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Angioneurotic Edema of Entire Genito-Urinary System
ANGIONEUROTIC EDEMA OF ENTIRE GENITOURINARY SYSTEM N. BLAUSTEIN New York City Received for publication July 10, 1926 NOMENCLATURE AND DEFINITION
Quincke's disease, Quincke's edema, hereditary edema, familial edema, giant urticaria (Milton), urticaria edematosa, urticaria tuberosa, hydrops hypostrophos (Schlesinger), and angioneurotic edema are all synonymous, although the latter term implies a knowledge of its pathology which is not as yet established. Angioneurotic edema is a condition characterized by the spontaneous appearance of localized and circumscribed edema in various regions of the body. General attention was not called to the disease until its description by Quincke in 1882. He called it "acute circumscribed edema." ETIOLOGY
In the majority of the cases no exciting cause can be discovered . Nervous influences appear to be the most important factors . Neuropathic heredity appears to have some influence upon the disease, but nervous manifestations in the patient himself are more important. Sex and periodicity of life are not of any material consequence, as, apparently, it occurs with equal frequency in both sexes, although there is a slight predominance in the male, during any period of life. Likewise, the sites of appearance of the lesions are not selective, as the lesions have been observed in practically every region of the body, and in the buccal, thoracic and abdominal cavities and their visceras. The duration of the attack varies from a few hours to six to 379
380
N. BLAUSTEIN
ten days, and the reappearance of new lesions gradually diminishing in number and prominence. SENSITIZATION TO FOREIGN PROTEINS (ALLERGY)
The suggestion made by almost countless observers that the condition is a manifestation of protein sensitiveness finds some support in the fact that almost all outbreaks follow some gastrointestinal upset. ·while it is true that this resembles much the urticaria and localized edema seen in cases of idiosyncrasy and food poisoning, conditions which in turn are allied to anaphylactic phenomena, it may eventually be determined that in these we deal with something more than simple uncomplicated vasomotor disturbances. However, of the endogenous poisons, the result of perverted metabolism- anywhere from the moment the morsel of food is rolled round the tongue until its constituents have been through the furnaces and are cast out as ashes and smoke- we talk a great deal but we know nothing, so far at least, as this disease is concerned. The outstanding positive fact about the disease is the hereditary nature of its role. Dinkelacker, Quincke, Strubing and others have reported families in which it has occurred. The hereditary form of this disease is usually severe as illustrated by Griffith who reports that both father and daughter died of acute edema of the larynx during atta,cks. We are much in the dark as to our knowledge whether the disease is transmitted through the father or mother and in this respect the Mendelian laws have been sadly neglected, not entirely commensurate with their wide usefulness in their application to other hereditary characteristics. The most remarkable case on record is that cited by Osler in whom the disease ran through five generations with almost clocklike regularity (see table 1)·. The ordinary type of Quincke's edema may occur in hysterical subjects, but the association is not so common as with neurasthenia. Edgeworth reported a series of cases in which transitory edema of a segmental distribution occurred in young subjects, and in three of the seven cases
_-\.NGIOXEUROTIC EDEMA OF GENITO-URIXARY SYSTEM
381
there were disturbances of sensation suggestive of hysteria. Sydenham first recognized an edema associated with hysteria. Charcot made it the subject of several important studies. TABLE 1
Genealogical table showing angioneurotic edema in the family of twenty I
II
Samuel
III
\
3 children, all affected one died of it
· IV
One girl affected
Hamilton
Rebecca Died of it George
Margaret Born 1762 Died 1834
V
{
i
Thomas Lizzie 2 children age d seventeen and eleven, one of whom had an attack
Almira Mary Julia Katie Edward Maggie George
Allan 10 children 3 affected Emma-Single
MollieMarried No children John ill.
f
l
4 children 1 affected
PATHOLOGICAL PHYSIOLOGY
If we understood the pathology of an urticarial wheal we rnight discuss intelligently these remarkable varieties of local edema. The accumulation of fluid in the tissues, is as a rule intercellular rather than intracellular. Intracellular accumulations do occur,
382
N. BLAUSTEIN
under normal as well as under abnormal circumstances, since the cells serve as reservoirs for fluid, but a pathological accumulation of fluid is not generally recognized as edema until the intercellular fluid increases. It is the spreading apart of the tissue cells
FIG.
1.
ROE!'.TGEKOGRAM TAKEN THIRTY-SIX HOURS AFTER O NS ET AT WHICH TIME EDEMA HAD SUBSIDED CoNSIDER.-IBLY
by intercellular fluids which gives to the tissue the characteristic loss of elasticity. The edematous organs or tissues ftre found to have lost much of their opncity, and may nppear almost agatelike.
