Studies in Some Capillary Fragility States in Dermatology

STUDIES IN SOME CAPILLARY FRAGILITY STATES IN DERMATOLOGY I. Tnx EFFECT OF HESPERIDIN AND HEsPEJUDIN METHYL CHALCONE' LEON GOLDMAN, M.D., AND EDGAR M. CORRILL, M.D. From the Department of Dermatology and ,Syphilology of the College of Medicine of the Uni-

versity of Cincinnati and the Chronic Disease Hospital of Cincinnati

As the term indicates, capillary fragility means, clinically, capillary ruptures

with visible hemorrhages in tissues. The factors associated with capillary

fragility are the pressure of blood in the vessels, the character of the blood itself such as platelet and coagulation defects, and finally the character of the capillary wall, morphologically and functionally. Since many of the widespread dermatoses do involve the superficial vascular plexuses in the skin, fragility of these vessels should have some influence on the character and course of the development of these dermatoses. In some instances, the results of these tissue hemorrhages are obvious, in others the capillary fragility may be only potential and may be even transient. In dermatology, the study of the phenomenon of capillary fragility itself is much more interesting than the study of attempts of those forms of therapy which are supposedly specific for this fragility state. Capillary fragility can be diagnosed by inspection, of course, when severe, but can not be ruled out without detailed examinations. In general, the detailed ideal examination for capillary fragility may be summarized as follows: History 1. appearance of capillary ruptures 2. hypertension 3. diabetes 4. blood dyscrasias 5. other diseases as sepsis, allergies, intoxications, etc. Physical examination 1. complete physical examination with special emphasis on vascular disturbances a. evidence of capillary ruptures in skin, mucous membranes and fundi b. degree of sclerosis of the palpable vessels a. blood pressure readings d. extent and types of telangiectasia e. extent and degree of varicosities f. venous pressure determinations where indicated Laboratory data 1. complete blood count including platelets, bleeding and clotting times and clot retraction 2. prothrombin 3. vitamin C levels in blood and urine 1 The Hesperidin and Hesperidin Methyl Chalcone were supplied by the Department of Medicine of the Abbott Laboratories, North Chicago, Illinois. Read before the sixth Annual Meeting of the Society for Investigative Dermatology, Chicago, Illinois, June 13, 1944. 129

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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

4. serum calcium 5. infra-red photographs where indicated Positive pressure tests for capillary fragility 1. blood pressure cuff test—arm (1) 2. blood pressure cuff or tourniquet test—leg 3. "flicking" test of Jones and Tocantins (2) 4. Warkany pressure test (3)

This detailed type of examination is limited chiefly to the hospital patient. In the out-patient dispensary, the physical examination, the blood pressure ci4ff test or the completely variable "flicking" test are used as methods of evaluating the degree of capillary fragility. Tests for capillary fragility have been studied ever since Koch's (4) work in 1890 with purpura in children and Rumpel (5) (1909) and Leede's (6) (1911) work on skin hemorrhages

in scarlet fever. The positive capillary fragility test produces its result by an increase in intracapillary pressure caused by the interference with the venous return. This disturbance results in relatively gross capillary damage. Perhaps in dermatology, the study of

less severe degrees of capillary permeability, such as the passage of fluid through the capillary wall, would be of more interest and concern (7). The Wright modification of the Gothuin Technic as outlined by Beaser, Rudy and Seligman (1) seems to be the best standardized pressure test technic for capillary fragility available today. In regard to this positive pressure type of test, the length of the time interval

and also the discomfort of the fifteen minutes of maintained pressure midway between the systolic and diastolic pressure, is an objection to the widespread practical use of this method. In the out-patient dispensary, especially, this interval can be used for securing more history details from the patient and for the remainder of the physical examination. Another objection to this modified Gothlin technic as indicated by Beaser, Rudy and Seligman (1), is the fact that a proper level of pressure has not been determined as yet for the patient with hypertension. Moreover, we have found that the distribution of petechiae produced by this pressure test may be diffuse or spotty and if we confined ourselves to an area 4 cm. below the elbow, this area may be entirely free of petechiae. Therefore, we have

moved this 2.5 cm. circle into a fairly uniform area of petechiae, usually directly in the antecubital fossa and we have still considered 20 as the upper limit of normal. We believe also that the character of the petechiae should be described in addition to the number as: 1. to size and shape a. small b. large (1) circular (2) irregular (3) linear c. mixed 2. to color intensity

a. faint

b. intense (1) reddish (2) bluish The visualization of the petechiae may be facilitated by the use of a strong light, a magnifying glass and some (two to four) minutes after the pressure has been released (end point of capillary hemorrhaging?) by the application of oil or xylol on the skin to visualize the deeper hemorrhages and gentle pressure on the skin to produce some anemia. Griffith and Lindauar (8) have recently proposed a petechial index after Gothlin. A normal index is eight or less. To answer some of the objections to the time required for this technic

CAPILLARY FRAGILITY STATES

131

they indicate that second stage of fifteen minutes may be omitted under certain conditions. Griffith and Lindauer state "that a normal test is not significant if done within three weeks

of a previous test."

With obvious reasons, the upper extremities have been used as the commonest sites for capillary fragility testing. Yet these should not be the only ones considered. In dermatology, attention is frequently directed to the lower extremities and some form of pressure tests should be done here also. These tests are much more difficult to do on the legs and are frequently unsatisfactory. Perhaps a larger cuff should be used on the lower extremity. We have tried the tourniquet test, pressure cuff both about the thigh and below the knee and the "flicking" test. Differences in readings between the arms and legs will be mentioned in the discussions of the cases. The modified "flicking" test and the Warkany pressure test are practical unstandardized methods for the rapid detection chiefly of marked capillary fragility. For the "capillary ifick test" modified after Jones and Tocantins (2), a tourniquet is put around the arm for five minutes and after four minutes of tourniquet pressure, the distended veins of the elbow are flicked twice by the thumb and middle finger of the examiner. A control flicking may be done just above the tourniquet on the arm. After the release of the tourniquet, the petechiae in the elbow area are counted. Zero to ten petechiae are assumed to be "normal." With this number, this too sensitive and unstandardized test will be positive in approximately twenty per cent of normal individuals. With moderate and severe states of capillary fragility the skin not over veins will show petechiae in significant numbers. The Warkany (3) pressure test, is especially valuable for children. In this test the distant portion of the little finger is squeezed for two minutes by the thumb and forefinger of the examiner and the number of petechiae visible on the flexor surface of the tip of the little finger is counted. This test is similar to Hecht's "pinching" test on the trunk, reported in 1907. It should be emphasized again that potential capillary fragility may exist, of course, in the absence of visible evidence of capillary ruptures. This potential phase can be elicited by the pressure tests for capillary fragility.

