vision and hearing during deferoxamine therapy

5
Vision and hearing during therapy deferoxamine Alan Cohen, MD, Marie Martin, RN, Jeannie Mizanin, RN, Dan F. Konkle, PhD, and Elias ~hwartz, MD From the Division of Hematology, Children's Hospital of Philadelphia, the Department of Com- munication Disorders, Children's Seashore House, Philadelphia, and the Departments of Pedi- atrics and of Otorhinolaryngology and Human Communication, University of Pennsylvania School of Medicine, Philadelphia To determine the frequency of eye and auditory complications and their rela- tionship to drug dosage and iron stores in patients receiving deferoxamine, we studied 52 regularly transfused patients who received deferoxamine by subcu- taneous or intravenous infusion in doses from 26 to t36 mg/kg/day, and whose serum ferritin levels of t85 to t7,775 ~g/L reflected a wide range of iron stores. Forty-nine patients (94%) had no evidence of drug-induced visual or auditory abnormalities. Symptomatic loss of vision and hearing developed in one patient; both problems improved when chelation therapy was stopped. Of the 5t symptom-free patients, one had a mild degree of macular stippling and one had a mild, bilateral, high-frequency sensorineural hearing loss. Eye and ear abnormalities in the symptom-free patients did not progress despite continua- tion or resumption of chelation therapy at the same dosage. Patients with oph- thalmologic and audiologic abnormalities did not receive higher doses of de- feroxamine and did not have lower serum territin levels than patients without such abnormalities. These findings demonstrate that eye and ear abnormalities during chelation therapy with deferoxamine may not occur uniformly at as high a frequency as previously reported, even in patients who receive large doses of the chelating agent or who have only modest amounts of excessive iron. (J PEDIATR 1990;117:326-30) Iron chelation therapy with deferoxamine removes exces- sive iron and helps prevent organ damage in patients receiving regular erythrocyte transfusions.1 Until recently, deferoxamine was considered to be generally free of major side effects. However, since 1983, numerous reports have attributed impairment of vision and hearing to chelation therapy with deferoxamine.2q2 Eye abnormalities have in- cluded impaired acuity, retinal stippling, peripheral visual field loss, defective dark adaptation, thinning of retinal ves- Supported in part by a contract from the Commonwealthof Penn- sylvania. Submitted for publication Dec. 19, 1989; accepted Feb. 8, 1990. Reprint requests: Alan Cohen, MD, Children's Hospital of Phila- delphia, 34th St. and Civic Center Blvd., Philadelphia, PA, 19104. 9/25/19995 sels, and abnormal visual evoked responses. The audiologic abnormality has been a bilateral, high-frequency hearing loss. These eye and hearing abnormalities have occurred in as many as 38% to 45% of patients in some centers. 9, 12 Because of data suggesting that toxic effects may be re- lated to high doses of deferoxamine in patients with small HL Hearing threshold level [ amounts of excessive iron, investigators have recommended that patients receive no more than 50 mg/kg/day of deferoxamine.9 For some patients, however, this alteration in treatment may markedly decrease the rate of iron removal, and the adverse effect on iron balance may outweigh the potential reduction in toxic effects. To evalu- ate whether the incidence of visual and auditory impairment 326

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Page 1: Vision and hearing during deferoxamine therapy

Vision and hearing during therapy

deferoxamine

Alan Cohen , MD, Marie Mart in, RN, Jeann ie Mizanin, RN, Dan F. Konkle, PhD, and Elias ~ h w a r t z , MD

From the Division of Hematology, Children's Hospital of Philadelphia, the Department of Com- munication Disorders, Children's Seashore House, Philadelphia, and the Departments of Pedi- atrics and of Otorhinolaryngology and Human Communication, University of Pennsylvania School of Medicine, Philadelphia

To determine the f requency of eye and auditory compl icat ions and their rela- tionship to drug dosage and iron stores in patients receiv ing deferoxamine, we studied 52 regularly transfused patients who received deferoxamine by subcu- taneous or intravenous infusion in doses from 26 to t36 mg/kg /day , and whose serum ferritin levels of t85 to t7,775 ~g/L ref lected a wide range of iron stores. Forty-nine patients (94%) had no ev idence of drug- induced visual or auditory abnormalit ies. Symptomatic loss of vision and hearing deve loped in one patient; both problems improved when chelat ion therapy was stopped. Of the 5t symptom-free patients, one had a mild degree of macular stippling and one had a mild, bi lateral, high-frequency sensorineural hearing loss. Eye and ear abnormali t ies in the symptom-free patients did not progress despi te cont inua- tion or resumption of chelat ion therapy at the same dosage. Patients with oph- thalmologic and aud io log ic abnormali t ies did not receive higher doses of de- feroxamine and did not have lower serum territin levels than patients without such abnormali t ies. These findings demonstrate that eye and ear abnormal i t ies during chelat ion therapy with deferoxamine may not occur uniformly at as high a f requency as previously reported, even in patients who receive large doses of the chelat ing agent or who have only modest amounts of excessive iron. (J PEDIATR 1990;117:326-30)

