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Acrodynia
COMMENTS CURRENT
ON LITERATURE
Acrodynia A c R O D Y N I A (pink disease, dermatopolyneuritis) constitutes a syndrome characterized by many unusual symptoms which fall nevertheless into a definite clinical pattern. Possible etiologies suggested have included avitaminosis; general dietary deficiency; chronic bacterial infection; infection with unspecified viral agents or with fungi such a s those commonly occurring on maize, rye, or other plants; and various chemical agents, especially arsenic or mercury. Following Bilderback's 1 early accounts of the disease, Feer 2 was impressed with such clinical manifestations as hypertension, tachycardia, and excessive sweating, and concluded that the condition resulted from overactivity of the autonomic nervous system. In 1948 Warkany and Hubbard a indicted mercury ingestion or exposure to mercury as the chief etiologic factor in acrodynia. They were able to compile data indicating that most, if not all, cases of acrodynia are the result of an idiosyncrasy to mercury. Within the next decade other reports followed, identifying mercury as the most important cause of the condition. The diagnosis is based primarily on the clinical appearance and the distinctive course of the disease. Characteristic clinical manifestations include extreme irritability and restlessness alternating with periods of apathy; insomnia, anorexia, profuse perspiration with attendant thirst; pink hands and feet, rosy cheeks, scarlet tip of the nose, and variable skin rashes with desquamation. Itch-
ing may be so severe that the child will rub the body, especially the extremities, against the bed or other furniture, initiating trophic ulceration. Photophobia is often pronounced and salivation excessive. The pulse is rapid, and the blood pressure elevated. Pain in the extremities may be severe. Over a period of time there is loss of the hair and nails, and in extreme cases 10ss of terminal phalanges. The pronounced hypotonia permits the patient to assume bizarre positions, some of which may be maintained for long periods of time. In few clinical conditions does the patient appear so obviously miserable. Similarity between the clinical manifestations of acrodynia in young children and those seen in association with mercury and arsenic poisoning in industrial workers led Warkany and Hubbard a to make the first systematic search for heavy metals in the urine of infants with this condition. Mercury was the only one detected, and occurred in 25 of 28 infants in the group studied initially. Since these early observations mercury has been detected in the urine of a large number of infants with acrodynia, especially in districts where mercurial medications have been used. In localities where mercurial lotions, diaper rinses, and teething powders were popular the incidence was greater in children under 1 year of age, whereas in those regions where mercurial vermifuges were employed the greater incidence was in older children, between the ages of 2 and 4 years. Urinary 607
608
Comments on current literature
m e r c u r y excretions in excess of 10 .ug per liter is considered of diagnostic significance. F o l l o w - u p studies on patients with m e r c u r y poisoning have been rare, especially in the U n i t e d States. T h e m o r t a l i t y rate seems to vary in different countries, but is thought to be about 12 per cent on the average. Bronc h o p n e u m o n i a is a c o m m o n complication. Autopsies p e r f o r m e d on children dying from m e r c u r y poisoning have revealed no consistent pathology. Nonspecific changes, however, have been observed with identifiable lesions in the brain, spinal cord, ganglia, a n d p e r i p h e r a l nerves. T r e a t m e n t of a c r o d y n i a has not been entirely satisfactory. I m p r o v e m e n t usually follows the use of d i m e r c a p r o l (BAL) which is a chelating agent for mercury, either alone or in c o m b i n a t i o n with oral tolazoline (Priscoline). Ganglionic blocking agents such as h e x a m e t h o n i u m b r o m i d e have given symptomatic relief in some instances. T h e r a p y with e d a t h a m i l calcium sodimn ( E D T A ) a n d nonspecific agents such as m u l t i p l e vitam i n preparations a n d brewer's yeast has not given consistent results. T h e observation that u r i n a r y excretion of m e r c u r y is often increased d u r i n g penicillin t h e r a p y for infection led to the use of penicillin t h e r a p y in acrodynia. Results, however, have been equivocal. S o m e w h a t later N-acetyI-u, Lpenicillamine was shown by studies in laboratory animals to be m o r e effective t h a n other penicillamine derivatives in protection against induced inorganic m e r c u r y poisoning a n d considerably less toxic. This derivative has been employed also in the successful treatm e n t of some industrial workers with mercury poisoning acquired in gilding processes. M e r c u r y in house p a i n t as a possible source of poisoning in a child was r e p o r t e d recently by Hirschman, Feingold, a n d Boylen 4 in the N e w England Journal of Medicine. U r i n a r y elimination of m e r c u r y was increased greatly by the use of N-acetyl-u, L-penicillamine. A suspected source of mercury was thought to be a water-base house p a i n t containing an organic c o m p o u n d , phenyl m e r c u r i c p r o p r i o n a t e , as a deterrent against the growth of molds. Both ingestion
