- Email: [email protected]
Aplastic anemia following stovarsol (acetarsone) therapy
APLASTIC ANEMIA FOLLOWING STOVARSOL (ACETARSONE) THERAPY D. LESESNE S~IT~, JR., M.D., AND ROBERT A. LYON, M.D. CINCINNATI, OHIO
the last eighteen months, stovarsol (aeetarsone) has been used F OR exclusively in the treatment of children with syphilis in the clinic of the Cincinnati General Hospital. The results of the therapy have been satisfactory in the group of seventy children who have been treated regularly. Complications of the medication have been few in number and of a very mild nature except in the instance of the patient whose illness is reported here. CASE REPORT
Famdly History.--The p a t i e n t ' s m o t h e r died of p n e u m o n i a , been g i v e n b r o t h e r s of well. One sister died no h i s t o r y
lIer father has a n t i s y p h i l i t i c t r e a t m e n t . I t i s K a h n t e s t at p r e s e n t is n e g a t i v e . Two t h e patient, a g e d f o u r t e e n a n d s i x t e e n years, respectively, are living a n d sister, eleven ?'ears old, is n o w r e c e i v i n g a n t i s y p h i l i t i e t r e a t m e n t . One at t h e a g e of six m o n t h s , t h e cause of d e a t h b e i n g unknown. T h e r e is of a n y blood d y s c r a s i a i n t h e f a m i l y .
Past History.--The p a t i e n t is said to h a v e been a f u l l - t e r m , n o r m a l i n f a n t at birth. She h a s h a d measles, m u m p s , a n d chickenpox, b u t no serious illness u n t i l t h e p r e s e n t one. I n A u g u s t , 1932., at t h e a g e of six years, she was t r e a t e d i n t h e P e d i a t r i c Clinic of t h e C i n c i n n a t i General H o s p i t a l for kerato-iritis. T h e W a s s e r m a n n r e a c t i o n was f o u n d to be s t r o n g l y positive a n d a n t i s y p h i l i t i e t r e a t m e n t was i n s t i t u t e d on Nov. 2, 1932. T e n doses of a b i s m u t h p r e p a r a t i o n were a d m i n i s t e r e d i n t r a m u s c u l a r l y at weekly intervals, a n d t h i s was followed b y six i n t r a v e n o u s injections o f 0.1 gin. of n e o a r s p h e n a m i n e at t h e s a m e intervals. T h e s e t r e a t m e n t s were completed on Dec. 14, 1932. S t o v a r s o l w a s b e g u n on Dee. 28, 1932, in doses c o r r e s p o n d i n g to the IvIaxweI1-Glaser~ m e t h o d . T h e dosage was as follows: 1~ t a b l e t tablet 1A t a b l e t ~/~ t a b l e t 1~ t a b l e t t~blet 1 tablet
once a 2 times 3 times 4 times 3 times 4 times 2 times
d a y f o r one week a d a y for one week a d a y f o r one week a d a y for one week a d a y f o r one week a d a y f o r one week a d a y for one week
E a c h t a b l e t c o n t a i n e d 0.25 gm. of stovarsol. T h e ~otal dosage for t h e seven-week course w a s fifty-six t a b l e t s or 14 gin. of t h e drug. A rest period of one m o n t h was allowed b e t w e e n courses in t h i s i n s t a n c e . N o other d r u g s were g i v e n d u r i n g t h e period of t r e a t m e n t u n t i l t h e p a t i e n t e n t e r e d t h e hospital. T h e child received f o u r courses of t h i s m e d i c a t i o n , c o m p l e t i n g t h e last on Sept. 17, 1933. D u r i n g t h e first seven m o n t h s of a n t i s y p h i l i t i c t r e a t m e n t , t h e child g a i n e d 9 pounds, a n d t h e only clinical maa~ffestation o f syphilis, t h e kerato-iritis, d i s a p p e a r e d except f o r a s m a l l scar wMch r e m a i n e d on t h e r i g h t cornea. The W a s s e r m a n n a n d :From the D e p a r t m e n t of Pediatrics, College of Medicine, U n i v e r s i t y of Cineinnati, a n d The Children's tIospital. 624
SMITH AND LYON:
APLASTIC ANEh[IA
625
K a h n tests continued to be strongly positive. A red blood cell count made d u r i n g the last course of t r e a t m e n t was 3,440,000 cells a n d the hemoglobin was 64 per cent by the Sahli method. At the child's last visit to the clinic on Sept. 10, 1932, it was noted t h a t her skin was rather pale and sallow in appearance, but she h a d no complaints. She did not r e t u r n until her admission to the hospital on lqov. 14, 1933.
