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Ophthalmologic Features of Thallium Poisoning
Ophthalmologic Features of Thallium Poisoning Homayoun Tabandeh, F.R.C.Ophth., Jonathan G. Crowston, M.R.C.Ophth., and Graham M. T h o m p s o n , F.R.C.Ophth.
Thallium intoxication is characterized by the development of painful peripheral neu ropathy, alopecia, mental disorders, and in severe cases, respiratory failure and death. Toxic optic neuropathy is also a feature. Oph thalmologic features of thallium poisoning include optic neuropathy, blepharoptosis, lens opacities, and ophthalmoplegia. A 44year-old man with criminal sublethal thalli um poisoning was examined one month after he was seen in the neurology department with classic systemic features. He was found to have diminished contrast sensitivity, a tritan defect in color vision, and a relative cecocentral scotoma before he developed optic atro phy. in 1861 by Crooks, 1 thalli um has been responsible for many occupation al, accidental, deliberate, and therapeutic poi sonings. In the past it had been used in the treatment of syphilis, gonorrhea, dysentery, tuberculosis, and ring worm of the scalp.1·2 In the first half of this century, it was widely used as a pesticide. Lamy3 found that in high doses this heavy metal is lethal to animals. Buschke and Langer4 described the pathologic effects of thallium sulfate. Present use includes the pro duction of scintillation counters and imitation jewelry. Its ability to transmit long-wave radia tion has given thallium a role in lens manufac ture. Thallium is colorless, odorless, and tasteless. These properties have made it an ideal poison both for rodents and for use by psychopathic poisoners. 5 · 6 Its use as a homicidal poison is said to be widespread. 7 Numerous reports have discussed the systemic effects and toxicology of thallium poisoning. However, little has been S I N C E ITS DISCOVERY
Accepted for publication Nov. 8, 1993. From the Department of Ophthalmology, St. George's Hospital, London, United Kingdom. Reprint requests to Homayoun Tabandeh, M.R.C.P., F.R.C.Ophth., Department of Ophthalmology, St. George's Hospital, London SW 17 OQT, Great Britain.
written about the ocular effects of intoxication by this metal.
Case Report A 44-year-old man had a two-week history of general malaise and unsteadiness and a nineday history of a skin rash over his hands and legs. Over the next week he developed nausea, vomiting, and painful legs, and he became increasingly confused. On examination he was found to have a markedly impaired mental score, bilateral horizontal jerky nystagmus, bi lateral weakness of the facial cranial nerves, blepharoptosis, and global weakness of the limbs particularly proximally. Tendon reflexes, plantar responses, and coordination were with in normal limits. Vibration sense and proprioception were globally reduced. He had a papulomacular rash over the skin of his hands and legs and there was alopecia of his scalp (Figs. 1 and 2). An electroencephalogram showed gen eralized slowing of activity. Nerve conduction studies demonstrated the features of a peripher al sensorimotor neuropathy. Computed tomog raphy and magnetic resonance imaging results were normal. Painful peripheral neuropathy together with alopecia raised the possibility of thallium intoxication. Further investigations disclosed a blood thallium level of 108 g/1 (normal, < 2 g/1) and a urine thallium level of 1,350 g/1 (normal, <200 g/1). Thallium intoxi cation was diagnosed, and high potassium sup plements and potassium ferric hexacyanoferrate II were begun. Subsequently the thallium levels diminished, and the patient gradually recovered. The cause of poisoning could not be established. Accidental or suicidal ingestion was excluded and the case was referred for criminal investigation. A month later, ophthalmologic examination showed a corrected visual acuity of R.E.: 20/20 and L.E.: 20/40. Anterior segments, pupillary reflexes, optic disks, pursuit and saccadic eye movements were normal. There was bilateral blepharoptosis and a mild horizontal jerk nys-
©AMERICAN JOURNAL O F OPHTHALMOLOGY 117:243-245, FEBRUARY, 1994
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AMERICAN JOURNAL OF OPHTHALMOLOGY
February, 1994
Fig. 2 (Tabandeh, Crowston, and Thompson). Maculopapular skin rash, which progressed to scabbing.
