in his 1908 article in which he reviewed the clinical literature and described 215 cases of spinal cord trauma. De Quervain apparently was unaware of the 1905 paper by Ram& y Cajal (217), but

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he declared that animal experiments had failed to show more than a slight beginning of nerve fiber regeneration (abortive regeneration). His thorough treatment of the subject did much to establish the clinical view that central neurons show little regenerative power and, therefore, the severed spinal cord should not be expected to undergo functional restitution. The concept of abortive regeneration in the central nervous system arose mainly from the studies of Ram6n y Cajal, which he brought together in a book (219, 220) published in Spanish at the beginning of the First World War. He found that nerve fibers in the transected spinal cord of young animals began to regenerate as they did in severed peripheral nerves but noted that the process lasted only about 10 to 14 days, after which the new growth stopped and no further regeneration took place. Contemporary investigators confirmed his observations. The fact that central neurons can regenerate anatomically was proved, and not all investigators were discouraged from continuing the search for answers to the question of why functional restitution could not be achieved. THE

TRANSECTED

HUMAN

SPINAL

CORD

The early animal experimentation had been conducted with the view of finding relief for the human condition. Brown-SCquard (41) cited case histories in support of his belief that central nervous regeneration could occur. The older literature contains numerous reports suggestive of structural regeneration or partial restitution of function in human subjects, but few in which complete transection of the cord had been verified at operation. Lockhart (154) reviewed the reports in 1955, one of which is particularly interesting. Stewart and Harte (242) published an account of a 26-year-old woman who, in January 1901, had her spinal cord severed at TlO by a bullet and was taken at once to the nearby Pennsylvania Hospital where a laminectomy was performed. According to one member of the operating team, resident physician Charles Mitchell (personal communication to W.F.W.), the transection was complete. Stewart lifted the two cord stumps, remarking that, according to authorities, cases such as this rarely survive and regeneration never takes place, but, he said, how do they know. Whereupon, they sewed the ends together and, leaving the dura mater open, inserted a drain and closed the wound. The patient remained in the hospital until October 1903, during which time her general health was good and she developed no decubitus lesions. Sixteen months after the surgery it was reported (242) : “The patient voluntarily flexes the toes, flexes and extends the legs, flexes and extends the thighs and rotates the thighs. While sitting, the extended leg can be raised from the floor. . . . The patient slides out of bed into her chair

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by her own efforts and is able to stand with either hand on the back of a chair, thus supporting much of the weight of the body. . . . The patient has the sense of touch, temperature, pain and position all over.” Other members of the medical profession in Philadelphia had occasion to observe this exceptional patient. One neurologist, William G. Spiller, unwilling to concede regeneration but puzzled by the voluntary nature of the patient’s movements, suggested that she had a duplex spinal cord, only one component of which may have been transected ! The years passed and when war came research efforts subsided while skepticism about the possibility of spinal cord regeneration increased. Clinical experiences with war injuries between 1914 and 1915 strengthened the feeling of hopelessness.Not many men survived wounds of the back; fewer than 10% of them were living after 1 year. But the patient of Stewart and Harte was still alive.3 Cadwallader (43), who had not seen her previously, performed a neurological examination in 1920 and found her to be a spastic paraplegic with no evidence of function below the Ievel of her Iesion. He concluded that errors of observation had been made in 1902 and ended his report by saying “it can, therefore, be assured that regeneration of the spinal cord does not take place after complete section and end-to-end suture.” The patient lived for 2-l years. At a postmortem examinetion conducted by Mitchell, a single spinal cord was found. It exhibited a constricting fibrous scar at the transection site, resembling in that respect that of animals that had survived long after transection of their cords (270). During the war, after partial functional restitution had been claimed by Lortat-Jacob et al. (155 j, other attempts were made (59) to suture the severed human spinal cord. Claude and Lhermitte (55) verified complete spinal cord transection in one patient and at necropsy later found indications of regenerating fibers. In other subjects with transected cords he found no evidence of return of motor functions, but two patients showed partial return of sensation after a long period of time during which the syndrome of paraplegia had been complete (149). The presence of myelinated nerve fibers in groups forming neuromalike structures in the hunian spinal cord at or adjacent to sites of longstanding compression or traumatic injury has been considered by some to be evidence of regeneration. The investigations were reviewed by Druckman and Mair (73 j, and recently Klintworth ( 110) and Wolman (279) presented examples of this condition. Wolman concluded that, no less than 12 months after the injury, “such neuromas do not originate from dysplastic foci, but from regeneration, not only of perivascular nerve plexuses but also of many other damaged extra- and intra-medullary 3

Dr. Stewart died in 1919

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neurones.” The nerve fibers in these structures had neurolemma sheaths, and resembled those of peripheral nerves. The origin of the sheath cells was unclear. Ghatak and co-workers (100) examined the spinal cord from a patient who had had long-standing multiple sclerosis. They found demyelinated plaques containing axons that had been remyelinated by neurolemma cells, some of which could be traced to dorsal roots. In the rat, Duncan (77) produced “hypermyelinated” nerve fibers by compression of the spinal cord. He suggested that they were central fibers altered by the compression, demyelination being followed in time by remyelination by neurolemmalike cells of undetermined origin, possibly altered intramedullary elements. More recently, it has been shown in rats that dorsal root fibers regenerating into a lesion of the dorsal funiculus bring with them neurolemma cells (144). The hints of possible regeneration of nerve fibers in severed human spinal cords raised hope for functional restitution that was dampened by unimpressive results from animal experiments, and there have been few recent claims of successful efforts to repair damaged cords in human subjects (15). On the other hand, not everyone was ready to accept a view that the severed central neuron lacks the potential for regeneration, i.e., that functional restitution is out of the question. IMMATURITY

IN RELATION

TO REGENERATION

Chambers (53) reviewed this topic in 1955. Although it had been known for years that regeneration can occur in the central nervous system of some of the lower vertebrates, it was the 1922 observation by Koppanyi and Weiss (142), that adult fishes with severed cord regained the ability to swim, that led Gerard and Koppanyi (99) to investigate the possibility of functional restitution in the immature spinal mammal. They reasoned that injured spinal neurons of young rats, like those of fishes, might possess a potential for regeneration that is lost with maturation. Ramon y Cajal’s observations (217, 218) of axon sprouting, especially those in the transected or hemisected spinal cords of three young kittens (217), lent support to their hypothesis. It was unfortunate that the experiment of Gerard and Koppanyi (99), done at a time when belief in the impossibility of central nervous regeneration had become accepted, should have been so poorly designed and poorly controlled. They tried to sever the fetal rat spinal cord by piercing the uterine wall and blindly cutting into the back of some of the fetuses shortly before term. When the rat pups were born a day or so later, the investigators had difficulty in identifying those that had been operated