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
383
The normal permeability of the capillary walls for certain substances is known to be very great, in that these substances pass through freely and rapidly in either direction. What is the change which permits of an exudate? Is it neurotic, an alteration under nervous influences of the rate at which the vascular cells secrete the fluid, or is it a physical change under the influence of the irritation, which permits of a more rapid osmosis through the capillary membranes. In Quincke's edema we have to suppose in certain areas a vulnerability of the capillary walls which permits of an exudate at so rapid a rate that the efferent channels cannot deal with it, and in consequence the lymph spaces are distended and the skin swells. Why this should occur in the genital organs and bladder today and in the eyelids or lips tomorrow, these are questions for which we as yet have no adequate answer. Although the edema itself is only a symptom, it is well to bear this in mind, that the clinical features and the remarkable heredity suffice to raise it to the dignity of a disease. The vascular change is a vasomotor phenomenon, but we know so little about the true causes that there are few departments in which speculation is so easy and at the same time so useless that it behooves us to get out of the regular orthodox and old time path and propound something which, at least, in meaning ranks higher than the older usages. ETIOLOGIC THEORY BASED ON PHYSIOLOGICAL CONCEPTIONS
That the evidence of the accompanying gastro-intestinal symptoms points strongly to a protein-split poison operating in the system very much similar to any other circulating toxins in the system can not be denied. All the true proteins contain a poisonous group. This group is present in pathogenic bacteria as well as in animal and vegetable proteins and their effects on higher animals are the same. Although chemically they are not identical, physiologically they are so closely similar that up to the present time we have not been able to distinguish one from the other by the symptoms induced. One can not resist the temptation of formulating a theory t o fit
384
N. BLAUSTEIN
these facts with a true insight into the realm of probable certainty. Indeed, the theory unfolds itself and as Vaughan says, all proteins are constructed on the same model and contain a chemical nucleus, archon, or key-stone. This is the poisonous group and is practically the same in all proteins. One protein differs from all others in its secondary and possibly its tertiary groups. In these lies the specificity of proteins. Living proteins function through their secondary and tertiary groups. When the primary group is detached from its own subsidiary and specific groups it manifests its poisonous action through the avidity which it has for the secondary groups of other proteins and consequently the living protein is deprived of its capability of functioning normally. This is only a theory, but it is one which naturally suggests itself. The chemical nucleus does not become a poison until stripped in part at least, of its secondary groups, and the intensity of its poisonous action is determined by the thoroughness with which the secondary groups have been removed. When this combination is disrupted, which may be accomplished either by chemical agents or by enzymes, the chemical nucleus is set free and it becomes, in the presence of living proteins, a poison because it disrupts the same. In peptic digestion the poison becomes active at about the stage of the formation of peptone, and it has been known that peptones are quite highly poisonous when administered parenterally. Up to the present, however, we do not know whether the peptone is itself poisonous or whether its poisonous action is due to a mixture with some other digestive product. But we do know that as alimentary digestion proceeds the protein poison itself is destroyed. Wells and Pick and Yamanouchi's studies have shown that the influence of the digestive ferments of the alimentary canal on the sensitizing properties of protein is an interesting and important subject, since it bears upon the possibility of sensitization by administration through the digestive tract. They bring forth the suggestion that the sensitizing groups in the protein molecule is not itself a protein, or at least not a biuret body. However, the sensitizing group is destroyed in normal digestion,
----
-----
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
385
and it is only under abnormal conditions that protein sensitization results through the alimentary canal. To this phase of the question I will refer later. THE PHENOMENA AND MECHANISM OF ANAPHYLAXIS PURPORTING TO SUPPORT ETIOLOGIC THEORY
Portier in 1902 coined the word "anaphylaxis" meaning without protection. V. Pirquet proposed the word "Allergie" for the same condition, meaning altered energy. Although the latter is more appropriate, both terms have been used interchangably. Biedl and Kraus say, "By anaphylaxis we mean that state of specific hypersensitiveness induced in animals by protein injections, and in which symptoms of poisoning follow subsequent injections of the same protein in doses which would have no effect upon untreated animals." Now, the substance which induces the anaphylactic state is generally known as the "antigen." This implies that it gives rise to the production of an antibody. But it is not the protein as such that creates the state of anaphylaxis. When foreign proteins are taken into the alimentary canal they must be digested before they are absorbed. This means that their large molecules must be split into smaller ones, and this must be continued until there are no more protein molecules left. Every protein molecule contains a poisonous group, and in normal alimentary digestion this group is rendered non-poisonous by further clearage before absorption takes place. When a foreign protein is introduced into the blood or tissue it stimulates certain body cells to elaborate that specific ferment which will digest that specific protein. When such a protein first comes in contact with the body cells, the latter are unprepared to digest the former, but this function is gradually acquired. The protein contained in the first injection is slowly digested, and no ill effects are observable. When subsequent injections of the same protein are made, the cells, prepared by the first injection, pour out the specific ferment moreforomptly and the effects are determined by the rapidity with ;,hich the digestion takes place. The poisonous group in