Iron chelation therapy with deferoxamine removes exces- sive iron and helps prevent organ damage in patients receiving regular erythrocyte transfusions. 1 Until recently, deferoxamine was considered to be generally free of major

side effects. However, since 1983, numerous reports have attributed impairment of vision and hearing to chelation therapy with deferoxamine. 2q2 Eye abnormalities have in- cluded impaired acuity, retinal stippling, peripheral visual field loss, defective dark adaptation, thinning of retinal ves-

Supported in part by a contract from the Commonwealth of Penn- sylvania. Submitted for publication Dec. 19, 1989; accepted Feb. 8, 1990. Reprint requests: Alan Cohen, MD, Children's Hospital of Phila- delphia, 34th St. and Civic Center Blvd., Philadelphia, PA, 19104.

9/25/19995

sels, and abnormal visual evoked responses. The audiologic abnormality has been a bilateral, high-frequency hearing loss. These eye and hearing abnormalities have occurred in as many as 38% to 45% of patients in some centers. 9, 12

Because of data suggesting that toxic effects may be re- lated to high doses of deferoxamine in patients with small

HL Hearing threshold level [

amounts of excessive iron, investigators have recommended that patients receive no more than 50 mg/kg/day of deferoxamine. 9 For some patients, however, this alteration in treatment may markedly decrease the rate of iron removal, and the adverse effect on iron balance may outweigh the potential reduction in toxic effects. To evalu- ate whether the incidence of visual and auditory impairment

326

Page 2: Vision and hearing during deferoxamine therapy

Volume 117 Vision and hearing during deferoxamine therapy 3 2 7 Number 2, Part 1

Table I. Iron stores and chelation history

Thalassemia major Sickle cell d isease Other disorders (n = 27) (n = 18) (n = 7)

Age (yr) Duration of chelation therapy (yr) Serum ferritin levels (~g/L)

Patients with <2000 ug/L (No.) Dose of deferoxamine (mg/kg/day)

Subcutaneous* Intravenous* Patients with values >t00 mg/kg/day (No.) Patients receiving supplemental vitamin C (No.)

6-35 (18) 8-26 (16) 5-75 (21) 2-12 (8) 1-11 (5) 1-10 (5) 185-17,775 ( 2 7 4 1 ) 190-12,225 (5740) 351-2914 (1588)

15 5 4

26-90 (52) 32-85 (48) 36-132 (84) 79-136 (112) 97-135 (113) 108

4 8 4 8 5 2

Values in parentheses are means. *See text regarding number of patients receiving subcutaneous and intravenous chelation therapy.

is uniform in different centers, and to determine whether the toxic effects are related to dosage of deferoxamine or degree of iron overload, we studied regularly transfused patients who have received chelation therapy for as long as 12 years. These patients represent an unusually wide range of age, dosage of deferoxamine, duration of chelation therapy, and amount of excessive iron.

M E T H O D S

Fifty-two regularly transfused patients who received chelation therapy with deferoxamine were investigated. The study group included 27 patients with thalassemia major, 18 with sickle cell disease, 4 with Diamond-Blackfan syndrome (congenital hypoplastic anemia), and 3 with other transfu- sion-dependent hematologic disorders. Most patients re- ceived a nightly subcutaneous infusion of 2 gm of deferox- amine for 10 to 12 hours. Fifteen patients who were poorly compliant with subcutaneous therapy or who had extremely large iron stores were later treated with nightly intravenous infusions of 6 to 12 gm of deferoxamine. Patients received 100 to 250 mg of vitamin C a day during chelation therapy if supplementation increased deferoxamine-induced uri- nary iron excretion.

