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Peripheral Vascular Disturbances Post-Traumatic Vasomotor Disorders

Harris B. Shumacker, Jr., M. D. and David L. Abramson, M. D.

    Although injury to an extremity is generally followed by signs and symptoms readily explained upon the basis of the trauma sustained and the resultant dysfunction, there are in certain instances other changes superimposed which can be accounted for only on the assumption that some reflex disorder has been initiated by the local tissue damage.

    Since 1900, when Sudeck1 first described a syndrome in which acute atrophy of bone followed an inflammatory process, this reflex post-traumatic state has been the subject of numerous studies and has attracted widespread interest. The many terms 2 which have been employed to describe this clinical condition bear witness not only to the widespread disturbances that may occur but also to the lack of agreement on what constitutes the characteristic primary alteration. The most constant finding is some type of vasomotor dysfunction. In the affected limb there is usually increased vasomotor tonus or hyperemia, also increased blood flow. Because of such manifestations, the comprehensive term post-traumatic vasomotor disorders would seem the most appropriate designation for the whole group of heterogeneous reflex affections which may follow trauma.

    This category of post-traumatic vasomotor disorders does not include such related conditions as major causalgia and phantom limb pain which are syndromes with such characteristic features that they are best considered as separate entities. Marked sympathetic overactivity may be present in certain instances of occlusion or division of peripheral arteries as the result of trauma. In those conditions, however, in which the occlusion of the vessel has a significant effect upon the nutrition of the extremity, part of the subsequent difficulty arises from the direct decrease in the local blood flow, and this type of vasospastic alteration is likewise best separated from the post-traumatic vasomotor disorders. There is also good reason to exclude from this group the vasospastic states which follow cold thermal injuries, that is, frostbite, trenchfoot, and immersion foot, as well as the vasospastic states associated with deep thrombophlebitis. Finally, those vasospastic disorders which

1 Sudeck, P.: Ueber die acute entz?ndliche Knochenatrophie.Arch. f. klin. Chir. 62: 147-156, 1900.
2 Among the names which hae been given to the syndrome are the following: Sudeck's atrophy, acute bone atrophy, post-traumatic osteoporosis, post-traumatic painful osteoporosis, traumatic arthritis, peripheral trophoneurosis, reflex nervous dystropy, reflex sympathetic dystrophy, post-traumatic dystrophy, monor causalgia, traumatic angiospasm, chronic traumatic edema, and post-traumatic edema.


are apparently the sole result of disuse donot belong in the category of posttraumatic vasospasticdisorders. All of the conditions just listed have a number of featuresin common, but eachpossesses certain special characteristics which make it advisable todeal with it as a distinctsyndrome.

    It is generally accepted that the primary mechanism responsible for posttraumatic vasospastic disorders is some type of reflex disturbance initiated by the local injury.It is also accepted that the components of the sympathetic nervous system are in some manner involved in the reflex are.Beyond this, no agreement has been achieved. Numerous theories have been advanced, but no definite proof exists to establish the correctness of any.Similarly, no agreement has been reached concerning the real cause of the osteoporosis which so commonly occurs in association with post-traumatic vasomotor dysfunction.

    Concerning the true incidence of these late complications of injuries no data are available, but the series of cases analyzed in this chapter may be assumed to be representative with respect to both clinical manifestations and response to therapy.

    Because the patients were seen after they had been treated in other Army installations, information concerning initial manifestations and early therapy is subject to the criticism that it was collected by other observers. Every effort, however, was made to reconstruct the sequence of events and the results of early treatment through a careful perusal of prior clinical records, plus detailed questioning of each patient with regard to early phases of his condition. Data concerning late manifestations and results of late treatment are based upon close personal observations during the period of hospitalization.

    It is important to bear in mind in any analysis of a post-traumatic vasomotor disorder that the patient with a limb painful or swollen, or in which there is annoying coldness or hyperhidrosis, has a strong tendency to keep it at rest, and that disuse may of itself cause certain alterations which are characteristically considered part of the post-traumatic syndrome, namely, reduction of blood flow, coldness, cyanosis, hyperhidrosis, edema, and osteoporosis. For this reason it is often difficult to evaluate the relative roles of trauma and of the reflexes initiated by trauma, on the one hand, and of the resultant disuse of the part on the other. Furthermore, it is important to recognize that emotional stress or instability and other more pronounced neuropsychiatric conditions may also be associated with evidences of increased sympathetic activity. Persons who have undergone trauma may bring these psychiatric mechanisms into play as the result of discouragement concerning recovery, because of motivation for compensation, or because of the hope of other rewards of incapacitating illness including avoidance of duty in the Army. In any evaluation of vasomotor difficulties following service-incurred trauma it is necessary, therefore, to keep in mind the possible role of both disuse and psychiatric factors.



    One hundred and forty-two patients, all males, with post-traumatic vasomotor disorders were received in the vascular center of Mayo General Hospital during World War II after they had been treated at other Army installations. In 1 instance 2 limbs were affected in the same patient. The age range in this series was from 20 to 38 years, the average age, 27 years.

    The disorder became manifest after soft tissue wounds in 58 patients, after sprains in 19, and after crushing or other external injuries in 11. In 14 patients it followed compound fractures of small bones, and in 7, simple fractures of such bones. In 24 patients it resulted from compound fractures of long bones, and in 5, from simple fractures of these. In 3 it was the consequence of infection, while in 1 patient the surgical removal of a small cyst was apparently the initiating cause. In addition to the precipitating injuries just listed, 19 patients had associated nerve paralysis and 4 had sustained lacerations of minor arteries. One had incurred a mild frostbite at the time of injury.

    A foot was affected in 110 patients and a hand in 31. In addition, 1 soldier had vasomotor disturbances in an upper and a lower extremity following injuries to these. In patients without a previous tendency to coldness of the hands or feet, evidence of increased vasomotor tone was frequently present not only in the injured limb but also to a lesser extent in the contralateral limb; sometimes these manifestations were present in all 4 limbs. In such instances the symptoms in the uninjured extremities were generally slight, although 1 soldier developed such severe cold sensitivity in both hands following injury to the left forearm that he required bilateral dorsal sympathectomy.