Fig. 1 (Tabandeh, Crowston, and Thompson). Scalp alopecia, blepharoptosis, and facial weakness in thallium intoxication (photograph modified to limit identification). tagmus. Contrast sensitivity was diminished across all spatial frequencies in both eyes. The Farnsworth-Munsell 100-hue test demonstrat ed tritanomaly, which was worse in the left eye. Normal results from a previous army medical examination, no past ocular or neurologic dis orders, and absence of a family history of color blindness reduced the likelihood of a pre-exist ing color vision defect. Automated perimetry showed bilateral relative cecocentral scotomas. The patient developed mild optic atrophy two months after the onset of symptoms. Nine months after the initial manifestation, there was residual impairment of the patient's higher mental functions, mild weakness, and a persistent color vision defect.
Discussion The clinical picture of thallium intoxication is variable; however, the diagnosis is often sus pected in the presence of the triad of symptoms: (1) alopecia and skin rash, (2) painful peripher al neuropathy, and (3) confusion and lethargy. The lethal dose for humans is 15 to 20 m g / k g of body weight; nonfatal intoxication occurs below this dose. The first symptoms of poison ing are abdominal pain, gastroenteritis, tachy-
cardia, and headache, which usually occur within 12 hours. A characteristic dark, pigmented band appears in the scalp hair within four days. Neurologic symptoms appear in two to five days and include confusion, hallucina tions, and convulsions. In severe cases coma, respiratory paralysis, and death occur within one week. When smaller doses are taken pain ful peripheral sensorimotor neuropathy and ataxia are the outstanding symptoms. Other neurologic features include cranial nerve pal sies, optic neuropathy, choreoathetosis, trem or, and encephalopathy. Scalp alopecia is the best known symptom of chronic thallium poi soning, which begins ten days after the inges tion and is completed within one month. 8 8 Skin may be involved by acneiform eruptions, a papulomacular rash, and dystrophy of the nails (Mee's strips). Autonomie dysfunction, hyper tension, cardiomyopathy, electrocardiographic changes, testicular toxicity, hypokalemia, re nal failure, abnormal liver function, leukocytosis, and thrombocytopenia have been report ed. Electroencephalography shows nonspecific slow wave activity, and electromyography is suggestive of distal axonopathy. Ophthalmologic manifestations include loss of the lateral half of the eyebrows, eyelid skin lesions, blepharoptosis, facial nerve palsy, in ternal and external ophthalmoplegia, and nys tagmus. Noninflammatory keratitis and lens opacities have also been described. 1012 Optic atrophy as a sequel to thallium-induced toxic optic neuropathy is well reported. 9 · 1316 Func tional changes include impairment of contrast sensitivity, abnormal color vision (tritanoma ly), impaired visual acuity, and central or ceco central scotomas. There is also electroretino-
Vol. 117, No. 2
Thallium Poisoning
graphic abnormality and a delayed visualevoked response. Optic neuropathy and cranial nerve palsies are the most marked features. The changes in visual function are essentially those related to the optic nerve damage. Electrophysiologic studies carried out on rabbits injected with intravitreal doses of thallium demonstrat ed that the retina, particularly the photoreceptor layer, is susceptible to the effect of thallium, and the degree of impairment depends on the time and dose of exposure. 