386
N. BLAUSTEIN
the protein molecule may be set free so rapidly and in amount sufficient to kill the animal. This in brief is an explanation of the phenomena and chemo-physio-pathology of anaphylaxis. SYMPTOMATOLOGY
Gay and Southard were the first to study the pathological changes induced by anaphylaxis. A fall in blood pressure is the outstanding clinical feature. The genesis of the fall in blood pressure becomes an interesting question. The condition of the pulse shows that it is not due to weakness of the heart's muscle. It is due to decreased peripheral resistance from marked peripheral vasodilatation. The vasodilatation is due to a transitory paralysis of the peripheral vasomotor apparatus. This being the accepted belief of today it remains for us to determine the mechanism of production of angioneurotic edema. Having accepted the theory as far as it pertains to general anaphylaxis we must assume that angioneurotic edema is a clinical manifestation of a state of "regional anaphylactic vasoparalysis. It is not my purpose to coin an expression intended to convey to the reader the discovery of a new pathological state or disease. I use the term "regional anaphylactic vasoparalysis" merely because it conveys a correct idea and is the best applicable expression to the mind's eye, thus giving it a comprehensive meaning and not merely a theoretical phantom. I can conceive of no confusion which this term would entail in the minds of the reader, but I can conceive of the incalcuable advantage it has over the term "angioneurotic edema." To coin new expressions without endowing them with meaning and reality would be profanity, but a new expression which clarifies a situation hitherto beset with a mysterious meaninglessness through its want of a correct understanding should find encouragement through its acceptance. TREATMENT
Careful inquiry should be made as to the influence of diet, and, as a rule, some change should be made or certain articles cut off. Coffee or tea may be the offending agents. High colonic irriga-
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
387
tions are useful. Many drugs have been recommended and their number is legend. Calcium is the drug par excellence. The extract of parathyroid is almost a specific. Suprarenal extract in conjunction with thyroid also gives good results. Never use any strong purgatives. REPORT OF CASE
History. Mr. Ch. W., aged thirty-six, Russian, white, married, and a salesman by occupation was seen by me in consultation with Dr. L., his family physician, on the morning of February 10, 1926, eight hour~ after the onset of the present complaint. His previous history makes mention of having had swollen cheek, lip and eyelids on several occasions without any ascertainable cause. Patient attributes these local swellings to insect bites for want of a better explanation. Every attack of swelling came on while on his vacation on a farm in Connecticut. After close questioning it was. revealed that he partook of some goat's milk while there and drank it quite freely. These swellings used to last several hours with accompanying itching and some numbness of the areas involved. His family history was rather interesting and gone into at some length. There were five brothers and four sisters in all in the family. The youngest brother used to get swollen ear lobules regularly since boyhood about once in two years. Five years ago this brother died from "brain fever" after an illness of thirty~six hours with the appearance of localized swellings scattered over the body. His eyes were completely shut by the swelling. Death was very likely due to edema of the brain. One sister had water in both knee joints about once a year. She died in convulsions after child-birth at the age of twenty-nine. Father died of strangulated hernia and vomiting of blood for two days at the age of fifty-one. The patient has a boy of seven who on five different occasions had a swollen tongue and mumps on two occasions. His personal history is unimportant. Present history. February 10, 1926, patient awoke at 3 a.m. with a severe burning and pain at urethral meatus. Pain was cutting in character in the perineal region and had aching in the lower limbs. Had a desire to urinate every five minutes without voiding a drop and so did not get any gratification f1om repeated attempts. Felt dizzy, nauseous and had several vomiting spells of blood-tinged bile and stringy mucus. He began to feel a dragging sensation in the scrotum and penis.
-------------
388
N. BLAUSTEIN
Had same aching in both loins. At this time his penis, scrotum and both parotid glands became markedly swollen. The pain gradually disappeared as the swelling increased. There was some numbness. He had not voided up to the time when I saw him with Dr. L. at 11 a.m. Physical examination. Patient of small stature, rather stout and look1ng extremely pale, complexion pasty, expression dull and listless and hard of hearing. Of the hitter condition he never complaAned before. Eyes, nose, mouth and throat were negative. Chest: Few sonorous rales over both bases. Heart: Beats regular, slightly accelerated; pulse small, compressible, regular and 90 per minute. Temperature 97°F. by rectum. Abdomen: Somewhat distended and tympanitic; no pain; no masses felt. Liver edge 3 fingers below free margin of rib. There was marked tenderness in both loins, more over the right side. Spermatic cords in both groins enlarged but not tender. Penis, scrotum, perineum enormously edematous, pale, shiny and pitting. Urethral meatus obscured by edema of the glands (see x-ray). Pleading with the patient to void was unsuccessful. I decided to pass a No. 12F soft rubber catheter and obtained 60 cc. of a pale mucoid fluid, blood streaked here and there. No active bleeding. Chemical analysis of catheterized fluid Specific gravity.. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . Protein nitrogen ... . . .... .. . . . .. . . . . ..... .. .... . . . Non-protein nitrogen . . . . . . . . ...... . .. . ... . .... . ... Uric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sugar . . .. ... . . ... . . ... .. .. . . ... . . . ... . . . . . . ....... Total ash ........ .. .. ....... . . . . . ...... . ... . ... . ... NaCl. . . . .. . .. . .. . ...,. .. . . . . . . ........ . . .. . . .. ... ..