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upon, reporting that the wounds had healed without trace in some cases. No histological examination was carried ouL4 Hooker and Nicholas (126, 127, lS9) promptly challenged the findings of Gerard and Koppanyi and reported negative results in their own experiments in which they interrupted continuity in the fetal rat spinal cord, mainly by coagulation through the uterine wall and fetal back with a cautery. They observed coordination of hind limb with forelimb movements after birth and believed this to be due to transmission by pressure stimuli rather than conduction through spinal neurons. Most animals were killed soon after observation of their motility and reflexes, and the spinal cords were examined histologically. The investigators did not use specific stains for nerve fibers and were unable to detect signs of regeneration in the damaged spinal cord. The negative results of Hooker and Nicholas, nonetheless, were readily accepted in support of the prevailing view of nonregenerability in the mammalian central nervous system. Reports of successful regeneration in the rat were published by Migliavacca (173, 174) about that time. Among his animals were a rat with spinal cord severed in utero 7 days before birth and another with it transected 2 days after birth. Resumption of voluntary hind limb movements in those animals was thought to have been detected 22 to 2.5 days later, but the movements were not coordinated with those of the forelegs, and Rossi and Gastaldi (224), in their 1935 review, expressed doubt about the completeness of the spinal cord transections. Ssamarin (239) in 1926, on the other hand, had noticed some regeneration in the transected cord of 3-month-old rabbits. The first controlled experimental study yielding positive results was that published in 1940 by Sugar and Gerard (245) who transected the thoracic spinal cord of rats 3 to 5 weeks old with a sharp knife. They then grafted fetal brain tissue, muscle, or degenerated sciatic nerve into the gap produced by the transection. Voluntary movements of the hind limbs began to appear in 13 rats a month or more after the operation. Electrical stimulation of the brain in some cases resulted in hind limb movements. The investigators stained sections of the spinal cords in the region of the lesion with a silver technique and demonstrated nerve fibers, believed to be of central origin, bridging the transection scar. The results with sciatic nerve grafts were especially good, but this important clue was not followed immediately. Nine years later, Freeman and his associates (93) began to publish reports of successful experiments with 6-week-old female rats. Freeman (90) later reviewed the studies from his laboratory, involving a large 41 had been asked to study had been completely cut (W.

some of the rats F. Windle).

but could

find

none

whose

spinal

cord

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AND

WINDLE

number of animals among which a few had undergone restitution of voluntary hind limb movements and other coordinated behavioral responses more than a month after complete transection of the spinal cord. Histologically, it was shown that small numbers of nerve fibers traversed the site of the lesion. Shurrager and Dykman (236) described spinal cats and dogs which exhibited well-developed walking, considered by the investigators to be due to spinal cord conditioning. The spinal cords had been transected when the animals were young, some only a few days old (i.e., before they were old enough to walk). Evidence was lacking that nervous connections had failed to develop (270, p. 223). Newborn and young dogs and cats were used also by Freeman (89) who reported on the development of locomotion after transection of the spinal cord at an early age. Stelzner and his colleagues (241) have described results of experiments in neonatal and weanling rats that cast new light on the findings of Shurrager and Dykman (236). They severed the thoracic spinal cord of rats between birth and 5 days of age and noted that hind limb function of a reflex nature persisted as the animals matured. On the contrary, rats with the cord transected at the weaning stage remained paraplegic. Absence of supraspinal connections in the neonatally operated rats was thought to explain the “survival of function” effect. Success was not always achieved in young animals. Spinal cord transection was done in rats 5 to 7 days old by McMasters (163) as part of a larger series in a study of the effects of therapeutic agents. None of the animals exhibited voluntary control over the hind quarters. A report by Nygren et al. (192) in 1971 stands in sharp contrast with most earlier ones. They transected the cord or performed chemical axotomy (with 6-OH-dopamine) in rats 1 to 14 days old and later found extensive axon sprouting by monoamine-containing fibers. Older rats showed less vigorous sprouting. Many investigators remained skeptical about claims of successful restitution of function after transection of the mammalian spinal cord. The significance of immaturity at the time of transection and partial success with nerve grafts was not at once apparent. There had been unsuccessful attempts to confirm the findings of Sugar and Gerard (245). Some other investigators (16, 82) had tried to use sciatic nerve grafts in transected spinal cords of rats of various ages and each sex, reporting that there were no signs of restitution of function, nor did the histological sections reveal regenerating nerve fibers in the spinal cord. Hess (124) transected the spinal cord in fetuses of the guinea pig, a rodent that is born in an advanced stage of development. The subjects were examined no later than 12 days postoperatively for possible regeneration, and within that brief period results were negative.

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The structure of fiber tracts in the central nervous system, particularly the spinal cord of the young rat, is quite different from that of the tracts in adults, an observation that became increasingly evident after the advent of electron microscopy of ultrathin sections of tissue. Luse (158) in 1956 found the fiber tracts of the newborn rat and mouse spinal cord to be made up of unmyelinated nerve fibers in compact arrangement with hardly any detectable interstitial space. Many sections contained no neuroglia cells among the nerve fibers. As methods of tissue fixation were improved, other investigators (116, 214, 260) found greater separation by more space between fibers. Neuroglia cells, particularly oligodendrocytes, increased rapidly in number, which resulted in myelination in the rat and mouse, clearly seen in those animals at 5 days of age at widely separated sites along fibers (141). The fine structure of the human fetal corticospinal tract at 23 weeks of gestation was found to resemble that of the rat at birth (171). The structure of the rat corpus caIlosum was found to resemble that of the spinal cord tracts, myelination reaching a peak in about 30 days (234). Just prior to the electron microscopical study of Luse (lSS), Hess (121-123) published reports of investigations of “ground substance” in the developing spinal cord of mice , guinea pigs, and rats. He stained sections of normal spinal cord by the periodic acid-Schiff (PAS) method for polysaccharides, mucopolysaccharides, and glycolic fatty acids. The reaction by light microscopy began to be positive in the mouse spinal cord after 5 to 6 days, which Hess believed coincided with time of development of the blood-brain barrier. His conclusion that the PAS method had stained a ground substance in the spinal cord was questioned by Dempsey and Luse (67) because they could find insufficient space for ground substance in their electron micrographs. They suggested that PAS may have stained folded membranes of oligodendrocytes, which made their appearance at the time the staining reaction became positive. Hess’s findings take on new significance in view of the result of experiments by nlatinian and Andreasian (168). The latter investigators infused hyaluronidase solutions intrathecally after transecting the spinal cord of female rats 6 weeks old. Scar-tissue formation was reduced and the animals exhibited functional restitution as well as structural regeneration at the transection site. The enzyme was thought to have altered the interstitial environment for regenerating nerve fibers (zG!c ;tifra). Several investigators, the first of whom was Ranson (221) in 1903, considered immaturity to be a factor in regeneration of nerve fibers across cuts made in the cerebrum. Ranson believed that the few myelinated fibers encountered in the young rat must have arisen from nerve cells that had not developed at the time he incised the cortex. The suspicion of cell division by neuroblasts in the adult rat brain was strengthened by