In conclusion, a reliable and practical and standardized test for capillary fragility is still needed, especially for the detection of early changes from normal. The severe case is obvious. When a test is used, its details should be described and its repetition especially after an "interval" is desirable. The patients whom we studied were divided into two main groups, namely, those with obvious and those with potential capillary fragility. Because of our special interest in the stasis syndrome, such cases were considered in a separate

class although they belong to both groups of capillary fragility. In addition, a small experimental group of patients with contact dermatitis and with contact stomatitis were treated to determine the preventive effect of hesperidin methyl chalcone on the positive patch or positive mucous membrane contact test reactions. Hesperidin methyl chalcone was used also intravenously in an experimental study of its effect on reactions to massive arsenotherapy at the Intensive Therapy Center of the Department of Dermatology at the Cincinnati General Hospital. The reason for our interest in vitamin P was our usual lack of success with

vitamin C therapy in dermatological patients. This included the use of large doses of ascorbic acid intravenously. Save for the occasional case of clinical

PACTORS

OP SIGNIPICANCE

W

Hemorrhages occurred during severe reducing diet, no blood C

9.

(R) Purpura hemorrhagica

Visceral hemorrhages included cerebral hemorrhages,exitus (5 mm.)

T

W with healed ulcer T-leg (graft) and petechiae 6. (C) Petechiae Patient a physician; no W cause could be found, allergic? W 7. (G) Petechiae with ovarian dysfunction No other factors could C-F 8. (F) Petechiae with be found menopause

W

30-40

25

40

40

10—15

50

42

5

20

30

60

TYPE OP NThSBER PRESSURE OP TEST PETECEIAE

function tests 0 Secondaryanemia, type W undetermined Detailed examination C-F negative save for T-leg menopause—no blood C level

level—scurvy? 5. (H) Statis syndrome Diabetes hypertension

4. (L)

Petechiae with psoriasis

menopause

3. (D) Petechiae with

petechiae

2. (R) Spider naevi with

rhagic bullae

1. (H) Petechiae with ac- Chronic cholecystitis; quired epidermolysis blood vit. A 24; blood bullosa with hemorcarotene 96; liver

DIAGNOSIS

RESULTS RE,rARRS

Methyl chalcone 60 No improvement Massive vitamin A mgm. daily for total therapy had been 1.0 gm. given also Crude 3.0 gm. daily for No improvement Liver and iron used total 300 gm. also Methyl chalcone 60 Improvement save Possible dietary facfor lower leg mgin. daily for total tor was checked by of 1.0 gm. increased food intake patient had also endocrinetherapy Methyl chalcone 60 Marked improve- In addition patient mgm. daily for total ment, no change took adequate diet of 0.5 gm. in the psoriasis Methyl chalcone 60 No improvement Supportive bandages mgm. daily for total also used of 0.5 gm. Methyl chalcone 60 No improvement mgm. daily for total of 0.5 gm. Had also estrogen Methyl chalcone 60 Improvement mgm. daily for total therapy,B complex of 0.5 gm. Crude 2.0 gm. daily Improvement Some improvement of for 200 distant vision reported by attending physician, had also endocrine therapy Crude 2.0 gin. daily to- No improvement tel 20 methyl chalcone 90 mgm. daily total 0.9 mgm.

TYPE OP KESPERIDUS

TABLE 1 Cases with obvious capillaryfragility

0

0

o

Bacterial allergy Had also sulfathiazole with petechiae hypersensitivity with focal eczeniatoid reaction, also lichen planus (J) Unilateral localized Petechiae would show lichen planus-purno isomorphic repuric type with pesponse, C level 0.37 techiae

17.

16.

15.

14.

2

25

40

30

30

Hesperidinmethyl ehalcone 60 mgm. total 300 mgm. Hesperidinmethyl chalcone i.v., 200 mgm. Intravenous hesperidin Improvement methyl chalcone 200 mgm. Methyl chalcoxie intravenous, 4 doses every 5 days of 50 mgm. each

rest on hospital diet Purpura disappeared; fragility test 25 after first dose and 10 after fourth dose

Patient was at bed

No improvement

Methyl chalcone 60 No improvement in peteehiae, mgm. daily for total of 2.0 gm. lichen plnus or of the sulfathiazole hypersensitivity varied Methyl chalcone 60 The lichen planus le13—41 sions gradually bemgm. daily for total 2.4 gm. daily for total came atrophic, still 186.0 gm. bluish brown, the capillary fragility tests showed increased fragility after the hesperidin therapy 25 No improvement Large transient purHesperidin methyl ehalcone 60 mgm. for puric areas aptotal 300; 600 mgin. peared on the lower methyl chalcone; I.V. legs after the start 300 mgm. given with of hesperidin and calcium and repeated vitamin K therapies weekly injections of 200 mgm. for 3 weeks 50 Intravenous hesperidin No improvement Had ascorbic acid also in large doses methyl chalcone 50—55

* Positive pressure tests: W, Wright modificationof Gothlin technic; C-F, capillary flicking test; T, tourniquet test (fifteenminutes).

W (K) Neurodermatitis No systemic findings with petechiae save surgical menopause W (H) Congenital fami- No secondary anemia lial hereditary telan- at time of observation giectasia W (M) Poikilodermaatro- Marked hypertension; latent syphilis; blood phicans vasculare C vitamin 0.39 W (L) "Nutritional de- C level not obtained ficiency" with purpura W (K) Tinea epidermo- Hypertension 150/105; latent syphilis phytosis with purT-leg pura of lower legs

13.

