- Email: [email protected]
Sensorineural hearing loss in children with thalassemia major in Northern Greece
International Journal of Pediatric Otorhinolaryngology
ELSEVIER
35 (1996)
223-230
Sensorineural hearing loss in children with thalassemia major in Northern Greece G. Kontzoglou”,*, A. Koussib, J. Tsatrab, G. Noussios”, V. Vital”, G. Sagarakis”, M. Athanassioub “E.N.T. blst Department
Department, Hippokration Hospital, Thessaloniki, Greece qf Paediatrics of Aristotelian University, Thessaloniki, Greece
Received 5 July 1995; revised 26 October 1995; accepted 4 November 1995
Abstract Eighty eight (88) P-thalassemic patients undergoing regular transfusion- chelation therapy with desferrioxamine (DFO) were studied for ENT problems from 1988 to 1993, as DFO has been implicated for auditory neurotoxicity. The mean age of the patients was 9.66 f 3.1 years, their pre-transfusion haemoglobin level was 9 f 2 g/dl, serum ferritin level was 2065 f 898 rig/ml and the daily DFO dose was 50.7 + 9.5 mg/kg for 5 days/week. The ENT study included, ENT examination, pure tone audiometry, speech audiometry, tympanometry, tone decay test and ABR. During this 6-year study 24/88 (27%) patients developed bilateral or ipsilateral sensorineural hearing loss in high tone frequencies, sometimes exceeding 80 dB, which was attributed to DFO toxicity. Therefore, a reduction or temporary withdrawal of DFO followed. After this intervention 12/24 patients recovered almost completely, 7/24 remained stable and 5/24 presented aggravation of their hearing loss. This study confirms the DFO induced auditory neurotoxicity and the necessity of periodical audiology control of P-thalassemic patients for prompt diagnosis and management of this complication. Keywords:
p-Thalassemia;
Children;
Desferrioxamine;
Neurotoxicity;
Hearing
loss
1. Introduction
Desferrioxamine (DFO) is, to date, the only chelation reducing iron overload in thalassemic patients.
agent with the ability
* Corresponding author, Panorrnou 2, 544 54, Thessaloniki, Macedonia, Greece. 0165-5876/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI
0165-5876(95)01308-3
of
224
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
DFO has been implicated as having auditory neurotoxicity, causing sensorineural hearing loss (SNHL) in these patients [3,6,7,9]. SNHL has been the subject of many investigations and studies during the past years [3,6-131. The conclusions of these studies showed that auditory neurotoxicity was related to: 1. the high level of serum ferritin; 2. the high dose of DFO associated with low serum ferritin [4,6]; 3. the young age of the patients as well as [6]; 4. the length of the treatment. The purpose of this study is to evaluate damages of the acoustic organ in our thalassemic patients and to proceed to immediate interventions when these are found.
2. Materials
and methods
Eighty-eight patients with thalassemia major, a consecutive sample of subjects in regular transfusion-chelated therapy attended to by the same investigators, were entered in a prospective longitudinal audiology study in 1988. Forty-six were males (52.3%) and forty-two were females (47.7%). Their age ranged from 6 to 25 years, with a mean age of 9.66 f 3.1 years. Their pre-transfusion haemoglobin (Hb) level was 9-l 1 g/dl, while serum ferritin was 2065 + 898 rig/ml. The daily dose of DFO was 50.7 f 9.5 mg/kg for 5 consecutive days/week. All 88 patients had an ENT examination and audiology tests such as, pure tone audiometry, speech audiometry, tympanometry, tone decay test and ABR. In pure tone audiometry the frequencies 125, 250, 500, 1000, 1500, 2000, 3000, 4000, 6000 and 8000 Hz were checked. Special emphasis and care was given on high tone frequencies (3000-8000 Hz). All patients were being followed every 3-6 months (6 months for those with normal audiological findings and 3 months for those with abnormal) for 6 years, (1988-1993). The lo-20 international system of electrode placement was used in evoked potential study. Brainstem auditory evoked potentials were performed in all 24 patients, using the Medelec MS 92a machine in a soundproof and electrically shielded room at an ambient temperature of 23°C. The latencies of waves I, III and V as well as interpeak latencies of I-III-III-V and I-V were all analyzed. Thus, both peripheral and central lesions could be tested. In order to have a baseline hearing measurement an audiometric check, which included pure tone audiometry, speech audiometry and tympanometry, was performed in 29 young outpatients. These patients were subsequently admitted in the Pediatric and ENT department and were found to have no otologic problems. The above audiometric check defined exactly the subjects’ range of hearing frequencies (especially between 3000-8000 Hz) and the hearing level was always found to be < 20 dB. The findings of these 29 patients were used as a baseline.