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Altman’s (11) findings of H3-thymidine-tagged, newly formed, nerve cells after making stab wounds in the brain, but was doubted for the spinal cord by Wall (264). Sechzer (233) described nerve fibers traversing incisions made lateral to the corpus callosum, but could not be certain whether they were axon sprouts or new axons, which had been demonstrated by de Meyer (172). Flint and Berry (87), on the other hand, found no regeneration across cuts in the corpus callosum of 40-day-old rats. Elsewhere in the central nervous system, regenerative capacity has been found to be related to immaturity. Severance of the lateral olfactory tract of 3-day-old hamsters was followed by growth of axon sprouts around the lesion to the pyriform cortex, whereas no such growth took place in 43-day-old hamsters (69). Lund and Hauschka (157) successfully transplanted pieces of the fetal superior colliculus to the colliculus of the newborn rat. Neural connections were established by visual afferent fibers of the host; later the synaptic endings degenerated when the contralateral eye was removed. FACTORS

INFLUENCING MATURE

REGENERATION MAMMALS

IN

A conference on Regeneration in the Central Nervous System, sponsored by the National Institute of Neurological Diseases and Blindness, was held in 1954 to evoke interest in basic research in that field (270). Although it brought together most of the people who had been working on regeneration and resulted in assembling a bibliography, it missed the mark, for few American investigators during the next 15 years continued to study the problem of central nervous regeneration ; however, it did stimulate such research in the Soviet Union (209). Interest was reawakened in 1970 after the first Palm Beach Conference, sponsored by the National Paraplegia Foundation (113) ; since that time three additional conferences have been held to consider basic research in neurobiology that is applicable to the problems of central nervous regeneration (109, 111, 114). These conferences established a conviction in the minds of scientists that the problems of spinal cord injury will be amenable to solution. We shall examine some evidence fundamental to this view. Terlninal Axon Sprouting. The process by which severed axons in the central nervous system undergo regeneration was described by Ram& y Cajal (220). How generally it occurs has been the subject of controversy. There are regions in the central nervous system where regeneration by terminal axon sprouting clearly does take place. The olfactory region of pigeons was mentioned earlier (1%). Further, Kiernan (137) demonstrated that neurosecretory fibers of the rat hypophyseal stalk can regen-

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erate, but only among pituicytes and not among neurolemma cells of implanted autografts of peripheral nerve. The relationship between regenrating neurosecretory nerve fibers and pituicytes appears to be similar to that of regenerating peripheral nerve fibers and neurolemma cells. Such a relationship is lacking in other parts of the brain. The capacity of neurons of the spinal cord to grow in Iength throughout the rat’s life was investigated by Bernstein (23). He found that, between the age of 4 weeks and 9 months, the corticospinal tract grew by increasing the fiber diameter but not by increasing the number of fibers; his study did not include the early postnatal weeks. Hildebrand (125) reported evidence of the disappearance of spinal cord neurons in kittens 1 to 3 weeks postnatally. Recently Conradi and Ronnevi (60) described the spontaneous postnatal elimination of synapse on spinal motor neurons of the cat. Sotelo and Palay (238) found evidence of a continuous remodeling of central nervous elements. Plasticity appears to be a fundamental characteristic of the mammalian central nervous system, not only in the young but throughout life (79, 162, 240). Collateral Axon Sprouting. When some of the fibers of a peripheral nerve supplying muscle were cut, Edds (SO) discovered that neighboring intact fibers sent out sprouts that reached the degenerating muscle and caused it to regenerate. Collateral axon sprouting was found by Liu and Chambers (151) to take place also in the dorsal funiculi of the cat spinal cord, providing evidence of another mechanism of response to injury in the central nervous system in addition to that of terminal sprouting. This important aspect of the regeneration problem was reviewed recently by Guth (111, 112). Collateral axon sprouting may not take place in all regions of the nervous system with equaI facility. Kerr (135, 136) and Beckermann and Kerr (19) failed to find it at the level of overlap between trigeminal spinal tract fibers and those of the dorsal funiculus of the spinal cord. On the other hand, Goldberger (102) and Murray and Goldberger (104, 178) found collateral sprouting in the cat spinal cord, and Bernstein and Bernstein (25) reported it in the spinal cord of rats. Raisman (216), after transectioning the medial forebrain bundle, demonstrated that collateral sprouts can form synapses in mature rats. A possible trophic regulation of axon sprouting has been discussed by Diamond and his co-workers (70). Lynch and associates ( 160) have demonstrated selectivity of sprouts after making lesions in the dentate gyrus of monkeys. Bernstein and collaborators (26-28, 159) showed that, after spinal cord hemisection in the rat and monkey, collateral axon sprouting resulted in reinnervation of the synaptic endings of neurons that had been denervated by the hemisection. They pointed out that terminal axon sprouting did

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not contribute to this process within the time it took for collaterals to grow from the intact parts of the spinal cord. McCouch and co-workers (161) explored the functional significance of collateral axon sprouting in the spinal cord of the cat and monkey, and Goldberger (103) discussed recovery of movements after lesions in the central nervous system of monkeys. Both terminal and collateral axon sprouting were demonstrated in mature animals by means of a histochemical technique for catecholaminecontaining neurons that are present in some regions of the spinal cord (63) as well as elsewhere in the central nervous system. The studies of Bjijrklund and his colleagues (30, 31) were reviewed recently (114). Svendgaard and associates (246)) who examined acetylcholine esterasepositive axons of the rat brain, have provided a list of references to the literature. In the spinal cord, Nygren and co-workers (191) described the functional regeneration of 5-hydroxytryptamine-containing nerve terminals after producing chemical axotomy of the bulbospinal tract with 5,6-dihydroxytryptamine. Thus the concept of collateral axon sprouting has become thoroughly established, but its role in functional restitution after spinal cord injury is not clear. Relation of Sex to Regcncration. No one has explored for possible sex differences in regenerative capability of central neurons. There is no proof that a difference exists, but the possibility that a female hormonal factor may be involved was suggested recently (272). Retrospectively, it was noted that the most successful experiments by the University of Pennsylvania investigators [e.g., (229) ] were done on female cats and dogs. Female animals have been utilized generally because they are less prone than males to urinary tract infections, but other factors may be involved. Barriers to Regeneration. Nerve fibers of whatever source regenerating into the zone of inflammation at the spinal cord transection were found to associate with elements of loose connective tissue, but they tended to be deflected by dense connective tissue and were blocked by astroglial membranes that quickly formed (58, 273, 275). This was evident throughout the nervous system. Fertig et al. (86) transected the cerebral frontal lobe of adult male and female rats and noted that axons regenerating in this location were encountered most often in those parts of the lesion occupied by loose connective tissue which appeared to have provided contact guidance to the sprouting axons. Furthermore, they found no regenerating nerve fibers in regions devoid of connective tissue. Campbell and associates (52, 190) reported the association of regenerating central neurons with connective tissue cells. In adult male cats rendered paretic or paraplegic by a blow of stan-