W

(F) Hemorrhagic sar- Prothrombin slightly coma of Kaposiwith elevated; platelets localizedpurpura 125—185,000;blood C and ecchymoses with 0.25 secondary infection

W

W

12.

11.

10. (S)

cc

L'rj

'-5

cc

0

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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

and subclinical scurvy patients which we have seen, and one excellent result in Schamberg's disease (C level in blood not lowered) in addition to elastic bandages on the legs, and some questionable results in a patient with scleropoikioderma, the remainder of our therapeutic trials in dermatOlogical patients with capillary fragility states have been a failure. In another case of Schamberg's disease with decreased capillary fragility tests in the legs also, a deliberate attempt was made to try to prove this increased capillary fragility on the legs by means of treatment with positive and negative pressure glass boot (Paveaux) used for peripheral

vascular disease. After several treatments with this, the discrete lesions of Schamberg's Disease on the legs were transferred into a solid brown hemosideric

pigmentation "stocking" extending from just below the ankles to the edge of the cuff of the apparatus. No vitamin C was given to this patient. After this experience he left the clinic. Blood vitamin C levels were of no help either in the diagnosis of the capillary fragility state or in response to vitamin C therapy. The blood vitamin C level was of help only in ruling out scurvy, that is scurvy

is not present with blood levels above 0.6. Scarborough (9) has indicated that "a deficiency of ascorbic acid is not necessarily complicated by low capillary

resistance." In patients with reactions to arsenic in the arsenotherapy of syphilis, especially with dermatitis, it was difficult to determine the role of vitamin C since many diverse therapies were always tried at the same time.

There has been much controversy concerning the concept of vitamin P. Hazel (10) claims "that is highly questionable whether such a vitamin exists." Although yellow plant pigments, the flavones were studied since 1931 by Akamatsu and in 1935 by Fukuda, there was no great interest until the reports by Armento and Szent-Gyorgi in 1936 of the "vitamin-like action of two crude flavone preparations from lemon peel, citrin and eriodiction, the treatment of abnormal capillary permeability and fragility (11)." Conflicting reports were then published on the value of this group. In 1938 Szent-Gyorgi (12) reported that he could not confirm his results of two years previously. Detrick, Dunn, McNamara and Hubbard (13) found that in vitamin C deficient guinea pigs, citrin neither decreased the hemorrhagic condition

of scurvy nor prolonged the life of the animal. Although the original work done by Szent-Gyorgi and his associates was with extracts of Hungarian red pepper and lemon juice (12), the substances used in present day experiments are made usually from oranges and lemons. Extracts from lemon peel include hesperidin glucoside and eriodicytol glucoside, but orange peel contains chiefly hesperidin glucoside and no eriodicytol (11). It is important to remember that various general factors determine type of extract secured. These factors include ripening of the fruit and the type isolation technic adopted. Although there is not complete agreement on this subject (14), for the purpose of this report it may be assumed that the forms of hesperidin include: 1. crude—water soluble yellow pigment, inert pectinous material; 2. chalcone—supposedly the biologic active component, made from hesperidin by treatment with alkali, unstable in storage and heating in neutral water;

CAPILLARY FRAGILITY STATES

135

3. methyl chalcone—made by methylation of the hydroxyl group

a. readily soluble in water b. causes depression of blood pressure c. has an effect in capillary fragility. Rudy, Beaser and Seligman (15) have summarized critically the reports on the use of vitamin P clinically and indicate the wide variety of patients for whom

these compounds have been tried. Moreover, these authors themselves obtained negative results with both orally and parenterally administered vitamin P in diabetic patients with increased capillary fragility and also in two patienta with thrombopenic purpura and one case of rheumatoid arthritis. The time interval oL the capillary fragility test after the intravenous compound was not given. Scarborough (0) believes that some forms of purpura may be on a nutritional basis. These hemorrhages, in ascorbic acid deficiency, may be large and be found in the subcutaneous tissue and in muscle. The hemorrhages of de-

creased capillary resistance are fine in type and are circumpilar. He further believes, that vitamin P deficiency is characterized by a decreased capillary resistance, feelings of lassitude and easily induced fatigue, pains in the shoulders

and legs and no hematological abnormality. Goldfarb (16, 17) has had some success in the treatment of psoriasis with citrin lemonade. Experiences with vitamin P in arsenotherapy will be detailed later. In seventeen patients with obvious capillary fragility, crude hesperidin and hesperidin methyl chalcone in adequate doses were seemingly without any lasting clinical effect as regards capillary fragility. In the patients in whom clinical improvement was reported there were other and more likely factors which could explain this improvement. In these patients, likewise, the pressure tests became normal as the condition improved. In three patients in this group, and in three patients from medical services, the methyl chalcone was used intravenously. Mild reactions from the hesperidin were noted in only one case even when it was used intravenously both in this and in our other series of cases. No immediate blood pressure reductions were observed. In all the intravenous

cases the capillary fragility tests were repeated within ten to fifteei minutes after the intravenous injections and in four patients significant decreases in capillary fragility were obtained and in several patients this decrease was reported to have been obtained repeatedly. In Case 12 (the Kaposis (1)) sometimes a slight decrease was obtained. In Case 7 there was a slight increase which was not maintained after four doses were given. There was no significant clinical improvement in any of the patients. Additional clinical notes are worthy of recording on some of the cases. In case 1, epidermolysis bullosa with petechiae, there has been little comment in the

literature on capillary fragility in this acquired form although of course, hemorrhagic bullae have been noted before. It is interesting that in four of our patients, all women, the capillary fragility was associated, at least in time relationship, with endocrine disturbances. It is probable also that the clinical improvement was due to the endocrine therapy. Five cases of lichen planus were examined for capillary fragility, two of these patients

