- Email: [email protected]
OCULAR TOXICITY OF HIGH-DOSE INTRAVENOUS DESFERRIOXAMINE
181
allowing for incomplete ascertainment, so that it is likely to be insubstantial problem. in conclusion, we have shown that patients with suspected AMI who are hyperglycaemic (10 mmol/1) are likely to be diabetic, and that this is likely to be pre-existing undiagnosed diabetes rather than "stress" hyperglycaemia independent of diabetes, which is an infrequent event. a not
Vi’e thank the doctors and nurses of the coronary care unit of the Freeman and the staff of the clinical biochemistry laboratory at the Royal Victoria Infirmary for their help.
Hospital
Correspondence should be addressed to D. J. H., Department of Clinical Biochemistry and Metabolic Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP. REFERENCES
NG, Frank S. Value of glycosylated haemoglobin measurements after acute myocardial infarction. JAMA 1981; 246: 1690-93. Opie LH, Stubbs WA. Carbohydrate metabolism in cardiovascular disease. Clin
1. Soler
2.
Endocrinol Metab 1976; 5: 703-29. SP, Chamberlain MJ, Hinton P. Intravenous glucose tolerance, insulin, glucose and free fatty acid levels for myocardial infarction. Br Med J 1969; iv: 776-78. 4. Datey KK, Nanda NC. Hyperglycaemia after acute myocardial infarction. N Engl J Med 1969; 276: 262-65. 5. Pearson D. Intravenous glucose tolerance in myocardial infarction. Postgrad Med J 1971; 47: 648-50. 6. Sowton E. Cardiac infarction and the glucose tolerance test. Br Med J 1962; i: 84-86. 7. Hayes EJ, Gleason RE, Soeldner JS, Wacks M, Blankstein L. Measurement of haemoglobin A1 by liquid chromatography and by agar gel electrophoresis compared. Clin Chem 1981; 27: 476-79. 8. World Health Organisation Expert Committee on Diabetes Mellitus. Second Report 1980. WHO Technical Report Series No 646. Geneva: WHO. 9. Keen H, Tang Fui S. The definition and classification of diabetes mellitus. Clin Endocrinol Metab 1982; 11: 279-305. 10. Bunn HF Evaluation of glycosylated haemoglobin in diabetic patients. Diabetes 1981; 30: 613-17. 11. Compagnucci P, Cartechini MG, Bolli G, Pierpaolo DF, Santeasanio F, Brunetti P. The importance of determining irreversibly glycosylated haemoglobin in diabetics. Diabetes 1981, 30: 607-12. 12. Porte P, Halter JB. The endocrine pancreas and diabetes mellitus. In: Williams RH, ed. Textbook of endocrinology. Philadelphia: W. B. Saunders, 1981: 716-843. 13. Opie LH. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction Am J Cardiol 1975; 36: 938-53. 3. Allison
OCULAR TOXICITY OF HIGH-DOSE INTRAVENOUS DESFERRIOXAMINE SALLY C. DAVIES J. L. HUNGERFORD G. B. ARDEN
R. E. MARCUS M. H. MILLER E. R. HUEHNS
Departments of Haematology and Ophthalmology, Middlesex Hospital; Department of Haematology, University College London; and Moorfields Eye Hospital, London Desferrioxamine was given intravenously, at higher doses than previously reported, to counter the effects of transfusion-induced iron overload in four patients with beta thalassaemia major. In two of them retinal abnormalities developed, presenting with night blindness and field defects, which improved on withdrawal of
Summary
the
drug. Introduction
DESFERRIOXAMINE has been used since the early 1960s for the treatment of transfusional iron overload. Although many patients have received it for several years, few side-effects have been reported. There may be mild local reaction at the injection site, and cataracts have been reported in five patients.’ There is one report of an anaphylactic reaction2 and we have seen a further two cases. (Two of these patients were successfully desensitised, and the third died after attempts at iron removal with diethylenetriamine penta-acetic acid.) Desferrioxamine was originally given by intramuscular
injection, but since the mid 1970s continuous infusion, either intravenous3 or subcutaneous,4 has been used with improved results.5 We have observed no toxic effects from 50-60
mg/kg subcutaneous desferrioxamine, given daily for 6 days a week, during 100 patient years. Such a regimen will gradually reduce iron overload in previously unchelated, heavily transfused
patients,5
but many, particularly young men, do The of iron overload then developeffects comply. diabetes, hypoparathyroidism, and cirrhosis as well as cardiac arrhythmias and cardiomyopathy. In our group of young adults with 0-thalassaemia major we have seen three deaths in the past two years from the cardiac effects of iron overload. Therefore we decided to give large doses of desferrioxamine by continuous intravenous infusion in several patients with serious cardiac involvement. (No plateau in the amount of iron excreted has been seen even at very high doses,6 and we chose the intravenous route because subcutaneous administration of large doses can be painful.) In two of the four patients treated so far, previously unreported ocular complications have developed. not
