IDIOSYNCRASY TO AMMONIATED MERCURY OINTMENT

I:~EPORT OF Two CASES

PAUL HARPER, ~.D.

N ~ w H A v ~ , C o ~ .

T H E u s e o f a m m o n i a t e d m e r c u r y o i n t m e n t is so c o m m o n t h a t i t

s e e m s w o r t h w h i l e t o e m p h a s i z e t h e d a n g e r o f i d i o s y n c r a s y . ~ I n

t lhe t w o c a s e s h e r e p r e s e n t e d t h e s e v e r i t y o f t h e r e a c t i o n as w e l l a s

t h e p e c u l i a r s w e l l i n g a n d c y a n o s i s o f t h e h a n d s a n d f e e t i s d i s t i n c t i v e .

T h e s e t w o p a t i e n t s a r e o f a d d e d i n t e r e s t s i n c e t h e l i t e r a i u r e o f t h e

p a s t o n e h u n d r e d y e a r s d e s c r i b e s o n l y f i v e c a s e s o f p o i s o n i n g v f r o m

l o c a l a p p l i c a t i o n o f t h e d r u g . D u r i n g t h e s a m e p e r i o d t h e r e a r e r e -

p o r t s o f f o u r t e e n c a s e s o f p o i s o n i n g f r o m a m m o n i a t e d m e r c u r y t a k e n b y m o u t h . 4' 6, 7, 9, lo, ~z, ~ , is, 19, ~, ~2, 34 T h e s y m p t o m s w e r e t h o s e o f

a c u t e g a s t r o e u t e r i t i s a n d c o l l a p s e w i t h s t o m a t i t i s i n s o m e of t h e l e s s

a c u t e ea ses . T h e r e w e r e f o u r d e a t h s . I t i s p r o b a b l e t h a t a t o x i c r e -

a c t i o n f r o m l o c a l a p p l i c a t i o , u is m o r e c o m m o n t h a n t h e l i t e r a t u r e

w o u l d i n d i c a t e , e s p e c i a l l y a s w e h a v e r e c e n t l y l e a r n e d o f f o u r c a s e s 16

i n a d d i t i o n t o t h o s e r e p o r t e d h e r e - - - o n e g e n e r a l i z e d r e a c t i o n a n d t h r e e

c a s e s w h e r e t h e r e a c t i o n w a s l o c a l i z e d t o t h e a r e a o f a p p l i c a t i o n . I n

T a b l e I a r e s u m m a r i z e d d a t a f r o m t h e p r e v i o u s l y r e p o r t e d c a s e s a n d

f r o m t h e t w o f o l l o w i n g r e c o r d s .

CAS~ 1.--M. A. (tiosp. ]~Iist. ~4368), white female, aged twenty months. The fam- ily and past history were noncontributory. The present illness began May 8, 1926, with the appearance of a few vesicles on the feet. Ichthyol ointment was applied for several days; the eruption spread slowly. On the eleventh day, the pat ient was seen in the New Haven Hospital Dispensary and presented excoriated impetiglnous lesions over the dorsa of both feet and a similar lesion behind the left ear, also a few vesicles on the legs and thighs. Ammoniated mercury, 10 per cent, was applied. Tha t evening a generalized rash appeared. The next morning, May 19, the child was admit ted to the hospital. Temperature, 38.2 ~ C. The child was well developed and nourished. In addit iou to the impctiginous lesions already described she presented a papulovesicular eruption on a thickened erythematous base over the entire body except the scalp. There were small excoriated areas over the chest and neck exuding serum. The toes and the dorsa of both feet were red, swollen, and almost denuded of epithelium, leaving a raw, weeping surface. There was a crusted, moist exudate about the lef t ear. The lips were fissured, the buccal mem-

From the Department of Pediatrics, Yale University School of Medicine and the Pediatric Department of the New Haven I-Iospital.