1. 0168 14 mgm. per 100 cc. 12 mgm. per 100 cc. trace 0 . 0654 per cent 0.814 per cent 0 .80 per cent
Cystoscopic examination. The procedure as would be expected was rather a difficult one as the bladder did not tolerate distension with any fluid medium necessary for observation. Distension with 3 ounces of boric acid solution was extremely painful and shocking to the patient. After a most tried session I could make a hasty observation of the interior of the bladder. The interior of the bladder appeared dull and extremely pale. Gelatinous edema was present throughout. To the eye it recalled the appearance and consistency of Whartons Jelly. The upper and lateral walls approximating as the segments of a closed
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
389
umbrella. The bladder had neither actual nor potential capacity. The small amount of fluid injected under difficulty distended only that part of the bladder immediately behind the prostatic urethra. The ureteral orifices could not be located, having receded in the edematous folds around them. The bladder neck was likewise of a gelatinous appearance and consistency and more fair comparison with an extreme trilobar prostatic hypertrophy seen in senile prostatics. The mucous membrane of the entire urethral canal gave the impression of being on the verge of cracking. The edema subjecting it to great tension and pressure. The patient began to void urine, in small amounts eighteen hours after the onset of anuria. The localized edematous areas subsiding and completely disappeared thirty-six hours after onset. One hour after I first saw him he was under close observation in a hospital having every facility for clinical and laboratory study. From the evidence at hand it appears that the ureters as well as the kidneys shared in and were part of an attack of angioneurotic edema or what I prefer to term "regional vasomotor anaphylaxis" of the entire genito-urinary system. The nature of the catheterized specimen, the negative venereal history, the complete anuria, the regions affected, the cystoscopic picture, the relevant family history as well as the previous history and the fact that the condition was transient, returning normal to all appearances within four days rules out the possibility of the presence of any other condition and merits the report of the case. SUMMARY
1. Angioneurotic edema is a manifestation of protein sensitiveness. 2. The hereditary nature is a potent factor of the disease. 3. The pathological physiology is an intercellular accumulation of fluid. 4. This pathological state is the result of a local vulnerability of the capillary walls which permits of an exudate into the tissues. 5. This vascular change is influenced by a vasomotor complex. 6. The poison circulating in the system and producing this complex phenomenon is a protein group contained in all protein food molecules.
390
N. BLAUSTEIN
7. Under normal conditions this poisonous group is destroyed during the progress of digestion. 8. In angioneurotic edema this poisonous group gains entrance into the system and brings about a pathological state in various segments or areas of the body. 9. The cells in the areas affected together with their blood and nerve supply have been "shocked" in the sense of anaphylaxis. 10. I propose ihe term "regional anaphylactic vasoparalysis" which conveys a clearer conception of the malady. REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27)
Manatschrift F. Prakt. Dermatologie, 1882. Cossirer's Monograph. Surgeon-General's Library, 2nd series, vol. xii. CRISPIU: Collected papers of the Mayo Clinic, 1915, vii. STARR: Nervous Diseases, Organic and Functional. MussER: Medical Diagnosis. Amer. Jour. Med. Sc., 1888, xcv, 362. Brit. Med. Jour., 1902, i, 1470. Quart. Jour. Med., 1909, ii, 135. GLORIEUX: Jour. de Neural., February 20, 1911. HoRBITZ : Munch. Med. Wach., November 14, 1911. CRoUDER, T. R., AND J. R.: Arch. Internal Med., December, 1917. CODD, J. A.: Brit. Med. Jour., June 16, 1917. EDGEWORTH, F. H .: Quart. Jour. Med., 1909, ii, 2135. Loe. cit. Zeitsch. f. Immunitats forschung, i, 676; Wien. Klin. Wach., 1909, 1513. Munch. Med. Wach., 1906. Kraus and Levaditi's Handbuch d. Technik u . Metbodik d. Immunitats forschung. Erganzungs band. Jour. Med. Res., 1908. Jour. Amer. Med. Assoc., 1909. BULLOCK, WM. : Angioneurotic Edema. Eng. Lab. Mem. Treas. of Human Inheritance, Part III, 1909, p. 38. FAIRBANKS: Hereditary edema. Amer. Jour. Med. Sc., 1904, 127; 877. GRIFFITH: Remarks on case of hereditary localized edema proving fatal by laryngeal obstruction. Brit. Med. Jour., 1902, i, 1470. MoRRis: Angioneurotic edema. Amer. Jour. Med. Sc., .1904, 128; 812; 1905, 130; 382. . OSLER, WM.: Hereditary angioneurotic edema. Amer. Jour. Med. Sc., 1888, xcv, 362. OsLER, WM.: On the visceral manifestations of the erythema group of skin diseases. Ibid., 1904, cxxvii, 1. OsLER AND McCRAE: System of Medicine.