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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

had clinical capillary fragility and one had potential capillary fragility. All three patients were of middle age and without any known factors for this capillary fragility. A youth with generalized severe lichen planus had no capillary fragility. Case 10 of this series had had allergic purpura (bacterial allergy?) for years. After the use of nose drops containing sulfathiazole, a focal eczematoid sulfathiazole eruption developed on an old healed burn area previously treated with sulfathiazole ointment. Associated with this was a very severe urticaria and angioneurotic oedema. Negative passive transfer tests, both intradermal and patch, were obtained with sulfathiazole solution (not incubated in serum.) A generalized lichen planus developed in this patient and has recurred since. No isomorphic response would develop from the petechiae but the lichen planus lesions were occasionally purpuric. Patch tests to sulfathiazole were of the eczematoid type and did not change into lichen planus types even when done during flare up episodes of lichen planus. Bacterial skin tests likewise did not become purpuric although at times they were severe. Case 11 revealed a unilateral purpuric lichen planus with confirmation of this diagnosis obtained on biopsy with the Prussian Blue reaction. Here too, the isomorphic response, did not occur from the pressure tests, nor from scratching the skin. Only deep smooth brownish pigmentation followed the scratching but there were no lichen planus lesions. At present, this patient could be considered as unilateral localized purpuric and hemosideric lichen planus. She was treated over a period of approximately four months and after this time showed no striking clinical response, the purpuric lichen planus gradually becoming browner. The capillary fragility tests actually showed some increased fragility with 13 as her pretreatment level and 41 as final post treatment test. Earlier after more than two months of therapy with the crude hesperidin her fragility tests were 28 and 27. Case 12 was an elderly man without hypertension who developed an indurated bluish tumor of the scalp following trauma. This tumor had persisted for six months and was associated with repeated episodes of soft tissue hemorrhage. In spite of the scalp location, hemorrhagic sarcoma of Kaposi seemed likely because of the angiomatous and telangiectatic

areas about this tumor and gradual spread of the tumor and the good general health of the

patient. This diagnosis was confirmed by biopsy. His laboratory tests as the charts indicates were abnormal and likewise his capillary fragility. There was no response to small doses of oral methyl chalcone. Occasionally there was some reduction in the capillary fragility test when the methyl chalcone was given intravenously, once together with calcium and ascorbic acid, but this reduction was not constant. Vitamin K was used also. The hemorrhage and discoloration faded somewhat but the tumor was unaffected. X-ray therapy was started on the tumor. The tumor then became infected secondarily and required incision and drainage. In another patient with extensive hemorrhagic sarcoma of Kaposi including upper and lower extremities, an elderly Italian man, capillary fragility tests were negative both on the arm and leg. This was surprising on the leg because of the purpuric ciaracter of some of the areas. These tests were done before and after roentgen

therapy Certainly in this patient because of the actual presence of the lesions in both extremities and associated lymphoedema there must have been increased intracapillary pressure. No venous pressure studies were done. Intravenous hesperidin was used on the medical service on several patients. An elderly lady (patient of Dr. Ogura) with biliary cirrhosis and thrombocytopenic purpura was given intravenous hesperidin. Shortly after this, the previously strongly posifive fragility test became negative but soon became strongly positive again. These tests were all done when the patient was in shock. Another patient on the medical service (patient of Dr. Richard Vilter) with Henoch's purpura showed transient but definite changes in the capillary fragility tests immediately after intravenous hesperidin. Three cases of nutritional deficiencies with purpura were observed and all these occurred during the course of reduction diets. Although no blood C levels were obtained the patients were clinically scurvy. One showed improvement, including the capillary fragility

test, when an adequate diet and hesperidin were used (Case A). One patient showed a

CAPILLARY FRAGILITY STATES

137

transient improvement in the capillary fragility test after 200 mgs. of the chalcone were

given intravenously (case 16). Immediately following the injection this patient complained of a chill and headache. This disappeared quickly. The patient was not given vitamin C. He left the hospital before additional studies could be secured and since no vitamin C levels were obtained on him, the diagnosis of scurvy could not be made definitely

in his case.

In a dermatological patient the state of potential fragility can be suspected (in the absence of petechiae) by the bluish cast to some of the lesions, especially on the lower extremities and by a linear reddish streaking of some of the excoria-

tions. Even without such hints and without the systemic background for the lowering of capillary resistance such as hypertension, diabetes, blood dyscrasia, etc. one can frequently detect such "potential" capillary changes by the positive pressure test. This is shown in table 2 by the appearance of capillary fragility

in diverse conditions including even generalized contact dermatitis. In one patient seen some years ago with hemorrhagic poison ivy dermatitis, the strongly positive tourniquet test, done in those days, became negative after the dermatitis

subsided. Three cases of rosacea without hypertension showed capillary fragility, two mild and one severe. The severe fragility was found in a young woman. To date these fragility states are still present one not affected by oral hesperidin, the other not given hesperidin. Capillary fragility was found in four eases of spider naevi, one of these in a child. Two of the cases were congenital in origin, one was associated with pregnancy and one with rosacea. Six cases of severe urticaria were studied in sufficient detail. Two were acute and four were of the chronic type with the etiology undetermined. Two of the acute cases were psychogenic in type. One of these, a middle aged woman with hyper-

tension and moderately severe coronary disease, showed approximately 100 petechiae on capillary fragility testing with many of these hemorrhages huge, fluffy and bluish, in type. With the spontaneous disappearance of the urticaria under sedation, the capillary fragility test was reduced to only 20—30 and of the

fine pale type. She received no hesperidin. Rapaport and Klein (12) have noted increased fragility in allergic children. They reported improvement with vitamin P. The value of the leg and arm capillary fragility tests was demonstrated in a young girl with erythema nodosum, probably streptococcic in origin. The test was negative on the arm during the early phase of the disease and moderately positive on the legs, 10—15 with the tourniquet test. There was pain and increased bluishness of the lesions on the legs tested. With the subsidence of the erythema nodôsum, the faint bluish areas were not influenced by the test and a tourniquet test and a Wright modification of the Gothlin test on the leg showed no petechiae at all. A patient with erysipeloide epidermophytide with large varicosities had negative capillary fragility tests on the forearm and negative tourniquet tests on the affected and unaffected leg. When an individual with a previous and established capillary fragility develops a generalized dermatitis some of the lesions may have purpuric qualities not only on the lower extremities but even on the upper arm. Scratch marks

No previous history of spider naevi

Pollen asthma nickel contact tests positive patient 44 years old 8. (S) Rosaceawith spider naevi No hypertension, no gastro-intestinal disturbances

7. (K) Atopic dermatitis

naevi

6. (W) Pregnancy with spider

turbances

Severe vasomotor dis-

5. (M) Contact dermatitis (oil)

tasia

No hypertension

(B) Contact dermatitis (hair Diabetes dye)

4. (B) Rosacea with telangiec-

3.