    In all but 1 patient the vasomotor disorder began during Army service. Twenty-five patients, however, had had a tendency to coldness of the hands or feet prior to the vasomotor difficulty, and an equal number had noted hyper hidrosis in varying degrees in the past. A history of previous injury to the affected limb was obtained in 5 individuals, and of frostbite or trenchfoot in 4. Eighty patients used tobacco. There was no really relevant family history in any of these although such vascular difficulties as varicose veins, vascular thrombosis, or hemorrhage had occurred in the families of 12.


    Initial Symptoms and Signs. The most usual story elicited on questioning of the patients was that severe pain associated with swelling, coldness, and cyanosis, often with excessive sweating, developed in the affected hand or foot shortly after injury. Active use of the extremity was impossible because of pain on movement or on weight-bearing. A few had no significant pain but instead noted evidence of excessive sympathetic activity, such as coldness, cyanosis, and hyperhidrosis. In some, edema, out of proportion to the injury sustained, was the most striking finding, while in others increased vasomotor


tonus without edema was noted. Markedweakness of the involved limb was almost constantlypresent. In a number of instances weakness of the affected limbamounted to virtual paralysis. Inthe order of frequency, the most prominent initial symptoms and signsobtained throughquestioning and a study of clinical records were as follows: pain in 97patients, swelling of theaffected hand or foot in 95, cyanosis in 93, coldness in 72,hyperhidrosis in 52, numbness in 26,and pallor in 3.

    The symptoms listed were generally noticed within periods ranging from several days to a few weeks after injury. In some patients, however, whose initial trauma required immobilization of the limb in plaster, signs and symptoms suggestive of a post-traumatic vasomotor disturbance did not become evident until the cast was removed and the man became ambulatory. The preceding complaints could be explained solely on the basis of the local tissue injury.

    It should be pointed out that there was nothing in the history or the clinical record of these patients to suggest that the early circulatory alterations recorded were the result of vasodilatation and increased blood flow, as Miller and De Takats 3 have observed in some patients in civil practice. In practically all of the combat-incurred post-traumatic vasomotor disorders, the prominent initial findings were those of sympathetic overactivity.

    Initial Therapy. While details of the early therapy applied to the patients under discussion are unfortunately meager, it is quite clear that in the majority of instances no active effort was made during the first few weeks after wounding to treat anything but the local injury. Wounds were properly debrided and foreign bodies excised when these procedures were indicated. Limbs in which fractures had been sustained were immobilized in plaster. These measures seem to have been adequately applied. Only a few patients were treated by casts when there was no fracture or other specific indication for this measure. Compresses were applied locally and sulfonamide drugs given by mouth or penicillin administered parenterally when infection was present.

    When it became apparent that some profound vasomotor disturbance was superimposed upon the local injury, other methods of treatment were instituted. Methods most commonly employed were contrast warm and cold baths, whirl pool baths, Buerger's exercises, massage, and local heat. Little serious effort seems to have been made to establish early active motion and weight-bearing. Sympathetic blocks were employed in 32 patients but in only 2 were they done during the first month of the vasomotor difficulty. One of these patients showed continued improvement after 2 blocks had been carried out during the second week following injury. When examined several months later he had few sequelae. The other patient derived transient benefit from a single block performed on the day of the injury, and significant and lasting improvement from several more performed 5 months later.

3 Miller, D. S., and De Takats,G.:Post-traumatic dystrophy of the extremities. Sudeck'satrophy. Surg., Gynec. & Obst. 75: 558-582, Nov 1942.


    Late Symptoms and Signs. An average of about 5? months elapsed between occurrence of the initial injury to patients included in this series, and the time of their admittance to the Mayo General Hospital. In the interval the correct diagnosis had usually been established although some conditions were still considered to be caused by deep venous thrombosis, thromboangiitis obliterans, or some other primary vascular disorder.

    In Table 48 are listed the chief complaints elicited on admittance and the physical findings noted upon examination. Pain, edema, coldness, and cyanosis were still the most common symptoms. Nearly one-fifth of the patients had sensitivity of the affected part, to cold; in a few instances this disturbance was extremely severe. Other patients complained of stiffness or numbness. Some had chronic ulceration. Pain was primarily experienced on weight-bearing or other activity. Although it was commonly described as an aching sensation, it was throbbing in some instances and burning in others. In most cases it prevented normal physical activity and its long duration had usually completely destroyed the patient's confidence in his ability to use the affected limb properly. Two patients had moderate burning pain when the limb was at rest, but its inconstancy eliminated true major causalgia from consideration as a diagnosis.


    Of the 111 patients with vasomotor difficulties involving the lower extremities admitted to the vascular center of Mayo General Hospital, 21 were confined


to bed when first admitted, 32 wereambulatory with the use of crutches, and 16 more could getabout with canes. Forty-two walked without aid but with a definitelimp. Those withinvolvement of the upper extremities tended to guard the affected limband to avoid using it.

    In every instance examination revealed motor weakness of the affected limb (Table 48) which sometimes amounted to virtual paralysis. Muscle atrophy was commonly evident and stiffness of the joints quite frequent. Hyperesthesia was occasionally present but not always associated with a definite sensory nerve injury. Edema o? varying degrees was present in about half of the patients.(Fig.54A and B.)In some instances it was massive even after prolonged bed rest (Fig.55A and B) in a few it was present despite elevation of the extremity, but in the majority it was mild or moderate. Cyanosis was observed in the majority of patients, in the horizontal position in some instances but in others only in dependency. Rubor and pallor were uncommon. Hyperhidrosis of varying degrees was often present; in some patients the sweat literally ran off the involved hand or foot.

    The affected member was generally cool or cold. In the majority of patients accurate thermocouple studies of skin temperature were carried out; in the remaining, temperature was judged by palpation alone. In 80 instances the affected limb was cooler than the contralateral uninjured limb. In some of these patients the differences in temperature were considerable while in others they were slight, especially when the normal limb was itself excessively cool. In 40 in whom temperatures of the abnormal and normal extremity were approximately equal, both limbs tended to be cool or cold. In some of these individuals the affected limb cooled more rapidly than the uninjured limb upon exposure to a cold environment.

    In 22 patients the involved hand or foot was warmer than the contralateral limb. In 21 of the 22, the thermocouple readings of the affected part were at the lower level of the normal range or even cooler. In the remaining patient the skin temperature was abnormally high as a result of infection.