17 The mechanism for toxic effects of thallium is not fully understood. It may be that thallium, which has a high affinity for Na-K ATP'ase and -SH containing enzymes, causes disruption of cell membrane stability. Histopathologic stud ies have shown axonal degeneration to be a primary pathologic change. There are also close similarities between thallium intoxication and thiamine deficiency and arsenical neuropa thies. Thallium neurotoxicity may be related to the interaction of this ion with riboflavin, with consequent effects on energy generation mech anisms associated with tissue flavoproteins. 6 Thallium moves in the body along potassium pathways and is thus excreted via salivary glands and bile. In the gut it is reabsorbed, thereby causing a continuous intoxication. Treatment with potassium ferric hexacyanoferrate II removes it from the gut, thus breaking the cycle.18 The prognosis of thallotoxicosis depends on the total amount ingested, the time course of the ingestion, and the individual susceptibility. The reported mortality rate is 6% to 13% with over half of the survivors being left with residu al neurologic deficit. Abnormal vision together with tremor, muscle weakness, convulsions, and coma are associated with residual neuro logic deficit.19·20 In summary, this is a case of thallium poison ing with diminished contrast sensitivity, a tritan impairment of color vision, and a relative cecocentral scotoma in the presence of slightly impaired visual acuity. Mild optic atrophy de veloped later. Other features included blepharoptosis, bilateral facial nerve palsies, and fine horizontal nystagmus. At nine-month followup most features had improved, however there was persistent defect in color vision and higher mental function. Thallium intoxication should be considered in the differential diagnosis of toxic optic neu ropathy. Contrast sensitivity and color vision are abnormal before the appearance of other
245
clinical signs of optic neuropathy and provide early evidence of optic nerve involvement.
References 1. Crooks, W On existence of a new element probably of sulphur group. Chemical News 3:193, 1861. 2. Saddique, A., and Patterson, C. D.: Thallium poisoning. A review. Vet. Hum. Toxicol. 25:16, 1983. 3. Lamy, M. A.: Sur les effets toxiques du thallium. C. R. Acad. Sei., Paris. 57:442, 1863. 4. Buschke, A., and Langer, E.: Die Forensische und gewerbl-hygienische Bedeutung des Thalliums. Munch. Med. Wochnschr. 74:1494, 1927. 5. Burnett, J. W.: Thallium poisoning. Cutis 46:112, 1990. 6. Cavanagh, J. B.: What have we learnt from Gra ham Frederick Young? Reflections on the mechanism of thallium neurotoxicity. Neuropathol. Appl. Neurobiol. 17:3, 1991. 7. Moeschlin, S.: Thallium poisoning. Clin. Toxi col. 17:133, 1988. 8. Grossman, H.: Thallotoxicosis. Report of case and review. Paediatrics 16:868, 1956. 9. Kallner, A.: Thallium-Vergiftung bei Kinder. Ann. Paediatr. 167:188, 1946. 10. Richet, C : De la toxicité du thallium. C. R. Soc. Biol. Paris. 1:252, 1899. 11. Castelao, A.M.: Cataract due to thallium. Med Espan. 5:395, 1941. 12. Duke-Elder, S.: Textbook of Ophthalmology, vol. 3. London, H. Kimpton, 1947, p. 3153. 13. Kaps, L.: Kriminelle tödliche subakute Thalli um Vergiftung. Wien. Klin. Wochenschr. 40:967, 1927. 14. Lillie, W. I., and Parker, H. L.: Retrobulbar neuritis due to thallium poisoning. JAMA 98:1347, 1932. 15. Allsop, J.: Thallium poisoning. Aust. Ann. Med. 2:144, 1953. 16. Symonds, W. J. C: Alopecia, optic atrophy and peripheral neuritis of probably toxic origin. Lan cet 2:1338, 1953. 17. Shamshinova, A. M., Ivanina, T. A., Yakovlev, A. A., Shabalina, L. P., and Spiridonova, V. S.: Electroretinography in the diagnosis of thallium intoxica tion. J. Hyg. Epidemiol. Microbiol. Immunol. 34:113, 1990. 18. Rauws, A. G.: Thallium pharmacokinetics and its modification by Prussian blue. Naunyn Schmiede bergs Arch. Pharmacol. 284:294, 1974. 19. Munch, J. C: Human thallotoxicosis. JAMA 102:1929, 1934. 20. Reed, D., Crawley, J., Faro, S., Pieper, S., and Kurland, L.: Thallotoxicosis. Acute manifestations and sequelae. JAMA 187:96, 1963.