Case-reports Patient 1 A 19-year-old woman had been regularly transfused since the age of six months, her average haemoglobin being 9 -5g/dl. At age 7 she had a splenectomy and at age 15 she was started on intramuscular desferrioxamine 500 mg daily (self administered). At age 17 this was changed to 2-55g five times a week by subcutaneous overnight infusion; her compliance was always poor. Angina pectoris, with frequent ventricular ectopic beats, developed at age 11; hypoparathyroidism at age 14; and diabetes mellitus at age 19. At this time her serum ferritin was 6000 g/L She was given intravenous desferrioxamine via a Hickman catheter over 50 days with a 4-day break-2 days at 115 mg/kg per 24 h, 2 days at 175 mg/kg per 24 h, 33 days at 235 mg/kg per 24 h, followed by the 4 day break then 3 days at 75 mg/kg per 24 h and 6 days at 100 mg/kg per 24 h. Over this period she excreted a total of 7’0gof iron in her urine and faeces and her serum ferritin fell to 4500 g/1. At the start of high-dose desferrioxamine therapy the ophthalmic findings were normal, with visual acuities of 6/6 in both eyes. A full ocular examination was done weekly. During the fifth week of highdose treatment the patient complained of blurring of vision, and posterior lens opacities were detected in each eye. The biochemical control of her diabetes and hypoparathyroidism was excellent, and it was felt that the sudden development of cataracts must be attributed to the desferrioxamine, which was stopped. After full discussion the patient decided that her clinical improvement was more important than any possible long-term consequences from progression of the cataract, and the desferrioxamine was restarted after 4 days at a lower dose. Within a few days she complained of inability to see in dim light and impaired peripheral vision on both sides. The symptoms suggested "tunnel vision". The visual acuity was 6/7 -5 right and left, and colour vision was normal. On ophthalmoscopy she now had bilateral retinal pigmentary changes with a stippled appearance throughout the fundus and thinning of the retinal vessels (fig 1). The scattered pigment had the effect of masking the normal background fluorescence on fluorescein angiography (fig 2). The intravenous desferrioxamine was again stopped. On visual field examination there was peripheral field loss with bilateral annular scotomas (fig 3). The central fields were normal. Dark adaptation was tested by scotopic static perimetry, and was defective. This reduction in dark adaptation was particularly striking in the midperiphery of the field of vision-an area corresponding to the annular scotoma in each eye. The electro-oculogram (EOG) was grossly subnormal, showing no light rise whatever in either eye. The Ganzfeld electroretinogram (ERG) was equally subnormal, indicating more than 2 log units loss in scotopic sensitivity bilaterally. there was similarly a very poor response on the pattern
182
Fig I-Fundus photographs of left disc and macula (a) and the fundus above the left macula (b) in patient 1, showing retinal pigmentary changes.
ERG, which could hardly be recorded. The pattern visually evoked response (VER) was normal in each eye, in accord with the normal visual acuities. The visual acuities and colour vision remained normal after withdrawal of high-dose desferrioxamine and over three weeks the ocular symptoms resolved. By three months the visual fields had improved considerably (fig 4), though there remained an island of field loss within the original annular scotoma in the right eye. Whilst the EOG remained grossly subnormal, the Ganzfeld ERG had improved and only 0 -5log unit loss in sensitivity could be detected in each eye. Dark adaptation similarly recovered to 0 -5log unit loss bilaterally and the pattern ERG became recordable, though still subnormal. The lens opacities were less apparent but the retinal pigmentation remained unchanged.
Patient 2* A man of 20 years had received regular blood transfusions from the age of ten months, maintaining an average haemoglobin of 10 g/dl. He had a splenectomy at age 17 years. He was started on
intramuscular desferrioxamine 500 mg a day when 6 years old. When he was 18 this was changed to 2-55g six times a week by overnight subcutaneous infusion with oral vitamin C. After this his haemoglobin was maintained above 10 g/dl. At age 19, in 1982, atrial fibrillation developed, leading to cardiac failure, and he had increasing angina and liver dysfunction. His serum ferritin was 9300
g/1.
He was admitted severely ill and treated with digoxin and diuretics as well as intravenous desferrioxamine-4 days at 90 mg/kg per 24 h and then 12 days at 120 mg/kg per 24 h-via a Hickman catheter. Over this period he excreted 4 -6gof iron in his urine. Initially he improved considerably but he then deteriorated and the desferrioxamine was stopped. The findings on ophthalmic examination, EOG, and ERG were normal and the patient had no eye symptoms. The deterioration continued and he died three weeks later.
Patient 3* A woman aged 25 years had received regular blood transfusions since the age of 1. Splenectomy was done when she was 15. Desferrioxamine was started at 500 mg a day intramuscularly when she was 9, and was changed to 2 - 5 g six times a week subcutaneously with oral vitamin C when she was 21. Thereafter her haemoglobin was maintained above 10 g/dl. At 14 years of age she had cardiac failure and hepatosplenomegaly secondary to constrictive pericarditis, and 6 years later she required a pericardiectomy. When she was 23 years old there was a recurrence of congestive cardiac failure and liver impairment. Her serum ferritin was greater than 10 000 g/1. She was treated as an outpatient with 40 mg frusemide daily, but still had ankle oedema. Desferrioxamine 135 mg/kg per 24 h was infused for 10 days through a central venous line and she excreted 2 -1gof iron in her urine and faeces. After this she felt so much better that she decided to continue intensive chelation therapy subcutaneously as an outpatient. She is now free from ankle oedema and requires no diuretics. This patient never had any eye symptoms and, except for longstanding myopia, findings on ophthalmic examination were normal.