In 88 patients oscillometric and skintemperature studies were made with the following results

Oscillometric and temperature recordings lessthan in normal extremity - 32

Oscillometric readings less and temperatureequal - 17

Oscillometric readings and temperatureapproximately equal - 14

Oscillometric readings less and temperaturehigher - 10

Oscillometric readings equal and temperatureless - 10

Oscillometric readings and temperaturegreater than in normal extremity - 3

Oscillometric readings greater buttemperature less - 2

    One notable observation on physical examination of these patients was that, although all had evidence of some vasomotor alteration and many presented edema, cyanosis, coldness, and hyperhidrosis, a considerable number exhibited some one of these changes out of proportion to the others. For example, some individuals suffered from intense cyanosis without a great deal


of edema, coldness, or increased sweating.Others presented massive edema with minimalchanges in color, temperature, or sweating. Still others showed extremelocal reduction intemperature or considerable hyperhidrosis or both, without significantedema or cyanosis.

    Most of the patients had assumed the attitude and behavior of the chronic invalid. They were weary from prolonged disability and hospitalization and their viewpoint toward the possibility of eventual recovery was usually hopeless or relatively hopeless. Some appeared to embrace the concept that their condition was sufficiently disabling for them to look forward to separation from the service. In only 11 of the 142 patients, however, was a true neuropsychiatric disorder diagnosed by psychiatric consultants. In this small group the general attitude and behavior differed in no great degree from the attitude and behavior of the group as a whole except that a few showed evidences of anxiety. On the other hand, all 11 patients had certain local findings which were helpful in segregating them from other patients. The most common observation was a forced effort in response to a request to perform a certain movement. The effort was associated with a gross tremor or with little or no movement of the part but with obvious contraction not only of the muscles ordinarily utilized in the movement requested but of their antagonists as well. When, for example, a patient was attempting to extend his foot in response to a request, it was often apparent that both the extensors and the flexors were being brought into a state of tonic contracture so that no movement at all resulted except possibly a coarse tremor. This sign, more than any other, was helpful in establishing the presence of a psychomotor block.

    Special Examinations. In a number of patients reflex dilatation by means of body warming was carried out. In all but 2 the rate of rise in skin temperature was parallel in the affected and in the normal extremity. In the 2 exceptions a lag was noted in the injured limb. In all instances, however, there was no difference in the ultimate temperature elevation in the injured extremity as contrasted with the normal one, despite lower initial controlled skin temperature readings in the involved limb.

    In several patients the reactive hyperemia test was performed. Results in the affected limb were uniformly normal, except in one patient in whom there was a delay in the appearance of the flush.

    Records of roentgenologic examination of the hands or feet made prior to admittance to Mayo General Hospital were available in 51 of the 142 patients. In 42 there was evidence of generalized or spotty osteoporosis. The charge was minimal in 6, moderate in 28, and marked in 8.In the other 9 no abnormalities were observed on the roentgenograms.


    The treatment given the 142 patients with post-traumatic vasomotor disorders at the vascular center of Mayo General Hospital can be divided into


four categories, namely, active exercise andphysical therapy, neuropsychiatric measures, lumbarsympathetic block, and lumbar sympathectomy. As a matter ofconvenience, the treatment ofosteoporosis will be considered separately. It is recognized that thesedivisions are somewhatarbitrary and overlapping.

    For example, whether or not a neuropsychiatric disorder was present, and regardless of whether expert psychiatric treatment was required, it was felt necessary to gain the confidence of the patient and to impress upon him both the necessity for his active cooperation and the favorable outcome that might be expected if he cooperated. Such instructions and suggestions on the part of the attending physician constituted, in reality, psychiatric treatment. Again, no matter what other type of therapy was carried out, active use of the involved extremity was part of the routine. It was learned early in the management of these patients that little could be accomplished by psychiatric interviews, sympathetic blocks, or sympathectomy unless the patient was repeatedly urged to take advantage of any resulting improvement in his condition by following up the gain with persistent use of the affected limb. It was only in this manner that atrophy, weakness, stiffness, and improper stance or gait could ultimately be corrected.

Active Exercise and Physical Therapy

    In 95 of the 142 patients, active use of the involved extremity supplemented by physical therapy constituted the chief treatment employed. When the patients were first seen the importance of activity was pointed out and explained to them in terms which they could readily understand. The role that disuse was playing in their condition was stressed and it was emphasized that a vicious cycle had been set up which would result in continued difficulty as long as inactivity persisted.

    In those individuals who had demonstrable edema of a lower extremity, an attempt was made to bring the swelling under control before anything else was done. These patients were put to bed with the extremity elevated until all swelling had disappeared. If edema recurred on activity, an elastic support was used together with periods of bed rest with the limb elevated. Careful observation of the patient made it possible to permit activity to a degree slightly less than that at which edema reappeared. The use of the elastic support was continued until swelling was no longer present on dependency.

    If a patient was confined to bed on his admittance to the hospital, the therapeutic program was aimed at making him ambulatory as rapidly as circumstances permitted. A short period of ambulatory with crutches and then with a cane was sometimes necessary before unaided walking was accomplished. Widespread petechial hemorrhages sometimes appeared in the skin of the affected extremity when a patient first began to walk after a prolonged period of immobilization of the limb. They usually cleared up promptly as activity


increased. Patients who were admitted usingcrutches or canes were persuaded to discard themimmediately. Since all patients who had been bedridden or who had beenusing aids usuallyshowed timidity and favored the affected limb when they first began towalk, careful attentionwas paid early in the reconditioning program to the acquisition of anormal stance or gait. It wasnot always easy to accomplish this, partly because pain was frequentlyassociated with earlymovement (though it tended to decrease as the men became more active)and partly becausemost tended to estimate their improvement by the distance they couldcover rather than by thecorrectness of their gait. They were made to understand, however, thatmore benefit was derivedfrom walking a short distance properly than a long distance improperly.Emphasis was placed onthe fact that only when a correct gait was employed would all themuscles be brought into playand strengthening and improvement in tone accomplished.

    In addition to the active use of the affected limb which was the principal type of physical therapy utilized, substantial benefit was usually obtained through gentle massage and directed active and resisted exercise of all the weak muscles. Passive exercises and manipulations were found to be of little help. Whirlpool baths were used on some of the first patients to be treated, but in general no improvement was observed following their use and so they were omitted. It was necessary to emphasize to all of the patients that they could accomplish much more by voluntary exercise at frequent intervals throughout the day than by sole reliance on the relatively short period of treatment supervised by the physical therapist.

    The same principles of treatment were employed for the upper and for the lower extremities.