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dardized force, Wakefield and Eidelberg (263) encountered axon sprouts in the region of inflammation. Electron micrographs revealed them to be accompanied by neurolemma cells as early as 14 days after the injury. Some of the fibers became myelinated by the neurolemma cells, which the investigators suggested may have come from dorsal roots injured by the blow. Blakemore (33) reported that asons. which had been tlemyelinated in the rat spinal cord by the action of 6-aminonicotinamicle, became remyelinated by neurolemma cells, the origin of which was unclear. The same conclusion was reached in studies of remyelination after demyelinatiton by diphtheria toxin (117) and in chronic experimental allergic encephalomyelitis (337). On the other hand, Gledhill and colleagues (101) produced local demyelination in the spinal cord of adult cats and found electron microscopically that remyelination was accomplished by oligodendrocytes. The origin of oligodendrocytes in the monkey spinal cord was studied by Phillips (211). Their precursors were found to begin to wander into the fetal lateral funiculus at about 62 days of gestation, and numerous active oligodendrocytes were encountered at 67 to 90 days. The literature on the neuroglia-myelin relationship has been reviewed by Uunge (42). The fine structure of the traumatized spinal cord of the rat was first described in 1960 by Schlote and Hager (27). An astroglial reaction to transection of the spinal cord in the rabbit and rat extended to the entire gray matter in 3 to 5 days, regressing in 15 to 30 days, according to Galabov and Dimova (98). Adrian ( 1) described proliferation of cells after injury of the spinal cord, and I’helps (2lOj reported on the development of glia-vascular relationships, factors that are involved in establishment of barriers to the progress of ason sprouts. Under normal conditions, there is a sharply defined zone in the mammalian dorsal spinal nerve rootlet where peripheral axons, ensheathed by neurolemma cells, take on the characteristics of central axons by becoming ensheathed by oligodendrocptes. Regeneration usually has been found to stop at that place (139, 176, 203). H owever, Kimmel (138) noted that a few regenerating fibers that succeeded in passing the rootlet-cord junction did grow into the dorsal funiculus, mainly by skirting the barrier and going into the cord via the pia mater. More recent experiments (44, 50, 52a) have demonstrated regenerating axons entering the spinal dorsal funiculus in greater numbers, but no evidence of functional connections was reported. Barnes and Worrall (17) succeeded in inducing axons of ventral roots which had been anastomotically aligned with proximal stumps of several dorsal roots to regenerate into the cat spinal cord. Those investigators explained their success by assuming that the rapidly regenerating ventral

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root axons reached the dorsal root-cord junction before a mechanical pia-glial barrier had been able to form and block their entrance into the spinal cord. Whether or not neurolemma cells accompanied them was not reported. Investigators generally have recognized that the formation of dense scar tissue at the site of spinal cord injury presents a barrier to the progress of axon sprouts (37, 64, 270). Brown and McCouch (37) tried to bridge spinal cord transection in cats, using grafts of nervous tissue, but only succeeded in creating more scar tissue. On the other hand, Schadewald and Rasmussen (226) severed the dorsal fasciculus of adult cats at the junction of the spinal cord with the brain stem and in half of them inserted pieces of degenerating sciatic nerve into the gap, after which sulfanilamide powder was sprinkled over the tissue. A fibroblastic response ensued and, at various time up to 6 weeks, the investigators found regenerating nerve fibers of the fasciculus gracilis passing out rostrad, even into muscles and along blood vessels. These fibers appeared to be present wherever there was a young connective tissue, along strands of which they grew. Bernstein and Bernstein (24) created an artificial barrier to regeneration of central neurons in the goldfish. The l-year-old fish regained ability to swim 20 to 25 days after spinal cord transection when no barrier was imposed (22). However, when a thin piece of Teflon was placed between the severed ends of the spinal cord, a glia-connective tissue barrier formed; at that site, the regenerating nerve fibers made inappropriate synaptic connections and ceased to grow. A second, more rostra1 transection of the cord, after removal of the piece of Teflon, was followed by regeneration in which the nerve fibers passed on through the connectivetissue scar. Willis et al. (267) studied development of scar tissue at intervals after cutting the corpus callosum of 40-day-old rats. Basement membrane material was first identified 10 days after the operation and by 20 days it was continuous along the entire course of the knife cut. Recently Berry and Henry (20) placed knife wounds in the cerebrum of rats 1 to 38 days after birth to investigate the formation of scar tissue. The line of the lesion was marked by amorphous material at 1 to 8 days postpartum and many nerve fibers were seen bridging the wound. Typical adult scar tissue began to appear by day 10 and was mature by day 12. No nerve fibers were encountered in the lesion at that time. Again, immaturity was a factor in the results, ENHANCEMENT

OF CENTRAL

REGENERATION

Two significant reactions of the spinal cord to injury, terminal axon sprouting of severed nerve fibers and collateral axon sprouting of intact

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1.5

fibers adjacent to the denervated fields of the damaged ones, have been identified. Neither one, in the natural course of events, results in noteworthy functional restitution in the mammalian spinal cord. Terminal axon sprouts, finding their way blocked, form synapses on inappropriate structures and cease to grow. All elements of the blockade have not been identified, but enough information is at hand to permit investigating measures for extending the regeneration and for circumventing the naturally occurring abortive processes. The search, under way for many years, is beginning to net results. One approach has been to investigate factors that regulate and stimulate protein synthesis in damaged nerve cells and axoplasmic flow in the processes. These have been reviewed recently by Grafstein (107, 108). Another approach has been to investigate methods of aiding the progressive outgrowth of axon sprouts into and through the region of spinal cord injury where scar tissue forms. Pyrogens and HoruLoncs. A fortuitous observation by Chambers [cited in (209) ] that a spinal bitch, to which bacterial pyrogens had been administered in the course of investigating neural centers of temperature regulation (.54), responded to stimulation of its bladder by howling, led to experiments on the effect of pyrogens on central nervous system regeneration. The results have been reviewed elsewhere (57, 270, 271). The principal pyrogenic agent used was a preparation, known as Piromen (Baxter Laboratories), derived from a Pscudouzonas species and supplied in lyophilized form in sufficient quantity for experiments over a period of several years. Later, a more purified polysaccharide, from which most protein moieties were removed, was made available commercially. The latter preparation may have lacked some of the activity of the original material (209, 268a, 274) and, so, was unsuccessfully used to replicate the earlier results. The main effect of administering bacterial pyrogens to mature animals with spinal cord transection was alteration of the character of the tissues at the severed ends of the cord and in the gap (273, 276). Glial membrane formation was inhibited ; this was illustrated especially well by experiments in which the centrally connected end of a severed facial nerve was implanted into the cerebral cortex, into which it sent regenerating motor axon sprouts (275). The effect of adrenocorticotropbic hormone (ACTH) was similar to that of Piromen. Not only were regenerating nerve fibers traversing the transection site demonstrated histologically in the spinal cord of the mature cat, they were also found to conduct impulses for short distances beyond the lesion (228, 229). Restitution of voluntary hind limb movements was not attained, although some spinal cats that received Piromen therapy for long periods