Patient 4* A 24-year-old man had been transfused regularly from six months of age, requiring splenectomy at 16 years. Intramuscular
Fig 2-Fluorescein angiogram pigmentary disturbance.
of left macula in
patient 1, showing
*These patients were among those reported in 1974 by Barry et at. Patients 2 and 3 were in the chelated group; patient 4 was not at that time chelated.
183
pig 3-Visual fields in patient 1 during high-dose desferrioxamine.
Fig 4-Visual fields in patient
1 after withdrawal of high-dose desferrioxamine.
desferrioxamine 500 mg a day was started when he was 8, and a subcutaneous regimen when he was 19. From age 22 to 24 he had four episodes of pericarditis and supraventricular tachycardias, and by 1982 his serum ferritin was 11 000 pgll. He was admitted as an emergency with pneumonia and congestive cardiac failure which improved on treatment with intravenous antibiotics, digoxin, and diuretics. Two days after admission intravenous desferrioxamine was started without vitamin C-165 mg/kg per 24 h for 2 days, then 220 mg/kg per 24 h for 6 days. 8 days after the start of intravenous desferrioxamine he complained that the previous evening, in poor light, his vision had been so bad that he had been unable to get about. The desferrioxamine was stopped. On examination, visual acuity was 6/36 bilaterally. Colour vision was severely impaired in both eyes and, although his visual acuity should have been adequate for the tests, he was completely unsuccessful with the Ishihara and the City University colour plates. A small central scotoma was detected in each eye by visual field examination (fig 5), corresponding to the reduced acuity and
impaired colour vision; there was bilateral central loss in dark adaptation by scotopic static perimetry. On peripheral field examination there was generalised constriction rather than annular
very poor response on the pattern ERG. Although a light rise could be detected on an EOG done on the left eye, this was severely A Ganzfeld ERG performed on reduced at 141% (normal>185%). the right eye was subnormal and showed 1 3 log units loss of scotopic sensitivity. Because of the patient’s poor general condition, not all the tests could be done on both eyes. No lens opacities were seen. There was no evidence of retinal pigment release but there was thinning and tortuosity of the retinal vessels. After withdrawal of high-dose desferrioxamine there was a rapid subjective improvement in vision, but the patient still complained of slight difficulty in seeing at night. 21 days after withdrawal of desferrioxamine visual acuities were 6/9 (right) and 6/12 (left). By this time colour vision was normal, the visual fields were less constricted, and the central scotoma in each eye had disappeared (fig 6). Dark adaptation was correspondingly improved as was the pattern VER. Two months after the end of treatment the EOG was 174% (right) and 190% (left). The Ganzfeld ERG showed only 0-14 log unit loss of scotopic sensitivity on both sides, but the pattern ERG was still subnormal. No lens opacities or retinal pigmentation was a
were seen.
loss, but on dark adaptation the greatest loss was detected in the mid
Discussion
-
periphery. The pattern VER showed a reduction in sensitivity in each eye. This was commensurate with the subnormal visual acuity. There
Fig 5-Visual fields in patient 4 during high-dose desferrioxamine.