Audiograms and ophthalmologic examinations were per: formed every 6 to 12 months for 1 to 4 years. Hearing sen- sitivity was assessed by pure tone air and bone conduction, with auditory thresholds defined by means of the modified ascending Hughson-Westlake procedure. 13 Normal hear- ing was defined as threshold sensitivity equal to or more than a 20 dB hearing threshold level. A newly discovered bilateral sensorineural hearing threshold at less than 20 dB HL at frequencies greater than 1000 Hz, or a hearing threshold worsening by more than 10 dB in comparison with the preehelation test result, was considered to be possibly related to drug toxicity. Patients with conductive hearing loss (air conduction thresholds <20 dB HL, bone conduc-

tion >20 dB HL, >_ 15 dB air-bone gap), sensorineural loss at frequencies less than 1000 Hz, or unilateral sensorineu- ral loss at any frequency were judged to have hearing ab- normalities that were not related to chelation therapy. Ophthalmologic assessment included measurement of vi- sual acuity and visual fields, slit-lamp examination, and di- rect and indirect ophthalmoscopy.

R E S U L T S

Iron stores and chelation histories. As of May 1989, fif- ty-two patients had received regular erythrocyte transfu- sions for 4 to 34 years (Table I). Serum ferritin levels were 185 to 17,775 #g/L (mean 3327 #g/L). Thirteen patients had ferritin levels less than 1000 #g/L, and 11 patients had ferritin levels between 1000 and 2000 #g/L.

Forty-six patients, including 24 with thalassemia major, 15 with sickle cell disease, and 7 with other hematologic disorders, had received 2 or 2.5 gm of deferoxamine as a daily subcutaneous infusion for 1 to 12 years (mean 7 years). Weight-adjusted subcutaneous doses for deferox- amine were 26 to 132 mg/kg (mean 55 mg/kg), and the daily dose exceeded 50 mg/kg in 19 patients. Fifteen patients, including five with thalassemia major, nine with sickle cell disease, and one with Diamond-Blackfan syn- drome, had received 5 to 12 gm of deferoxamine by daily intravenous infusion for 1 to 4 years (mean 2.3 years). With this route of administration, the weight-adjusted daily dose was 79 to 136 mg/kg (mean 112 mg/kg), exceeding 100 mg/kg in 13 patients.

Sixteen patients had a combination of a serum ferritin concentration <2000 #g/L and a daily dose of deferoxam- ine >50 mg/kg. These patients included nine with thalassemia major, four with sickle cell disease, and three with Diamond-Blackfan syndrome.

Ophthalmologic findings. Of 52 patients, 51 reported no change in vision. Of these 51 patients, one had an abnor-

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3 2 8 Cohen et al. The Journal of Pediatrics August 1990

Table II. Deferoxamine dose and serum ferritin levels in patients with eye and ear abnormalities

Serum ferritin level Deferoxamine dose Patient No. Abnormality (/~g/L) (mg/kg/day)

1 Night blindness 351 38 Bilateral sensorineural hearing loss 585 38

2 Maeular stippling 590 108 3 Bilateral sensorineural hearing loss 5090 40

mality on ophthalmologic examination that may have been due to drug toxicity (Table II). A 25-year-old woman with Diamond-Blackfan syndrome (patient 2)'had a mild amount of macular stippling when first examined 24 months after beginning daily intravenous deferoxamine therapy at a dose of 108 mg/kg. Her ferritin level at the time of the ophthal- mologic examination was 590 ~tg/L. She began subcutane- ous chelation (36 mg/kg/day) 1 month later because of catheter-related complications, and 20 months later she re- turned to intravenous therapy at the original dosage. The ocular findings did not change. The serum ferritin level is currently 2834 #g/L.

Symptomatic visual changes developed in one patient. A 75-year-old man (patient 1) with myelodysplasia associated with the 5 q - abnormality was referred for chelation ther- apy from a hematology center where he had received eryth- rocyte transfusions for 2 years before beginning daily sub- cutaneous deferoxamine therapy at a dose of 38 mg/kg. Ophthalmologic examination before chelation therapy showed a visual acuity with best correction of OD 20/60 and OS 20/25. Retinal examination was normal. After 20 months of chelation therapy, when the serum ferritin level was 351 #g/L, the patient reported a dramatic decrease in his vision in dim light. His acuity with best correction was unchanged and retinal examination findings were normal. The dose of deferoxamine was reduced to 1.5 gm. Six weeks later, chelation was discontinued. Within 2 weeks of the dose reduction, the patient noted partial resolution of visual symptoms. Complete resolution occurred several months after deferoxamine was discontinued.

Audiologie findings. Of 52 patients, 51 had no symptom- atic hearing loss. One of these 51 patients, a 26-year-old woman with sickle cell disease, had a bilateral 25 dB loss at 4000 and 8000 Hz. Data regarding dosage of deferoxamine and serum ferritin level are shown in Table II. High- frequency hearing loss in the symptom-free patient did not progress despite continuation of chelation therapy at a sim- ilar dose.