Present l~lness.--On Nov. 3, 1933, the patient, t h e n seven years of age, bruised her right h a n d in t h e door of a n automobile. The superficial wound was cleaned and dressed, and 1,500 units of t e t a n u s antitoxin were given. A roentgenogram showed no evidence of f r a c t u r e of the bones. The wound healed well, b u t within a few days a large bluish area appeared in the s u r r o u n d i n g skin which became very painful and tender. Simultaneously, she became listless and complained of aching of the joints. On the third day following the injury, Nov. 6, she had a severe chill which was followed by an elevation of t e m p e r a t u r e which ranged between 98 ~ F. and 104 ~ ~. during the next eight days. The f a t h e r also noted t h a t t h e child was~ very pule. On the seventh day following t h e i n j m T , Nov. 10, a ~ ' g u m b o i l " appeared on the upper left jaw, in the regio~ of the premolar teetl 4 which was incised. On t h e n i g h t of l~ov. 14 the child appeared desperately ill and vomited a small amount of watery ituid; she was brought to the pediatrics ward of the Cineinnati General Hospital. Physical Ezaqnination.--At the time of admission to the hospital, she was in a semicomatose condition. She g r u n t e d with each expiration, was restless, and seemed acutely ill. There appeared to be hyperesthesia of the whole body surface. ~r purpuric areas were noticed on the abdomen, the lower extremities, and especially in the region of the i n j u r y to the right hand. The superficial veins stood out prominently on the pale icterie cutaneous surface. The mucous membranes of the mouth and conjunctivae were almost colorless. There was an old scar on the right cornea. Some hemorrhagic areas were present about the g u m margins, and on the g u m surface of the upper left jaw there was a circular area of necrosis, 2 cm. in diameter, which was surrounded by an area of redness and edema. A similar lesion was noted on the left tonsil which appeared almost gangrenous. The cervical lymph nodes were moderately enlarged. The respiratory rate w a s 22 per minute. The percussion note over the chest was not impaired, b u t on auscultation a suppression of b r e a t h sounds was noted and a few medium, moist r~les were heard over the right chest posteriorly, especially in the regions j u s t above a n d below the spine of the scapula. The heart r a t e was 92 per minute. The area. of cardiac dullness was greatly increased in all directions, the apex beat being diffuse and about 3 cm. to the left of the nipple line. At this point a thrill was palpable. A systolic m u r m u r was audible at the apex, and there was a suggestion of a gallop r h y t h m . The liver was palpable for a distance of 4 em. below the costal margin. The superficial and deep reflexes were normal. Laboratory Findings D~ring' First Twenty-Four Hours of Hospitalization.-Bloo~: There were 980,000 red blood cells per cubic millimeter, these being well filled with hemoglobin and practically normal in size and shape. The hemoglobin content was 2.35 gm. per cent, or 17 per cent by the Sahli method; white cell count, 2,000. The differential count was lymphoeytes, 77 per cent; monoeytes, 10 per cent; polymorphonuclear neutrophiles, 7 per c e n t i eosinophiles, 1 per cent; transitionals, 3 per cent; undetermined cells, 2 per cent. Platelets were practically absent. The clotting time (capillary tube method) was six and one-half minutes. The bleeding time was greatly prolonged. The blood culture was negative. Urine Examination : Acid reaction, acetone three-plus, no sugar, no albumin, no blood by chemical test, microscopic examination negative. Arsenic Content of the Urine: 0.02 milligrams per cent of AsfOs (an amount which was t h o u g h t to be of no clinical significance). A n electrocardiogram showed signs of diffuse myocardial disease.
626
THE
JOURNAL
OF
PEDIATRICS
Roentgenologic examination of the long bones, the skull, and pelvis revealed no abnormalities in the intimate struetu~:e. On Nov. 16, ]933~ a roentgenogram of the chest showed an enlarged heart, but the configuration was not pathognomonic of any specific lesion. R,uther extensive peribronchial infiltration was present throughout the lungs, suggesting early bronchopneumonia. Progress.~(See Treatment.) On Nov. 20, 1933, the sixth day after admission to the hospital~ the red cell count was 3,285,000. The differential white cell count was polymorphonuclear neutrophiles, 12 per cent; lymphocytes, 79.5 per cent; monocytes, 8 per cent; plasma cells~ 0.5 per cent; retieulocytes, 0.1 per cent. Practically no platelets were seen. The red cells were slightly smaller than normal and were well filled with hemoglobin. There was no alteration in the shape of these cells, no stippling, and no nucleated red cells were seen. The polymorphonuelear neutrophiles were mostly of the band form, and certain toxic changes were observed, such
l~ig. 1.~Section of bone marrow of the tibia, Nov. 23, 1933. (Low magnification.) as large, deeply staining granules with some vacuolization. The lymphocytes and monocytes were fairly normal in appearance. The blood picture was that of an aplastic anemia. On Nov. 23, 1933~. a section of bone marrow was obtained from the tibia and stained with hematoxylin and eosin (paraffin section). On microscopic examination the section revealed a great preponderance of f a t t y tissue with very few blood cells. The blood cells present were mainly of the lymphocytic series with a marked dearth of cells of the myeloeytic series. On examination of the entire section only normoblasts were found, and no megakaryocytes were seen. The only cells of the myelocytic series found were a few degenerate polymorphonuclears. The proportion of cells to fat resembled that of adult bone marrow in this region, but the differentia] count on the ceils present would be abnormal even for adult marrow. Summary : Ap]astic bone marrow with striking deficiency in the proportion of cells of the following types: (1) myelocytic, (2) erythrocytie, and (3) megakaryoeytic. (Fig. 1.)