16

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WINDLE

of time began to exhibit improved involuntary movements of the hind limbs 60 to 90 days after the operation ( 150). The progress of regeneration in the transected spinal cord of mature cats came to a halt after 8 months or more, and in 12 to 18 months the animals that had been treated with Piromen became indistinguishable from untreated spinal cats. A constricting scar of dense collagenous tissue formed at the transection site [Figs. 13-16 in (58) 1, the effect of which was to destroy the neural growth that had been made. This led to a condition similar to that in the patient of Stewart and Harte (242, 269). It became evident that if regenerating nerve fibers, i.e., terminal sprouts, in the mammalian spinal cord were to be able to make functional connections, it would be necessary to find ways of preventing development of such constricting scars as were encomitered in cats and human beings. The conditions in monkeys were no better (52). Not all investigators using pyrogens to obtain regeneration in spinal animals were successful. Several used commercially available Piromen or a similar product of another manufacturer in small series of cats and rats and found no regenerating nerve fibers (13, 145, 193), although one of the authors noted that scar tissue was less than in control animals (13). Other investigators used Piromen of the original crude form and reported positive responses ( 152, 252). Thulin (252) gave the pyrogen to nine cats and four kittens with spinal cord transection at L7 to Sl in two and at the middle or upper thoracic region in the others. The spinal cords were wrapped in Millipore membrane after being transected (vide infru). Action potentials were evoked above and below the lesion 5 to 21 months later. McMaster (163) used ACTH and Piromen of the commercially available type in treating rats in which the spinal cord was severed at 5 to 7 days of age. Best results were obtained with the animals operated at 7 days of age. Sixteen of 140 rats receiving Piromen and 5 of 50 rats on ACTH showed functional return 21 days or more after initiating therapy. Applying cocaine to the spinal cord rostra1 to the lesion abolished voluntary movements of the hind limbs temporarily ; the controls showed no indications of regeneration. Investigators in the Soviet Union, whose interest in the problem began as early as 1956 (76, 283)) used a bacterial pyrogen, Pyrogenal, in experiments comparable to those conducted in this country. Their similar results led them to seek means of preventing scar tissue from impeding regeneration in the severed spinal cord. The reports of Nesmeyanova and her colleagues (184, 185, 187, 188) will soon be available in English translation (186). The work of Matinian and Andreasian has been translated (169).

SPINAL

CORD

Ii’iJURY

17

Millipore Filter Menlbra~ze. A method was devised by Campbell and his associatesin 1957 (1s. 15, 46) to protect the region of spinal cord severance from encroachment by collagenous scar tissue. It consisted of enclosing the severed ends of the cord in a wrapping of porous filter material, marketed as Millipore. With it, the investigators achieved considerable successin adult cats. Even though a glial reaction occurred, terminal axon sprouts were oriented longitudinally and many of them grew across the transection site. Conduction of nerve impulses was reported by Thulin (252), but the animals were kept alive for an insufficient length of time to determine whether voluntary locomotion could be restored. The Millipore membrane eventually became calcified, which terminated its usefulness. Functional transection of the spinal cord of the cat by freezing a narrow segment of it (212) resulted in maintenance of better form than could be achieved by wrapping the cord in Millipore. No scar formed, and the segment that had been frozen became richly vascularized. After 2 weeks, axon sprouts were seen entering the segment, and by 6 weeks they had crossed it. Immunity. Pyrogens act on the endocrine system, probably stimulating the hypothalamus and hypophysis to affect other endocrine organs (186, 268a). The effect of ACTH is similar. It was proposed that one of its effects is suppression of an autoimmune response to proteins released in the traumatized spinal cord and that this inhibits regeneration (272). Feringa and associates (83-85, 11.5) explored this possibility in female spinal rats given immunosuppressive drugs. They found no histological evidence that the scar tissue at the transection site was affected by the therapy used, although they did encounter conduction of nerve impulses through the lesion in a few animals. Berry and Riches (21) discussed an immunological approach to regeneration in the central nervous system. Results in this area are inconclusive. N~rzw Growtlz Factor. Possible beneficial effects of the nerve growth factor on regeneration of intraspinal sensory neurons were studied by Scott and Liu (231, 232). After crushing the dorsal funiculus in seven kittens weighing 750 to 900 g, administration of nerve growth factor appeared to enhance regeneration. Improved action potentials were recorded 19 mm rostra1 to the lesion. One kitten that was given Piromen and heavy doses of nerve growth factor showed axon sprouting, and two others on low doses did not (232). Other investigators (32) noted that nerve growth factor seemed to enhance outgrowth of monoaminergic axon sprouts. Positive results could have been due to increased vigor of protein synthesis by the neuron (230). Ensy~cs. The fact that certain proteolytic enzymes have been used

18

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WINDLE

effectively in treating human disorders of connective tissue, such as scleroderma and keloid tumors, led to consideration of their use to reduce scar tissue in spinal cord injury. Such enzymes affect the microenvironment of the central nervous system, and some of them, notably collagenase, increase the permeability of the blood-brain barrier, possibly affecting basement membrane collagen (223). The enzyme trypsin acts in inflammation to restore biological continuity, according to Martin (165), improving circulation and preventing further cell damage ; with trypsin, Martin found that the incidence of necrosis and abscess formation was reduced. Yu and Bunge (286) added trypsin to tissue cultures of fetal rat spinal ganglia, and “within minutes . . . the matrix of the culture was altered and the nerve fascicles loosened.” Axons appeared to be resistant but the axolemma and the neurolemma cells were affected by trypsin. In 1952, Freeman and his colleagues (164, 256) began to investigate possible effects of intrathecally applied solutions of trypsin in reducing scar formation after spinal cord hemisection in dogs. They found that the treated dogs regained function sooner than the untreated ones and that collagenous scars and glial membranes were reduced at the lesion site. Later they improved their technique of administering the enzyme solution through an indwelling catheter into the subarachnoid space in female dogs with midthoracic hemisection of the spinal cord (94). The action of trypsin in reducing scar formation at the site of spinal cord transection in mature male and female rats has been confirmed by Pettegrew (208). Enzymatic debridement in spinal cord lesions was accomplished by Perkins and associates (207). Matinian and Andreasian in the Soviet Union have used hyaluronidase, trypsin, and elastase to improve conditions for neural regeneration in the severed spinal cord of 6-week-old female rats (166-168). Their research was described in a book published in Russian in 1973 (168) and translated into English recently (169). Several aspects of their research have been reported in America (170, 209). The rat spinal cord was transected at T.5 or T6 in a manner assuring complete severance and avoiding other trauma (209). Controls were given carrier solutions and the experimental rats received enzymes intrathecally at the transection site during the operation and intramuscularly thereafter, several schedules being followed. With trypsin, intramuscular injections were begun 2 h after operation and were repeated daily for 10 to 15 days. Hyaluronidase was ineffectual when given intramuscularly, but injections of trypsin or elastase appeared to potentiate the effects of its topical administration. Dosages apparently varied. The Soviet investigators found that the treated rats lived longer than the untreated ones, and the incidence of infections was lower. Recovery of