April 1964
of the Paint a n d i n h a l a t i o n of its vapors could have occurred in the child concerned. This 5-year-old white boy had been in good health until 3 months before admission when he began to experience generalized abdominal pain during or soon after meals. A month before admission pruritus of ~the hands became marked, and pain in the shoulders, arms, legs and knee ioints developed. Often muscular weakness of the lower extremities prevented the child from standing or walking. Two weeks before admission a tentative diagnosis of rheumatic fever had been made at another hosp!tal. Two determinations of the erythrocyte sedimentation rate were reported as 4 ram. and 5 mm. pet] hour. The antistreptolysin O titer and an electrocardiogram were normal. The child became increasingly more irritable and complained of constant pain in the extremities. He was transferred to another hospital where .the diagnosis of possible mercury poisoning was made. A urinary level of 0.09 mg. of mercury per liter was obtained at this time. The child was referred to the Children's Service of Massachusetts General H0spitalfor further evaluation and treatment. On admission to this hospital the boy showed the typical signs and symptoms of acrodynia, including abdominal and joint pain, irritability, swinging changes 'of mood, marked photophobia, sweating, pink color of hands, desquamation, hypertension, hypotonia with salaam position, anorexia, and sleeplessness. Routine laboratory studies gave results within normal limits. An L. E. cell preparation was negative. Lumbar pnncture revealed a normal spinal fluid pressure, protein and sugar levels, and a normal colloidal gold curve. An electroencephalogram at this time was interpreted as an abnormal waking record because of asymmetry; an electroencephalogram made 3 days later, verified the abnormalities. Examination of the teeth revealed extensive caries and "loosening" of some of the teeth. Urinalysis gave results within normal limits; the urine contained traces of lead, but no protein or arsenic. Throughout the patient's illness urine specimens were analyzed quantitatively for mercury by a modification of the Monkmon procedure, a very sensitive method for the detection of mercury. Excretion of mercury increased on penicillamine treatment from 0.1 mg. per liter to 0.5 mg. per liter on the fifth day of treatment. The patient was treated with N-acetyl-u, L-penicillamine, 0.125 Gm. administered 4 times daily (30 mg. per kilogram of body weight per
Volume 64
Number 4
day). The urinary levels of mercury rose with uieatment, diminished on discontinuation, and increased again when treatment was reinstituted. Clinical improvement followed penicillamine therapy, except for the child's behavior which continued to be a problem. After a 3 week hospital stay, the child was allowed to go home. His behavior, somewhat improved on discharge, became progressively worse, necessitating readmission Ii days after discharge. A 6 day course of peniciIlamine was instituted, with marked improvement in behavior, although no significant increase in mercury excretion occurred. After 8 days in the hospital the boy was sent home and has maintained his improvement. Follow-up examination 10 months later showed this boy to be in reasonably good condition, with only a trace of mercury in the urine (0.0t6 mg. per liter). I n a critical discussion of mercury poisoning and its treatment, the authors emphasize that the a m o u n t of mercury which is of etiologic significance in some children may be very small, and the clinical manifestations slow to appear. T h a t the patient was the only m e m b e r of his family clinically affected by the mercury is attributed to his greater exposure during the painting of the rooms, to the possible ingestion of the paint, or perhaps to greater individual sensitivity to mercury. The mother stated that the boy helped with the painting and was with her during all the painting of the bedroom and kitchen. T h e entire living quarters for the family of 4 were very limited, especially the sleep!ng area. Concentration of metallic mercury in the paint used was found to be 0.02 per cent on the basis of weight or a percentage of 0.036 of phenyl mercuric proprionate. Experimental concentration studies on the paint, carried out with the aid of a General Electric Mercury V a p o r Detector, indicated that this product was capable of emitting an average concentration of 0.21 mg. of mercury per cubic meter of enclosed air, a higher concentration than that acdepted for continuous exposure for industrial workers? A painted test panel continued to emit mercury vapor in diminishing amounts for a period of 6 weeks in spite of continuous air exchange.
