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Chronic thallium poisoning: Rapid diagnosis and treatment
Volume 65 Number 3
ing single overdoses of u p to 1,075 mg. in children a n d as high as 8,000 mg. by adults, has been reported.
REFERENCES 1. Reports on File at Hoffmann-La Roche Inc., Nutley, New Jersey (made available on request by the author).
Brie[ clinical and laboratory observations
2. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 219. 3. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 212. 4. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 214.
46 1
of pediatrics, ed. 7, Saunders Company, of pediatrics, ed. 7, Saunders Company, of pediatrics, ed. 7, Saunders Company,
Chronic thallium poisoning: Rapid diagnosis and treatment Paddy Taber, M.D. LOS
ANGELES~
CALIF.
T ~ A L L I U M i s a very toxic heavy metal commonly used as a rodenticide. Peanuts and grains are coated with t h a l l i u m salts for use in rodent control; as such, they present a n attractive item for ingestion by young children. T h e following report concerns a child with thallotoxicosis together with a brief review of the literature regarding therapy. A rapid m e t h o d for laboratory diagnosis a n d a rational form of therapy for thallium poisoning is presented.
CASE REPORT A 3-year-old, white male was admitted to the St. Louis Children's Hospital on March I8, 1961, with a history of ingestion of an undetermined amount of thallium-coated peanuts 1 month prior to admission. At that time, attempts to induce emesis with saline were unsuccessful. No symptoms were noted u n t i l 1 week prior to
From the Department of Pediatrics, University of Cali[ornia Medical Center, Los Angeles 24, Cali[.
admission when ptosis, dysarthria, restricted movement and myoclonic jerking of his left leg became evident. Three days before he was seen alopecia was noted. His prior health had been good; growth and development were normal. On physical examination. His weight was 13.7 kilograms, pulse 120, respiratory rate 24, temperature 37.6 ~ C., and blood pressure 110/70. His sensorium was dulled. Gross alopecia of the scalp was present. The eyebrows were not affected. There was bilateral ptosis. The gait was markedly ataxic with a left foot drop and there was weakness of the left arm. The deep tendon reflexes were decreased throughout. Laboratory findings. Hemoglobin was 11.4 Gin. per 100 ml.; hematocrit 30 per cent; white blood count 8,200 per cubic millimeter with 1 per cent band neutrophils, 18 per cent segmented neutrophils, 80 per cent lymphocytes, 1 per cent monocytes, and normal platelets. Routine urine analysis was normal. Urine thallium the day after admission was 8,80 mg. per liter, urinary thallium after 47 days of therapy, 0.06 mg. per liter. X-rays were negative for heavy metal lines in long bones. An electrocardiograph revealed incomplete bundle branch block.
462
Brie[ clinical and laboratory observations
Hospital course. Initial management was adapted from standard texts of toxicology1, 2 and consisted of 10 c.c. thiosulfate IV once a day, 1 teaspoon Os-Cal 3 times a day, and a multiple vitamin preparation. Two days after admission BAL, 0.33 c.c., intramuscularly, 4 times a day, 500 mg. cystine 2 times a day, and 5 mg. of Brewer's Yeast 3 times a day were added, a No changes were noted during the first five days of hospitalization. Subsequently, the patient became less irritable and more responsive to his environment. At this point, potassium chloride and methionine were added to the cystine and Brewer's Yeast. The other medications were discontinued. The patient's affect improved markedly in the course of the following week. Epilation ceased, the foot drop and ptosis began to improve. The patient was discharged 13 days after admission and continued to receive cystine, methionine, and potassium chloride. Two months later he appeared alert, ptosis was not present, and his hair had returned. The only apparent residual effect was a slightly widened gait and minimal left ankle weakness. DISCUSSION This patient demonstrates the characteristic features of thallium poisoning. T h e insidious, bizarre, neurologic complaints present a clinical challenge. T h e correct diagnosis usually is not suspected