The patient with myelodysplasia described above had a bilateral, high-frequency, sensorineural hearing loss (55 dB HL at 4000 and 8000 Hz) before beginning chelation ther- apy. After 18 months of treatment with deferoxamine, when

the serum ferritin level was 585 #g/L, the patient com- plained of further hearing loss. An audiogram showed a 65 dB HL loss at 3000, 4000, and 8000 Hz. When deferoxam- ine was reduced in dosage and later stopped because of ophthalmotogic abnormalities, the patient noted a gradual improvement in hearing. Audiometry has not been re- peated.

Relationship between complications, drug dosage, and iron overload. Patients with ophthalmologic and audiologic abnormalities did not receive higher doses of deferoxamine, nor did they have lower serum ferritin levels than patients without such abnormalities (p >0.5 by Student t test). The ratio of drug dosage to serum ferritin level also did not differ between affected and unaffected patients (p >0.5). How- ever, the small number of patients with abnormalities sharply reduced the power of finding such differences between affected and unaffected patients.

D I S C U S S I O N

The spectrum of visual and auditory impairment during deferoxamine therapy extends from isolated abnormalities in visual evoked responses to profound loss of sight and hearing. In a thalassemia treatment center in Canada, 9 of 89 patients had symptomatic visual loss or abnormal mac- ular pigmentation, and 22 patients had bilateral sensorineu- ral hearing loss. 9 Audiometric screening of 153 patients in a thalassemia treatment center in Italy revealed a bilateral high-frequency hearing deficit of more than 30 dB in 38% of patients) 2 Numerous case reports and small series describing visual impairment, retinal abnormalities, and hearing loss have complemented these investigations. Ces- sation of chelation therapy and, in some instances, subse- quent reintroduction of deferoxamine at a lower dose have frequently led to improvement in vision and hear- ing.2-6, s-10, 14

Some investigators have suggested that the clinical char- acteristics of patients in whom eye and ear abnormalities develop during chelation therapy point to high doses of de- feroxamine and modest levels of iron overload as risk fac- tors for toxic effects. 9, 12, 15 Some affected patients have re-

ceived 3 to 12 gm of deferoxamine by intravenous infusion 2, 5; in one patient, a sudden acceleration in the rate

Page 4: Vision and hearing during deferoxamine therapy

Volume l 17 Vision and hearing during deferoxamine therapy 3 2 9 Number 2, Part 1

of infusion was followed by acute loss of vision. 11 Reports of eye and ear abnormalities with lower doses of deferox- amine in patients with normal iron stores suggest that the

relationship between' dose of chelating agent and amount of chelatable iron may be a more important determinant of toxic effects than dosage alone. 6, 7, 10 Porter et al. 15 showed

that the risk of ototoxic effects is increased when the ratio of dose of deferoxamine divided by the serum ferritin level exceeds 0.025. Deferoxamine that does not bind excessive iron may chelate other metals or may inhibit iron-dependent enzyme activity. 16, 17 Studies of patients with rheumatoid

arthritis have identified binding of copper by deferoxamine as a possible cause of ocular damage, perhaps as a result of oxidative damage to cell membranes. 17

Not all of the eye and ear abnormalities that have occurred during deferoxamine therapy can be attributed to either the dosage of the chelator or the level of chelatabte iron. Macular depigmentation has occurred in patients re- ceiving conventional dosages of deferoxamine for treatment of iron overload. 9 Sensorineural hearing loss has occurred

with unusual frequency in patients with primary hemo- chromatosis, 18 as well as in patients with transfusional iron overload who have received little or no deferoxamine. 19, 20

Thus the occurrence of hearing abnormalities during che- lation therapy may be due in some patients to the underly- ing problem of excessive iron accumulation, rather than to the administration of deferoxamine.

In our current study, auditory impairment occurred less commonly during chelation therapy than in three earlier investigations (p <0.019, 12 or <0.0215 by chi-square anal- ysis with Yates correction). The frequency of ophthalmo- logic abnormalities in our study was 2 of 52 patients, or 4%, in comparison with 9 of 80, or 11%, in the only other large study 9 (p >0.10). The age (with the exception of a 75-year- old man) and transfusion history of the patients were com- parable to those in previous studies, and many of the patients had received high doses of deferoxamine and had modest levels of iron overload. In 28 patients the ratio of deferoxamine dosage to serum ferritin level exceeded the level of 0.025 associated with ototoxic effects by other investigators15; yet only one of these patients had a senso-

rineural hearing deficit. These findings suggest that eye and ear abnormalities that occur in regularly transfused pa- tients during chelation therapy may be due to factors other than the dosage of deferoxamine or the relationship between the amount of deferoxamine received and the degree of iron