SMITH AND LYON:
APLASTIC ANEMIA
62~
The p a t i e n t ' s condition remained critical during the first ten days in the hospital. For a few days she was very drowsy and weak, b u t slowly she became more alert and rational. The restlessness and hyperesthesia disappeared slowly. A f t e r each transfusion the color of the skin and mucous membranes improved. The r~les in the left chest had practically disappeared by the t e n t h day, by which time the h e a r t had decreased somewhat i n size and the gallop r h y t h m and thrill h a d disappeared. On November 24, the t e n t h day after admission, a hemorrhage began at the site of the old ulcer on the gum m a r g i n ; this was checked b y the extraction o2 the upper left premolar and b y packing the region. The bleeding time of the p a t i e n t on this day was one hour. Purpuric spots on the ski~ were still numerous. On November 30, the sixteenth day after admission, it was necessary to perform a myringotomy on the left ear drum, and u serosunguineous material draiued from this ear for several days. At this time the urine was grossly' bloody; this condition lasted for only a few days and was apparently relieved by the transfusions of whole blood. On Dec. 20, 1933, the red cell count was 3,930,000; the white cell count, 3,700. The differential count was p01ymorphonuclear neutrophiles, 12 per cent; lymphoeytes, 79.5 per cent; monocytes, 8.0 per cent; plasma cells, 0.5 per cent; reticulocytes, 0.1 per cent. l~ractically no p]atelets were seen. The red blood cells seemed smaller than normal; there was no poikilocytosis, very little anisocytosis, and the cells appeared to be well filled with hemoglobin. No stippled or nucleated red cells were seen. The polymorphonuclears were mostly of the band form and showed the same toxic changes as o~ the previous examln~tlon. The absence of p]atelets a n d the low percentage of polymorphonuclears with marked toxic changes in them demonstrated t h a t the bone marrow was still under the influence of some severe depressant. On Feb. 5, 1934, the red cell couut was 3,600,000; the white cell count, 6,700. The differential count was polymorphonuclear neutrophiles, 27.5 per cent; lymphoeytes~ 68 per cent; monocytes, 4.5 per cent. The platelets had increased in number since the previous exalnination but were still below normal. The polymorphonuclears did not show much toxic degeneration. The red blood cells were normal in size, and the appearance of the hemoglobin indicated definite signs of regeneration since polychromatophilia was a prominent feature and normoblasts were seen. The whole picture indicated marked improvement. On Feb. 7, 1934, she was discharged from the hospital. Outco~e of the Case.--The patient returned to the clinic twice for observation. On each occasion there was a great improvement in her color and general health. The heart had returned to its normal size. The only syphilitic manifestation was the old corneal scar on the left eye. The Wassermann, I~iahn and 1Vieinieke reactions of the blood were negative on Apr. 25, 1934, but the K a h n was two-plus on ffune 20, 1934. On Feb. 21, 1934, the red cell count was 3,800,000; the hemoglobin, 91 per cent. The differential count was polymoll~honuclear neutrophiles~ 20 per cent; lymplmeytes, 73 per cent; monocytes: ~6.5 per cent; plasma cells, 0.5 per cent. The reticuloeyte count was 2.5 per cent. The blood picture was about the same as upon previous examination. On Apr. 25, 1934, the red blood count was 4,320,000; the hemoglobin, 79 per cent; the white cell count, 9,350. The differential count was polymorphonuclear neutrophiles, 55.5 per cent; lymphoeytes, 40 per cent; n~onoc,ytes~ 2.5 per cent; plasma cells, 2.0 per cent. Flatelets were presel~t in normal numbers. The general condition of the blood had greatly improved since the last examination. T r e a t m e n t . - - k SUlnmary of certain specific therapeutic measures employed during the p a t i e n t ' s stay in the hospital is as follows:
628
T H E JOURNAL OF PEDIATRICS Blood transfusion~ 180 c.c. S o d i u m t h i o s u l p h a t e , 15 g r a i n s . Blood t r a n s fusion, 300 e.c., 150 c.c.; glucose a n d 10 c.c. liver e x t r a c t i n t r a v e n o u s l y . Sodium t h i o s u l p h a t e , 15 g r a i n s ; blood t r a n s f u s i o n , 250 c.c. Blood t r a n s f u s i o n , 300 c.c.; s o d i u m t h i o s u l p h a t e , 11 g r a i n s . Blood t r a n s f u s i o n , 250 e.c.; liver extract, 23 c.c.