    Results. As improvement appeared, the patients usually underwent a change in attitude and became decidedly more optimistic concerning the outcome of their disability. Concomitantly with their altered state of mind, they seemed to pursue the program more vigorously and to improve more rapidly. As a result, edema diminished and gait became relatively normal. If discomfort persisted it was less severe and appeared only after the patient had walked for distances varying from 1 to 3 or more miles. Along with this improvement there were observed an increase in muscle power and an alleviation of the vasomotor disturbances. Almost invariably limbs which had been cold, wet, and cyanotic when first seen, gradually became warmer, dryer, and of better color.

    In 50 of the 95 patients in whom active exercise and physical therapy were the chief methods of treatment, results were satisfactory. Five of the remaining patients were under observation for too brief a time to permit final evaluation of results. In the other 40, few, if any, beneficial effects were noted. It should be emphasized again that in some respects many of the patients analyzed under other methods of treatment also represent failures with active exercise and


physical therapy, since these measures wereemployed adequately in all but a few patients priorto the institution of other methods.

    One patient may be considered as typical of those in whom active exercise and physical therapy produced successful results:


    When this patient entered the Mayo General Hospital he was unable to use his fingers and complained of marked edema, pain, coldness, and hyperhidrosis of the right hand. The bones of the right forearm had been fractured on several occasions prior to the onset of symptoms. When the hand was first examined all of the fingers were edematous and stiff (Fig. 54A). He was given an ordinary surgical glove to wear and encouraged to use the fingers as much as possible. At the same time, an intensive course of physical therapy was instituted. Part of this called for the patient to squeeze a soft rubber ball. This he did during most of the day. At the end of 14 days, edema had completely disappeared and he could move the fingers of the right hand almost as well as those of the left (Fig. 54B).

Figure 54. A. Massive edema of right hand in patient with vasomotor disorder following trauma. B. Disappearance of edema several weeks after institution of intensive active exercise and physical therapy.

    Disposition. By the time the patients in this group were ready for disposition those who had demonstrated a satisfactory response to therapy were either free of residual vasomotor signs and symptoms or whatever manifestations persisted were minimal. In some the rather generalized increase in vascular tonus previously present had tended to decrease as the affected limb was restored to a more normal state. Even when patients were not completely recovered, however, it was felt that further hospitalization for the vasomotor condition was unnecessary-and might be actually harmful--since there was every reason to believe that symptoms and signs would become less and less apparent with continued physical activity and the passage of time.

    Twenty-nine of the 95 patients in this group were therefore transferred to various other sections of the hospital for the correction of other medical or surgical conditions, 14 were sent to convalescent facilities for advanced re-


conditioning, 5 were discharged directly toduty, and the remainder were separated from theservice.

Neuropsychiatric Measures

    Standard neuropsychiatric measures were used in 9 of the 11 patients in this group. In 8, treatment was carried out by the psychiatrist. In the ninth patient it was carried out by the ward officer under the direction of the psychiatrist. The routine usually included suggestive therapy under sodium amytal narcosis or hypnosis. Careful, concerted efforts were always made to give the patient insight into his condition and to make him understand that he had no organic disorder which would prevent his recovery if he would continue to push himself to the limit in the active use of the affected limb.

    In the 2 remaining patients psychiatric measures were not regarded as necessary. In 1 of these the psychiatrist thought that the complaints of cyanosis, coldness, swelling, and pain in the foot on weight-bearing were largely psychosomatic, but they cleared up so satisfactorily under ordinary physical activity that psychiatric measures were not invoked. When this patient was transferred to a convalescent hospital for advanced reconditioning his only complaint was aching in the affected foot after he had walked for a distance of 3 miles. The other patient made fair progress with active exercise of the affected upper extremity until improvement reached a plateau; he was left with some residual cyanosis, increased sweating, and weakness.

    Results. The results of psychiatric treatment in the 9 patients treated were classified as good in 4, poor in 4, and fair in 1.

    Two patients in whom no improvement was observed after psychiatric measures were transferred to a neuropsychiatric center for more intensive therapy. One of them (Case 8, Table 49) had complained of swelling, hyper hidrosis, and cyanosis of the foot following a compound fracture of the proximal phalanx of a toe, the result of an accidentally self-inflicted wound 9 months prior to admittance. His symptoms did not improve with activity but there was some reduction in swelling following lumbar sympathectomy. Initial progress was excellent but after he returned from a convalescent furlough he still had some swelling and weakness of the foot. The psychiatrist was of the opinion that definite hysteria was present, since improved strength in the foot and more normal walking could be demonstrated under hypnosis. Several subsequent treatments were given but, the final result was poor.

    The second patient transferred to a neuropsychiatric center for further treatment had also been admitted with swelling, cyanosis, weakness, and pain in the foot on weight-bearing. He had improved considerably with active exercise and physical and occupational therapy but following a convalescent furlough complained of increased weakness and pain and, in addition, of nervousness, anorexia, and insomnia. He had also developed a tremor and some weakness in one of his hands. The psychiatrist felt that this man was suffering




from an anxiety state and when no improvementwas secured with sodium amytal narcosis andother treatment, recommended his transfer to another hospital.

    In a third patient in whom an unsatisfactory result was obtained with neuropsychiatric measures, definite evidence of conversion hysteria was present but considerable, though incomplete, improvement occurred after sympathectomy (Case 3, Table 49).

    Of the 4 patients in whom the results were classified as good 2 are of interest:

Case Reports

    The first was a patient who was admitted to the vascular center of Mayo General Hospital 4 months after an injury to the right leg. He received this injury when he was kicked during a football game. He gave a history of previous trauma to the same limb 1 year earlier, followed by pain, swelling, and cyanosis which decreased slowly and finally disappeared. Within a few days after the recent injury the return of these same symptoms and signs were noticed. They increased in severity and eventually he could walk only on crutches. A series of 10 sympathetic blocks resulted in transient improvement in the strength of the affected foot. When examined it was immediately evident that he was unwilling to do very much for himself. He appeared apprehensive and was rather jumpy while being questioned. There was marked paresis of all the movements of the foot and ankle but efforts were associated with tremor and with tonic contractions of the antagonistic muscles.