Thallium intoxication is characterized by the development of painful peripheral neu ropathy, alopecia, mental disorders, and in severe cases, respiratory failure and death. Toxic optic neuropathy is also a feature. Oph thalmologic features of thallium poisoning include optic neuropathy, blepharoptosis, lens opacities, and ophthalmoplegia. A 44year-old man with criminal sublethal thalli um poisoning was examined one month after he was seen in the neurology department with classic systemic features. He was found to have diminished contrast sensitivity, a tritan defect in color vision, and a relative cecocentral scotoma before he developed optic atro phy. in 1861 by Crooks, 1 thalli um has been responsible for many occupation al, accidental, deliberate, and therapeutic poi sonings. In the past it had been used in the treatment of syphilis, gonorrhea, dysentery, tuberculosis, and ring worm of the scalp.1·2 In the first half of this century, it was widely used as a pesticide. Lamy3 found that in high doses this heavy metal is lethal to animals. Buschke and Langer4 described the pathologic effects of thallium sulfate. Present use includes the pro duction of scintillation counters and imitation jewelry. Its ability to transmit long-wave radia tion has given thallium a role in lens manufac ture. Thallium is colorless, odorless, and tasteless. These properties have made it an ideal poison both for rodents and for use by psychopathic poisoners. 5 · 6 Its use as a homicidal poison is said to be widespread. 7 Numerous reports have discussed the systemic effects and toxicology of thallium poisoning. However, little has been S I N C E ITS DISCOVERY
Accepted for publication Nov. 8, 1993. From the Department of Ophthalmology, St. George's Hospital, London, United Kingdom. Reprint requests to Homayoun Tabandeh, M.R.C.P., F.R.C.Ophth., Department of Ophthalmology, St. George's Hospital, London SW 17 OQT, Great Britain.
written about the ocular effects of intoxication by this metal.
Case Report A 44-year-old man had a two-week history of general malaise and unsteadiness and a nineday history of a skin rash over his hands and legs. Over the next week he developed nausea, vomiting, and painful legs, and he became increasingly confused. On examination he was found to have a markedly impaired mental score, bilateral horizontal jerky nystagmus, bi lateral weakness of the facial cranial nerves, blepharoptosis, and global weakness of the limbs particularly proximally. Tendon reflexes, plantar responses, and coordination were with in normal limits. Vibration sense and proprioception were globally reduced. He had a papulomacular rash over the skin of his hands and legs and there was alopecia of his scalp (Figs. 1 and 2). An electroencephalogram showed gen eralized slowing of activity. Nerve conduction studies demonstrated the features of a peripher al sensorimotor neuropathy. Computed tomog raphy and magnetic resonance imaging results were normal. Painful peripheral neuropathy together with alopecia raised the possibility of thallium intoxication. Further investigations disclosed a blood thallium level of 108 g/1 (normal, < 2 g/1) and a urine thallium level of 1,350 g/1 (normal, <200 g/1). Thallium intoxi cation was diagnosed, and high potassium sup plements and potassium ferric hexacyanoferrate II were begun. Subsequently the thallium levels diminished, and the patient gradually recovered. The cause of poisoning could not be established. Accidental or suicidal ingestion was excluded and the case was referred for criminal investigation. A month later, ophthalmologic examination showed a corrected visual acuity of R.E.: 20/20 and L.E.: 20/40. Anterior segments, pupillary reflexes, optic disks, pursuit and saccadic eye movements were normal. There was bilateral blepharoptosis and a mild horizontal jerk nys-
©AMERICAN JOURNAL O F OPHTHALMOLOGY 117:243-245, FEBRUARY, 1994
243
244
AMERICAN JOURNAL OF OPHTHALMOLOGY
February, 1994
Fig. 2 (Tabandeh, Crowston, and Thompson). Maculopapular skin rash, which progressed to scabbing.