Nov. 14, 1933: :Nov. 15, 1933:
:Nov. 16~ 1933: :Nov. 19, 1933: Nov. 25, 1933:
i
#,
5
o ss f
in gillion~
j"
J
4.
/
h
s
i
i r
i
/
?
/ i I il
/ / 11
RBC
|
i iI
5 Ii II
W'BO
in
11 Thousands
l
, ~ f
WBC 9
--%
! !
P
C h a r t 1 . - - I l l u s t r a t i n g the course of t h e red a n d white counts during the illness. The arrows at the top indicate blood t r a n s f u s i o n s . :Nov. 27, 1933: Dec. 3, 1933 : Dec. 4, 1933 : Dec. 5, 1933 : Dec. Dec. Dec.
7~ ]933 : 9, 1933 : 6, 1933 :
Blood t r a n s f u s i o n , 180 c.c. Blood t r a n s f u s i o n , 500 c.c. P e n t n u c l e o t i d e , 10 c.c. i n t r a m u s c u l a r l y . Blood t r a n s f u s i o n , 400 e.c.; pentnucleotide, 10 e.c. i n t r a m u s c u l a r l y . P e n t n u c t e o t i d e , 10 c.c. i n t r a m u s c u l a r l y . Blood t r a n s f u s i o n , 400 c.c. A d d i t i o n of v i t a m i n c o n c e n t r a t e s , liver extract, a n d iron c o m p o u n d s to diet.
SMITH AND LYON: Dec. 14, 1933: Dec. 23~ 1933: Jan. 22, 1934:
APLASTIC ANEMIA
629
Extra calcium added to diet in the form of dicalcium phosphate and calcium glueonate. Blood transfusion~ 400 c.c. Blood transfusion, 400 c.c.
A graphic representation of the course of tim red and white blood cell counts may be seen in Chart 1. SUMMARY
The patient was a sevemyear-old girl with congenital syphilis, who suddenly developed a severe form of aplastic anemia apparently due to the arsenicals used in the treatment. The antisyphilitie treatment had extended over a period of ten months and had consisted of ten injections of a bismuth preparation, six injections of 0.1 gm. of neoarsphenamine (total of 0.6 gm.) and four courses of stovarsol (total of 56 gin.) Treatment included eleven Mood transfusions, and the child gradually improved during the next four mouths making a complete recovery. COMMENT
To the best of our knowledge, no previous reports of aplastic anemia following the use of stovarsol have appeared in the medical literature. Agranulocytosis was observed in a patient treated with stovarsol by W. Haberfeld and M. Rudolph. 2 Agranuloeytosis and purpura hemor~ rhagiea occurred in a patient reported by E. Benhamou, P. Temim, and and R. Lofrani2 The rarity of blood dyscrasias following the use of other antisyphilitie arsenicals (arsphenamine, neoarsphenamine, sulpharsphenamine, tryparsamide, etc.) was illustrated by a review of the literature made by F. P. McCarthy and R. Wilson 4 who found reports of only thirty-four eases of aplastie anemia with a mortality rate of 83 per eent; twelve of thromboeytepenia; seven of thrombocytopenia and granuloeytopenia; and twelve of agranuloeytosis and granulocytopenia. For assistance in the examination of the blood Dr. Murray Rich, of th6 medical department, for the content of the p a t i e n t ' s tissues, to Dr. ~obert Kehoe, department of physiology, and for the examinations to Dr. Pearl Zeek, of the department of pathology, University of Cincinnati. REFERENCES
smears, we are indebted to determination of the arsenic of the Kettering Laboratory, of th6 bone marrow sections College of Medicine of the
1. Maxwell, C. H., Jr., and Glaser, J.: Am. J. Dis. Child. 43: 1461, 1932. 2. IIaberfeld, W., and Rudolph, M.: Wien. klin. Wchnschr. 46: 942, 1933. 3. Benhamou, E.; Temim, P.; and Lofr.~ni, R.: Bull et m6m. Soc. m~d. d. hhp. de Paris 49: 1162j 1933. 4. McCarthy, F. P., and Wilson, R., Jr.: J. A. M. A. 99: 1557, 1932.