*"Idiosyncrasy" is the term used in writing of the two cases here reported for reasons given in the section entitled "Comment." "'Poisoning" was the term used in the majori ty of cases from the l i terature and will be used in this paper when refer- ring to those eases.

79~

t:~ARPEtr IDIOSYNCRASY TO AI~IMONIATED MERCURY OINTMENT 795

b ranes were r eddened and the re was an e ry thema tous e rup t ion on the h a r d and soft pala te . There was s l igh t generM g landu la r en la rgement . The liver was down two f i nge rb r ead t h s ; t he spleen was fe l t a t the le f t costal nmrg in .

La~boratory Data.--Blood W a s s e r m a n n and tubercu l in (~/~o rag.) tes t s werc ~cga- rive. Red blood cells, 5~000,000 per c.nun. ; hemoglobin , 80 per cen t ( S a h l i ) ; whi te blood cells, 15,000 pe r c .mm.; po lymorphonuelcars , 58 pe r cen t ; lymphocytes , 27 per cen t ; l a rge mononuc lea r s , 6 per cent ; eosinophils , 9 per cent. Repea ted ur ine

exami na t i ons were nega t ive .

Treatmen.t (v(nc~ Co~rse.--The pa t i en t was r e s t r a ined to p reven t scra tch ing . Boric acid compresses were appl ied to the excor ia ted sur faces , vase l ine to the res t of the body. I m p r o v e m e n t was r ap id and the sk in was nea r l y n o r m a l by the twenty- f o u r t h day , J u n e 1.

D~agunstie Ski~ Tests.--On J u n e 1 a smal l mnoun t o f a m m o n i a t e d m e r c u r y was appl ied to a n a r ea 5 cm. in d i amete r below the r i gh t scapula . W i t h i n six hours there was a n e r y t h e m a t o u s b lush over t, he back i wi th in twelve hour s th i s h a d be- come a m i n u t e ves icu lar e rup t ion over the back and neck ; and a f t e r twen ty - fou r hour s there was a papuloves ieu la r e rup t ion over the en t i re torso which g r adua l l y c leared d u r i n g t he nex t few days. Simi lar t e s t s wi th i ch thyo l o in tmen t and wi th vase l ine gave no react ion. The p a t i e n t was d i scharged cured on the t t f i r ty-s ix th day. I n spi te of w a r n i n g s t he child received smal l app l i ca t i ons of a m m o n i a t e d m e r c u r y on two subsequen t occasions wi th r e su l t an t r eac t ions which were less m a r k e d bu t s imi la r to t h a t descr ibed above.