2. (M) Lichen planus

40

60

W

50

40

30

40

40

50

NUMBER 01' PETECRIAR

W

W

T

W

W

W

W

Obese young individual

1. (D) Contact dermatitis (developer)

considerable edema legs, bluish cast to dermatitis, no hypertension No hypertension; chronic cholecystitis

TYPE 01' PRESSURE TEST

FACTORSOF SIGNIFICANCR

DIAGNOSIS

RESULTSAND REMARES

greatl3t

Methyl chalcone 60 No improvement, spider nae'vi removedby electro-desiccation mgm. daily for 0.5 and rosacea improved under gm. dietary restrictions and sulphide preparations

gm.

Methyl chalcone 60 Petechiae later appeared on legs but all disappeared after dermgm. daily for 0.12 matitis subsided gm. Methyl chalcone 60 No improvement, patient still in pregnancy period vitamin mgm. daily for 0.5 gm. C, calcium, vitamin K also given Methyl chalcone 60 No improvement in capillary mgm. daily for 0.5 fragility, dermatitis improved

gm.

Methyl chalcone 60 Improvement only as lichen planus subsided, occasional mgm. daily for 0.5 petechiae began to appear on gm. legs Methyl chalcone 60 No improvement during course of dermatitis, patient lost to mgm. daily for 0.5 observation gm. Methyl ehalcone 60 No improvement ingm. daily for 0.5

gm.

Methyl chalcone 60 Improvement occurred only after contact dermatitis subsided mgm. daily for 0.5

TYPE OP RESPERIDIN

TABLE 2 Cases with potential capillaryfragility

Hypertension

Obesity diabetes

15. (M) Urticaria psychogenic

16. (S) Nodular vasculitis

50 100 20—25

w W W T-leg

10—is

0

20—30

30

50

30

None given

None given

None given

None given None given None given

None given

None given

No change No change Improved when erythema nodosum cleared; lesions aggravated by T test; then W on legs, 0; T on legs, 0 Rosacea improved under local measures arid diet, fragility test not affected Test 20—30 after urticaria sub. sided under sedation When "nodular vasculitis" reappeared (rest, vaccines, penicillin, weight control) capillary fragility test normal

Petechiae appeared over neck and along scratch marks; capillary fragility disappearedwhen dermatitis subsided Improved before urticaria disappeared under vitamin C?

Wright modificationof Gothlin technic; C-F, capillary "flicking" test; T, tourniquet test (fifteen minutes).

Young girl, premenstrual

* Positive pressure tests: W,

w

C-F

for urticaria which proved to be psychogenic, no blood C value w Child 8 years old w Congenital W-arms Strep. T-legs

Severe elimination diet

petechiae

No previous history of

14. (H) Rosacea

11. (R) Spider naevi 12. (G) Spider naevi 13. (W) Erythema nodosum

with peteehiaescurvy

10. (H) Urticaria dermographism

9. (L) Poison ivy dermatitis

I-

C)

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THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

may be outlined with linear petechial hemorrhages. One woman whose history indicated a capillary fragility of some years duration developed localized scleroderma of the trunk and later a contact dermatitis. The localized soleroderma showed with regard to the vascular component, extensive telangiectatic markings without petechiae. Pressure with the fingers on the scleroderma area produced no petechiae. Many of the contact dermatitis papules and vesicles were pur-

puric. Blood pressure cuff test on one arm made all the lesions of contact dermatitis below the area of pressure purpuric and produced many petechiae. This capifiary fragility had no influence on the duration of the dermatitis and was present after the dermatitis cleared. Another patient with marked capillary fragility developed maculo-papular syphilides, none purpuric. There were no abnormal hematological findings. Pressure cuff produced purpuric changes only in some of the lesions on the tested arm. Alter the syphilis improved the capillary fragility was not marked. An infant with unusually severe hemorrhages from a small granuloma pyogenicum of the face was found to have a

capillary fragility. Examination revealed a hypoprothrombinemia. When one does positive pressure tests on individuals with dermatitis of the extremities

as indicated above, no definite patterns of petechial or purpuric changes or mottling can be established. Certain irregular areas assume darker hues, some of the lesions may present halos of peculiar light cherry red color. On the legs circumpilar mottlings may be scattered below the tourniquet. Superficial lesions of stasis syndrome become bluish red. Here too no definite patterns can be made out. it is possible that the variability of the patterns on the extremities is due to location of the venule or capillary (or other vascular component) involved, the depth in the skin of this vessel, the caliber of this vessel,

the degree of intravenous and intracapilary pressure and the degree of permeability of the vessel wall. Detailed testing of two severe bullous dermatitis herpetiformis cases in children and one mild ease in an adult showed no capillary fragility and no hemorrhage into the bullae below the pressure area. Stasis syndrome has been a long time study of one of us (L. G.) with special

emphasis on the prophylaxis and the therapy of the early phases. Together with Dr. Louis G. Herrmann of the Department of Surgery and Director of the Peripheral Vascular Disease Service of the Cincinnati General Hospital a detailed study of the stasis syndrome has been initiated. This study will include in addition to the general complete study of the patient, the analysis of the local vascular dynamics, cutaneous physiology and pathology, bacteriologic and mycologic examinations and immunologic responses and also soft tissue x-ray

studies of the degree and extent of dermal and subcutaneous fibrosis. This latter study is included because we have felt that severe drmai and subcutaneous fibrosis "honeycomb type" means a poor prognosis as regards the possibility of re-establishing good circulation in the lower leg. For an arbitrary classification of the clinical picture of stasis syndrome, we are dividing it into four phases. In any one of these phases dilated veins may

be present in varying degree or absent not only on inspection and thorough testing but even through infra-red pictures.