Comments
on c u r r e n t l i t e r a t u r e
6 09
T h e authors favor N-acetyl-l), L-penicillamine as the treatment of choice for acrodynia in children stating that it can be administered orally, and that the results compare favorably with those in patients t r e a t e d with BAL, with little or no evidence of toxicity. T h e patient described in the present report showed no signs of sensitivity to the drug such as rash, fever, Ieukopenia, or thrombocytopenia. "N-acetyl-D, L-penicillamine is the acetylated congener of D, L-penicillamine. Unlike D, L-penicillamaine, it will not increase urinary excretion of copper. It appears that N-acetyl-D, L-penicillamine is a more effective sulfhydryl donor. ''4 As shown by extensive investigations in experimental animals, the acetylated form is less toxic. These authors suggest that "there may be patients with some of the more subtle signs and symptoms of acrodynia in w h o m this diagnosis is not being considered, TM and emphasize that the antifungal mercury-containing paints should be limited to outdoor use and that the public should be made aware of the danger of exposure in young children. RUSSELL
j . B L A T T N E R , M.D.
REFERENCES
1. Bilderback, J. B.: Group of cases of unknown etiology and diagnosis, Northwest Med. 19: 263, 1920; Acrodynia, J. A. M. A. 84: 495, 1925. 2. Feer, E.: Eine eigenartlge Neurose des vegetativen Systems beim Kleinkinde, Ergebn. inn. Med. Kinderh. 24: 100, 1923; Eine eigenartige Neurose des vegetativen Systems beim Kleinkinde (Acrodynie, Erythr6dem, Pink disease, Jahrb. f. Kinderh. 10B: 267, 1925; Die spezifische vegetative Neuropathie des Kleinkindes (ki~adliche Akrodynie), Schwelz. med. Wchnschr. 65: 997, 1935. 3. Warkany, J., and Hubbard, D. M.: "Mercury in the urine of children with acrodynia, Lancet 1: 829, 1948; Acrodynia and mercury, J. PEmAT. 42: 365, 1953. 4. Hirschman, S. Z., Feingold, M., and Boylen, G.: Mercury in house paint as a cause of acrodynia: Effect of therapy with N-acetyl-D, L-penicillamine, New England J. Med. 269: 889, 1963. 5. American Conference of Governmental Industrial Hygienists, Twenty-fourth Annual Meeting, Washington, D. C., May 13-15, 1962; Reprints available: Secretary-Treasurer, American Conference Industrial Hygienists, 1014 Broadway, Cincinnati, Ohio.
ON LITERATURE
Acrodynia A c R O D Y N I A (pink disease, dermatopolyneuritis) constitutes a syndrome characterized by many unusual symptoms which fall nevertheless into a definite clinical pattern. Possible etiologies suggested have included avitaminosis; general dietary deficiency; chronic bacterial infection; infection with unspecified viral agents or with fungi such a s those commonly occurring on maize, rye, or other plants; and various chemical agents, especially arsenic or mercury. Following Bilderback's 1 early accounts of the disease, Feer 2 was impressed with such clinical manifestations as hypertension, tachycardia, and excessive sweating, and concluded that the condition resulted from overactivity of the autonomic nervous system. In 1948 Warkany and Hubbard a indicted mercury ingestion or exposure to mercury as the chief etiologic factor in acrodynia. They were able to compile data indicating that most, if not all, cases of acrodynia are the result of an idiosyncrasy to mercury. Within the next decade other reports followed, identifying mercury as the most important cause of the condition. The diagnosis is based primarily on the clinical appearance and the distinctive course of the disease. Characteristic clinical manifestations include extreme irritability and restlessness alternating with periods of apathy; insomnia, anorexia, profuse perspiration with attendant thirst; pink hands and feet, rosy cheeks, scarlet tip of the nose, and variable skin rashes with desquamation. Itch-
ing may be so severe that the child will rub the body, especially the extremities, against the bed or other furniture, initiating trophic ulceration. Photophobia is often pronounced and salivation excessive. The pulse is rapid, and the blood pressure elevated. Pain in the extremities may be severe. Over a period of time there is loss of the hair and nails, and in extreme cases 10ss of terminal phalanges. The pronounced hypotonia permits the patient to assume bizarre positions, some of which may be maintained for long periods of time. In few clinical conditions does the patient appear so obviously miserable. Similarity between the clinical manifestations of acrodynia in young children and those seen in association with mercury and arsenic poisoning in industrial workers led Warkany and Hubbard a to make the first systematic search for heavy metals in the urine of infants with this condition. Mercury was the only one detected, and occurred in 25 of 28 infants in the group studied initially. Since these early observations mercury has been detected in the urine of a large number of infants with acrodynia, especially in districts where mercurial medications have been used. In localities where mercurial lotions, diaper rinses, and teething powders were popular the incidence was greater in children under 1 year of age, whereas in those regions where mercurial vermifuges were employed the greater incidence was in older children, between the ages of 2 and 4 years. Urinary 607