the last eighteen months, stovarsol (aeetarsone) has been used F OR exclusively in the treatment of children with syphilis in the clinic of the Cincinnati General Hospital. The results of the therapy have been satisfactory in the group of seventy children who have been treated regularly. Complications of the medication have been few in number and of a very mild nature except in the instance of the patient whose illness is reported here. CASE REPORT
Famdly History.--The p a t i e n t ' s m o t h e r died of p n e u m o n i a , been g i v e n b r o t h e r s of well. One sister died no h i s t o r y
lIer father has a n t i s y p h i l i t i c t r e a t m e n t . I t i s K a h n t e s t at p r e s e n t is n e g a t i v e . Two t h e patient, a g e d f o u r t e e n a n d s i x t e e n years, respectively, are living a n d sister, eleven ?'ears old, is n o w r e c e i v i n g a n t i s y p h i l i t i e t r e a t m e n t . One at t h e a g e of six m o n t h s , t h e cause of d e a t h b e i n g unknown. T h e r e is of a n y blood d y s c r a s i a i n t h e f a m i l y .
Past History.--The p a t i e n t is said to h a v e been a f u l l - t e r m , n o r m a l i n f a n t at birth. She h a s h a d measles, m u m p s , a n d chickenpox, b u t no serious illness u n t i l t h e p r e s e n t one. I n A u g u s t , 1932., at t h e a g e of six years, she was t r e a t e d i n t h e P e d i a t r i c Clinic of t h e C i n c i n n a t i General H o s p i t a l for kerato-iritis. T h e W a s s e r m a n n r e a c t i o n was f o u n d to be s t r o n g l y positive a n d a n t i s y p h i l i t i e t r e a t m e n t was i n s t i t u t e d on Nov. 2, 1932. T e n doses of a b i s m u t h p r e p a r a t i o n were a d m i n i s t e r e d i n t r a m u s c u l a r l y at weekly intervals, a n d t h i s was followed b y six i n t r a v e n o u s injections o f 0.1 gin. of n e o a r s p h e n a m i n e at t h e s a m e intervals. T h e s e t r e a t m e n t s were completed on Dec. 14, 1932. S t o v a r s o l w a s b e g u n on Dee. 28, 1932, in doses c o r r e s p o n d i n g to the IvIaxweI1-Glaser~ m e t h o d . T h e dosage was as follows: 1~ t a b l e t tablet 1A t a b l e t ~/~ t a b l e t 1~ t a b l e t t~blet 1 tablet
once a 2 times 3 times 4 times 3 times 4 times 2 times
d a y f o r one week a d a y for one week a d a y f o r one week a d a y for one week a d a y f o r one week a d a y f o r one week a d a y for one week
E a c h t a b l e t c o n t a i n e d 0.25 gm. of stovarsol. T h e ~otal dosage for t h e seven-week course w a s fifty-six t a b l e t s or 14 gin. of t h e drug. A rest period of one m o n t h was allowed b e t w e e n courses in t h i s i n s t a n c e . N o other d r u g s were g i v e n d u r i n g t h e period of t r e a t m e n t u n t i l t h e p a t i e n t e n t e r e d t h e hospital. T h e child received f o u r courses of t h i s m e d i c a t i o n , c o m p l e t i n g t h e last on Sept. 17, 1933. D u r i n g t h e first seven m o n t h s of a n t i s y p h i l i t i c t r e a t m e n t , t h e child g a i n e d 9 pounds, a n d t h e only clinical maa~ffestation o f syphilis, t h e kerato-iritis, d i s a p p e a r e d except f o r a s m a l l scar wMch r e m a i n e d on t h e r i g h t cornea. The W a s s e r m a n n a n d :From the D e p a r t m e n t of Pediatrics, College of Medicine, U n i v e r s i t y of Cineinnati, a n d The Children's tIospital. 624
SMITH AND LYON:
APLASTIC ANEh[IA
625
K a h n tests continued to be strongly positive. A red blood cell count made d u r i n g the last course of t r e a t m e n t was 3,440,000 cells a n d the hemoglobin was 64 per cent by the Sahli method. At the child's last visit to the clinic on Sept. 10, 1932, it was noted t h a t her skin was rather pale and sallow in appearance, but she h a d no complaints. She did not r e t u r n until her admission to the hospital on lqov. 14, 1933.