CASE 2 . - - P . M. ( t tosp . I{ist. A33207) , whi te male, aged s ix teen months . The fam- i ly a n d pas t h i s t o r y were i r re levant . The p r e s e n t i l lness b e g a n ~eb . 9, 1934, wi th a s ingle i mpe t i g i nous bleb on the c h i n . New lesions cont inued to appea r on t he chin and a round the nose. A m m o n i a t e d mercury , 10 per cent, was app l ied to the lesions on the f o u r t h day and was reappl ied several t imes da i ly for n ine days . E a c h new appl ica t ion was added to the prev ious layer which was not wiped off except as the child removed i t by rubb ing . On t he n i n t h (tay a red macu l a r r a sh appea red over the body, and the f ace became swollen. A t en ta t ive d iagnos i s of German meas les was made. On the t e n t h d a y the chi ld became worse ; t empera tu re , 38.3 ~ C.; hand , swollen and cyano t ic ; i n c r e a s i n g swell ing of t he f ace ex t end ing to the neck. On the twe l f t h day : swell ing a n d cyanos is of the feet , otherwise unchanged . A m m o n i a t e d mercu ry d iscont inned. The re was l i t t le change d u r i n g the nex t two days , and the child was a d m i t t e d to the N e w ~ a v e n Hosp i t a l on the f i f t een th day, ~ b r u a r y 23. Tem- pera ture , 38.6 ~ C. The child was acute ly and ser iously ill. There was a ra ised morb i l l i fo rm r a s h on a th ickened e r y t h e m a t o n s base over the whole body. The face was so swollen t h a t the eyes were seen only t h r o u g h the s l i ts be tween pro- t u b e r a n t eyelids. The l lps also were puffy. There was a genera l i zed desquamat ion , and m a n y c rus ted f issures were oozing serous fluid which was s angu ineons in cer ta in areas . There was m a r k e d e n l a r g e m e n t of the cervical g l ands bu t no tenderness . The t ee th were di r ty , a n d the g u m s were swollen, dusky, and bled easily. The mucous m e m b r a n e s were reddened and showed smal l u lcera ted a r ea s on the palate , pha rynx , aud tongue . The h a n d s and fee t were. so g r e a t l y swollen as to sugges t dange r of b u r s t i n g t he t i gh t l y s t re tched skin, which var ied in color f rom blue to nea r l y black. The sk in was pee l ing in shee ts f r o m both h a n d s and feet , l eav ing a raw, weeping sur face . There was modera t e genera l g l a n d u l a r e n l a r g e m e n t b u t no photophobia , no l ac r imat ion , no hypotonia , no muscle weakness . The spleeu was fe l t a t the costal m a r g i n . The liver was down 1 era.

F ig . ] is a p h o t o g r a p h t aken on the th i rd day in the hospi ta l . The sh iny appear- ance o f the h a n d s g ives some ind ica t ion of the tenseness o f the swell ing. Desquama- t ion of the f ingers m a y be seen.

796 T H E J O U R N A L O~' PEDIATRICS

o ~ o ~ ~ 1 = ~ =~ ~ ~"~ ~

r~ ~ 0 .

o

I I I I i i i I 1 I I i I I I

i ~ ~ ~ ~ ~

HARPER: IDIOSYNCRASY TO AS~MONIATED !VIERCUIdY OINTIVI]~NT 797

Laboratory Data*.--Kahn and tuberculin tests were negative. Red blood cells, 5,000,000; hemoglobin, 85 per cent (Sahl i ) ; white blood cells, 14,000 per e.mm.; polymorphonuclears, 52 per cent; ]ymphocytes~ 36 per cent; large mononuclears, 6 per cent; eosinophils, 1 per cent; unclassified forms, 5 per cent. ]~epeated urine examinations were negative. Nonprotein nitrogen, 33 mg. per centi blood pressure, 100/65.

Tre~tme~t a~.d Course.--The child was placed without clothes under a l ight cradle which was mainta ined at a temperature of 26.6 ~ C. He was restrained to prevent scratching. A thin coating of sweet oil was applied twice daily. The child was afebri]e a f te r the th i rd day. Desquamation proceeded, and the skin gradually cleared. The sweiling of face and extremities slowly subsided, as did the cyanosis of the latter. The fissures healed; the mouth improved; and the ulcerated areas cleared. I tching, which was not present on admission, became an increasing feature during the early convalescence and then subsided.

Dia.gnost~,v SIcin :Tests.--On the twenty-fourth day, 1Yfarch 4, 2 per cent ammoniated mercury was appl ied to an area on the chest 5 era. in diameter. Af te r iifteon hours there was u raised~ rough erythematous eruption over this area. At this time 5

Fig. I.

per cent ammoniated mercury was applied to a similar area on the oppo,site side of the chest. Af ter six hours this region also showed a raised, rough erythematous surface. Wi th in twelve hours there was a pronounced erythema over the chest and abdomen and at the end of eighteen hours, there was sl ight swelling and blueness of the r ight foot and questionable swelling of the r ight hand. The i tching recurred to a marked degree, and the test areas desquamated a second time. Control tests with vaseline, lanolin, and mineral oil were negative. The same ammoniated mercury applied to another baby gave no reaction. The pat ient was discharged cured on the th i r t ie th day, March 10.