until the alopecia appears, which m a y be 3 to 4 weeks after ingestion. An early diagnosis can be m a d e with the use of a rapid, specific, qualitative urine test for thallium? I n acid solution thallium forms a characteristic red precipitate when mixed with sodium iodide and sodium bismuth. Equal aliquots of urine, 0.4 per cent sodium bismuth in 20 per cent nitric acid, and 10 per cent sodium iodide are mixed in a test tube. If thallium is present in the urine, a brick-red precipitate readily forms in the test tube. A negative test is indicated by absence of a precipitate. Both the sensitivity and specificity of this test are good. Thallium concentrations as low as 1.0 mg. per cent have given a precipitate. False positive determinations have not been observed with other heavy metals, such as lead, arsenic, and mercury. Quanti-
September 1964
tative determinations for thallium m a y be performed on 24 hour urine collections in a few commercial laboratories in the United States. The plan of therapy was based on recent experimental work. I n 1948, Gross, Runne, and Wilson 5 observed that 1 or 2 per cent cystine and methionine in a diet would decrease epilation and increase survival in thallotoxic rats. Thyresson G verified this and attempted to explain the results. H e showed that thallium in vitro inhibited anaerobic glycosis. All intermediate metabolites of the Kreb's cycle were significantly depressed with the single exception of succinic acid. Furthermore, it is known that heavy metals, like thallium, combine with sulfhydryl (-SH) groups and inactivate enzyme systems. These sulfhydryl groups are especially important for transmethylation in the intermediate metabolism of fat, creatine, and, notably, hair. Cystine and methionine are the principal sources of sulfhydryl groups in metabolic processes. L u n & studied the effect of various agents on urine excretion of thallium in thallotoxic rats. Cystine or potassium chloride increased excretion by 50 per cent. Thiosulfate, E D T A , BAL, cation-exchange resins, diamox, mercurial diuretics, and steroids were not effective. In addition, L u n d investigated the effect of Dithisone (di-phenolthiocarbazone), a chelating agent used in the quantitative assay for thallium. H e was able to increase thallium excretion by 75 per cent and decrease rat mortality to zero: Although dithisone has reported diabetogenic and goitrogenic effects, Chamberlain s has used it with h u m a n beings and has reported no toxicity to date. SUMMARY
A case of thallotoxicosis in a 3-year-old, white male is reported. A rapid laboratory test for thallium is described which has not previously been published in the pediatric literature. A rational plan of therapy is suggested which consists of cystine, methionine,
Volume 65
Number 3
a n d potassium chloride. Dithisone, t h o u g h p o t e n t i a l l y hazardous, m a y also be used.
This patient was referred by C. Read Boles, M.D., St. Louis, Missouri. Appreciation is acknowledged to Dr. Stanley W. Wright for review of this manuscript.
REFERENCES 1. Goodman, L. A., and Gilman, A.: The pharmacological basis of therapeutics, ed. 2, New York, 1958, The MacMillan Company, pp. 990-991. 2. Driesbach, R. H.: Handbook of poisoning: Diagnosis and treatment, ed. 2, Los Altos, 1959, Lange Medical Publication, p. 101.
Brief clinical and laboratory observations
463
3. Gleason, N. N., Gosselin, R. E., and Hodge, H. C.: Clinical toxicology of commercial products, Baltimore, 1957, Williams & Wilkins Company, pp. 177-178. 4. Wenger, P., and Rusconl, V.: A new specific reaction for the identification of thallium, Helvet. chit. acta 26: 2263, 1943. 5. Gross, R., Runne, E., and Wilson, J. W.: Studies on the effect of thallium poisoning of the rat. The influence of cystine and methionine on alopeeia and survival periods, J. Invest. Dermat. 10: 119, 1948. 6. Thyresson, N.: Influence of dietary factors, especially Brewer's Yeast, cystine and B vitamins on the course of thallium poisoning in the rat, Aeta dermat. 30: 9417, 1950. 7. Lund, A.: The effect of various substances on the excretion and toxicity of thallium in the rat, Acta pharmaeol et toxicol. 12: 260, 1956. 8. Chamberlain, T.: Thallium poisoning, Pediatrics 22: 1170, 1958.