    The psychiatrist felt that this patient had hysteria and treated him with suggestive therapy under sodium amytal narcosis. During this procedure the affected foot, which had been cold, wet, and extremely cyanotic, became warm, dry, and of good color. The patient could move it freely and strongly through a full range of motion. He was made to walk and did so with a practically normal gait. After this single treatment, which was followed by careful and full explanations regarding the nature of his condition and progress, he improved daily. When he was discharged after being hospitalized for a month, the foot was normal in color and warmth, edema was no longer present, and there was only a slight reduction in motor power. The range of motion was normal. He experienced no pain until he had walked a mile and a half. There was, however, no improvement in the moderate osteoporosis present on admittance.

    The second patient was admitted to the hospital 4 months after he had sustained injuries of the soft tissue of the left thigh and leg from a shell fragment. The injury had been followed by immediate paralysis and numbness of the foot but flexion and sensation on the sole had returned at the end of 6 weeks. At the time of admittance he complained of swelling, cyanosis, coldness, and sweating of the left foot, with tingling and aching pain on attempted weight-bearing. He walked with crutches. Examination of the left foot showed cyanosis, a reduction in skin temperature, moderate hyperhidrosis, paralytic limitations of eversion, and complete loss of extension of the affected foot and toes. There was some hypesthesia of the foot, with anesthesia in the distribution of the saphenous and the lateral sural nerves.

    The neurosurgeon had no doubt that the patient had a sciatic nerve injury with partial peroneal paralysis. Efforts at active use of the limb with a foot-drop brace were futile, and since a fairly good response was obtained with sympathetic block, a lumbar sympathectomy was performed (Case 10, Table 50). There was considerable improvement following this procedure and weight-bearing was possible with the use of crutches; at the end of a week he discarded these for a cane. The foot was now warm and dry, and there was only minimal edema in the leg and none in the foot. There was also less pain on walking.





    Two months later the sciatic nerve was explored and found to respond well to faradic stimulation. A week after the operation psychiatric consultation established a diagnosis of hysteria. As the result of a single interview under sodium amytal narcosis the patient regained all movements, had return of sensation, and walked unaided normally and without pain.

    This case illustrates most emphatically the necessity of bearing in mind the possible psychiatric basis of post-traumatic vasomotor complaints and of instituting appropriate psychiatric therapy before attempting other, more heroic procedures.

    Disposition. Except for the 2 soldiers transferred to neuropsychiatric centers for further treatment, all the patients in the group treated by neuropsychiatric measures were separated from the service even though some of them showed marked improvement in, or even recovery from, the vasomotor disorders for which they had been hospitalized.


    Thirty-two patients received sympathetic blocks prior to their admittance to Mayo General Hospital; the procedure was carried out on an average of 6 months after the onset of the disorder, with a range of from 1 to 22 months. From 1 to 28 blocks had been given to each individual.

    Sympathetic blocks were carried out in a number of the patients with post-traumatic vasomotor disorders after they were received at the Mayo General Hospital, but in only 7 instances was the method employed as a therapeutic measure. In the remaining patients the blocks were carried out as a test procedure to determine the advisability of sympathectomy.

    Results. An analysis of the medical records, supplemented by questioning the patients, made it appear that 12 of the 32 patients who received sympathetic block prior to their arrival at the Mayo General Hospital had noticed no subsequent change in their condition other than some temporary elimination of coldness, cyanosis, and sweating during the period of anesthesia. In 13 patients there appeared to be definite though transient benefits from the procedure. In 4 patients there was evidence of slight or moderate permanent improvement, and in 3 patients good permanent results were obtained.


    In evaluating the sympathetic blocks performed before the patients were seen at the Mayo General Hospital, it was apparent that in a few instances effective anesthesia of the sympathetics had not been obtained. This was evidenced by the fact that the limb remained cold and wet following the injection. In others the possible therapeutic effect upon walking was compromised by associated inadvertent blocking of the somatic nerves, with resulting temporary anesthesia and paralysis, which prevented the use of the lower extremities during the period of the effective sympathetic block. Futhermore, it was apparent that in most of the patients no effort had been made to make the patient walk or otherwise actively exercise his affected limb immediately after the injection. In only a few of the patients was advantage taken of the improvement by insistence upon progressively increased use of the limb and it was in this group that some benefit over a period of hours or days was noted following the procedure. There is no question that if sympathetic blocks are to achieve maximum benefit, the involved extremity must be subjected to weight-bearing and walking or other active exercise immediately after the injection, and that activity must be continued to the point of tolerance. Only when such a plan is employed can the effectiveness of the procedure properly be evaluated.

    Two of the 7 patients in whom sympathetic blocks were employed as a therapeutic measure after they reached the Mayo General Hospital had syndromes characterized by coldness, hyperhidrosis, and weakness of the hand. Another had rather marked edema of the hand without any other significant change. The remaining 4 patients complained of edema, coldness, cyanosis, and hyperhidrosis of the injured foot. Treatment was instituted from 6 to 12 months following injury. Three patients received only a single sympathetic injection while 4 had 2 treatments each. In every instance there was definite, steady improvement following the blocks, manifested by marked diminution in coldness, hyperhidrosis, and edema, return of good color, also increase in motor power and function. Each of these patients had previously been making earnest efforts to use the extremity actively and to the best of his ability but without apparent improvement. From the sequence of events there was little doubt that the block rather than other therapeutic efforts was primarily responsible for the altered clinical picture. It is of interest that pain was not a prominent complaint in any of the patients who experienced lasting improvement as a result of sympathetic block.


    Sympathectomy was the principal method of treatment in 34 patients in 1 of whom the operation was performed twice. Three of these patients have already been mentioned in the neuropsychiatric category but are again analyzed under this heading for the sake of completeness.

    In all in whom the lower extremity was involved, lumbar sympathectomy was carried out under spinal anesthesia through an anterior extraperitoneal


approach; the second and third lumbarsympathetic ganglia, with the intervening chain, wereexcised. Sympathectomy of the upper extremity was performed through aposterior muscle-splitting incision with resection of a portion of thethird rib and of the transverse process. Thesecond and third thoracic ganglia were decentralized; the chain wassevered between the thirdand fourth ganglia and the isolated segment encased in a silk cylinder.Intradural section of thesecond and third anterior nerve roots and extradural section of thecorresponding posterior rootswere steps in the procedure. There were no deaths and no complicationsin any of these patients.