141

CAPILLARY FRAGILITY STATES

Phase I—petechiae, zero to minimal cutaneous reactions Phase II—petechiae, hemosiderosis, erythemato-squamous reaction Phase III—petechiae, hemosiderosis, erythemato-squamous and eczematoid reactions, edema, induration Phase IV —ulcer, edema, dermatitis

We are reporting a portion of our study on Phase I. This work includes observation of eleven patients for periods varying from one and one-hall to two and one-half months at the Chronic Disease Hospital. The patients were all up-patients and had the Wright Modification of the Gothlin technic done on the upper extremities and the tourniquet test (fifteen minutes) done on the lower extremities. The tests were repeated at intervals. No local therapies were used. In this group of patients, all in the upper age groups, fragility was increased in six, but only in three without hypertension. Tests on the legs were uniformly

unsuccessful but did not, at least seem to aggravate Phase I of the stasis syn-

SM3OTH, CLEAR

SCALING

REDNEU. LYMPHOEDEMA• ECZCIII&TOID DERMATITIS. IDES

PflECHIAt PEkIOSIDEROSIS

+ + OR 0

+ORO SUBJECTIVE

0

++ + OR ++

+ ORtt 010 SUGHT PIURITUS, BURNING

+ OR It ++

+ ORttOtO PAIN, BURNING, PRURITUS

ULCfR, LThWdOCOCMA, CCZCMATOID DUMAmp% IDES

+ OR ++ ++

+01+1 010 PAIN, BURNIH6, PRURUUS

FIG. 1. CLINICAL PHASES OF THE STASIS SYNDROME

drome. In spite of the long maintained dosage schedule, save for the few cases treated only with intravenous hesperidin methyl chalcone, clinical improvement

was not striking. In spite of changes in the capillary fragility tests, many of them not significant, none of the lesions were aggravated under hesperidin therapy. The relationship between blood pressure level and number of petechiac

was shown clearly and again ifiustrates the need for a "proper level" for the hypertensive patient. In common with our experiences with other types of cases, four of the six patients given intravenous hesperidin methyl chalcone showed some transient decrease in the capillary fragility test, two showed an actual increase. No depression of blood pressure was noted in any of the cases

in whom the intravenous therapy was given. In one patient with a blood vitamin C level of 0.53, 5.1 gm. of ascorbic produced no improvement clinically nor in the capillary fragility test. Case 2 was also given ascorbic acid without

improvement. In another patient, not of the Chronic Hospital series, large doses of vitamin C given over a period of three months did not affect the in-

TABLE 3 Capillary fragility studies in stasis syndrome (11 patients) BLOOD

PRES- —

RAISE

SURE

POSITIVE PRESSURE TESTS

.__. — — — —

AGE LEVEL

TYPE EESPERWSN AND TOTAL DOSAGE

RESULTS AND REMARKS

FOR TEST

1. G. H

78 125

12 2 36 0 17 3 Crude 104.0gm. Some improvechalcone, 420

ment

mgm.

2. G. Z

66 100

13 2 24 0 39 0 Crude 170.0 gm. No improve30 1 15 1 M. chalcone, ment, blood 4.2 gm.

C. 0.37, also no

improvement

under 4.2 gin. ascorbic acid

3; T. N

71

105

49 4 24 2 58 1 25

1

15 0 4. J. M

76

85

19 0

Somgm.I.V., 5 doses

8 4 36 3 22 1

20 0 30 0 12 0

5. W. T

70 125

62 2 15

1

22

1

11 0 6. L. T

7. W. M

54 140

71

105

Crude 128.0 gm. Some improve. merit M. chalcone,

Crude 90.0 gm. No improvement M. chalcone, 50 mgm. I.V., S doses

28 2 Crude 125.0 gm. No improve.

32 0

M. chalcone,

merit

50 mgm. LV., 5 doses

57 0 40 0 24 2 M. chalcone 50 No improve12

1

mgm. I.V., 5

merit, vitamin

doses

C 0.53

23 0 36 2 M. chalcone 50 No improvemgm. I.V., 5

merit

doses

8. J. C

77

110

20

1

50 0 18 1 M. chalcone 50 No improve. mgm. IV., 5

merit

doses

9. L. T

54

135 24 2 21 0 23 0 No hesperidin No improve. merit, given 5.1 gm. ascorbic acid

10. G. D

65

105

33

1

14 1

Crude 30.0 gm. Some improvemerit M. chalcone, 2.41 gm.

11. W. W

78

150

61 2

23 1

Crude 39.0 gm. No improve. ment M. chalcone, 2.6 gm.

Positive pressure tests: arm, Wright modification of Gothlin technic; leg, tourniquet,

fifteen minutes. Tests during therapy, usually when changed to another type of hesperidin. Tests after intravenous hesperidin methyl chalcone, tests done after first and then after

last injection. 142

CAPILLARY FRAGILITY STATES

143

creased capillary fragility nor the petechial and purpuric aspects, in Phases 11111 of the stasis syndrome. With the pressure technics now available, we have not proved intrinsic capillary fragility even in the lower extremity in Phase I although clinically there is evidence of damage to vessel wall. However, it seems likely that the capillary fragility when it is present in Phase I is more often a localized process and due in part to structural changes in the vessel wall as part of the vascular scierosing process and also to the increased hydrostatic pressures of the venous columns. Systemic conditions by producing circulating noxious agents may initiate or aggravate vessel wall damage in the lower extremities. Although only few vitamin C levels were done, vitamin C therapy previously had not been found to be of much value in the systemic therapy of this phase. The only practical recommendations available at present are first, measures to improve the circulation by means of rest, elevation and supportive bandages and the avoidance of increased local heat, and second, measures to prevent irritation sensitization and infection of the skin in this area by means of proper detergents especially in cold weather, bland oils and creams, early therapy for minor lesions and as far as possible, prevention of local trauma. The general therapy includes the treatment of any systemic condition present, especially if this condition adds to increased intra-vascular pressure or to actual damage of vessel wall. From work with rabbits, Goldstein, Stolman and Goldfarb (20) concluded that when methyl chalcone was given together with mapharsen, more animals survived than when mapharsen was given alone. They believed further that the methyl chalcone did not inhibit the spirocheticidal activity of mapharsen

