Vision and hearing during deferoxamine therapy Alan C o h e n , MD, Marie Martin, RN, J e a n n i e Mizanin, RN, Dan F. Konkle, PhD, a n d Elias ~ h w a r t z , MD From the Division of Hematology, Children's Hospital of Philadelphia, the Department of Communication Disorders, Children's Seashore House, Philadelphia, and the Departments of Pediatrics and of Otorhinolaryngology and Human Communication, University of Pennsylvania School of Medicine, Philadelphia To determine the frequency of eye and auditory complications and their relationship to drug d o s a g e and iron stores in patients receiving deferoxamine, we studied 52 regularly transfused patients who received d e f e r o x a m i n e by subcutaneous or intravenous infusion in doses from 26 to t36 m g / k g / d a y , 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 e v i d e n c e of d r u g - i n d u c e d visual or auditory abnormalities. Symptomatic loss of vision and hearing d e v e l o p e d in one patient; both problems improved when chelation therapy was stopped. Of the 5t symptom-free patients, one had a mild d e g r e e 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 continuation or resumption of chelation therapy at the same dosage. Patients with opht h a l m o l o g i c and a u d i o l o g i c abnormalities did not receive higher doses of deferoxamine and did not have lower serum territin levels than patients without such abnormalities. These findings demonstrate that e y e and ear abnormalities during c h e l a t i o n therapy with d e f e r o x a m i n e may not o c c u r uniformly at as high a frequency as previously reported, even in patients who receive large doses of the chelating a g e n t or who have only modest amounts of excessive iron. (J
PEDIATR1990;117:326-30)
Iron chelation therapy with deferoxamine removes excessive 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 included impaired acuity, retinal stippling, peripheral visual field loss, defective dark adaptation, thinning of retinal vesSupported in part by a contract from the Commonwealthof Pennsylvania. Submitted for publication Dec. 19, 1989; accepted Feb. 8, 1990. Reprint requests: Alan Cohen, MD, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA, 19104. 9/25/19995
326
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 related 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 evaluate whether the incidence of visual and auditory impairment
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Vision and hearing during deferoxamine therapy
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Table I. Iron stores and chelation history
Age (yr) Duration of chelation therapy (yr) Serum ferritin levels (~g/L) Patients with t00 mg/kg/day (No.) Patients receiving supplemental vitamin C (No.)
Thalassemia m a j o r (n = 27)
Sickle cell disease (n = 18)
O t h e r disorders (n = 7)
6-35 (18) 2-12 (8) 185-17,775 ( 2 7 4 1 ) 15
8-26 (16) 1-11 (5) 190-12,225 (5740) 5
5-75 (21) 1-10 (5) 351-2914 (1588) 4
26-90 (52) 79-136 (112) 4 8
32-85 (48) 97-135 (113) 8 5
36-132 (84) 108 4 2
Values in parenthesesare means. *See text regardingnumberof patientsreceivingsubcutaneousand intravenouschelationtherapy.
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.
tion >20 dB HL, >_ 15 dB air-bone gap), sensorineural loss at frequencies less than 1000 Hz, or unilateral sensorineural loss at any frequency were judged to have hearing abnormalities that were not related to chelation therapy. Ophthalmologic assessment included measurement of visual acuity and visual fields, slit-lamp examination, and direct and indirect ophthalmoscopy.
METHODS
RESULTS
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 transfusion-dependent hematologic disorders. Most patients received a nightly subcutaneous infusion of 2 gm of deferoxamine 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 urinary iron excretion. Audiograms and ophthalmologic examinations were per: formed every 6 to 12 months for 1 to 4 years. Hearing sensitivity was assessed by pure tone air and bone conduction, with auditory thresholds defined by means of the modified ascending Hughson-Westlake procedure. 13 Normal hearing 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
PEDIATR1990;117:326-30)
Iron chelation therapy with deferoxamine removes excessive 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 included impaired acuity, retinal stippling, peripheral visual field loss, defective dark adaptation, thinning of retinal vesSupported in part by a contract from the Commonwealthof Pennsylvania. Submitted for publication Dec. 19, 1989; accepted Feb. 8, 1990. Reprint requests: Alan Cohen, MD, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA, 19104. 9/25/19995
326
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 related 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 evaluate whether the incidence of visual and auditory impairment
Volume 117 Number 2, Part 1
Vision and hearing during deferoxamine therapy
327
Table I. Iron stores and chelation history
Age (yr) Duration of chelation therapy (yr) Serum ferritin levels (~g/L) Patients with t00 mg/kg/day (No.) Patients receiving supplemental vitamin C (No.)
Thalassemia m a j o r (n = 27)
Sickle cell disease (n = 18)
O t h e r disorders (n = 7)
6-35 (18) 2-12 (8) 185-17,775 ( 2 7 4 1 ) 15
8-26 (16) 1-11 (5) 190-12,225 (5740) 5
5-75 (21) 1-10 (5) 351-2914 (1588) 4
26-90 (52) 79-136 (112) 4 8
32-85 (48) 97-135 (113) 8 5
36-132 (84) 108 4 2
Values in parenthesesare means. *See text regardingnumberof patientsreceivingsubcutaneousand intravenouschelationtherapy.
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.
tion >20 dB HL, >_ 15 dB air-bone gap), sensorineural loss at frequencies less than 1000 Hz, or unilateral sensorineural loss at any frequency were judged to have hearing abnormalities that were not related to chelation therapy. Ophthalmologic assessment included measurement of visual acuity and visual fields, slit-lamp examination, and direct and indirect ophthalmoscopy.
METHODS
RESULTS
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 transfusion-dependent hematologic disorders. Most patients received a nightly subcutaneous infusion of 2 gm of deferoxamine 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 urinary iron excretion. Audiograms and ophthalmologic examinations were per: formed every 6 to 12 months for 1 to 4 years. Hearing sensitivity was assessed by pure tone air and bone conduction, with auditory thresholds defined by means of the modified ascending Hughson-Westlake procedure. 13 Normal hearing 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