    Decision to perform sympathectomy was made on the basis of a number of factors. In patients with ulcers, it rested primarily upon the chronicity of these lesions and the presence of associated vasospasm. In patients with evidence of excessive sympathetic activity, sympathetic procaine anesthesia proved a reliable test for judging results which would follow sympathectomy. In those with edema, preliminary testing with procaine block was not a reliable indication of the effects to be expected of sympathectomy. In a very few, a demonstrable transient diminution in swelling occurred, but in a number of others it was necessary to determine whether the increase in the size of the extremity which occurred during an hour of walking immediately following the injection was less than that observed during a comparable interval on another occasion. If it was thought to be less following the injection, then sympathectomy was resorted to. In most patients with edema, however, no really convincing evidence concerning the result to be anticipated from sympathectomy could be derived from a preliminary sympathetic block. In spite of the indefinite results of preliminary testing, the therapeutic effect of sympathectomy was frequently extremely satisfactory.

    In patients with pain, results of preliminary testing with sympathetic procaine anesthesia were also so variable as to be considered unreliable. Following the injection some patients were surprised to find that they could move the affected part freely through a wide range of motion without any discomfort and that they could walk or otherwise exercise either with no pain or with much less discomfort than previously experienced. In such instances it was felt that sound evidence existed that sympathectomy would be effective. In others, however, sympathetic anesthesia had no beneficial effect upon the pain associated with exercise, yet in these good results frequently followed sympathectomy.

    Results. To simplify the analysis, patients upon whom sympathectomy was performed have been divided into 4 groups, namely, those with considerable persistent edema, those with pain on walking, those with excessive sympathetic activity, and those with chronic ulceration of the skin. This division is somewhat arbitrary since symptoms and signs were seldom limited to any one of the categories mentioned. Some of the patients with edema, for example, had pain also on weight-bearing and presented evidence of vasoconstriction, while


those whose chief complaint was pain onweight-bearing likewise presented excessivevasomotor tonus, often associated with slight or moderate edema.Similarly, patients withchronic ulceration gave evidence of increased vasomotor activity andsuffered from edema anddiscomfort on walking. Nonetheless, this division serves a usefulpurpose in presenting theinformation in a more concise fashion and selection has been madeaccording to the primaryindication for operation.

    In 7 of the 8 patients upon whom sympathectomy was performed primarily because of persistent edema (Table 49), the procedure was carried out on a average of about 7 months after injury, the range being 4 to 11 months. In1 patient edema was only moderate, in 2 it was marked, in the 5 remaining it was massive. All of these had had a trial of bed rest, with elevation of the affected limb, and later, when they became ambulatory, of elastic support. In 6 of the 8 patients edema persisted with bed rest alone, and in 4 of these 6 it did not subside even after a prolonged period of elevation. Six patients had evidence of vasospasm and 1, in whom infection was present, also had definite local hyperemia (Case 4).

    In 1 of the patients in this group (Case 1) in whom edema was associated with an ununited fracture of the tibia, exploration. was undertaken with the idea of performing a bone graft, but the procedure had to be abandoned be cause of the marked waterlogging of all the tissues. There was considerable reduction in the edema following sympathectomy and when the bone graft was subsequently undertaken, the surgeon estimated that the condition had improved by about 90 percent. In another patient, however, in whom massive edema was associated with a compound fracture and osteomyelitis of the ankle (Case 5), only slight improvement followed sympathectomy.

    One case from this group is of special interest:

Case Report

    This patient, with massive edema (Case 4), had sustained a soft-tissue injury of the left foot from a shell fragment. The foot and leg were enormously swollen and local infection was present (Fig. 55A) associated with fever and weight loss. Intensive treatment consisting of repeated debridement, repeated incision and drainage, and sulfonamide and penicillin therapy over a long period, with immobilization and elevation of the limb, had produced no improvement whatsoever. A sympathetic block produced no demonstrable diminution of the edema but pain was transiently diminished. Sympathectomy was performed 5 months after the injury.Within 36 hours the circumference of the foot had been reduced by 1? inches, that of the leg by 4? inches. Over the next few days the edema disappeared completely, as did the infection, and healing occurred with only a tiny ulcer remaining. Subsequent recurrence of the infection, with transient recurrence of edema, responded well to elevation and rest. Following this episode the wound healed completely (Fig. 55B), edema disappeared entirely, and the patient could walk normally and with comfort.

    The other 5 patients in the group upon whom sympathectomy was performed for persistent edema presented other signs and symptoms more commonly seen following injury. Four were unable to bear weight properly be-


Figure 55.  A. Massive edema and ulceration of left foot and lower leg in patient with post traumatic vasomotor disorder and resistant infection. No improvement followed continued bed rest, elevation of the extremity, and sulfonamide and penicillin therapy.  B. Healing of ulcer and disappearance of edema after lumbar sympathectomy.

cause of pain, the fifth walked with adecided limp. All complained of weakness, 1 had a virtualparalysis, and 3 had hypesthesia. Three of the 5 had signs of intensesympathetic hypertonuswith coldness and hyperhidrosis. The fourth had persistenthyperhidrosis and cyanosis. The fifthhad a cool foot which, however, was warmer than the contralateral limb.By means of anoscillometer it was determined that the volume flow of blood to theinjured extremity wasgreater than that to the uninjured one. In 3 of these 5 patients (Cases2, 6, and 7) there was eitherpartial or complete subsidence of edema following sympathectomy. Allcould wall-, better,without discomfort and for longer distances, than before operation.Hypesthesia was improved orwas no longer present. In 1 patient (Case 7), who was hospitalizedsufficiently long forconclusions to be warranted, there was no recurrence of edema duringthe period of observation.

    The other 2 patients upon whom sympathectomy was performed for persistent edema have been discussed previously under the heading of neuropsychiatric therapy. One, who had transient improvement in edema following sympathectomy (Case 8, Table 49), was eventually found to have a conversion hysteria which responded poorly to psychotherapy. The history of the second patient, (Case 3) is instructive because it illustrates the therapeutic effect of sympathectomy in an hysterical individual who also showed poor response to psychotherapy:

Case Report

    Following a crushing injury of the left foot, this patient had marked swelling, coldness, hyperhidrosis, and hypesthesia (Fig. 56A). Paralysis was almost complete. No improvement was observed following psychiatric interviews and no benefit other than transient


Figure 56.  A. Edema of left foot inpatient with post-traumatic vasomotor disorder and hysteria 11 months after injury. This picture was taken after 3 weeks of continuous bed rest with elevation of the extremity. Response to psychotherapy was poor.  B. Appearance of foot 10 days after lumbar sympathectomy. Note almost complete disappearance of edema.

warmth and dryness of the footfollowedsympathetic block. Sympathectomy was performed 11months after the original injury. Within 48 hours after operation theedema, which had persistedwith bed rest and elevation, practically disappeared. The patient,although. he walked with alimp and required a foot-drop brace and a cane, was converted from abed ridden to anambulatory patient (Fig. 56B) during this brief period. Furtherpsychotherapy was of no valueand, since a plateau of improvement had been reached, he was separatedfrom service.