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
225
3. Results The results of the examinations of 88 patients have been evaluated in the course of two periods, the first one from 1988- 1990 and the second from 1991 to 1993 (continued). During the first period none of 88 patient presented with SNHL [l 11. During the second period, 24 out of 88 (27%) patients presented with SNHL in high tone frequencies (3000-8000 Hz). Fourteen from twenty-four (58%) of the last group were males and lo/24 (42%) were females. For the purpose of the present investigation, normal hearing was classified as between 0 and 20 dB, similar to our baseline, moderate hearing loss between 20 and 45 dB and severe loss greater than 45 dB [1,2,8] (Table 1). SNHL was moderate in 15124 (62.5%) patients, of whom 9 were male and 6 female, (7 ipsilateral - 8 bilateral) and severe in 9/24 (32.5%) patients, of whom 5 were male and 4 female (2 ipsilateral - 7 bilateral). SNHL was bilateral in 15 patients and ipsilateral in 9 patients and sometimes exceeded 80 dB. All audiology tests confirmed the cochlear lesion [3,7-10,12,13]. As in pure tone audiometry hearing loss was present only in high tone frequencies (sign of baseocochlear lesion), tympanometry test was within normal limits and speech audiometry was also normal as the lesion involved high tone frequencies only. Tone decay test was negative in all patients, sign of cochlear lesion. ABR did not show any appreciable abnormality, indicating that the lesion was possibly located in the cochlea, rather than in any other part of the auditory pathway. 3.1. Intervention Due to the absence of other toxic agents and the normal audiological findings during the first period of this study, the presented sensorineural hearing loss was attributed to DFO toxicity. As it has already been stated DFO dose was 50.7 + 9.5 mg/kg 5 days a week (a rather high dose for update data). Thus a modification in DFO dose followed: (a) temporary withdrawal of the drug for approximately 3 months and re-introduction of DFO therapy using lower doses (20-40 mg/kg 5 days a week) in patients with severe hearing loss, and (b) temporary reduction of DFO dose in patients with moderate hearing loss. Table 1 Hearing results before intervention Hearing loss
Normal hearing Moderate loss Severe loss
Patient nos. 88
64 15 9
Sex Male
Female
32 9 5
32 6 4
Classification of 24/88 patients, before any intervention, according to the level of hearing loss and sex. Normal hearing was classified as being between 0 and 20 dB, moderate hearing loss between 20 and 45 dB and severe loss greater than 45 dB.
226
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
Table 2 Hearing results after intervention Evolution of hearing
Recovered Aggravated Stable
Patient (nos. 24)
12 5 I
Sex Male
Female
7 3 3
5 2 4
Results after the intervention, classified in categories (recovered, aggravated, stable) according to sex.
3.2. Results after intervention After the above intervention in DFO dose, in 12/24 patients (50%) 7 male and 5 female, audiological findings became normal and hearing loss recovered almost completely after 3-6 months. 5/24 patients (20,83%), 3 male and 2 female, presented with aggravation of their audiological findings (increase of hearing loss) while the rest 7/24 (29,17%), 3 male and 4 female remained stable (Table 2). Eleven out of the 12 patients who recovered had moderate hearing loss (5 bilateral and 6 ipsilateral) and one had severe (ipsilateral). Aggravation was seen in 5 patients, of whom one had moderate (ipsilateral) and 4 severe (one ipsilateral and 3 bilateral) hearing loss before the intervention. Hearing loss remained stable in 7 patients, 3 with moderate (3 bilateral) and 4 with severe (4 bilateral), initial hearing loss. 4. Discussion During the past years many studies have been published on DFO toxicity on different organs, such as the retina and inner ear [3,6-131. On this basis all patients with thalassemia major of our unit, 6-25 years of age, having been on a program of transfusion-chelation for 4-15 years, were being entered in a preventive audiometric check since 1988. Results have been evaluated during two periods of therapy. During the first period, 1988- 1990, no patient presented abnormal audiological findings. However, during the second period 1991- 1993, 24/88 patients presented sensorineural hearing loss especially in high tone frequencies (Table 3). According to Hybel [5] this type of hearing loss is consistent with drug-induced toxicity. Although our study group included young patients (mean age 9.66 + 3.1), SNHL developed in the older group of patients (mean age 10.8 + 2.7 years) in contrast to the subjects with normal findings (mean age 9.1 f 3.2) statistically significant difference (P < 0.05). DFO dose was 52 f 7.2 mg/kg x 5 days/week in the group with abnormal findings while in the other group it was 50 f 10.4 mg/kg/ x 5 days/week no statistically significant difference (P > 0.05). Serum ferritin was found to be relatively lower in patients with SNHL (1888 + 896 rig/ml) than in patients with normal findings (2134 f 896 rig/ml), although there was no statistically significant difference (P > 0.05).