With the large doses of desferrioxamine substantial of iron were excreted, and two patients had objective
amounts
184
Fig 6-Visual fields in patient 4 after withdrawal of high-dose desferrioxamine. improvement in cardiac status. Two, moreover, felt so much Finally, we feel that in selected cases this form of treatment an that to is better intensive subcutaneous justified, provided that the dose is increased gradually, to a they opted pursue of 125 mg/kg per 24 h. If ophthalmic had maximum One man and one substantial woman, however, regimen. loss of vision, confirmed by objective investigations. Except complications occur, desferrioxamine should be stopped for the pigmentary changes in patient 1, these abnormalities until clinical resolution, when the drug can be started again in lower dosage. resolved almost completely after drug withdrawal. 1 has been in of lens described man, opacities Development We thank Dr R. J. K. Brown for help with patient 1. but rapid visual failure as a toxic effect of desferrioxamine has Correspondence should be addressed to S. C. D., Department of not to our knowledge been reported previously. The night Haematology, Middlesex Hospital, Mortimer St, London WI. blindness, annular field loss with a geographically similar REFERENCES defect of dark adaptation, and associated EOG and ERG abnormalities are characteristic of degenerative disorders of 1. Bloomfield SE, Markenson AL, Miller DR, Peterson CM. Lens opacities in retinal photoreceptors involving the rods. These are thalassemia. J Ped Ophth Strab 1978; 15: 154-56. 2. Miller KB, Rosenwasser LJ, Bessette JM, Beer DJ, Rocklin RE. Rapid desensitisation indistinguishable from the changes seen in the various forms for desferrioxamine anaphylactic reaction. Lancet 1981; i: 1059. of retinitis pigmentosa. Pigmentary changes are usual in this 3 Propper RD, Shurin SB, Nathan DG. Reassessment of the use of desferrioxamine Bin iron overload. N EnglJ Med 1976; 294: 1421-23. group of diseases, but the natural history normally extends 4. Propper RD, Cooper B, Rufo RR, Nienhuis AW, Anderson WF, Bunn F, Rosenthal A, over many years and recovery does not occur. The loss of Nathan DG. Continuous subcutaneous administration of desferrioxamine in patients with iron overload. N Engl J Med 1977; 297: 418-23. central acuity and colour vision together with central scotoma 5. Hoffbrand AV, Gorman A, Laulicht M, Garidi M, Economidou J, Georgiopoulou P, and EOG, ERG, and VER abnormalities is characteristic of Hussain MAM, Flynn DM. Improvement in iron status and liver function in patients with transfusional iron overload with long-term subcutaneous degenerations affecting the cones. Retinal pigmentary desferrioxamine. Lancet 1979; i: 947—49. changes are not a prominent feature of these disorders. 6. Pippard MJ, Callender ST, Finch CA. Ferrioxamine excretion in iron-loaded man. It is currently held that, whilst degeneration of one or other Blood 1982; 60: 288-94. 7. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in form of photoreceptor may predominate, abnormalities of thalassaemia major: effect on liver iron concentration, liver histology, and clinical rod and cone function can arise together. In patient 1 the progress. Br Med J 1974; ii: 16-20. 8. Zaino EC. Desferrioxamine and trace metal excretion in chelation therapy in chronic picture is predominantly of a rod defect but some cone iron overload: In: Zaino EC, Roberts RH, eds. Chelation and chronic iron overload involvement is shown by the persistent pattern ERG (CIBA Medical Horizons Symp). New York, 1977: 95-107. 9. Rao SS, Satapathy M, Sitaramayya A. Copper metabolism in retinitis pigmentosa changes, while in patient 4 there is a mixed rod and cone patients. Br J Ophthalmol 1981; 65: 127-30. defect. 10. Silverstone B, Berson D, Kuperman O. Copper metabolism changes in pigmentary The mechanism behind the retinal toxicity of retinopathies and high myopia. Metab Paediatr Ophthalmol 1981; 5: 45-48. 11. Wise JB. Treatment of experimental siderosis bulbi, vitreous haemorrhage and corneal desferrioxamine is not clear. Chelation of iron is unlikely to blood staining with desferrioxamine. Arch Ophthal 1966; 75: 698-707. be the explanation, but desferrioxamine chelates several other 12. Brueckner R, Hess R, Keberle H, Pericin C, Tripon J. Pathological lenticular changes in animals after long-term administration of elevated doses of Desferal. Helv Physiol metals. The stability constant of desferrioxamine for Fe3+ is Acta 1967; 25: 62-77. 10’ whilst for Cut it is 1014, Zn2+ and Co2+ 10’andNP"+ 1010 and urinary excretion of Cu and Zn is increased during "The functions of medicines are not limited to the demonstrable, desferrioxamine infusions.8 This raises the possibility that conventional medical effects ... A drug manufacturer marketing a the ocular abnormality may be due to the removal of another useless or dangerous product; an advertiser defining as an metal from the retina. In this connection it is noteworthy that ’indication’a non-illness situation (a mother crying as her child goes abnormalities of copper metabolism have been desribed in off to school for the first day, and the advertisement saying she is retinitis pigmentosa,9,10 whilst the ocular and other ’depressed’ and needs a powerful anti-depressant drug); a physician manifestations of zinc deficiency are quite different. Another prescribing in lieu of taking time to diagnose or talk to a patient; oura possibility is that the effect of desferrioxamine is due to health bureaucrat using medicines policy as a lever for his previous iron-mediated damage of the blood-retina barrier, promotion; these are all examples of functions of medicines ... because very high systemic doses to animals have not These examples expose the gulf between a formal view of medicinal functions and the psychological and social functions on the part of produced retinopathy whilst small quantities injected and into the result in necrosis.11,12 dispensers and users ... Medicines policy cannot easily be Clinically directly eye here implemented until one knows what people are really doing and why, the toxic effects described closely electrophysiologically how to reach them to educate them (whether doctors or patients), resemble those in various forms of tapetoretinal dystrophy. and what ’irrational’ substitute conduct to expect in advance, Although no firm association has so far been established should one remove a substance without providing a replacement for between these conditions and abnormalities of metal ions, the it in a specific function. A pragmatist will attend to such issues; they current findings may warrant reappraisal of the position, constitute the real world."-Richard Blum, Andrew Herxheimer, Catherine Stenzl, and Jasper Woodcock. Pharmaceuticals and particularly in view of the substantial reversibility of the health policy. London: Social Audit Ltd, 1983. changes described.
allowing for incomplete ascertainment, so that it is likely to be insubstantial problem. in conclusion, we have shown that patients with suspected AMI who are hyperglycaemic (10 mmol/1) are likely to be diabetic, and that this is likely to be pre-existing undiagnosed diabetes rather than "stress" hyperglycaemia independent of diabetes, which is an infrequent event. a not
Vi’e thank the doctors and nurses of the coronary care unit of the Freeman and the staff of the clinical biochemistry laboratory at the Royal Victoria Infirmary for their help.