a
Quincke's disease, Quincke's edema, hereditary edema, familial edema, giant urticaria (Milton), urticaria edematosa, urticaria tuberosa, hydrops hypostrophos (Schlesinger), and angioneurotic edema are all synonymous, although the latter term implies a knowledge of its pathology which is not as yet established. Angioneurotic edema is a condition characterized by the spontaneous appearance of localized and circumscribed edema in various regions of the body. General attention was not called to the disease until its description by Quincke in 1882. He called it "acute circumscribed edema." ETIOLOGY
In the majority of the cases no exciting cause can be discovered . Nervous influences appear to be the most important factors . Neuropathic heredity appears to have some influence upon the disease, but nervous manifestations in the patient himself are more important. Sex and periodicity of life are not of any material consequence, as, apparently, it occurs with equal frequency in both sexes, although there is a slight predominance in the male, during any period of life. Likewise, the sites of appearance of the lesions are not selective, as the lesions have been observed in practically every region of the body, and in the buccal, thoracic and abdominal cavities and their visceras. The duration of the attack varies from a few hours to six to 379
380
N. BLAUSTEIN
ten days, and the reappearance of new lesions gradually diminishing in number and prominence. SENSITIZATION TO FOREIGN PROTEINS (ALLERGY)
The suggestion made by almost countless observers that the condition is a manifestation of protein sensitiveness finds some support in the fact that almost all outbreaks follow some gastrointestinal upset. ·while it is true that this resembles much the urticaria and localized edema seen in cases of idiosyncrasy and food poisoning, conditions which in turn are allied to anaphylactic phenomena, it may eventually be determined that in these we deal with something more than simple uncomplicated vasomotor disturbances. However, of the endogenous poisons, the result of perverted metabolism- anywhere from the moment the morsel of food is rolled round the tongue until its constituents have been through the furnaces and are cast out as ashes and smoke- we talk a great deal but we know nothing, so far at least, as this disease is concerned. The outstanding positive fact about the disease is the hereditary nature of its role. Dinkelacker, Quincke, Strubing and others have reported families in which it has occurred. The hereditary form of this disease is usually severe as illustrated by Griffith who reports that both father and daughter died of acute edema of the larynx during atta,cks. We are much in the dark as to our knowledge whether the disease is transmitted through the father or mother and in this respect the Mendelian laws have been sadly neglected, not entirely commensurate with their wide usefulness in their application to other hereditary characteristics. The most remarkable case on record is that cited by Osler in whom the disease ran through five generations with almost clocklike regularity (see table 1)·. The ordinary type of Quincke's edema may occur in hysterical subjects, but the association is not so common as with neurasthenia. Edgeworth reported a series of cases in which transitory edema of a segmental distribution occurred in young subjects, and in three of the seven cases
_-\.NGIOXEUROTIC EDEMA OF GENITO-URIXARY SYSTEM
381
there were disturbances of sensation suggestive of hysteria. Sydenham first recognized an edema associated with hysteria. Charcot made it the subject of several important studies. TABLE 1
Genealogical table showing angioneurotic edema in the family of twenty I
II
Samuel
III
\
3 children, all affected one died of it
· IV
One girl affected
Hamilton
Rebecca Died of it George
Margaret Born 1762 Died 1834
V
{
i
Thomas Lizzie 2 children age d seventeen and eleven, one of whom had an attack
Almira Mary Julia Katie Edward Maggie George
Allan 10 children 3 affected Emma-Single
MollieMarried No children John ill.
f
l
4 children 1 affected
PATHOLOGICAL PHYSIOLOGY
If we understood the pathology of an urticarial wheal we rnight discuss intelligently these remarkable varieties of local edema. The accumulation of fluid in the tissues, is as a rule intercellular rather than intracellular. Intracellular accumulations do occur,
382
N. BLAUSTEIN
under normal as well as under abnormal circumstances, since the cells serve as reservoirs for fluid, but a pathological accumulation of fluid is not generally recognized as edema until the intercellular fluid increases. It is the spreading apart of the tissue cells
FIG.
1.
ROE!'.TGEKOGRAM TAKEN THIRTY-SIX HOURS AFTER O NS ET AT WHICH TIME EDEMA HAD SUBSIDED CoNSIDER.-IBLY
by intercellular fluids which gives to the tissue the characteristic loss of elasticity. The edematous organs or tissues ftre found to have lost much of their opncity, and may nppear almost agatelike.