overload. Some investigators have suggested that the dosage of de-

feroxamine not exceed 50 mg/kg/day in light of the reported toxic effects9; other investigators have recom- mended higher or ferritin-dependent limits. 2, 11,15 How-

ever, these restrictions may decrease the rate of iron

removal, thereby increasing the risk of iron-induced organ

damage. The incidence of eye and auditory complications in our current study indicates that dosage restrictions may not be appropriate for all patients, and that the risk of drug-re- lated toxic effects must be weighed carefully against the risk of iron overload. For some patients, such as those with iron- induced heart disease, this balance may favor the regular use of high doses of deferoxamine. Until specific risk factors for toxic effects are identified, all patients receiving iron chelation therapy with deferoxamine should have regular eye examinations and auditory assessments, and should be told to report immediately any changes in vision or hearing.

We thank Nancy Witham, MS, CCC-A, for her assistance in the performance of the audiologic studies. We also thank Dr. Philip Blatt for assisting in the investigation of his patient.

REFERENCES

l. Cohen A. Management of iron overload in the pediatric patient. Hematol Oncol Clin North Am 1987;1:521-44.

2. Davies SC, Hungerford JL, Arden GB, Marcus RE, Miller MH, Huehns ER. Ocular toxicity of high-dose intravenous desferrioxamine. Lancet 1983;2:181-4.

3. Simon P, Ang KS, Meyrier A, Allain P, Mauras Y. Desferri- oxamine, octtlar toxicity, and trace metals [Letter]. Lancet 1983;2:512-3.

4. Borgna-Pignatti C, DeStefano P, Broglia AM. Visual loss in patient on high-dose subcutaneous desferrioxamine [Letter]. Lancet 1984;1:681.

5. Lakhanpal V, Schocket SS, Jiji R. Deferoxamine (Desferal)- induced toxic retinal pigmentary degeneration and presumed optic neuropathy. Ophthalmology 1984;91:443-51.

6. Guerin A, London G, Marchais S, Metivier F, Pelisse J. Acute deafness and desferrioxamine [Letter]. Lancet 1985; 2:39-40.

7. Rubinstein M, Dupont P, Doppee JP, Dehon C, Ducobu J, Hainaut J. Ocular toxicity of desferrioxamine [Letter]. Lan- cet 1985; 1:817-8.

8. Blake DR, Winyard P, Lunec J, et al. Cerebral and ocular toxicity induced by desferrioxamine. Q J Med 1985;56:345-55.

9. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deforoxamine infusions. N Engl J Med 1986;314:869-73.

10. Pengloan J, Dantal J, Rossazza C, Abazza M, Nivet H. Oc- ular toxicity after a single intravenous dose of desferrioxa- mine in 2 hemodialyzed patients [Letter]. Nephron 1987; 46:211-2.

11. Dickerhoff R. Acute aphasia and loss of vision with desferri- oxamine overdose. Am J Pediatr Hematol Oncol 1987;9:287- 8.

12. Albera R, Pia F, Morra B, et al. Hearing loss and desferrioxa- mine in homozygous beta-thalassemia. Audiology 1988; 172:207-14.

13. Carhart R, Jerger J. Preferred method for clinical determina- tion of pure-tone thresholds. J Speech Hear Dis 1959;24:330- 45.

14. Gallant T, Boyden MH, Gallant LA, Carley H, Freedman M. Serial studies of auditory neurotoxocity in patients receiving deferoxamine therapy. Am J Med 1987;83:1085-90.

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3 3 0 Cohen et al. The Journal of Pediatrics August 1990

15. Porter JB, Jaswon MS, Huehns ER, East CA, Hazell JWP. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 1989;73:403-9.

16. DeVirgiliis S, Congia M, Turco MP, et al. Depletion of trace elements and acute ocular toxicity induced by desferrioxamine in patients with thalassaemia. Arch Dis Child 1988;63:250-5.

17. Pall H, Blake DR, Winyard P, et al. Ocular toxocity of des- ferrioxamine: an example of copper-promoted auto-oxidative damage? Br J Ophthalmol 1989;73:42-7.

18. Bourguet J, Bourel M, Simon M, Le Huerou L. H6mochro- matose et surdit& Rev Oto-Neuro-Ophthalmol 1970;42:215- 24.

19. Logothetis J, Constantoulakis M, Economidou J, et al. Thalassemia major (homozygous beta-thalassemia). Neurol- ogy 1972;22:294-304.

20. De Virgiliis S, Argiolu F, Sanna G, et al. Auditory involvement in thalassemia major. Acta Haematol 1979;61:209-15.

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