    Sympathectomy was performed in 10 patients who complained of pain on weight-bearing and in 2 who had pain at rest (Table 50). At the time of operation 1 was confined to bed and refused to walk, 5 walked with crutches, and 2 with canes. The other 4 walked with a limp and favored the injured limb. In 9 of the 12 there was positive evidence of vasospasm and 9 had slight or moderate edema. Cyanosis was present in all 12.

    One of the patients who had moderate improvement after syrnpathectomy has already been mentioned (Case 10). He was subsequently found to have hysteria and a complete cure occurred after a single interview under sodium amytal narcosis.

    In the remaining patients results varied from good to excellent. Some were able to walk several miles before the onset of discomfort while others had no residual pain at all. Both patients who had complained of rest pain showed considerable improvement. In every instance edema either disappeared or was


present only to a slight degree, even afterprolonged dependency. All patients now had warm,dry feet and only one showed residual cyanosis. Muscle strength alsoimproved in everyinstance. By the time the patients left the hospital, there was anincrease in the size of themuscles even if definite atrophy had previously existed.

    It is important to emphasize that in this group, except for 1 or 2 patients treated early in the experience, all had been subjected to a rigid regimen of active exercise prior to operation without definite relief from symptoms. Even the few who followed no planned program of calisthenics had been encouraged to walk and to exercise the affected limb.

    On the indication of excessive-sympathetic activity (Table 51), 13 operations were performed on 12 patients. Eight of the procedures were dorsal and




5 were lumbar sympathectomies. Ten of the 12patients in this group complained beforeoperation of excessive coldness, generally associated with bothcyanosis and hyperhidrosis, atordinary environmental temperatures. Six had cold sensitivitymanifested by marked coldness,stiffness, and discomfort on exposure to a low temperature. The 5 withinvolvement of the lowerextremity all had slight or moderate edema and 1 had also pain onweight-bearing. One (Case27), who had had an amputation of a finger, had moderate phantomlimbsymptoms.

    Following operation, 7 patients had complete relief and the other 5 were very much improved. Cold sensitivity was diminished in each patient in whom it had been present. The limbs were dry, warm, and well colored following operation. Hypesthesia, which had been present in 1 (Case 24), was considerably improved. Corrective operative procedures upon the affected limbs in 2 (Cases 21 and 22) were followed by prompt healing of the wounds.

    In 2 patients (Table 52) operation was performed chiefly because of the persistence of chronic ulcers.In both, although repeated efforts at skin graft ing had failed, healing occurred fairly promptly after sympathectomy. In 1 (Case 34) it was apparent before sympathectomy was performed that transfer of full thickness skin would eventually be required, but it was thought that the chance of success would be enhanced if this could be done after epithelization of the ulcer and correction of the vasospastic disorder. In 3 other patients chronic ulcers healed satisfactorily with rest and saline compresses, without sympathectomy.



    In all patients treated by sympathectomy, strenuous active exercises were insisted upon after a short period of convalescence. It was the universal experience that such activity could be undertaken with little or no discomfort after the operation and that steady subsequent improvement would occur as the patient continued to take advantage of his increased ability to perform physical exercise.

    Except for one patient transferred to a neuropsychiatric center (Case 8, Table 49), a second discharged because of hysteria (Case 3, Table 49), and a third separated because of marked pes planus (Case 21, Table 51), all those treated by sympathectomy in whom no further surgery was necessary for correction of other combat-incurred defects were transferred to convalescent facilities for advanced reconditioning or return to duty.

Effect of Treatment Upon Osteoporosis

    Comparative roentgenograms of patients with osteoporosis made at the time of admittance to the hospital and some months later after institution of treatment were available for study in 24 cases. In 11 of the patients no alteration in the degree of osteoporosis was noted in the final roentgenograms. In this group the first film, taken between 3 to 14 months after the original trauma (an average of about 9 months), showed slight, osteoporosis in 2, moderate bone changes in 8, and marked changes in 1. Final roentgenograms were obtained from 4 to 17 months after injury, with an average of about 11 months. Average time interval of observation was thus about 2 months.

    The other 13 patients showed definite improvement in respect to osteoporosis in the films taken after treatment. The original films were taken from 2.5 to 6 months after trauma with an average of about 5 months.These first


films, revealing a reversal toward the normalstate, were obtained from 5 to 12 months afterinjury. There was an average, then, of about 4 months between theoriginal films and the filmswhich indicated improvement. The original roentgenograms showed slightosteoporosis in 1patient, moderate bone changes in 6, and marked changes in 6.Of the 6patients who originallyshowed marked changes, 1 showed normal structure in the final film and4 showed onlymoderate osteoporosis. In the remaining patient the films revealed onlyslight improvement. In 3of 6 patients who originally had moderate osteoporosis, evidence ofonly mild involvement waspresent after treatment; in the other 3 the roentgenograms revealed anormal or practicallynormal condition. The single patient who originally had slightosteoporosis had normalappearing bones on the last examination.

    In analyzing the roentgenologic changes in osteoporosis from the standpoint of treatment employed in these patients, it is of interest that 4 out of 9 patients treated by exercise, physical therapy, or psychotherapy, and 9 of 15 patients treated by sympathectomy, showed some improvement. Two other patients treated by sympathectomy, in whom no change in the degree of osteoporosis was observed after treatment, had fractures of the long bones which had required prolonged immobilization before operation, and it is possible that the factor of continued disuse may have played a role in the persistence of the osteoporosis.


    Patients who have sustained trauma to an extremity usually have symptoms readily explained as the result of local tissue injury. A certain number, however, have superimposed upon these, other manifestations which can be interpreted only on the basis of some reflex activity initiated by the local trauma. Patients with vasomotor disorders of this kind may have an initial and transient period of hyperemia, or their difficulties may begin with signs of intense vasoconstriction. Later, the great majority show evidence of sympathetic hyperactivity. Primary manifestations in the acute stage are predominantly pain and swelling, although in a smaller number of patients coldness, hyperhidrosis, and cyanosis are more prominent. Later in the course of the illness the commonest complaints are swelling and pain on exercise and weight-bearing. Coldness, cyanosis, and hyperhidrosis are frequently noted and some suffer from distressing cold sensitivity. Many have edema which is present at rest, though it is more frequently noted when the limb is dependent. Persistent ulceration may be present when the skin is denuded.