Present l~lness.--On Nov. 3, 1933, the patient, t h e n seven years of age, bruised her right h a n d in t h e door of a n automobile. The superficial wound was cleaned and dressed, and 1,500 units of t e t a n u s antitoxin were given. A roentgenogram showed no evidence of f r a c t u r e of the bones. The wound healed well, b u t within a few days a large bluish area appeared in the s u r r o u n d i n g skin which became very painful and tender. Simultaneously, she became listless and complained of aching of the joints. On the third day following the injury, Nov. 6, she had a severe chill which was followed by an elevation of t e m p e r a t u r e which ranged between 98 ~ F. and 104 ~ ~. during the next eight days. The f a t h e r also noted t h a t t h e child was~ very pule. On the seventh day following t h e i n j m T , Nov. 10, a ~ ' g u m b o i l " appeared on the upper left jaw, in the regio~ of the premolar teetl 4 which was incised. On t h e n i g h t of l~ov. 14 the child appeared desperately ill and vomited a small amount of watery ituid; she was brought to the pediatrics ward of the Cineinnati General Hospital. Physical Ezaqnination.--At the time of admission to the hospital, she was in a semicomatose condition. She g r u n t e d with each expiration, was restless, and seemed acutely ill. There appeared to be hyperesthesia of the whole body surface. ~r purpuric areas were noticed on the abdomen, the lower extremities, and especially in the region of the i n j u r y to the right hand. The superficial veins stood out prominently on the pale icterie cutaneous surface. The mucous membranes of the mouth and conjunctivae were almost colorless. There was an old scar on the right cornea. Some hemorrhagic areas were present about the g u m margins, and on the g u m surface of the upper left jaw there was a circular area of necrosis, 2 cm. in diameter, which was surrounded by an area of redness and edema. A similar lesion was noted on the left tonsil which appeared almost gangrenous. The cervical lymph nodes were moderately enlarged. The respiratory rate w a s 22 per minute. The percussion note over the chest was not impaired, b u t on auscultation a suppression of b r e a t h sounds was noted and a few medium, moist r~les were heard over the right chest posteriorly, especially in the regions j u s t above a n d below the spine of the scapula. The heart r a t e was 92 per minute. The area. of cardiac dullness was greatly increased in all directions, the apex beat being diffuse and about 3 cm. to the left of the nipple line. At this point a thrill was palpable. A systolic m u r m u r was audible at the apex, and there was a suggestion of a gallop r h y t h m . The liver was palpable for a distance of 4 em. below the costal margin. The superficial and deep reflexes were normal. Laboratory Findings D~ring' First Twenty-Four Hours of Hospitalization.-Bloo~: There were 980,000 red blood cells per cubic millimeter, these being well filled with hemoglobin and practically normal in size and shape. The hemoglobin content was 2.35 gm. per cent, or 17 per cent by the Sahli method; white cell count, 2,000. The differential count was lymphoeytes, 77 per cent; monoeytes, 10 per cent; polymorphonuclear neutrophiles, 7 per c e n t i eosinophiles, 1 per cent; transitionals, 3 per cent; undetermined cells, 2 per cent. Platelets were practically absent. The clotting time (capillary tube method) was six and one-half minutes. The bleeding time was greatly prolonged. The blood culture was negative. Urine Examination : Acid reaction, acetone three-plus, no sugar, no albumin, no blood by chemical test, microscopic examination negative. Arsenic Content of the Urine: 0.02 milligrams per cent of AsfOs (an amount which was t h o u g h t to be of no clinical significance). A n electrocardiogram showed signs of diffuse myocardial disease.
626
THE
JOURNAL
OF
PEDIATRICS
Roentgenologic examination of the long bones, the skull, and pelvis revealed no abnormalities in the intimate struetu~:e. On Nov. 16, ]933~ a roentgenogram of the chest showed an enlarged heart, but the configuration was not pathognomonic of any specific lesion. R,uther extensive peribronchial infiltration was present throughout the lungs, suggesting early bronchopneumonia. Progress.~(See Treatment.) On Nov. 20, 1933, the sixth day after admission to the hospital~ the red cell count was 3,285,000. The differential white cell count was polymorphonuclear neutrophiles, 12 per cent; lymphocytes, 79.5 per cent; monocytes, 8 per cent; plasma cells~ 0.5 per cent; retieulocytes, 0.1 per cent. Practically no platelets were seen. The red cells were slightly smaller than normal and were well filled with hemoglobin. There was no alteration in the shape of these cells, no stippling, and no nucleated red cells were seen. The polymorphonuelear neutrophiles were mostly of the band form, and certain toxic changes were observed, such
l~ig. 1.~Section of bone marrow of the tibia, Nov. 23, 1933. (Low magnification.) as large, deeply staining granules with some vacuolization. The lymphocytes and monocytes were fairly normal in appearance. The blood picture was that of an aplastic anemia. On Nov. 23, 1933~. a section of bone marrow was obtained from the tibia and stained with hematoxylin and eosin (paraffin section). On microscopic examination the section revealed a great preponderance of f a t t y tissue with very few blood cells. The blood cells present were mainly of the lymphocytic series with a marked dearth of cells of the myeloeytic series. On examination of the entire section only normoblasts were found, and no megakaryocytes were seen. The only cells of the myelocytic series found were a few degenerate polymorphonuclears. The proportion of cells to fat resembled that of adult bone marrow in this region, but the differentia] count on the ceils present would be abnormal even for adult marrow. Summary : Ap]astic bone marrow with striking deficiency in the proportion of cells of the following types: (1) myelocytic, (2) erythrocytie, and (3) megakaryoeytic. (Fig. 1.)