in vitro but it actually had an independent spirocheticidal activity on the spirochaete. The brain damage in arsenical encephalitis they interpreted as due to increased permeability of the capillary wall. Gorrie (21) reported an arsenical purpura hemorrhagica with severe thrombopenia, treated with hesperidin and ascorbic acid. In a small series of nine patients receiving the five day continuous intravenous drip with only 200 mgm. mapharsen daily, preceded by two injections of bismuth,

the effect of intravenous hesperidin methyl chalcone was studied. The Wright Modification of Gothlin technic was done before therapy started, during therapy and after therapy was completed. During and after the intravenous drip the tests were not done on the arm in use or immediately after use. No increased capillary fragility was detected in eight of the nine patients at any time. This small series included also one fatal case of hemorrhagic encephalitis starting abruptly on the sixth day after a completely uneventful five day period of continuous drip. In only one of the patients could increased fragility be demonstrated and that

only on the sixth day and seventh day. This patient developed thrombophlebitis appearing after a transient type of phlebitis developed in the opposite arm and forearm. No capillary fragility tests were done during the acute phase of the angiospasms but later on the sixth day, this test done on the arm, which

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had a definite thrombophiebitis, showed 40 petechiae although this test had been

negative on the third day of the drip. Hesperidin was given intravenously to this patient, only one injection of 300 mgm. with some definite reduction change in the fragility test but this was only transient. In spite of the absence of decreased capillary fragility in the other patients, intravenous hesperidin methyl chalcone in doses 50 to 300 mgm. was used in an effort to help the nausea

and emesis and also to attempt to relieve the angiospasms which occurred in practically every case. The hesperidin was completely without effect. In our small series, other vitamin compounds were not used. The angiospasms, however, could be relieved by the use of Spasmalgin as suggested by Weiner (22).

In a patient not of this series, who developed vesicular arsenical dermatitis with petechiae and with normal hematological findings, the fragility test was positive, 35. The hesperidin methyl chalcone was given orally, 60 mgm. daily for a total of 1.0 gm. The petechiae did not disappear and the fragility test did not change until the arsenical dermatitis cleared. Hesperidin methyl chalcone was tried in daily doses of 60 mgm. for a period of two weeks in an individual who was known to be very sensitive to nickel, and who had had increased capillary fragility only during the course of her nickel

dermatitis. After the end of this time contact tests to nickel sulfate done on the skin and in the mouth with the technic which we have reported (23) showed strongly positive reactions in the skin and in the mucous membrane of the lip. A similar unsuccessful result was obtained in a patient who had a marked hypersensitivity to mercury and who presented linear petechiae in. her excoriations during the episode of her dermatitis. These petechiae disappeared and her in-

creased capillary fragility was reduced after the dermatitis subsided. The contact tests to mercury were done on the skin and on the buccal mucous membrane. Hesperidin methyl chalcone, given in the same doses and over the same time interval, was unsuccessful in preventing positive patch test reactions in three patients who exhibited no evidences of increased capillary fragility. Ascorbic acid had previously been used in this type of experiment without success. In general then, so-called vitamin P was of no clinical value to us in the prac-

tical therapy of the capillary fragility state in dermatology. However, there was an occasional rapid and fugitive and even striking effect on the capillary fragility test when the hesperidin methyl chalcone was given intravenously. This may mean that there is some factor in this compound which does affect capillary permeability. When the chemistry of this compound has been worked out in greater detail and its preparation standardized, then more uniform results may be obtained and greater quantities may be employed in clinical trial under critical analysis. The therapy of capillary fragility in the dermatological patient may be outlined briefly: 1. the general and/or the local treatment of the particular condition underlying the capillary fragility. 2. when evidences of vascular damage are found on the lower extremities efforts should be made to avoid aggravation of the condition by rest and

CAPILLARY FRAGILITY STATES

145

elevation of the leg, prevention of irritation and increased heating of the

skin. 3. ascorbic acid may be given in proved ascorbic acid deficiency.

4. calcium may also be used as one of the therapeutic agents of lesser importance. 5. intravenous hesperidin or hesperidin-like preparations should be used only

in purely investigative studies under controlled critical conditions. The present oral preparations now available are of no value. Brief note should be made also of the much more important occurrence of visceral capillary fragility, as for instance cerebral hemorrhage. In the case reported by Gorrie (21) retinal hemorrhages occurred after the purpura on the skin cleared. He mentions also that this sequence has been found with cerebral hemorrhages. The possibility of visceral capillary fragility must always be considered then in the analysis of the patient with petechiae and purpura and even with improvement in the state of capillary fragility in the skin. SUMMARY AND CONCLU5ION5

The study of the capillary fragility state in dermatology reveals this state to be a rather common one, usually not of great practical interest unless it be severe or on the lower extremities where it may initiate a stasis syndrome. Petechial, purpuric or hemosideric manifestations may be added to the cutaneous picture when capillary fragility complicates dermatitis. The need for a standardized capillary fragility test is still great especially in

the detection of the early or borderline case. The Wright Modification of the Gothlin technic appears to be the best standardized test available but this may be impractical under some circumstances and too sensitive in patients with hypertension. The unstandardized tourniquet, "flicking" and Warkany pressure tests may also be used. Tests for capillary fragility determinations on the lower extremities were unsuccessful.

Obvious capillary fragility with actual hemorrhages and potential capillary fragility, detected by capillary fragility tests, were found in a variety of common and uncommon dermatological conditions. A classification of stasis syndrome was given and the prevention and therapy of the early phases was emphasized. Crude hesperidin orally and hesperidin methyl chalcone both orally and in-

travenously were found to be of no value in the treatment of these capillary changes.