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
383
The normal permeability of the capillary walls for certain substances is known to be very great, in that these substances pass through freely and rapidly in either direction. What is the change which permits of an exudate? Is it neurotic, an alteration under nervous influences of the rate at which the vascular cells secrete the fluid, or is it a physical change under the influence of the irritation, which permits of a more rapid osmosis through the capillary membranes. In Quincke's edema we have to suppose in certain areas a vulnerability of the capillary walls which permits of an exudate at so rapid a rate that the efferent channels cannot deal with it, and in consequence the lymph spaces are distended and the skin swells. Why this should occur in the genital organs and bladder today and in the eyelids or lips tomorrow, these are questions for which we as yet have no adequate answer. Although the edema itself is only a symptom, it is well to bear this in mind, that the clinical features and the remarkable heredity suffice to raise it to the dignity of a disease. The vascular change is a vasomotor phenomenon, but we know so little about the true causes that there are few departments in which speculation is so easy and at the same time so useless that it behooves us to get out of the regular orthodox and old time path and propound something which, at least, in meaning ranks higher than the older usages. ETIOLOGIC THEORY BASED ON PHYSIOLOGICAL CONCEPTIONS
That the evidence of the accompanying gastro-intestinal symptoms points strongly to a protein-split poison operating in the system very much similar to any other circulating toxins in the system can not be denied. All the true proteins contain a poisonous group. This group is present in pathogenic bacteria as well as in animal and vegetable proteins and their effects on higher animals are the same. Although chemically they are not identical, physiologically they are so closely similar that up to the present time we have not been able to distinguish one from the other by the symptoms induced. One can not resist the temptation of formulating a theory t o fit
384
N. BLAUSTEIN
these facts with a true insight into the realm of probable certainty. Indeed, the theory unfolds itself and as Vaughan says, all proteins are constructed on the same model and contain a chemical nucleus, archon, or key-stone. This is the poisonous group and is practically the same in all proteins. One protein differs from all others in its secondary and possibly its tertiary groups. In these lies the specificity of proteins. Living proteins function through their secondary and tertiary groups. When the primary group is detached from its own subsidiary and specific groups it manifests its poisonous action through the avidity which it has for the secondary groups of other proteins and consequently the living protein is deprived of its capability of functioning normally. This is only a theory, but it is one which naturally suggests itself. The chemical nucleus does not become a poison until stripped in part at least, of its secondary groups, and the intensity of its poisonous action is determined by the thoroughness with which the secondary groups have been removed. When this combination is disrupted, which may be accomplished either by chemical agents or by enzymes, the chemical nucleus is set free and it becomes, in the presence of living proteins, a poison because it disrupts the same. In peptic digestion the poison becomes active at about the stage of the formation of peptone, and it has been known that peptones are quite highly poisonous when administered parenterally. Up to the present, however, we do not know whether the peptone is itself poisonous or whether its poisonous action is due to a mixture with some other digestive product. But we do know that as alimentary digestion proceeds the protein poison itself is destroyed. Wells and Pick and Yamanouchi's studies have shown that the influence of the digestive ferments of the alimentary canal on the sensitizing properties of protein is an interesting and important subject, since it bears upon the possibility of sensitization by administration through the digestive tract. They bring forth the suggestion that the sensitizing groups in the protein molecule is not itself a protein, or at least not a biuret body. However, the sensitizing group is destroyed in normal digestion,
----
-----
ANGIONEUROTIC EDEMA OF GENITO-URINARY SYSTEM
385
and it is only under abnormal conditions that protein sensitization results through the alimentary canal. To this phase of the question I will refer later. THE PHENOMENA AND MECHANISM OF ANAPHYLAXIS PURPORTING TO SUPPORT ETIOLOGIC THEORY
Portier in 1902 coined the word "anaphylaxis" meaning without protection. V. Pirquet proposed the word "Allergie" for the same condition, meaning altered energy. Although the latter is more appropriate, both terms have been used interchangably. Biedl and Kraus say, "By anaphylaxis we mean that state of specific hypersensitiveness induced in animals by protein injections, and in which symptoms of poisoning follow subsequent injections of the same protein in doses which would have no effect upon untreated animals." Now, the substance which induces the anaphylactic state is generally known as the "antigen." This implies that it gives rise to the production of an antibody. But it is not the protein as such that creates the state of anaphylaxis. When foreign proteins are taken into the alimentary canal they must be digested before they are absorbed. This means that their large molecules must be split into smaller ones, and this must be continued until there are no more protein molecules left. Every protein molecule contains a poisonous group, and in normal alimentary digestion this group is rendered non-poisonous by further clearage before absorption takes place. When a foreign protein is introduced into the blood or tissue it stimulates certain body cells to elaborate that specific ferment which will digest that specific protein. When such a protein first comes in contact with the body cells, the latter are unprepared to digest the former, but this function is gradually acquired. The protein contained in the first injection is slowly digested, and no ill effects are observable. When subsequent injections of the same protein are made, the cells, prepared by the first injection, pour out the specific ferment moreforomptly and the effects are determined by the rapidity with ;,hich the digestion takes place. The poisonous group in