Hospital
Correspondence should be addressed to D. J. H., Department of Clinical Biochemistry and Metabolic Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP. REFERENCES
NG, Frank S. Value of glycosylated haemoglobin measurements after acute myocardial infarction. JAMA 1981; 246: 1690-93. Opie LH, Stubbs WA. Carbohydrate metabolism in cardiovascular disease. Clin
1. Soler
2.
Endocrinol Metab 1976; 5: 703-29. SP, Chamberlain MJ, Hinton P. Intravenous glucose tolerance, insulin, glucose and free fatty acid levels for myocardial infarction. Br Med J 1969; iv: 776-78. 4. Datey KK, Nanda NC. Hyperglycaemia after acute myocardial infarction. N Engl J Med 1969; 276: 262-65. 5. Pearson D. Intravenous glucose tolerance in myocardial infarction. Postgrad Med J 1971; 47: 648-50. 6. Sowton E. Cardiac infarction and the glucose tolerance test. Br Med J 1962; i: 84-86. 7. Hayes EJ, Gleason RE, Soeldner JS, Wacks M, Blankstein L. Measurement of haemoglobin A1 by liquid chromatography and by agar gel electrophoresis compared. Clin Chem 1981; 27: 476-79. 8. World Health Organisation Expert Committee on Diabetes Mellitus. Second Report 1980. WHO Technical Report Series No 646. Geneva: WHO. 9. Keen H, Tang Fui S. The definition and classification of diabetes mellitus. Clin Endocrinol Metab 1982; 11: 279-305. 10. Bunn HF Evaluation of glycosylated haemoglobin in diabetic patients. Diabetes 1981; 30: 613-17. 11. Compagnucci P, Cartechini MG, Bolli G, Pierpaolo DF, Santeasanio F, Brunetti P. The importance of determining irreversibly glycosylated haemoglobin in diabetics. Diabetes 1981, 30: 607-12. 12. Porte P, Halter JB. The endocrine pancreas and diabetes mellitus. In: Williams RH, ed. Textbook of endocrinology. Philadelphia: W. B. Saunders, 1981: 716-843. 13. Opie LH. Metabolism of free fatty acids, glucose and catecholamines in acute myocardial infarction Am J Cardiol 1975; 36: 938-53. 3. Allison
OCULAR TOXICITY OF HIGH-DOSE INTRAVENOUS DESFERRIOXAMINE SALLY C. DAVIES J. L. HUNGERFORD G. B. ARDEN
R. E. MARCUS M. H. MILLER E. R. HUEHNS
Departments of Haematology and Ophthalmology, Middlesex Hospital; Department of Haematology, University College London; and Moorfields Eye Hospital, London Desferrioxamine was given intravenously, at higher doses than previously reported, to counter the effects of transfusion-induced iron overload in four patients with beta thalassaemia major. In two of them retinal abnormalities developed, presenting with night blindness and field defects, which improved on withdrawal of
Summary
the
drug. Introduction
DESFERRIOXAMINE has been used since the early 1960s for the treatment of transfusional iron overload. Although many patients have received it for several years, few side-effects have been reported. There may be mild local reaction at the injection site, and cataracts have been reported in five patients.’ There is one report of an anaphylactic reaction2 and we have seen a further two cases. (Two of these patients were successfully desensitised, and the third died after attempts at iron removal with diethylenetriamine penta-acetic acid.) Desferrioxamine was originally given by intramuscular
injection, but since the mid 1970s continuous infusion, either intravenous3 or subcutaneous,4 has been used with improved results.5 We have observed no toxic effects from 50-60
mg/kg subcutaneous desferrioxamine, given daily for 6 days a week, during 100 patient years. Such a regimen will gradually reduce iron overload in previously unchelated, heavily transfused
patients,5
but many, particularly young men, do The of iron overload then developeffects comply. diabetes, hypoparathyroidism, and cirrhosis as well as cardiac arrhythmias and cardiomyopathy. In our group of young adults with 0-thalassaemia major we have seen three deaths in the past two years from the cardiac effects of iron overload. Therefore we decided to give large doses of desferrioxamine by continuous intravenous infusion in several patients with serious cardiac involvement. (No plateau in the amount of iron excreted has been seen even at very high doses,6 and we chose the intravenous route because subcutaneous administration of large doses can be painful.) In two of the four patients treated so far, previously unreported ocular complications have developed. not
Case-reports Patient 1 A 19-year-old woman had been regularly transfused since the age of six months, her average haemoglobin being 9 -5g/dl. At age 7 she had a splenectomy and at age 15 she was started on intramuscular desferrioxamine 500 mg daily (self administered). At age 17 this was changed to 2-55g five times a week by subcutaneous overnight infusion; her compliance was always poor. Angina pectoris, with frequent ventricular ectopic beats, developed at age 11; hypoparathyroidism at age 14; and diabetes mellitus at age 19. At this time her serum ferritin was 6000 g/L She was given intravenous desferrioxamine via a Hickman catheter over 50 days with a 4-day break-2 days at 115 mg/kg per 24 h, 2 days at 175 mg/kg per 24 h, 33 days at 235 mg/kg per 24 h, followed by the 4 day break then 3 days at 75 mg/kg per 24 h and 6 days at 100 mg/kg per 24 h. Over this period she excreted a total of 7’0gof iron in her urine and faeces and her serum ferritin fell