Familial pheochromocytoma presenting as familial dysautonomia A case report
Alfred A. Smith, M.D., and Joseph Dancis, M.D.* NEW
YORK,
N.
Y.
R E c ~ N T L "Z, in this JOURNAL, a skin test with histamine was described as a n a i d in the diagnosis of familial d y s a u t o n o m i a ? T o date, this test has unfailingly d i f f e r e n t i a t e d the d y s a u t o n o m i c from control subjects. W e From the Departments of Psychiatry and Neurology, and the Department of Pediatrics, New York University School of Medicine. This study was supported by Grants MH-01434 and HD-00462 Jrom the United States Public Health Service and by grants from the National Foundation and Dysautonomia Association. Facilities of the Special Clinical Unit were used in this study. ~'Career Scientist, Institute of Child Health and Human Development, of the National Institutes of Health. Address, Professor of Pediatrics, New York University Medical Center, 530 First Avenue, N e w York, N. Y. 10016.
have recently become a w a r e of two o t h e r conditions, a t o p i c d e r m a t i t i s a n d familial p h e o c h r o m o c y t o m a , in w h i c h there m a y be a s u b n o r m a l response to i n t r a d e r m a l histamine. Because of the cutaneous lesions a n d typical history, a t o p i c d e r m a t i t i s poses no p r o b l e m in diagnosis a n d will not be f u r t h e r discussed. T h e p u r p o s e of this r e p o r t h o w ever is to stress the superficial similarities of d y s a u t o n o m i a a n d p h e o c h r o m o c y t o m a , to w a r n of the possible confusion arising from the histamine test, a n d to indicate the ease with which the differential diagnosis can n o w be made. T o illustrate these points, t h e findings in two c h i l d r e n with familial pheoc h r o m o c y t o m a will be briefly presented.
ing single overdoses of u p to 1,075 mg. in children a n d as high as 8,000 mg. by adults, has been reported.
REFERENCES 1. Reports on File at Hoffmann-La Roche Inc., Nutley, New Jersey (made available on request by the author).
Brie[ clinical and laboratory observations
2. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 219. 3. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 212. 4. Nelson, W. E.: Textbook Philadelphia, 1959, W. B. p. 214.
46 1
of pediatrics, ed. 7, Saunders Company, of pediatrics, ed. 7, Saunders Company, of pediatrics, ed. 7, Saunders Company,
Chronic thallium poisoning: Rapid diagnosis and treatment Paddy Taber, M.D. LOS
ANGELES~
CALIF.
T ~ A L L I U M i s a very toxic heavy metal commonly used as a rodenticide. Peanuts and grains are coated with t h a l l i u m salts for use in rodent control; as such, they present a n attractive item for ingestion by young children. T h e following report concerns a child with thallotoxicosis together with a brief review of the literature regarding therapy. A rapid m e t h o d for laboratory diagnosis a n d a rational form of therapy for thallium poisoning is presented.
CASE REPORT A 3-year-old, white male was admitted to the St. Louis Children's Hospital on March I8, 1961, with a history of ingestion of an undetermined amount of thallium-coated peanuts 1 month prior to admission. At that time, attempts to induce emesis with saline were unsuccessful. No symptoms were noted u n t i l 1 week prior to
From the Department of Pediatrics, University of Cali[ornia Medical Center, Los Angeles 24, Cali[.