DIAGNOSIS

In the differential diagnosis acrodynia, arsenic poisoning, pellagra, and

s e p t i c e m i a w i t h m e t a s t a t i c l o c a l i z a t i o n w e r e a l so c o n s i d e r e d . A c r o d y n i a

w a s s u g g e s t e d b y t h e b l u i s h r e d s w e l l i n g of t h e h a n d s a n d f e e t , t h e

d e s q u a m a t i o n , t h e g e n e r a l i z e d r a s h , t h e s t o m a t i t i s , a n d t h e i r r i t a b i l i t y .

A g a i n s t t h i s d i a g n o s i s w e r e t h e r e l a t i v e l y r a p i d o n s e t , t h e S h o r t cou r se ,

t h e a b s e n c e o f h y p o t o n i a , p h o t o p h o b i a , s w e a t i n g , a n d a n o r e x i a . 1Vfore-

798 T}IE J O U R N A L OF PEDIATRICS

over, the normal nonprote in ni t rogen and blood pressure are unusual in acrodynia.

Arsenic poisoning as seen in the epidemic amongst the beer dr inkers of Manchester , England, 1~, lr, ~a showed a combination of skin rash, stomatitis, facial puffiness, peripheral neuritis, cyanosis and edema of the hands and feet, which ear ly in tlle epidemic was repor ted as ery thromela lg ia 17 and beriberi . 16 The lack of known exposure to ar- senic, the absence of per ipheral neuritis, the br ief course, and the skin tests were all in opposition to this diagnosis in our patients.

Pe l lagra could account fo r the dermati t is , stomatitis, stud the swell- ing of the extremit ies , bu t p robably not fo r the blueness of the hands and feet. Both . children had had adequate diets. Pel lagra is rare in chi ldren under two years of age and was rendered unl ikely in these cases by the lack of central nervous system symptoms and by the rapid improvement following the wi thdrawal of ammoaliated mercury wi thout the use of a diet r ich in v i tamin G.

Septicemia might have caused the fever , the rash, and the desqua- mation. The swelling, of the hands might have been due to metastat ic foci of infection. This diagnosis was not long considered in view of the stomatitis, the low fever, the absence of leucoeytosis, the nega- t ive blood cultures and the course of the disease.

The diagaosis of ammoniated mercury poisoning depended upon the h i s to ry of the use of the drug, the recogni t ion that such a react ion was possible, the confi rmatory evidence of the skin tests, and, in one ease, the recur rence of symptoms fol lowing subsequentapp l ica* ion of am- monia ted mercury. F u r t h e r confirmation by analysis of the feces and ur ine fo r mercury would have bean desirable. However, it seemed tha t the diagnosis was a l ready clear. Skin tests with a more easily absorbed form of mercu ry were suggested bu t did not seem justified in view of the severe react ion to a re la t ive ly poor ly absorbed form (see Comment) .

COM1VIENT

I t is of interest to consider why toxie react ions to ammoniated mer- cu ry are so rare as compared with the re la t ive ly f requent poisoning resul t ing f rom the use of antisyphil i t ie mercur ia l ointments. Un- guen tum hyd ra rgy r i (U.S.P.) and unguen tum h y d r a r g y r i cinereum (Ph.O.), In this connection ~a lo f f 11 repor t s absorpt ion experiments with ammoniated mercury rubbed into the skin of volunteers. Oa~ the basis of urinalysis he concluded tha t only traces of mercury were absorbed. He cited the work of Biirgi s as repor t ing much grea ter absorpt ion of mercury a f t e r the use of g ray ointment (ungu'entum h y d r a r g y r i cinereum). Maloff believed tha t the r a r i t y of toxic effects f rom ammoniated mercury was accounted for' by its poor absorption and tha t this was due to its beiaxg a complex insoluble mercu ry corn- pound, NH2 HgC1, in eontrast to the b e t t e r absorbed metallic mercury

ttAI~PER: IDIOSYNCRASY TO AMMON1ATED MERCURY OINTMENT 799

mixtures of blue o in tment and g ray ointment. )/[oneorps ~'~ in a care- ful exper imenta l s tudy confirmed and g rea t ly e labora ted the work of Maloff, and Sol lman 2~ presents da ta on the absorp t ion of ~mguentum hyd ra rgy r i .