to 4500 g/1. At the start of high-dose desferrioxamine therapy the ophthalmic findings were normal, with visual acuities of 6/6 in both eyes. A full ocular examination was done weekly. During the fifth week of highdose treatment the patient complained of blurring of vision, and posterior lens opacities were detected in each eye. The biochemical control of her diabetes and hypoparathyroidism was excellent, and it was felt that the sudden development of cataracts must be attributed to the desferrioxamine, which was stopped. After full discussion the patient decided that her clinical improvement was more important than any possible long-term consequences from progression of the cataract, and the desferrioxamine was restarted after 4 days at a lower dose. Within a few days she complained of inability to see in dim light and impaired peripheral vision on both sides. The symptoms suggested "tunnel vision". The visual acuity was 6/7 -5 right and left, and colour vision was normal. On ophthalmoscopy she now had bilateral retinal pigmentary changes with a stippled appearance throughout the fundus and thinning of the retinal vessels (fig 1). The scattered pigment had the effect of masking the normal background fluorescence on fluorescein angiography (fig 2). The intravenous desferrioxamine was again stopped. On visual field examination there was peripheral field loss with bilateral annular scotomas (fig 3). The central fields were normal. Dark adaptation was tested by scotopic static perimetry, and was defective. This reduction in dark adaptation was particularly striking in the midperiphery of the field of vision-an area corresponding to the annular scotoma in each eye. The electro-oculogram (EOG) was grossly subnormal, showing no light rise whatever in either eye. The Ganzfeld electroretinogram (ERG) was equally subnormal, indicating more than 2 log units loss in scotopic sensitivity bilaterally. there was similarly a very poor response on the pattern
182
Fig I-Fundus photographs of left disc and macula (a) and the fundus above the left macula (b) in patient 1, showing retinal pigmentary changes.
ERG, which could hardly be recorded. The pattern visually evoked response (VER) was normal in each eye, in accord with the normal visual acuities. The visual acuities and colour vision remained normal after withdrawal of high-dose desferrioxamine and over three weeks the ocular symptoms resolved. By three months the visual fields had improved considerably (fig 4), though there remained an island of field loss within the original annular scotoma in the right eye. Whilst the EOG remained grossly subnormal, the Ganzfeld ERG had improved and only 0 -5log unit loss in sensitivity could be detected in each eye. Dark adaptation similarly recovered to 0 -5log unit loss bilaterally and the pattern ERG became recordable, though still subnormal. The lens opacities were less apparent but the retinal pigmentation remained unchanged.
Patient 2* A man of 20 years had received regular blood transfusions from the age of ten months, maintaining an average haemoglobin of 10 g/dl. He had a splenectomy at age 17 years. He was started on
intramuscular desferrioxamine 500 mg a day when 6 years old. When he was 18 this was changed to 2-55g six times a week by overnight subcutaneous infusion with oral vitamin C. After this his haemoglobin was maintained above 10 g/dl. At age 19, in 1982, atrial fibrillation developed, leading to cardiac failure, and he had increasing angina and liver dysfunction. His serum ferritin was 9300
g/1.
He was admitted severely ill and treated with digoxin and diuretics as well as intravenous desferrioxamine-4 days at 90 mg/kg per 24 h and then 12 days at 120 mg/kg per 24 h-via a Hickman catheter. Over this period he excreted 4 -6gof iron in his urine. Initially he improved considerably but he then deteriorated and the desferrioxamine was stopped. The findings on ophthalmic examination, EOG, and ERG were normal and the patient had no eye symptoms. The deterioration continued and he died three weeks later.
Patient 3* A woman aged 25 years had received regular blood transfusions since the age of 1. Splenectomy was done when she was 15. Desferrioxamine was started at 500 mg a day intramuscularly when she was 9, and was changed to 2 - 5 g six times a week subcutaneously with oral vitamin C when she was 21. Thereafter her haemoglobin was maintained above 10 g/dl. At 14 years of age she had cardiac failure and hepatosplenomegaly secondary to constrictive pericarditis, and 6 years later she required a pericardiectomy. When she was 23 years old there was a recurrence of congestive cardiac failure and liver impairment. Her serum ferritin was greater than 10 000 g/1. She was treated as an outpatient with 40 mg frusemide daily, but still had ankle oedema. Desferrioxamine 135 mg/kg per 24 h was infused for 10 days through a central venous line and she excreted 2 -1gof iron in her urine and faeces. After this she felt so much better that she decided to continue intensive chelation therapy subcutaneously as an outpatient. She is now free from ankle oedema and requires no diuretics. This patient never had any eye symptoms and, except for longstanding myopia, findings on ophthalmic examination were normal.