608
Comments on current literature
m e r c u r y excretions in excess of 10 .ug per liter is considered of diagnostic significance. F o l l o w - u p studies on patients with m e r c u r y poisoning have been rare, especially in the U n i t e d States. T h e m o r t a l i t y rate seems to vary in different countries, but is thought to be about 12 per cent on the average. Bronc h o p n e u m o n i a is a c o m m o n complication. Autopsies p e r f o r m e d on children dying from m e r c u r y poisoning have revealed no consistent pathology. Nonspecific changes, however, have been observed with identifiable lesions in the brain, spinal cord, ganglia, a n d p e r i p h e r a l nerves. T r e a t m e n t of a c r o d y n i a has not been entirely satisfactory. I m p r o v e m e n t usually follows the use of d i m e r c a p r o l (BAL) which is a chelating agent for mercury, either alone or in c o m b i n a t i o n with oral tolazoline (Priscoline). Ganglionic blocking agents such as h e x a m e t h o n i u m b r o m i d e have given symptomatic relief in some instances. T h e r a p y with e d a t h a m i l calcium sodimn ( E D T A ) a n d nonspecific agents such as m u l t i p l e vitam i n preparations a n d brewer's yeast has not given consistent results. T h e observation that u r i n a r y excretion of m e r c u r y is often increased d u r i n g penicillin t h e r a p y for infection led to the use of penicillin t h e r a p y in acrodynia. Results, however, have been equivocal. S o m e w h a t later N-acetyI-u, Lpenicillamine was shown by studies in laboratory animals to be m o r e effective t h a n other penicillamine derivatives in protection against induced inorganic m e r c u r y poisoning a n d considerably less toxic. This derivative has been employed also in the successful treatm e n t of some industrial workers with mercury poisoning acquired in gilding processes. M e r c u r y in house p a i n t as a possible source of poisoning in a child was r e p o r t e d recently by Hirschman, Feingold, a n d Boylen 4 in the N e w England Journal of Medicine. U r i n a r y elimination of m e r c u r y was increased greatly by the use of N-acetyl-u, L-penicillamine. A suspected source of mercury was thought to be a water-base house p a i n t containing an organic c o m p o u n d , phenyl m e r c u r i c p r o p r i o n a t e , as a deterrent against the growth of molds. Both ingestion
April 1964
of the Paint a n d i n h a l a t i o n of its vapors could have occurred in the child concerned. This 5-year-old white boy had been in good health until 3 months before admission when he began to experience generalized abdominal pain during or soon after meals. A month before admission pruritus of ~the hands became marked, and pain in the shoulders, arms, legs and knee ioints developed. Often muscular weakness of the lower extremities prevented the child from standing or walking. Two weeks before admission a tentative diagnosis of rheumatic fever had been made at another hosp!tal. Two determinations of the erythrocyte sedimentation rate were reported as 4 ram. and 5 mm. pet] hour. The antistreptolysin O titer and an electrocardiogram were normal. The child became increasingly more irritable and complained of constant pain in the extremities. He was transferred to another hospital where .the diagnosis of possible mercury poisoning was made. A urinary level of 0.09 mg. of mercury per liter was obtained at this time. The child was referred to the Children's Service of Massachusetts General H0spitalfor further evaluation and treatment. On admission to this hospital the boy showed the typical signs and symptoms of acrodynia, including abdominal and joint pain, irritability, swinging changes 'of mood, marked photophobia, sweating, pink color of hands, desquamation, hypertension, hypotonia with salaam position, anorexia, and sleeplessness. Routine laboratory studies gave results within normal limits. An L. E. cell preparation was negative. Lumbar pnncture revealed a normal spinal fluid pressure, protein and sugar levels, and a normal colloidal gold curve. An electroencephalogram at this time was interpreted as an abnormal waking record because of asymmetry; an electroencephalogram made 3 days later, verified the abnormalities. Examination of the teeth revealed extensive caries and "loosening" of some of the teeth. Urinalysis gave results within normal limits; the urine contained traces of lead, but no protein or arsenic. Throughout the patient's illness urine specimens were analyzed quantitatively for mercury by a modification of the Monkmon procedure, a very sensitive method for the detection of mercury. Excretion of mercury increased on penicillamine treatment from 0.1 mg. per liter to 0.5 mg. per liter on the fifth day of treatment. The patient was treated with N-acetyl-u, L-penicillamine, 0.125 Gm. administered 4 times daily (30 mg. per kilogram of body weight per