admission when ptosis, dysarthria, restricted movement and myoclonic jerking of his left leg became evident. Three days before he was seen alopecia was noted. His prior health had been good; growth and development were normal. On physical examination. His weight was 13.7 kilograms, pulse 120, respiratory rate 24, temperature 37.6 ~ C., and blood pressure 110/70. His sensorium was dulled. Gross alopecia of the scalp was present. The eyebrows were not affected. There was bilateral ptosis. The gait was markedly ataxic with a left foot drop and there was weakness of the left arm. The deep tendon reflexes were decreased throughout. Laboratory findings. Hemoglobin was 11.4 Gin. per 100 ml.; hematocrit 30 per cent; white blood count 8,200 per cubic millimeter with 1 per cent band neutrophils, 18 per cent segmented neutrophils, 80 per cent lymphocytes, 1 per cent monocytes, and normal platelets. Routine urine analysis was normal. Urine thallium the day after admission was 8,80 mg. per liter, urinary thallium after 47 days of therapy, 0.06 mg. per liter. X-rays were negative for heavy metal lines in long bones. An electrocardiograph revealed incomplete bundle branch block.
462
Brie[ clinical and laboratory observations
Hospital course. Initial management was adapted from standard texts of toxicology1, 2 and consisted of 10 c.c. thiosulfate IV once a day, 1 teaspoon Os-Cal 3 times a day, and a multiple vitamin preparation. Two days after admission BAL, 0.33 c.c., intramuscularly, 4 times a day, 500 mg. cystine 2 times a day, and 5 mg. of Brewer's Yeast 3 times a day were added, a No changes were noted during the first five days of hospitalization. Subsequently, the patient became less irritable and more responsive to his environment. At this point, potassium chloride and methionine were added to the cystine and Brewer's Yeast. The other medications were discontinued. The patient's affect improved markedly in the course of the following week. Epilation ceased, the foot drop and ptosis began to improve. The patient was discharged 13 days after admission and continued to receive cystine, methionine, and potassium chloride. Two months later he appeared alert, ptosis was not present, and his hair had returned. The only apparent residual effect was a slightly widened gait and minimal left ankle weakness. DISCUSSION This patient demonstrates the characteristic features of thallium poisoning. T h e insidious, bizarre, neurologic complaints present a clinical challenge. T h e correct diagnosis usually is not suspected until the alopecia appears, which m a y be 3 to 4 weeks after ingestion. An early diagnosis can be m a d e with the use of a rapid, specific, qualitative urine test for thallium? I n acid solution thallium forms a characteristic red precipitate when mixed with sodium iodide and sodium bismuth. Equal aliquots of urine, 0.4 per cent sodium bismuth in 20 per cent nitric acid, and 10 per cent sodium iodide are mixed in a test tube. If thallium is present in the urine, a brick-red precipitate readily forms in the test tube. A negative test is indicated by absence of a precipitate. Both the sensitivity and specificity of this test are good. Thallium concentrations as low as 1.0 mg. per cent have given a precipitate. False positive determinations have not been observed with other heavy metals, such as lead, arsenic, and mercury. Quanti-
September 1964
tative determinations for thallium m a y be performed on 24 hour urine collections in a few commercial laboratories in the United States. The plan of therapy was based on recent experimental work. I n 1948, Gross, Runne, and Wilson 5 observed that 1 or 2 per cent cystine and methionine in a diet would decrease epilation and increase survival in thallotoxic rats. Thyresson G verified this and attempted to explain the results. H e showed that thallium in vitro inhibited anaerobic glycosis. All intermediate metabolites of the Kreb's cycle were significantly depressed with the single exception of succinic acid. Furthermore, it is known that heavy metals, like thallium, combine with sulfhydryl (-SH) groups and inactivate enzyme systems. These sulfhydryl groups are especially important for transmethylation in the intermediate metabolism of fat, creatine, and, notably, hair. Cystine and methionine are the principal sources of sulfhydryl groups in metabolic processes. L u n & studied the effect of various agents on urine excretion of thallium in thallotoxic rats. Cystine or potassium chloride increased excretion by 50 per cent. Thiosulfate, E D T A , BAL, cation-exchange resins, diamox, mercurial diuretics, and steroids were not effective. In addition, L u n d investigated the effect of Dithisone (di-phenolthiocarbazone), a chelating agent used in the quantitative assay for thallium. H e was able to increase thallium excretion by 75 per cent and decrease rat mortality to zero: Although dithisone has reported diabetogenic and goitrogenic effects, Chamberlain s has used it with h u m a n beings and has reported no toxicity to date. SUMMARY
A case of thallotoxicosis in a 3-year-old, white male is reported. A rapid laboratory test for thallium is described which has not previously been published in the pediatric literature. A rational plan of therapy is suggested which consists of cystine, methionine,
Volume 65
Number 3
a n d potassium chloride. Dithisone, t h o u g h p o t e n t i a l l y hazardous, m a y also be used.