SMITH AND LYON:
APLASTIC ANEMIA
62~
The p a t i e n t ' s condition remained critical during the first ten days in the hospital. For a few days she was very drowsy and weak, b u t slowly she became more alert and rational. The restlessness and hyperesthesia disappeared slowly. A f t e r each transfusion the color of the skin and mucous membranes improved. The r~les in the left chest had practically disappeared by the t e n t h day, by which time the h e a r t had decreased somewhat i n size and the gallop r h y t h m and thrill h a d disappeared. On November 24, the t e n t h day after admission, a hemorrhage began at the site of the old ulcer on the gum m a r g i n ; this was checked b y the extraction o2 the upper left premolar and b y packing the region. The bleeding time of the p a t i e n t on this day was one hour. Purpuric spots on the ski~ were still numerous. On November 30, the sixteenth day after admission, it was necessary to perform a myringotomy on the left ear drum, and u serosunguineous material draiued from this ear for several days. At this time the urine was grossly' bloody; this condition lasted for only a few days and was apparently relieved by the transfusions of whole blood. On Dec. 20, 1933, the red cell count was 3,930,000; the white cell count, 3,700. The differential count was p01ymorphonuclear neutrophiles, 12 per cent; lymphoeytes, 79.5 per cent; monocytes, 8.0 per cent; plasma cells, 0.5 per cent; reticulocytes, 0.1 per cent. l~ractically no p]atelets were seen. The red blood cells seemed smaller than normal; there was no poikilocytosis, very little anisocytosis, and the cells appeared to be well filled with hemoglobin. No stippled or nucleated red cells were seen. The polymorphonuclears were mostly of the band form and showed the same toxic changes as o~ the previous examln~tlon. The absence of p]atelets a n d the low percentage of polymorphonuclears with marked toxic changes in them demonstrated t h a t the bone marrow was still under the influence of some severe depressant. On Feb. 5, 1934, the red cell couut was 3,600,000; the white cell count, 6,700. The differential count was polymorphonuclear neutrophiles, 27.5 per cent; lymphoeytes~ 68 per cent; monocytes, 4.5 per cent. The platelets had increased in number since the previous exalnination but were still below normal. The polymorphonuclears did not show much toxic degeneration. The red blood cells were normal in size, and the appearance of the hemoglobin indicated definite signs of regeneration since polychromatophilia was a prominent feature and normoblasts were seen. The whole picture indicated marked improvement. On Feb. 7, 1934, she was discharged from the hospital. Outco~e of the Case.--The patient returned to the clinic twice for observation. On each occasion there was a great improvement in her color and general health. The heart had returned to its normal size. The only syphilitic manifestation was the old corneal scar on the left eye. The Wassermann, I~iahn and 1Vieinieke reactions of the blood were negative on Apr. 25, 1934, but the K a h n was two-plus on ffune 20, 1934. On Feb. 21, 1934, the red cell count was 3,800,000; the hemoglobin, 91 per cent. The differential count was polymoll~honuclear neutrophiles~ 20 per cent; lymplmeytes, 73 per cent; monocytes: ~6.5 per cent; plasma cells, 0.5 per cent. The reticuloeyte count was 2.5 per cent. The blood picture was about the same as upon previous examination. On Apr. 25, 1934, the red blood count was 4,320,000; the hemoglobin, 79 per cent; the white cell count, 9,350. The differential count was polymorphonuclear neutrophiles, 55.5 per cent; lymphoeytes, 40 per cent; n~onoc,ytes~ 2.5 per cent; plasma cells, 2.0 per cent. Flatelets were presel~t in normal numbers. The general condition of the blood had greatly improved since the last examination. T r e a t m e n t . - - k SUlnmary of certain specific therapeutic measures employed during the p a t i e n t ' s stay in the hospital is as follows:
628
T H E JOURNAL OF PEDIATRICS Blood transfusion~ 180 c.c. S o d i u m t h i o s u l p h a t e , 15 g r a i n s . Blood t r a n s fusion, 300 e.c., 150 c.c.; glucose a n d 10 c.c. liver e x t r a c t i n t r a v e n o u s l y . Sodium t h i o s u l p h a t e , 15 g r a i n s ; blood t r a n s f u s i o n , 250 c.c. Blood t r a n s f u s i o n , 300 c.c.; s o d i u m t h i o s u l p h a t e , 11 g r a i n s . Blood t r a n s f u s i o n , 250 e.c.; liver extract, 23 c.c.