386
N. BLAUSTEIN
the protein molecule may be set free so rapidly and in amount sufficient to kill the animal. This in brief is an explanation of the phenomena and chemo-physio-pathology of anaphylaxis. SYMPTOMATOLOGY
Gay and Southard were the first to study the pathological changes induced by anaphylaxis. A fall in blood pressure is the outstanding clinical feature. The genesis of the fall in blood pressure becomes an interesting question. The condition of the pulse shows that it is not due to weakness of the heart's muscle. It is due to decreased peripheral resistance from marked peripheral vasodilatation. The vasodilatation is due to a transitory paralysis of the peripheral vasomotor apparatus. This being the accepted belief of today it remains for us to determine the mechanism of production of angioneurotic edema. Having accepted the theory as far as it pertains to general anaphylaxis we must assume that angioneurotic edema is a clinical manifestation of a state of "regional anaphylactic vasoparalysis. It is not my purpose to coin an expression intended to convey to the reader the discovery of a new pathological state or disease. I use the term "regional anaphylactic vasoparalysis" merely because it conveys a correct idea and is the best applicable expression to the mind's eye, thus giving it a comprehensive meaning and not merely a theoretical phantom. I can conceive of no confusion which this term would entail in the minds of the reader, but I can conceive of the incalcuable advantage it has over the term "angioneurotic edema." To coin new expressions without endowing them with meaning and reality would be profanity, but a new expression which clarifies a situation hitherto beset with a mysterious meaninglessness through its want of a correct understanding should find encouragement through its acceptance. TREATMENT
Careful inquiry should be made as to the influence of diet, and, as a rule, some change should be made or certain articles cut off. Coffee or tea may be the offending agents. High colonic irriga-
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tions are useful. Many drugs have been recommended and their number is legend. Calcium is the drug par excellence. The extract of parathyroid is almost a specific. Suprarenal extract in conjunction with thyroid also gives good results. Never use any strong purgatives. REPORT OF CASE
History. Mr. Ch. W., aged thirty-six, Russian, white, married, and a salesman by occupation was seen by me in consultation with Dr. L., his family physician, on the morning of February 10, 1926, eight hour~ after the onset of the present complaint. His previous history makes mention of having had swollen cheek, lip and eyelids on several occasions without any ascertainable cause. Patient attributes these local swellings to insect bites for want of a better explanation. Every attack of swelling came on while on his vacation on a farm in Connecticut. After close questioning it was. revealed that he partook of some goat's milk while there and drank it quite freely. These swellings used to last several hours with accompanying itching and some numbness of the areas involved. His family history was rather interesting and gone into at some length. There were five brothers and four sisters in all in the family. The youngest brother used to get swollen ear lobules regularly since boyhood about once in two years. Five years ago this brother died from "brain fever" after an illness of thirty~six hours with the appearance of localized swellings scattered over the body. His eyes were completely shut by the swelling. Death was very likely due to edema of the brain. One sister had water in both knee joints about once a year. She died in convulsions after child-birth at the age of twenty-nine. Father died of strangulated hernia and vomiting of blood for two days at the age of fifty-one. The patient has a boy of seven who on five different occasions had a swollen tongue and mumps on two occasions. His personal history is unimportant. Present history. February 10, 1926, patient awoke at 3 a.m. with a severe burning and pain at urethral meatus. Pain was cutting in character in the perineal region and had aching in the lower limbs. Had a desire to urinate every five minutes without voiding a drop and so did not get any gratification f1om repeated attempts. Felt dizzy, nauseous and had several vomiting spells of blood-tinged bile and stringy mucus. He began to feel a dragging sensation in the scrotum and penis.
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Had same aching in both loins. At this time his penis, scrotum and both parotid glands became markedly swollen. The pain gradually disappeared as the swelling increased. There was some numbness. He had not voided up to the time when I saw him with Dr. L. at 11 a.m. Physical examination. Patient of small stature, rather stout and look1ng extremely pale, complexion pasty, expression dull and listless and hard of hearing. Of the hitter condition he never complaAned before. Eyes, nose, mouth and throat were negative. Chest: Few sonorous rales over both bases. Heart: Beats regular, slightly accelerated; pulse small, compressible, regular and 90 per minute. Temperature 97°F. by rectum. Abdomen: Somewhat distended and tympanitic; no pain; no masses felt. Liver edge 3 fingers below free margin of rib. There was marked tenderness in both loins, more over the right side. Spermatic cords in both groins enlarged but not tender. Penis, scrotum, perineum enormously edematous, pale, shiny and pitting. Urethral meatus obscured by edema of the glands (see x-ray). Pleading with the patient to void was unsuccessful. I decided to pass a No. 12F soft rubber catheter and obtained 60 cc. of a pale mucoid fluid, blood streaked here and there. No active bleeding. Chemical analysis of catheterized fluid Specific gravity.. .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . Protein nitrogen ... . . .... .. . . . .. . . . . ..... .. .... . . . Non-protein nitrogen . . . . . . . . ...... . .. . ... . .... . ... Uric acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sugar . . .. ... . . ... . . ... .. .. . . ... . . . ... . . . . . . ....... Total ash ........ .. .. ....... . . . . . ...... . ... . ... . ... NaCl. . . . .. . .. . .. . ...,. .. . . . . . . ........ . . .. . . .. ... ..