    A patient with a painful or edematous extremity, or an extremity which is the site of distressing coldness and hyperhidrosis, is strongly tempted to keep it at rest. Disuse itself may bring about a reduction in the blood flow with associated coldness, cyanosis, hyperhidrosis, edema, muscle atrophy, and osteoporosis. These are all alterations which are part of the post-traumatic


syndrome. Consequently, it is often difficultto evaluate the relative roles of the trauma and thereflexes initiated by it on the one hand, and of the resultant disuseon the other.

    Continued disuse of the injured extremity also tends to bring about a rather fixed mental attitude which hampers return to normal activity. This factor may be the result of fear, discomfort, discouragement concerning recovery, or of some motivation to prolong the disability such as desire for compensation, avoidance of military duty, separation from service, or other rewards of invalidism.

    Finally, emotional stress and instability, as well as certain of the more clear-cut psychiatric conditions, are often associated with increased sympathetic activity. Not infrequently those who have sustained an injury may bring such emotional and psychiatric mechanisms into play. Any casualty with a post-traumatic vasomotor disturbance must therefore be studied from this standpoint as well as from the purely physical.

    Initial handling of the local injury should include such measures as debridement, removal of foreign bodies, reduction of fractures, and active treatment of infection. Although immobilization and bed rest should be utilized when they are indicated, early mobilization is advisable in most instances. Some patients, in fact, can prevent the post-traumatic syndrome, or overcome it when it develops shortly after injury, by simple persistence in forced active exercise. It is essential to instill in the patient confidence in his ability to make a satisfactory recovery, to eliminate any tendency toward chronic invalidism, and to correct any coexisting psychiatric ailment.

    In many individuals, however, the difficulty cannot be alleviated so simply. In some of these such a procedure as direct blocking of the sympathetic pathways by procaine infiltration produces markedly beneficial effects. Not infrequently, as soon as the injection is completed, pain and hypesthesia disappear, temperature and color return to normal, and motor function is restored. If a foot is involved, it is not unusual to find that after sympathetic blocks the patient can immediately bear weight and walk normally. In many persons a single injection will suffice, while in others a series of treatments is necessary. If a beneficial, but only transient, effect follows sympathetic anesthesia, it is quite possible that sympathectomy will produce a complete cure. Periarterial sympathectomy has been suggested for milder cases. In certain patients in -whom the site of local irritation, such as a painful scar or a thrombosed vessel is clearly evident, good results follow excision of the trigger points which might propagate the reflex disturbance. Sometimes local infiltration of procaine in the region of the injury results in dramatic improvement; this method is possibly also of value in preventing the development of posttraumatic disturbances.

    In the treatment of the later stages of post-traumatic vasomotor disorders, the situation is complicated both by the fixed mental attitude of the patient


which is that of the chronic invalid, and bythe extensive atrophy and motor weakness whichresult not only from the initial injury but also from the superimposeddisuse. It is important toutilize psychotherapy in encouraging continued and gradually increasingactive exercise of theaffected limb and to employ more specific psychotherapeutic measures inthose instances inwhich psychiatric factors are an accompaniment of, if not the primarybasis for, the disability.Regardless of any other type of treatment, it is important to avoidedema by a period of bed restwith elevation of the limb and, if necessary, by the use of an elasticsupport.

    In general, sympathetic blocks have little therapeutic value when the syndrome is of long duration, but may prove very useful in some patients, particularly those in whom edema is the primary manifestation or in whom evidence of increased sympathetic activity is predominant.

    If the measures outlined have been tried faithfully and yield unsatisfactory results, sympathectomy should be considered. If the patients are properly selected, results are usually excellent.

    Although numerous individual reports testify to the value of various therapeutic measures in the management of post-traumatic vasomotor disorders, it is impossible to establish from the data recorded in the literature the incidence of failures with the various methods of treatment. Experience with both military and civilian patients, however, emphasizes the importance of evaluating carefully all possible therapeutic aids in any given patient and of neglecting no useful adjuvant in treatment.

    The group of patients analyzed in this chapter were all individuals in whom sequelae of trauma persisted and who required prolonged hospitalization for vasomotor disorders. It is significant that initial therapy, except in two patients in whom sympathetic blocks were carried out promptly, included none of the procedures listed as desirable under the circumstances. One patient experienced steady improvement following two blocks during the second week after injury and had few sequelae when seen some months later. The other had transient benefit from the single block carried out on the day of injury and significant, lasting improvement from several blocks carried out several months later.

    An analysis of a group of military personnel has decided advantages. Military regulations afforded the opportunity to follow these patients carefully for as long a period of hospitalization as was required. Furthermore, in all patients in this series the same motive was present with regard to the rewards which might possibly arise from continued disability. Analysis of a comparable group of civilian patients is much more difficult. Such patients differ considerably in age and also in the factors which tend to make the persistence of complaints profitable or futile. Most civilians are necessarily hospitalized for as brief periods of time as possible and observations upon them limited to those intervals and to office visits. In general, however, experiences


with civilian and military patientscomplement one another. The manifestations of the post-traumaticdisorders and the results of their treatment have been much the same inboth militaryand civilian groups.

    The chief point ofinterest in regard totherapy which emerges from this study is that the degreeand duration of physical disability associated with post-traumaticvasomotor disorders aredependent in large part upon the amount of time that elapses betweenthe onset of the conditionand the initiation of active and adequate therapy. In most patients inthis series early therapy wasnegligible and ineffective and, as a result, distressing sequelaepersisted for many months andnecessitated prolonged hospitalization. In contrast to the long periodof hospitalization in thesepatients is the generally satisfactory course of events in civilianpatients who are treated activelysoon after injury. The period of incapacity is usually much shorter incivilian patients, especiallywhen possible financial compensation is not a factor.

    In the treatment of thelate manifestationsof post-traumatic vasomotor disorders the duration oftherapy is necessarily longer than in the early phases and a moreintense program of treatment isrequired. In addition, there is considerably less likelihood of acompletely successful outcomeand of the disappearance of all symptoms.