I n our cases i t is sugges ted tha t the symptoms were manifes ta t ions of an id iosyncrasy to m e r c u r y r a t h e r t h a n the resul t of absorpt ion of re la t ive ly la rge amounts of mercury . P r e sumpt ive evidence fo r this is found in the r ap id deve lopment of symptoms a f t e r appl icat ion of re la t ive ly small amounts of ammonia ted mercury , in the exper imenta l demons t ra t ion t ha t m e rcu ry in this fo rm is re la t ive ly poor ly absorbed, in the r ap id r ecove ry fol lowing the w i thd rawa l of the drug, in the absence of evidence of renal damage, and finally in the acute and severe reac t ions to skin tests.

SUMMARY

LoeM appl ica t ion of ammoniated mercu ry in two, eases gave a gen- eralized rash and stomati t is together with a peculiar' eyanosis and edema of the hands and feet. I t is believed tha* these signs and symptoms were the expression of all idiosyncrasy to mercury .

I~EFERaSNCES

1. Alexander, A., and Mendel, t{.: Deutsche reed. Wchnschr. 49: 1021, 1923. 2. Bechet~ P. E.: Arch. Dermat. & Syph. 1: 636, 1920. 3. Biirgi, Emil: Arch. f. Dermal u. Syph. 79: S1, 1906. 4. Cockle: Med. Times and Gaz., Imnd. 1: 302, 1882. 5. Deakin, S.: ~ri t . M. J-. 11: 1281, 1883. 6. Giles, J . : Lancet. 11: 9, 1857. 7. Graham, A . R . : Brit. IV[. J . 1: 329~ I868. 8. Green~ W. E.: Brit. M. J. 1: 853, 1884. 9. Hardy, It. N.: Brit. M. J. 11: 76~ 1876.

10. IKerner: Med. Ann. Heide]b. 1: 479, 1835. 11. Maloff, G.: Deutsche reed. Wchnschr. 54: 1381, 1928. 12. Ir W. t t . : Assoc. M. J. Lond. (now the Brit. IV[. J .) 11: 909, 1857. 13. 1Yloncorps, Carl: Arch. f. exper. Path. u. Pharmakol. 155: 51, 1930. 14. Moore, E . H . : Brit. M. J. Load. 11: 15, 1885. 15. l~ewhall, W. A., and Prytherck, J . R . : Brit. 5i. J. p. 1684, 1900. 16. Personal communications. 17. Reynolds, E. S.: Brit. M. J. pp. 1492, 1520, 1590 i and 1769, 1900. 18. Sundberg, A . G . : Brit. ~[. J . 1: 709, 1889. 19. Short, A. C.: Med. Times and Guz., Loud. 1: 444, 1860. 20. Sollman, Torald: A Manual of Pharmacology, ed. 4, p. 1078, Philadelphia,

1932, W. B. Saunders Company. 21. Stevens, E.: Brit. IV[. J. 1: 781, 1876. 22. Stevenson, T.: Guy's I-Iosp. Rep., Loud. 3. s. 19: 415, 1874. 23. Symposium: Epidemic of Peripheral Neuritis Traced to Arsenical COntamination

of Beer-Making Materials, Brit. M. J. pp. 1587, 1683, 1723, 1730, and 1815, 1900.

24. Taylor, E. S., and Pavy, 1~ W.: Guy's Hosp. :~ep. 6: 483, 1860.