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19

bladder control appeared earlier in the treated rats. This and other overt signs of functional restitution were reported in a high percentage of the animals on enzyme therapy. Responses of hind limbs to stimulating the foreparts of the body appeared in the enzyme-treated spinal rats and, in some cases, became well established in G to 8 months. Spontaneous COordinated movements of locomotion were present after 9 to 10 months. Nerve impulse passage across the lesion site of enzyme-treated spinal rats was demonstrated both rostrally and caudally. Cortical evoked potentials began to appear as early as 20 days after operation. They were of low amplitude and had latency periods nearly five times longer than normal. Even after 14 months the conduction took nearly three times longer than normal. Retransection of the spinal cord abolished the evoked potentials, and application of cocaine blocked them transiently. Rostrocaudal conduction was illustrated by an increase in the magnitude of the electromyogram of hind limb muscles obtained upon stimulation of the cerebral cortex. Finally, anatomical differences between treated and nontreated spinal rats were seen as a reduction in scar formation, improving vascularization, and fewer cavities in the region of the lesion. Neurological staining revealed the presence of nerve fibers traversing the site of the transection. Matinian reported (209) that, after functional regeneration had been attained, it was maintained and there was no subsequent constriction of the spinal cord by dense collagenous scar tissue. The effect of enzyme therapy was considered to be not only inhibition of the collagen formation but also some, as yet unspecified, action on the spinal cord parenchyma, making it a more permeable medium for regenerating nerve fibers. The enzyme tended to prevent accumulation of tissue hyaluronic acid (ground substance?), thus creating a more nearly normal medium for nerve growth. The successful results of enzyme studies in animals encouraged exploration of possible benefits to be derived from enzyme therapy in human spinal injury. Although little has yet been published (12, 194, 195), evaluation of the results with hyaluronidase and with a combination of hyaluronidase and trypsin, though cautiously presented, has indicated hope. Some success was thought to have been achieved in a few patients who were completely paraplegic or quadriplegic and lacked bladder control. The first sign of improvement was the reappearance of true voluntary bladder control. Much later the ability to move the toes began to be acquired (209). Other Agents. Irradiation of spinal cord lesions with X rays to diminish scar formation was used in adult female dogs with some success by Turbes and his associates (259), and a few other agents have been tried. A number of investigators (86, 163, 275) have reported that ACTH has effects

20

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similar to those of pyrogens, and Williams (266) recently noted enhanced outgrowth of axon sprouts with it. Fertig and associates (86), as well as Williams, found that treatment with triiodothyronine had beneficial effects on central nervous system lesions, Among other drugs effectively used experimentallly in brain lesions by Williams, concanavalin A (a lectin that binds glycoproteins) appeared to reduce microcavity formation. Possibilities of chemotherapy have not been extensively explored. CONCUSSION

AND

CONTUSION

OF THE

SPINAL

CORD

Traumatic injuries of the vertebral column result in functional and structural deficits in the spinal cord ranging from simple concussion to contusions of varying severity, some even producing anatomical transection. Civilian accidents frequently lead to permanent paraplegia in which, however, the spinal cord white matter is left largely intact, although incapable of functioning. Investigations on impact injury of the spinal cord were conducted sporadically until recently, interest increasing in war time and again rising with the number of highway accidents. The subject was reviewed in 1964 by Wolman (278) and in 1972 by Dohrmann (71). Closed Impact Injury. Most investigators in the early period studied effects of closed impact injury produced by various crude methods, none of which resulted in uniformly reproducible conditions (71). Reaction of the spinal cord to injury, along with head injuries, received attention briefly during World War II. Groat and his associates (110) struck unmeasured blows to the cat spinal column and described the resulting functional and structural changes. They defined concussion of the spinal cord as complete, though transient, functional block at the level of application of an adequate force, after which only subtle changes in neural structures were demonstrated. Brookhart and his colleagues (36) investigated effects on spinal cord function and structure of the passage through tissues of the cat’s back of high-speed missiles which often struck thoracic or lumbar spinous processes without hitting the spinal cord. The effects ranged from uncomplicated concussion to complete paraplegia lasting throughout the period of the study. These researches ended when federal contracts were canceled at the end of the war. There have been few other experiments involving closed impact injuries since that time (4). Open Impact Injury. The first experiments attempting to quantitate the force of blows on the spinal cord were those reported by Allen in 1911 and 1914 (9, 10). He exposed the spinal cord in dogs and, leaving the dura mater intact, dropped a weight on it through a tube. Severity of the blow was expressed as gram-centimeters of force. Temporary paraplegia could be produced by a force of 300 g-cm, and permanent paraplegia re-

SPINAL

CORD

INJURY

21

sulted from one of 400 g-cm. Allen found that edema and hemorrhage occurred in the contused spinal cord, reaching a peak in about 4 h. Other investigators, notably Freeman and Wright (96)) in more recent times have used slight modifications of Allen’s method to study spinal cord contusion and to explore ways to prevent the aftereffects in dogs as well as other mammals. Tarlov and his associates (247, 248) produced injuries of graded severity in dogs with inflatable balloons placed in the epidural space (248). Others (65, 249) used the latter method to study conduction changes in monkey cords. Compression of the spinal cord between forceps is another, though less controllable method (1 IS). There have been numerous reports of the pathology of the traumatized spinal cord, most of which showed a relationship to the strength of the blows delivered to the exposed spinal cord. Peele and Windle (20.5, 268). however, noted that inflammatory reactions, often marked, took place in the cat spinal cord after simply exposing it to operating room conditions for 30 min. Others (280) investigated effects of ischemia in the spinal cord of dogs, and more recently Hunt and his associates (153, B-I) have studied ischemia and edema after open-impact trauma in rhesus monkeys, reporting that lactate became elevated in~mecliately after a 300-g-cm blow and that edema reached a peak in 5 days. I’arious investigators (14, 74, 75, 105) have described the pathological changes in the spinal cord of cats and monkeys with forces ranging from 200 to 500 g-cm. The most severe blows rendered monkeys permanently paraplegic, the pathological changes beginning in the central gray matter and extending peripherally to include all the medullary parenchyma. Ducker and associates (75) concluded that spinal cord pathology from acute trauma in the monkey evolves by steywise sequential changes that are more central than peripheral. Subacute damage may be limited to gray matter necrosis or map progress to include neighboring white matter. Pathological changes can be continuing even in the presence of clinical improvement. Spreading of the edema from gray to white matter was described by Green and Wagner (106). Sequential changes in myelinated nerve fibers of the monkey spinal cord after blows producing transient paraplegia were studied by Dohrmann et al. (72). In electron micrographs, they found that some nerve fibers began to show enlarged periaxonal spaces 15 to 30 min after contusion, and by 4 h approximately one-fourth of all fibers were affected. Adrian and Williams (2) studied cell proliferation in the injured spinal cord. Histochemical changes in the cat spinal cord after inducing traumatic paraplegia were studied by Rakari and co-workers (132). Myclo~onzy after I~rlpact I~~j~vql. Allen (9) devised his method as a means of studying prevention of acute paraplegia due to impact injury of the spinal cord. He recognized that amelioration of the heightened intra-