Fig. 1 (Tabandeh, Crowston, and Thompson). Scalp alopecia, blepharoptosis, and facial weakness in thallium intoxication (photograph modified to limit identification). tagmus. Contrast sensitivity was diminished across all spatial frequencies in both eyes. The Farnsworth-Munsell 100-hue test demonstrat ed tritanomaly, which was worse in the left eye. Normal results from a previous army medical examination, no past ocular or neurologic dis orders, and absence of a family history of color blindness reduced the likelihood of a pre-exist ing color vision defect. Automated perimetry showed bilateral relative cecocentral scotomas. The patient developed mild optic atrophy two months after the onset of symptoms. Nine months after the initial manifestation, there was residual impairment of the patient's higher mental functions, mild weakness, and a persistent color vision defect.
Discussion The clinical picture of thallium intoxication is variable; however, the diagnosis is often sus pected in the presence of the triad of symptoms: (1) alopecia and skin rash, (2) painful peripher al neuropathy, and (3) confusion and lethargy. The lethal dose for humans is 15 to 20 m g / k g of body weight; nonfatal intoxication occurs below this dose. The first symptoms of poison ing are abdominal pain, gastroenteritis, tachy-
cardia, and headache, which usually occur within 12 hours. A characteristic dark, pigmented band appears in the scalp hair within four days. Neurologic symptoms appear in two to five days and include confusion, hallucina tions, and convulsions. In severe cases coma, respiratory paralysis, and death occur within one week. When smaller doses are taken pain ful peripheral sensorimotor neuropathy and ataxia are the outstanding symptoms. Other neurologic features include cranial nerve pal sies, optic neuropathy, choreoathetosis, trem or, and encephalopathy. Scalp alopecia is the best known symptom of chronic thallium poi soning, which begins ten days after the inges tion and is completed within one month. 8 8 Skin may be involved by acneiform eruptions, a papulomacular rash, and dystrophy of the nails (Mee's strips). Autonomie dysfunction, hyper tension, cardiomyopathy, electrocardiographic changes, testicular toxicity, hypokalemia, re nal failure, abnormal liver function, leukocytosis, and thrombocytopenia have been report ed. Electroencephalography shows nonspecific slow wave activity, and electromyography is suggestive of distal axonopathy. Ophthalmologic manifestations include loss of the lateral half of the eyebrows, eyelid skin lesions, blepharoptosis, facial nerve palsy, in ternal and external ophthalmoplegia, and nys tagmus. Noninflammatory keratitis and lens opacities have also been described. 1012 Optic atrophy as a sequel to thallium-induced toxic optic neuropathy is well reported. 9 · 1316 Func tional changes include impairment of contrast sensitivity, abnormal color vision (tritanoma ly), impaired visual acuity, and central or ceco central scotomas. There is also electroretino-
Vol. 117, No. 2
Thallium Poisoning
graphic abnormality and a delayed visualevoked response. Optic neuropathy and cranial nerve palsies are the most marked features. The changes in visual function are essentially those related to the optic nerve damage. Electrophysiologic studies carried out on rabbits injected with intravitreal doses of thallium demonstrat ed that the retina, particularly the photoreceptor layer, is susceptible to the effect of thallium, and the degree of impairment depends on the time and dose of exposure. 17 The mechanism for toxic effects of thallium is not fully understood. It may be that thallium, which has a high affinity for Na-K ATP'ase and -SH containing enzymes, causes disruption of cell membrane stability. Histopathologic stud ies have shown axonal degeneration to be a primary pathologic change. There are also close similarities between thallium intoxication and thiamine deficiency and arsenical neuropa thies. Thallium neurotoxicity may be related to the interaction of this ion with riboflavin, with consequent effects on energy generation mech anisms associated with tissue flavoproteins. 6 Thallium moves in the body along potassium pathways and is thus excreted via salivary glands and bile. In the gut it is reabsorbed, thereby causing a continuous intoxication. Treatment with potassium ferric hexacyanoferrate II removes it from the gut, thus breaking the cycle.18 The prognosis of thallotoxicosis depends on the total amount ingested, the time course of the ingestion, and the individual susceptibility. The reported mortality rate is 6% to 13% with over half of the survivors being left with residu al neurologic deficit. Abnormal vision together with tremor, muscle weakness, convulsions, and coma are associated with residual neuro logic deficit.19·20 In summary, this is a case of thallium poison ing with diminished contrast sensitivity, a tritan impairment of color vision, and a relative cecocentral scotoma in the presence of slightly impaired visual acuity. Mild optic atrophy de veloped later. Other features included blepharoptosis, bilateral facial nerve palsies, and fine horizontal nystagmus. At nine-month followup most features had improved, however there was persistent defect in color vision and higher mental function. Thallium intoxication should be considered in the differential diagnosis of toxic optic neu ropathy. Contrast sensitivity and color vision are abnormal before the appearance of other
245
clinical signs of optic neuropathy and provide early evidence of optic nerve involvement.