Nov. 14, 1933: :Nov. 15, 1933:
:Nov. 16~ 1933: :Nov. 19, 1933: Nov. 25, 1933:
i
#,
5
o ss f
in gillion~
j"
J
4.
/
h
s
i
i r
i
/
?
/ i I il
/ / 11
RBC
|
i iI
5 Ii II
W'BO
in
11 Thousands
l
, ~ f
WBC 9
--%
! !
P
C h a r t 1 . - - I l l u s t r a t i n g the course of t h e red a n d white counts during the illness. The arrows at the top indicate blood t r a n s f u s i o n s . :Nov. 27, 1933: Dec. 3, 1933 : Dec. 4, 1933 : Dec. 5, 1933 : Dec. Dec. Dec.
7~ ]933 : 9, 1933 : 6, 1933 :
Blood t r a n s f u s i o n , 180 c.c. Blood t r a n s f u s i o n , 500 c.c. P e n t n u c l e o t i d e , 10 c.c. i n t r a m u s c u l a r l y . Blood t r a n s f u s i o n , 400 e.c.; pentnucleotide, 10 e.c. i n t r a m u s c u l a r l y . P e n t n u c t e o t i d e , 10 c.c. i n t r a m u s c u l a r l y . Blood t r a n s f u s i o n , 400 c.c. A d d i t i o n of v i t a m i n c o n c e n t r a t e s , liver extract, a n d iron c o m p o u n d s to diet.
SMITH AND LYON: Dec. 14, 1933: Dec. 23~ 1933: Jan. 22, 1934:
APLASTIC ANEMIA
629
Extra calcium added to diet in the form of dicalcium phosphate and calcium glueonate. Blood transfusion~ 400 c.c. Blood transfusion, 400 c.c.
A graphic representation of the course of tim red and white blood cell counts may be seen in Chart 1. SUMMARY
The patient was a sevemyear-old girl with congenital syphilis, who suddenly developed a severe form of aplastic anemia apparently due to the arsenicals used in the treatment. The antisyphilitie treatment had extended over a period of ten months and had consisted of ten injections of a bismuth preparation, six injections of 0.1 gm. of neoarsphenamine (total of 0.6 gm.) and four courses of stovarsol (total of 56 gin.) Treatment included eleven Mood transfusions, and the child gradually improved during the next four mouths making a complete recovery. COMMENT
To the best of our knowledge, no previous reports of aplastic anemia following the use of stovarsol have appeared in the medical literature. Agranulocytosis was observed in a patient treated with stovarsol by W. Haberfeld and M. Rudolph. 2 Agranuloeytosis and purpura hemor~ rhagiea occurred in a patient reported by E. Benhamou, P. Temim, and and R. Lofrani2 The rarity of blood dyscrasias following the use of other antisyphilitie arsenicals (arsphenamine, neoarsphenamine, sulpharsphenamine, tryparsamide, etc.) was illustrated by a review of the literature made by F. P. McCarthy and R. Wilson 4 who found reports of only thirty-four eases of aplastie anemia with a mortality rate of 83 per eent; twelve of thromboeytepenia; seven of thrombocytopenia and granuloeytopenia; and twelve of agranuloeytosis and granulocytopenia. For assistance in the examination of the blood Dr. Murray Rich, of th6 medical department, for the content of the p a t i e n t ' s tissues, to Dr. ~obert Kehoe, department of physiology, and for the examinations to Dr. Pearl Zeek, of the department of pathology, University of Cincinnati. REFERENCES
smears, we are indebted to determination of the arsenic of the Kettering Laboratory, of th6 bone marrow sections College of Medicine of the
1. Maxwell, C. H., Jr., and Glaser, J.: Am. J. Dis. Child. 43: 1461, 1932. 2. IIaberfeld, W., and Rudolph, M.: Wien. klin. Wchnschr. 46: 942, 1933. 3. Benhamou, E.; Temim, P.; and Lofr.~ni, R.: Bull et m6m. Soc. m~d. d. hhp. de Paris 49: 1162j 1933. 4. McCarthy, F. P., and Wilson, R., Jr.: J. A. M. A. 99: 1557, 1932.