This patient was referred by C. Read Boles, M.D., St. Louis, Missouri. Appreciation is acknowledged to Dr. Stanley W. Wright for review of this manuscript.
REFERENCES 1. Goodman, L. A., and Gilman, A.: The pharmacological basis of therapeutics, ed. 2, New York, 1958, The MacMillan Company, pp. 990-991. 2. Driesbach, R. H.: Handbook of poisoning: Diagnosis and treatment, ed. 2, Los Altos, 1959, Lange Medical Publication, p. 101.
Brief clinical and laboratory observations
463
3. Gleason, N. N., Gosselin, R. E., and Hodge, H. C.: Clinical toxicology of commercial products, Baltimore, 1957, Williams & Wilkins Company, pp. 177-178. 4. Wenger, P., and Rusconl, V.: A new specific reaction for the identification of thallium, Helvet. chit. acta 26: 2263, 1943. 5. Gross, R., Runne, E., and Wilson, J. W.: Studies on the effect of thallium poisoning of the rat. The influence of cystine and methionine on alopeeia and survival periods, J. Invest. Dermat. 10: 119, 1948. 6. Thyresson, N.: Influence of dietary factors, especially Brewer's Yeast, cystine and B vitamins on the course of thallium poisoning in the rat, Aeta dermat. 30: 9417, 1950. 7. Lund, A.: The effect of various substances on the excretion and toxicity of thallium in the rat, Acta pharmaeol et toxicol. 12: 260, 1956. 8. Chamberlain, T.: Thallium poisoning, Pediatrics 22: 1170, 1958.
Familial pheochromocytoma presenting as familial dysautonomia A case report
Alfred A. Smith, M.D., and Joseph Dancis, M.D.* NEW
YORK,
N.
Y.
R E c ~ N T L "Z, in this JOURNAL, a skin test with histamine was described as a n a i d in the diagnosis of familial d y s a u t o n o m i a ? T o date, this test has unfailingly d i f f e r e n t i a t e d the d y s a u t o n o m i c from control subjects. W e From the Departments of Psychiatry and Neurology, and the Department of Pediatrics, New York University School of Medicine. This study was supported by Grants MH-01434 and HD-00462 Jrom the United States Public Health Service and by grants from the National Foundation and Dysautonomia Association. Facilities of the Special Clinical Unit were used in this study. ~'Career Scientist, Institute of Child Health and Human Development, of the National Institutes of Health. Address, Professor of Pediatrics, New York University Medical Center, 530 First Avenue, N e w York, N. Y. 10016.
have recently become a w a r e of two o t h e r conditions, a t o p i c d e r m a t i t i s a n d familial p h e o c h r o m o c y t o m a , in w h i c h there m a y be a s u b n o r m a l response to i n t r a d e r m a l histamine. Because of the cutaneous lesions a n d typical history, a t o p i c d e r m a t i t i s poses no p r o b l e m in diagnosis a n d will not be f u r t h e r discussed. T h e p u r p o s e of this r e p o r t h o w ever is to stress the superficial similarities of d y s a u t o n o m i a a n d p h e o c h r o m o c y t o m a , to w a r n of the possible confusion arising from the histamine test, a n d to indicate the ease with which the differential diagnosis can n o w be made. T o illustrate these points, t h e findings in two c h i l d r e n with familial pheoc h r o m o c y t o m a will be briefly presented.