22

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medullary pressure might prevent the development of paralysis, and, therefore, in five dogs receiving blows of 540 g-cm on the exposed dura mater, he “made a median longitudinal incision from 1 to 1.5 cm in length directly through the impact level and passing altogether through the spinal cord. These dogs made uneventful recoveries. . . .” 5 Freeman and Wright (96) years late incised the spinal cord in dogs after impact injuries from blows of 350- to 375-g-cm force. Their results of similar experiments in rats were somewhat better than those in dogs. Campbell and others (49, 253) applied the technique of myelotomy with some success in cats. Recently Parker and Smith (202) reported an improvement in the recovery rate from simply incising the dura mater in dogs that had received impact injuries ; however, this procedure was of little benefit after delaying 2 h (203). Other investigators (250, 2.51) found durotomy to be of no value unless accompanied by other therapeutic measures. Application of myelotomy to patients with closed spinal trauma was recommended only when it can be performed immediately after the injury (209). Surgeons are reluctant to incise a swollen spinal cord when they encounter it some time after an accident. It is doubtful that the procedure then can benefit the patient, as success with any form of therapy depends on acting promptly. The use of chemical agents is said to offer a more practical means of effecting decompression at the acute stage (209). Therapy with Chemical Agents. Treatment of human patients in the Soviet Union with pyrogens and enzymes (12, 194, 195, 222), has been discussed. What limited success was achieved appears to have stemmed not only from inhibition of scar-tissue formation but also from alteration of the interstitial environment in some way that was associated with a reduction in amount of edema and cavitation. Reduction of edema formation by administering concentrated solutions of urea to dogs suffering impacts of 375 g-cm was reported by Joyner and Freeman (130). The treated animals walked within 73 days with no visible neurological deficits, whereas one-half the control dogs still showed deficits at 120 days. At a recent meeting of the American Neurological Association, de la Torre and associates (255) described therapeutic results in dogs after using dimethyl sulfoxide to reduce edema formation from blows of 400-gs Allen may have been aware of Cushing’s 1910 report (62) that he had made a longitudinal incision in one of the posterior columns to remove a glioma from the cord of a young woman whose lower part of the body had become almost totally paralyzed. There were signs of returning function, motor and sensory, almost immediately. Spinal cord surgery thereafter became more frequent, and Horrax and Henderson (128) in 1939 removed an intramedullary tumor involving the entire spinal cord from medulla oblongata to conus, after which the patient recovered. Such cases demonstrated that an opened pia mater allows expansion of edematous spinal cord parenchyma and prevents spinal cord dysfunction.

SPINAL

CORD

INJURY

23

cm force. The animals treated with that drug showed greater functional improvement 4 weeks later than those treated with urea or with glucocorticosteroids (131). Several recent reports (45, 119, 120, 135) have dealt with steroid and other chemical agents. Osterholm and Mathews (201) presented experimental evidence supporting a theory that norepinephrine accumulation in the traumatized spinal cord provokes necrotic changes. They reported (199) a marked rise in norepinephrine in the cat spinal cord 30 min after injury, becoming four times greater than normal in 1 h. They declared (200) that administration of a-methyl tyrosine blocked the increase of norepinephrine and exerted a protective effect on the injured cord tissue, resulting in reduced incidence of hemorrhage and necrosis. Other investigators (254) were unable to confirm the apparent beneficial effect of a-methyl tyrosine. Some reported that the norepinephritie content of the cord tissues increased above the lesion but not at the impact zone (51). Questions raised by these and related investigations have been reviewed recently (197, 198, 262). Naftchi and his co-workrs (179, 192) investigated the faulty regulation of catecholamine metabolism after human spinal cord injury and studied the effects of drug therapies on the biogenic amine concentration in the traumatized animal spinal cord (180, lS1). Treatmefzt with Hypotllemia. Negrin (153) devised a method of locally cooling the traumatized spinal cord and described its successful use on one human patient. Albin and White and their colleagues (6) described a similar technique with which they and other groups of investigators (5, 7, 8, 33, 74, 253, 265) were able to reduce the edema that occurs after impact injuries of the spinal cord of the cat. It was possible to selectively reduce the temperature extravascularly without appreciably affecting the general body temperature. When the local temperature reached 13.2”C, sensory blockage and loss of cortical evoked potentials occurred. A blow of 400-g-cm force applied to the spinal cord at TlO in 10 monkeys was followed immediately by selective cooling, and marked neurological recovery ensued in all the animals within 17 days. A force of 300 g-cm was found to be the threshold for production of paraplegia in rhesus monkeys. When hypothermia was delayed until 4 h after a blow of that strength, restitution of function occurred (8, 265) ; however, a delay of S h was found to be too long. Clinical application of the method after acute spinal cord injury has been reported (8). Demian and White and co-workers (66) applied the technique in treating three human victims of spinal trauma. Even though more than 4 h had elapsed before cooling could be started, they noted beneficial effects, and one patient experienced resumption of motor function in the lower limbs.

24 RECONSTRUCTION

P~~HALA

OF

THE

AND

WINDLE

TRAUMATIZED

SPINAL

CORD

Effectiveness of any therapeutic measure for reversing traumatic spinal cord injury depends on its application in the early hours after the accident. In most cases, irreversible necrotic lesions develop before the patient can be treated, and there has been little hope for the paraplegic or quadriplegic patient whose condition has become static. The best chance of accomplishing any restoration of spinal cord function may be with reconstructive surgery. Modern techniques of microsurgery will come to play an important part in doing so. Efforts to transplant spinal cord tissue into the degenerated locus or between the ends of experimentally transected spinal cord have been attempted from time to time without success (281). However, Duncan and Bellegie (78)) who had placed pieces of rat sarcoma extradurally to produce compression of the spinal cord, found in one experiment that nerve fibers grew out of the dorsal funiculi and penetrated the tumor. Sager and Marcovici ( 225 j found that cultured embryonal tissue or tumor cells placed in the transection wound enhanced vascularity of the region and were thought to play a part in regeneration of the severed nerve fibers. Vertebral resection in compression fracture or deformity of the spine was utilized by Moser (175) and Love (156) to relieve tension on the spinal cord. Murray and associates (177) used this technique in rabbits after severing the spinal cord. Advantages of the procedure were unverified. Some investigators have tried to Bridging with Peripheral Nerves. bridge the gap in the transected spinal cord by inserting centrally connected peripheral nerves into the cord caudal to the lesion. Most of those experiments were carried out on dogs (95, 97, 129, 206, 257), and limited restoration of walking ability was reported. Histological evidence of synapse formation was noted (-358). Spinal nerves were used in most experiments, but Cseuz and Speakman (61) also used sympathetic trunks successfully. In related experiments by Clemente (56), a motor nerve was implanted in the brain successfully when formation of a scar barrier was inhibited. Le Gros Clark (147) had found penetrating axon sprouts only in the newborn brain. Freeman (91) reported an experiment with a human volunteer on whom a nerve-cord anastomosis was done. The subject died a little more than 4 months later and histological evidence of sprouting from the implanted nerve into the spinal cord was found, An unpublished account of successful use of this technique in a woman was given by Nakayama and Makino (272). Freeman (92) reviewed the results at his institute with that and other methods of surgical repair. Nerve Grafts. Sugar and Gerard (245) and Feigin and associates (82) used grafts of neural tissues in immature animals. Campbell and several