References 1. Crooks, W On existence of a new element probably of sulphur group. Chemical News 3:193, 1861. 2. Saddique, A., and Patterson, C. D.: Thallium poisoning. A review. Vet. Hum. Toxicol. 25:16, 1983. 3. Lamy, M. A.: Sur les effets toxiques du thallium. C. R. Acad. Sei., Paris. 57:442, 1863. 4. Buschke, A., and Langer, E.: Die Forensische und gewerbl-hygienische Bedeutung des Thalliums. Munch. Med. Wochnschr. 74:1494, 1927. 5. Burnett, J. W.: Thallium poisoning. Cutis 46:112, 1990. 6. Cavanagh, J. B.: What have we learnt from Gra ham Frederick Young? Reflections on the mechanism of thallium neurotoxicity. Neuropathol. Appl. Neurobiol. 17:3, 1991. 7. Moeschlin, S.: Thallium poisoning. Clin. Toxi col. 17:133, 1988. 8. Grossman, H.: Thallotoxicosis. Report of case and review. Paediatrics 16:868, 1956. 9. Kallner, A.: Thallium-Vergiftung bei Kinder. Ann. Paediatr. 167:188, 1946. 10. Richet, C : De la toxicité du thallium. C. R. Soc. Biol. Paris. 1:252, 1899. 11. Castelao, A.M.: Cataract due to thallium. Med Espan. 5:395, 1941. 12. Duke-Elder, S.: Textbook of Ophthalmology, vol. 3. London, H. Kimpton, 1947, p. 3153. 13. Kaps, L.: Kriminelle tödliche subakute Thalli um Vergiftung. Wien. Klin. Wochenschr. 40:967, 1927. 14. Lillie, W. I., and Parker, H. L.: Retrobulbar neuritis due to thallium poisoning. JAMA 98:1347, 1932. 15. Allsop, J.: Thallium poisoning. Aust. Ann. Med. 2:144, 1953. 16. Symonds, W. J. C: Alopecia, optic atrophy and peripheral neuritis of probably toxic origin. Lan cet 2:1338, 1953. 17. Shamshinova, A. M., Ivanina, T. A., Yakovlev, A. A., Shabalina, L. P., and Spiridonova, V. S.: Electroretinography in the diagnosis of thallium intoxica tion. J. Hyg. Epidemiol. Microbiol. Immunol. 34:113, 1990. 18. Rauws, A. G.: Thallium pharmacokinetics and its modification by Prussian blue. Naunyn Schmiede bergs Arch. Pharmacol. 284:294, 1974. 19. Munch, J. C: Human thallotoxicosis. JAMA 102:1929, 1934. 20. Reed, D., Crawley, J., Faro, S., Pieper, S., and Kurland, L.: Thallotoxicosis. Acute manifestations and sequelae. JAMA 187:96, 1963.