Patient 4* A 24-year-old man had been transfused regularly from six months of age, requiring splenectomy at 16 years. Intramuscular
Fig 2-Fluorescein angiogram pigmentary disturbance.
of left macula in
patient 1, showing
*These patients were among those reported in 1974 by Barry et at. Patients 2 and 3 were in the chelated group; patient 4 was not at that time chelated.
183
pig 3-Visual fields in patient 1 during high-dose desferrioxamine.
Fig 4-Visual fields in patient
1 after withdrawal of high-dose desferrioxamine.
desferrioxamine 500 mg a day was started when he was 8, and a subcutaneous regimen when he was 19. From age 22 to 24 he had four episodes of pericarditis and supraventricular tachycardias, and by 1982 his serum ferritin was 11 000 pgll. He was admitted as an emergency with pneumonia and congestive cardiac failure which improved on treatment with intravenous antibiotics, digoxin, and diuretics. Two days after admission intravenous desferrioxamine was started without vitamin C-165 mg/kg per 24 h for 2 days, then 220 mg/kg per 24 h for 6 days. 8 days after the start of intravenous desferrioxamine he complained that the previous evening, in poor light, his vision had been so bad that he had been unable to get about. The desferrioxamine was stopped. On examination, visual acuity was 6/36 bilaterally. Colour vision was severely impaired in both eyes and, although his visual acuity should have been adequate for the tests, he was completely unsuccessful with the Ishihara and the City University colour plates. A small central scotoma was detected in each eye by visual field examination (fig 5), corresponding to the reduced acuity and
impaired colour vision; there was bilateral central loss in dark adaptation by scotopic static perimetry. On peripheral field examination there was generalised constriction rather than annular
very poor response on the pattern ERG. Although a light rise could be detected on an EOG done on the left eye, this was severely A Ganzfeld ERG performed on reduced at 141% (normal>185%). the right eye was subnormal and showed 1 3 log units loss of scotopic sensitivity. Because of the patient’s poor general condition, not all the tests could be done on both eyes. No lens opacities were seen. There was no evidence of retinal pigment release but there was thinning and tortuosity of the retinal vessels. After withdrawal of high-dose desferrioxamine there was a rapid subjective improvement in vision, but the patient still complained of slight difficulty in seeing at night. 21 days after withdrawal of desferrioxamine visual acuities were 6/9 (right) and 6/12 (left). By this time colour vision was normal, the visual fields were less constricted, and the central scotoma in each eye had disappeared (fig 6). Dark adaptation was correspondingly improved as was the pattern VER. Two months after the end of treatment the EOG was 174% (right) and 190% (left). The Ganzfeld ERG showed only 0-14 log unit loss of scotopic sensitivity on both sides, but the pattern ERG was still subnormal. No lens opacities or retinal pigmentation was a
were seen.
loss, but on dark adaptation the greatest loss was detected in the mid
Discussion
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periphery. The pattern VER showed a reduction in sensitivity in each eye. This was commensurate with the subnormal visual acuity. There
Fig 5-Visual fields in patient 4 during high-dose desferrioxamine.