SPINAL

CORD

INJURY

25

others (47, 97, 282) tried preserved nerve homografts as well as autografts in adult cat spinal cord transection experiments. Kao and colleagues (134) used grafts of cultured cerebellar cortical tissue in an effort to inhibit scar formation following spinal cord transection in dogs. A similar study was simultaneously reported by Aihara (3) in female dogs. Recovery of motor function was noted 3 months after the autotransplants had been inserted into the gap between ends of the severed spinal cord, and silver staining revealed sprouting nerve fibers in the region of the transection. Later Kao (133) compared the healing 1)rocesses in the transected spinal cord of adult female dogs grafted with autogenous brain tissue, sciatic nerve, and nodose ganglion. He noted that the condition designated by Ram6n y Cajal as “autotomy” always developed in the transected cord in which the wound remained structurally disrupted at two sites, one within the spinal cord stump at the tissue-fluid interface lined by fibrous astrocytic processes and the other at the collagenous tissue disk which formed at the gap between the ends of the severed cord. Formation of the collagenous disk was inhibited by the graft issues. The tissue-fluid interface was unaffected by brain autografts but was suppressed by sciatic nerve autografts. Sructural continuity was achieved in the spinal cords with autogenous sciatic nerve grafts. Additional results of experimental reconstruction of the dog’s spinal cord after transection or impact damage were reported by Kao at a recent conference (209). He observed that post-traumatic spinal cord cavitation began with development of microcysts 1 or 2 mm from the point of trauma within the noncontused and nonhemorrhagic regions of the spinal cord stumps. Electron micrographs revealed that in each microcpst there was an axon terminal containing numerous Iysosomes. As the terminal ruptured, its lysosomes with their enzymes were released into the interstitial spaces and caused autolysis of the preserved l- or 2-mm segment of the spinal cord, thereby forming large cavities and producing the condition which he designated as “lysosomal spinal cord autotomy.” From his previous research (133), Kao concluded that this autotomy was a self-limiting process, and he reasoned that, if spinal cord repair by surgical means were to become a reality, he must first find out how to correct for the effect of lysosomal spinal cord autotomy. Instead of immediately grafting nerve tissue into the spinal cord at the time of injury, be delayed putting the graft in place until the process of autotomy had run its course, which was about 1 week in the dog. Then at a second operation be incised and removed the necrotic spinal cord tissue and placed fresh autografts of sciatic nerve in the gap between the two viable portions of the cord. No further autotomy took place; the grafted nerve adhered to both stumps without cavity formation.

26

PUCHALA

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WINDLE

Axons of the grafted nerve degenerated, and longitudinally oriented bands of neurolemma cells were formed. A month and more later, terminal axon sprouts were seen growing into the graft from the spinal cord ends. Electron micrographs of the grafted nerve revealed many myelinated as well as unmyelinated nerve fibers within bands of neurolemma cells. A change in type of ensheathing cell was found at the junction of the graft with the spinal cord. On the cord side, the myelinated axons were of the central type ensheathed by oligodendrocytes, and on the graft side they became ensheathed by neurolemma cells. Evidence of conduction through the graft was obtained and this raised the hope of accomplishing a return of voluntary hand limb movements for locomotion. Kao and associates (133a) recently described electron microscopical studies demonstrating that the regenerated axons crossing the grafted nerves are of central origin. Success in bridging the transection site depended on delaying the formation of glial basement membranes. The current rationale behind successful bridging of the spinal cord gaps is (a) The operative technique is improved to correct for the defect of spinal cord autotomy and allow grafted nerve to be accepted. (b) The cord stumps are not yet covered with astrocyte processes and basal laminae at the time of grafting, thus allowing penetration of neurolemma cells into the cord or regenerating axon sprouts into the grafted nerve. (c) The new cord stumps, formed after the lysosomal spinal cord autotomy was corrected, are characterized by terminal clubs and cones of growth of axons denuded of myelin sheaths and therefore free to be guided by the neurolemma cells. The extent of structural restitution by regenerating intraspinal nerve fibers after severance of the mammalian spinal cord is never very great. It may be expected, however, that even a small number of intraspinal neurons bridging the gap in a severed spinal cord will make useful functional connections. One does not know how many regenerated neurons are required and what type of connection they must make to bring about some degree of functional restitution. Because conduction times are long (168, 209), several synapses may be involved. Windle et al (277) made subtotal transections of the cat spinal cord and found that some locomotor ability remained when fewer than 10% of the fibers of the ventral funiculi on either side of the ventral sulcus remained intact. Would the same number of regenerated axons perform as well? CONCLUSIONS Prospects for structural and functional restitution in the spinal cord damaged by trauma of the vertebral column have improved as a consequence of results of research of the last decade. As was noted by Ramon

SPINAL

CORD

27

INJURY

y Cajal in three immature animals, neurons of the central nervous system do not lack growth potential. Two regenerative processes follow severance of the spinal cord. Terminal sprouts are formed by cut axons and, when the transection is incomplete, collateral sprouts may come from adjacent undamaged axons. Neither process by itself results in reestablishing effective synapses, as a rule. Passage of axon sprouts through damaged tissue of the spinal cord depends on the presence of appropriate elements to provide guidance, e.g., fibroblasts, neurolemma cells, or oligodendrocytes. Proliferation of astrocytes forms membranes that tend to impede growth of the sprouts. Production of ground substance of basement membranes appears to contribute to barrier formation. Collagenous scar tissue, forming an impenetrable mass, soon puts an end to the effective regeneration of central nerve fibers. Axon sprouts, finding their way blocked, make improper connections and cease to grow. Functional restitution can occur, however, after only a few of the sprouts make their way through or around the barrier. One of the unsolved problems is that of eliminating the scar-tissue barrier. Various chemical and mechanical methods have been tried in efforts to stimulate the outgrowth of sprouts and to reduce the imperviousness of the barrier to regeneration in the spinal cord. At present, the use of enzyme therapy during the acute stage appears to have been the most successful in reducing the development of ground substance and limiting collagen formation in animals, especially in young animals, with spinal cord transections. More basic research is needed for confirmation. Impact injuries of the spinal column usually do not sever the spinal cord, but the ensuing edema within a tightly restricting pia mater causes necrotic changes that quickly become irreversible. Successful prevention of this demands immediate treatment. The edema can be reduced by chemical means or with hypothermia, and and its devastating effect can be limited by myelotomy. But the difficulty comes in trying to get the subject to the hospital within a few hours after the accident. The problem of logistics has not been solved. Finally, the condition of persons whose paraplegic or quadriplegic state has become static appears not beyond solution. Surgical reconstruction of the damaged spinal cord has been accomplished in dogs and there is little doubt that it will eventually be applied to human subjects. The longheld conviction that nothing can be done to reverse states of paraplegia has given way to the realization that research is already pointing the way to effective treatment of the victims of traumatic spinal cord injury. REFERENCES 1. ADRIAN, E. 501-520.

K.

1968.

Cell

division

in injured

spinal

cord.

Amey.

J. dmt.

123:

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cord-An

4.

5.

6.

7.

8. 9.

10. 11. 12.

13.

14.

15. 16. 17. 18.

19.

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