In a small series of patients undergoing the intensive arsenotherapy, no decreased capillary resistance could be detected save in one patient who developed

a thrombophlebitis. The series also included a fatal case of hemorrhagic encephalitis. Hesperidin methyl chalcone did not prevent positive contact tests on the skin and in buccal mucous membrane, of individuals with previous episodes of con-

tact dermatitis and contact stomatitis. Transient and at times striking decreases in the positive capillary fragility

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test were noted occasionally immediately after the intravenous use of hesperidin

methyl chalcone. This suggests that some hesperidin mixtures may contain small amounts of a utilizable substance affecting capillary permeability. REFERENCES 1. BEAsER, CAPT. SAMUEL B., RUDY, ABRAHAM, AND SELIGMAN, ARNOLD M. Capillary

fragility in relation to diabetes mellitus, hypertension and age. Arch. Tnt. Med. 73: 19 (Jan.) 1944. 2. JONES, HAROLD W., AND TocANTrns, LEANDRO M. A simple test for capillary resis-

tance: the "flicking" test. Amer. J. Med. Sci., 185: 535 (April) 1933. 3. WARRANT, JoSEPH. Personal communications. 4. KOCH, C. Quoted by JONES AND TOCANTINS. 5. RUMPEL. Quoted by BEASRE, RUDY AND SELIGMAN. 6. LEEDE, C. Quoted by BEASER, RUDY AND SELIGMAN.

7. LANDIS, EUGENE M. The passage of fluid through the capillary wall. Amer. J. Med. Sci., 193: 297 (March) 1937. S. CEIFFITH, J. Q., JR., AND LINDAUER, M. A. Petechial index after Gothlin, personal communication. 9. SCARBOROUGH, HAROLD. Deficiency of vitamin C and vitamin P in man. Lancet 2: 644 (Nov. 23) 1940. 10. HAZEL, GEORGE R. Personal communications.

11. HIGEBY, RALPH H. Chemical nature of vitamin P. J. Am. Pharm. Assoc., 32: 74 (March) 1943. 12. RAPAPORT, HOWARD G., AND

KLEIN, SYLVIA. Vitamin P and capillary fragility. J.

Pediat., 18: 321 (March) 1941. 13. DETRICK, L. E., DUNN, MAX S., MCNAMARA, L., AND HUBBARD, M. E. The effect of

vitamin P (citrin) on vitamin C deficient guinea pigs. Jour. Lab. Clin. Med., 25: 684 (April) 1940.

14. WAwEA, C. A., AND WEBB, J. L. The isolation of a new oxidation reduction enzyme from lemon peel (vitamin P). Science, 96: 302 (Sept. 25) 1942. 15. RUDY, ABRAHAM, BEASEE, CAPT. SAMUEL B., AND SELIGMAN, ARNOLD M. Vitamin

therapy in increased capillary fragility of diabetes mellitus. Arch. Jut. Mcd., 73: 23 (Jan.) 1944.

16. GOLDFAEB, ARTHUR E. Treatment of psoriasis with lemon citrin (vitamin P) citrin lemonade and ascorbic acid. Arch. Dcrmat. & Syphilol., 43: 536, 1941. 17. GOLDFARB, ARTHUR E. The cause of psoriasis. New York State J. Med., 44: 111 (May 15) 1944.

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19. JIERRMANN, LoUIs G. Personal communications. 20. GOLDSTEIN, DAVID H., STOLMAN, ABRAHAM, AND GOLDFARB, ARTHUR E. The influ-

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21. GORRIE, D. R. Purpura hemorrhagica after arsenic therapy treated with vitamin P. Lancet, 1: 1005 (June 1)1940. 22. WEINER, ALFRED. Personal communications. 23. GOLDMAN, LEON, AND GOLDMAN, CAPT. BERNARD. Contact testing of the buccal mu-

cous membrane for stomatitis vencnata, Arch Dermat. & Syphilol., 50: 79, 1944. DR. SAMUEL M. PECE: I have been interested in this field for a number of years. We have shown in a number of publications (Peck, Samuel M., Rosenthal, Nathan, and Erf, Lowell A. Intradermal venom reaction as new method of determining capillary fragility. Proc. Soc. Exper. Biol. and Med., 35: 614—616, 1937.) (Peck, Samuel M., Rosenthal, Nathan,

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purpura. J. A. M. A., 106: 1783—1791 (May 23) 1936.) (Peck, Samuel M., Rosenthal, Na-

than, and Erf, Lowell A. Purpura, classification and treatment, with special reference to treatment with snake venom. Arch. Dermat. and Syph., 35: 831—864 (May) 1937.) that the usual methods for testing capillary fragility not only tests changes in the capillary walls, but changes in the supporting structures around the capillaries. The method for testing capillary fragility described in the presentation of Doctors Goldman and Corrill, as in the other methods, depends on the reactions to changes in intracapillary pressures. We were able to show that in certain purpuric eruptions, the purpura was due more to changes in the supporting structures around the capillaries than to changes in the capillary walls themselves. An increase in intracapillary pressure resulted in minute hemorrhages because of the damage to these supporting structures. By means of the venom test we

were able to obtain a more accurate estimation of changes in the capillary walls themselves because by this method we were testing the resistance of the endothelial cells to the hemorrhagic action of the mocassin venom. The changes in the supporting structures played no

role in this test. Dii. LEON GOLDMAN: Dr. Peck's discussion brings up the question that there is no tech-

nic. In regard to the suction tests I have agreed, and have discontinued them because they are so variable. We have adopted the tests recommended by those interested in this subject in the Department of Internal Medicine. There are three good reasons for decreased capillary resistance, or increased fragility. The most common, of course, occurs in people with hyperteusiou. It presents the greatest obstacle in routine testing in clinical practise. Capillary fragility may he due to an actual defect of the blood constituents themselves, such as platelet diminution or hemophilia, and lastly, there is the factor of permeability of the capillary wall, which cannot be studied in a controlled practical manner at the present time. We get positive capillary fragility tests in a variety of conditions. The strongest test we ever had was in an individual who had psychogenic urticaria, and who improved chiefly

on sedation.

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94

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