Volume 64
Number 4
day). The urinary levels of mercury rose with uieatment, diminished on discontinuation, and increased again when treatment was reinstituted. Clinical improvement followed penicillamine therapy, except for the child's behavior which continued to be a problem. After a 3 week hospital stay, the child was allowed to go home. His behavior, somewhat improved on discharge, became progressively worse, necessitating readmission Ii days after discharge. A 6 day course of peniciIlamine was instituted, with marked improvement in behavior, although no significant increase in mercury excretion occurred. After 8 days in the hospital the boy was sent home and has maintained his improvement. Follow-up examination 10 months later showed this boy to be in reasonably good condition, with only a trace of mercury in the urine (0.0t6 mg. per liter). I n a critical discussion of mercury poisoning and its treatment, the authors emphasize that the a m o u n t of mercury which is of etiologic significance in some children may be very small, and the clinical manifestations slow to appear. T h a t the patient was the only m e m b e r of his family clinically affected by the mercury is attributed to his greater exposure during the painting of the rooms, to the possible ingestion of the paint, or perhaps to greater individual sensitivity to mercury. The mother stated that the boy helped with the painting and was with her during all the painting of the bedroom and kitchen. T h e entire living quarters for the family of 4 were very limited, especially the sleep!ng area. Concentration of metallic mercury in the paint used was found to be 0.02 per cent on the basis of weight or a percentage of 0.036 of phenyl mercuric proprionate. Experimental concentration studies on the paint, carried out with the aid of a General Electric Mercury V a p o r Detector, indicated that this product was capable of emitting an average concentration of 0.21 mg. of mercury per cubic meter of enclosed air, a higher concentration than that acdepted for continuous exposure for industrial workers? A painted test panel continued to emit mercury vapor in diminishing amounts for a period of 6 weeks in spite of continuous air exchange.
Comments
on c u r r e n t l i t e r a t u r e
6 09
T h e authors favor N-acetyl-l), L-penicillamine as the treatment of choice for acrodynia in children stating that it can be administered orally, and that the results compare favorably with those in patients t r e a t e d with BAL, with little or no evidence of toxicity. T h e patient described in the present report showed no signs of sensitivity to the drug such as rash, fever, Ieukopenia, or thrombocytopenia. "N-acetyl-D, L-penicillamine is the acetylated congener of D, L-penicillamine. Unlike D, L-penicillamaine, it will not increase urinary excretion of copper. It appears that N-acetyl-D, L-penicillamine is a more effective sulfhydryl donor. ''4 As shown by extensive investigations in experimental animals, the acetylated form is less toxic. These authors suggest that "there may be patients with some of the more subtle signs and symptoms of acrodynia in w h o m this diagnosis is not being considered, TM and emphasize that the antifungal mercury-containing paints should be limited to outdoor use and that the public should be made aware of the danger of exposure in young children. RUSSELL
j . B L A T T N E R , M.D.
REFERENCES
1. Bilderback, J. B.: Group of cases of unknown etiology and diagnosis, Northwest Med. 19: 263, 1920; Acrodynia, J. A. M. A. 84: 495, 1925. 2. Feer, E.: Eine eigenartlge Neurose des vegetativen Systems beim Kleinkinde, Ergebn. inn. Med. Kinderh. 24: 100, 1923; Eine eigenartige Neurose des vegetativen Systems beim Kleinkinde (Acrodynie, Erythr6dem, Pink disease, Jahrb. f. Kinderh. 10B: 267, 1925; Die spezifische vegetative Neuropathie des Kleinkindes (ki~adliche Akrodynie), Schwelz. med. Wchnschr. 65: 997, 1935. 3. Warkany, J., and Hubbard, D. M.: "Mercury in the urine of children with acrodynia, Lancet 1: 829, 1948; Acrodynia and mercury, J. PEmAT. 42: 365, 1953. 4. Hirschman, S. Z., Feingold, M., and Boylen, G.: Mercury in house paint as a cause of acrodynia: Effect of therapy with N-acetyl-D, L-penicillamine, New England J. Med. 269: 889, 1963. 5. American Conference of Governmental Industrial Hygienists, Twenty-fourth Annual Meeting, Washington, D. C., May 13-15, 1962; Reprints available: Secretary-Treasurer, American Conference Industrial Hygienists, 1014 Broadway, Cincinnati, Ohio.