With the large doses of desferrioxamine substantial of iron were excreted, and two patients had objective
amounts
184
Fig 6-Visual fields in patient 4 after withdrawal of high-dose desferrioxamine. improvement in cardiac status. Two, moreover, felt so much Finally, we feel that in selected cases this form of treatment an that to is better intensive subcutaneous justified, provided that the dose is increased gradually, to a they opted pursue of 125 mg/kg per 24 h. If ophthalmic had maximum One man and one substantial woman, however, regimen. loss of vision, confirmed by objective investigations. Except complications occur, desferrioxamine should be stopped for the pigmentary changes in patient 1, these abnormalities until clinical resolution, when the drug can be started again in lower dosage. resolved almost completely after drug withdrawal. 1 has been in of lens described man, opacities Development We thank Dr R. J. K. Brown for help with patient 1. but rapid visual failure as a toxic effect of desferrioxamine has Correspondence should be addressed to S. C. D., Department of not to our knowledge been reported previously. The night Haematology, Middlesex Hospital, Mortimer St, London WI. blindness, annular field loss with a geographically similar REFERENCES defect of dark adaptation, and associated EOG and ERG abnormalities are characteristic of degenerative disorders of 1. Bloomfield SE, Markenson AL, Miller DR, Peterson CM. Lens opacities in retinal photoreceptors involving the rods. These are thalassemia. J Ped Ophth Strab 1978; 15: 154-56. 2. Miller KB, Rosenwasser LJ, Bessette JM, Beer DJ, Rocklin RE. Rapid desensitisation indistinguishable from the changes seen in the various forms for desferrioxamine anaphylactic reaction. Lancet 1981; i: 1059. of retinitis pigmentosa. Pigmentary changes are usual in this 3 Propper RD, Shurin SB, Nathan DG. Reassessment of the use of desferrioxamine Bin iron overload. N EnglJ Med 1976; 294: 1421-23. group of diseases, but the natural history normally extends 4. Propper RD, Cooper B, Rufo RR, Nienhuis AW, Anderson WF, Bunn F, Rosenthal A, over many years and recovery does not occur. The loss of Nathan DG. Continuous subcutaneous administration of desferrioxamine in patients with iron overload. N Engl J Med 1977; 297: 418-23. central acuity and colour vision together with central scotoma 5. Hoffbrand AV, Gorman A, Laulicht M, Garidi M, Economidou J, Georgiopoulou P, and EOG, ERG, and VER abnormalities is characteristic of Hussain MAM, Flynn DM. Improvement in iron status and liver function in patients with transfusional iron overload with long-term subcutaneous degenerations affecting the cones. Retinal pigmentary desferrioxamine. Lancet 1979; i: 947—49. changes are not a prominent feature of these disorders. 6. Pippard MJ, Callender ST, Finch CA. Ferrioxamine excretion in iron-loaded man. It is currently held that, whilst degeneration of one or other Blood 1982; 60: 288-94. 7. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in form of photoreceptor may predominate, abnormalities of thalassaemia major: effect on liver iron concentration, liver histology, and clinical rod and cone function can arise together. In patient 1 the progress. Br Med J 1974; ii: 16-20. 8. Zaino EC. Desferrioxamine and trace metal excretion in chelation therapy in chronic picture is predominantly of a rod defect but some cone iron overload: In: Zaino EC, Roberts RH, eds. Chelation and chronic iron overload involvement is shown by the persistent pattern ERG (CIBA Medical Horizons Symp). New York, 1977: 95-107. 9. Rao SS, Satapathy M, Sitaramayya A. Copper metabolism in retinitis pigmentosa changes, while in patient 4 there is a mixed rod and cone patients. Br J Ophthalmol 1981; 65: 127-30. defect. 10. Silverstone B, Berson D, Kuperman O. Copper metabolism changes in pigmentary The mechanism behind the retinal toxicity of retinopathies and high myopia. Metab Paediatr Ophthalmol 1981; 5: 45-48. 11. Wise JB. Treatment of experimental siderosis bulbi, vitreous haemorrhage and corneal desferrioxamine is not clear. Chelation of iron is unlikely to blood staining with desferrioxamine. Arch Ophthal 1966; 75: 698-707. be the explanation, but desferrioxamine chelates several other 12. Brueckner R, Hess R, Keberle H, Pericin C, Tripon J. Pathological lenticular changes in animals after long-term administration of elevated doses of Desferal. Helv Physiol metals. The stability constant of desferrioxamine for Fe3+ is Acta 1967; 25: 62-77. 10’ whilst for Cut it is 1014, Zn2+ and Co2+ 10’andNP"+ 1010 and urinary excretion of Cu and Zn is increased during "The functions of medicines are not limited to the demonstrable, desferrioxamine infusions.8 This raises the possibility that conventional medical effects ... A drug manufacturer marketing a the ocular abnormality may be due to the removal of another useless or dangerous product; an advertiser defining as an metal from the retina. In this connection it is noteworthy that ’indication’a non-illness situation (a mother crying as her child goes abnormalities of copper metabolism have been desribed in off to school for the first day, and the advertisement saying she is retinitis pigmentosa,9,10 whilst the ocular and other ’depressed’ and needs a powerful anti-depressant drug); a physician manifestations of zinc deficiency are quite different. Another prescribing in lieu of taking time to diagnose or talk to a patient; oura possibility is that the effect of desferrioxamine is due to health bureaucrat using medicines policy as a lever for his previous iron-mediated damage of the blood-retina barrier, promotion; these are all examples of functions of medicines ... because very high systemic doses to animals have not These examples expose the gulf between a formal view of medicinal functions and the psychological and social functions on the part of produced retinopathy whilst small quantities injected and into the result in necrosis.11,12 dispensers and users ... Medicines policy cannot easily be Clinically directly eye here implemented until one knows what people are really doing and why, the toxic effects described closely electrophysiologically how to reach them to educate them (whether doctors or patients), resemble those in various forms of tapetoretinal dystrophy. and what ’irrational’ substitute conduct to expect in advance, Although no firm association has so far been established should one remove a substance without providing a replacement for between these conditions and abnormalities of metal ions, the it in a specific function. A pragmatist will attend to such issues; they current findings may warrant reappraisal of the position, constitute the real world."-Richard Blum, Andrew Herxheimer, Catherine Stenzl, and Jasper Woodcock. Pharmaceuticals and particularly in view of the substantial reversibility of the health policy. London: Social Audit Ltd, 1983. changes described.