1. 0168 14 mgm. per 100 cc. 12 mgm. per 100 cc. trace 0 . 0654 per cent 0.814 per cent 0 .80 per cent
Cystoscopic examination. The procedure as would be expected was rather a difficult one as the bladder did not tolerate distension with any fluid medium necessary for observation. Distension with 3 ounces of boric acid solution was extremely painful and shocking to the patient. After a most tried session I could make a hasty observation of the interior of the bladder. The interior of the bladder appeared dull and extremely pale. Gelatinous edema was present throughout. To the eye it recalled the appearance and consistency of Whartons Jelly. The upper and lateral walls approximating as the segments of a closed
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umbrella. The bladder had neither actual nor potential capacity. The small amount of fluid injected under difficulty distended only that part of the bladder immediately behind the prostatic urethra. The ureteral orifices could not be located, having receded in the edematous folds around them. The bladder neck was likewise of a gelatinous appearance and consistency and more fair comparison with an extreme trilobar prostatic hypertrophy seen in senile prostatics. The mucous membrane of the entire urethral canal gave the impression of being on the verge of cracking. The edema subjecting it to great tension and pressure. The patient began to void urine, in small amounts eighteen hours after the onset of anuria. The localized edematous areas subsiding and completely disappeared thirty-six hours after onset. One hour after I first saw him he was under close observation in a hospital having every facility for clinical and laboratory study. From the evidence at hand it appears that the ureters as well as the kidneys shared in and were part of an attack of angioneurotic edema or what I prefer to term "regional vasomotor anaphylaxis" of the entire genito-urinary system. The nature of the catheterized specimen, the negative venereal history, the complete anuria, the regions affected, the cystoscopic picture, the relevant family history as well as the previous history and the fact that the condition was transient, returning normal to all appearances within four days rules out the possibility of the presence of any other condition and merits the report of the case. SUMMARY
1. Angioneurotic edema is a manifestation of protein sensitiveness. 2. The hereditary nature is a potent factor of the disease. 3. The pathological physiology is an intercellular accumulation of fluid. 4. This pathological state is the result of a local vulnerability of the capillary walls which permits of an exudate into the tissues. 5. This vascular change is influenced by a vasomotor complex. 6. The poison circulating in the system and producing this complex phenomenon is a protein group contained in all protein food molecules.
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7. Under normal conditions this poisonous group is destroyed during the progress of digestion. 8. In angioneurotic edema this poisonous group gains entrance into the system and brings about a pathological state in various segments or areas of the body. 9. The cells in the areas affected together with their blood and nerve supply have been "shocked" in the sense of anaphylaxis. 10. I propose ihe term "regional anaphylactic vasoparalysis" which conveys a clearer conception of the malady. REFERENCES (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27)
Manatschrift F. Prakt. Dermatologie, 1882. Cossirer's Monograph. Surgeon-General's Library, 2nd series, vol. xii. CRISPIU: Collected papers of the Mayo Clinic, 1915, vii. STARR: Nervous Diseases, Organic and Functional. MussER: Medical Diagnosis. Amer. Jour. Med. Sc., 1888, xcv, 362. Brit. Med. Jour., 1902, i, 1470. Quart. Jour. Med., 1909, ii, 135. GLORIEUX: Jour. de Neural., February 20, 1911. HoRBITZ : Munch. Med. Wach., November 14, 1911. CRoUDER, T. R., AND J. R.: Arch. Internal Med., December, 1917. CODD, J. A.: Brit. Med. Jour., June 16, 1917. EDGEWORTH, F. H .: Quart. Jour. Med., 1909, ii, 2135. Loe. cit. Zeitsch. f. Immunitats forschung, i, 676; Wien. Klin. Wach., 1909, 1513. Munch. Med. Wach., 1906. Kraus and Levaditi's Handbuch d. Technik u . Metbodik d. Immunitats forschung. Erganzungs band. Jour. Med. Res., 1908. Jour. Amer. Med. Assoc., 1909. BULLOCK, WM. : Angioneurotic Edema. Eng. Lab. Mem. Treas. of Human Inheritance, Part III, 1909, p. 38. FAIRBANKS: Hereditary edema. Amer. Jour. Med. Sc., 1904, 127; 877. GRIFFITH: Remarks on case of hereditary localized edema proving fatal by laryngeal obstruction. Brit. Med. Jour., 1902, i, 1470. MoRRis: Angioneurotic edema. Amer. Jour. Med. Sc., .1904, 128; 812; 1905, 130; 382. . OSLER, WM.: Hereditary angioneurotic edema. Amer. Jour. Med. Sc., 1888, xcv, 362. OsLER, WM.: On the visceral manifestations of the erythema group of skin diseases. Ibid., 1904, cxxvii, 1. OsLER AND McCRAE: System of Medicine.
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