M M F F F M M M M M M M F M M F M M M F M M F F
hearing
134’12 lo4 I2 9 13 II 6.5 6.5 6.5 I3
1.5 12 I2 ,()7’12
1,p* 135’12 g*11*
8””
13.5 13 13
I3 69,1 2
15 97.1z
cheek, mterventlon
55 63 50 64 44 59 57 57 54 46 61 50 53 50 45 50 64 46 47 54 46 45 46 36
check
loss 40 35 35 90 80 40 70 50 40 55 70 50 75 30 85 40 80 30 35 40 25 45 35 45
(dB)
patlents.
40+X-8000 400+80 400&8000 300+8000 300%8OCil 6CKlC-8000 300&8000 600&8000 600&8OM) 125~8ooO 500&8ooO [email protected] 4OOC~8000 6cKK-8000 4WO-8OOCl 4OOt~8000 600%8000 400%8OCil 6Oix-8000 400+8000 So00 600@8000 So00 4000~8tXJO
in 24/88 thallasemic
Moderate Moderate Moderate Moderate Moderate Moderate
SWUtY
Moderate
SWSK
Moderate
SERX
SWXe
SWeK
%WR
Moderate
SWZK
Moderate Severe
SWX
Moderate Moderate Moderate SWeIe
Hearmg
Frequency
Pure tone audiogram
Audiometry
Greece
dose and results
5 days
m Northern
@g/ml
major
Dose DFO per week)
with thalassemia
(“g/ml)
dose, audiometry
2650 1850 1300 1600 1750 1500 1170 1600 3750 2100 1600 1150 I IO0 2600 700 1600 1800 1500 1250 4800 1700 2500 2350 1400
Ferritm
loss m chddren
level, UFO
Age (years)
Sex, age. ferritm
I 2 3 4 5 6 1 8 9 10 II 12 13 I4 15 16 I7 I8 19 20 21 22 23 24
Sex
Table 3 Sensorincural
T.D. Test Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Nomxd Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
ABR 1 i 1 1 1 1 1 1 1 1 L 1 1 1 $ 1 s 1 1 1 1 I 1 1
45 40 30 45 3 months1 50 45 33 45 36 3 months1 25 30 40 6 months1 30 3 months1 40 40 42 35 40 40 20
Intervention bw/W
30
30
20
25
dose DFO
of follow-up
Improvement Improvement Improvement Aggravation Same condition Improvement Same condition Improvement Aggravation Improvement Improvement Same conditton Improvement Same conditmn Aggravation Same conddion Improvement Same condition
Improvement Improvement Same condition Aggravation Aggravation
Results month)
(6-U
2 c.
F
b 5 2 OS
G. Kontzoglou et al. / Int. J. Pediatr. Otorhinolaryngol. 35 (1996) 223-230
228
We postulate that hearing loss in our patients is due to DFO toxicity firstly because none of our patients had any hearing impairment during the first period of our research (1988- 1990) and secondly during the second period there was no other cause of ototoxicity such as infections, damage of acoustic organs, head injury or use of any known ototoxic drugs except DFO. The mechanism of DFO induced ototoxicity .is not yet completely understood [8]. It may be due to chelation of other trace minerals (Zn, Cu, Mn) or to direct toxic effect of unchelated DFO, which may interfere with iron-dependent enzymes [5,8]. Reports of ototoxicity in patients with /3-thalassemia due to high doses of DFO and low serum ferritin levels suggest that the relationship between the dose of the chelating agent and the measurable size of the iron stores may be a more important determinant factor of toxic effects than dosage alone [5,6,8]. Young age of the patient, route of drug administration and constitution of the patients, are parameters that have also been implicated [5,8]. We suppose that the development of SNHL is the result of a combination of various different factors such as, the level of serum ferritin, the dose of DFO, the age of the patients and probably the local conditions in the inner ear which, with time, contribute to the development of DFO toxicity. It is well known that sometimes cochlear lesions are reversible if the causative agent is promptly removed. In our patients hearing improved in 12/24 (50%) deteriorated in 5 (20.83%) and remained stable in the remaining 7/24 (Figs. l-4). We suggest that our good results are probably due to prompt diagnosis and to therapeutic intervention through modification of the chelation scheme. There was no statistically significant difference between males and females, neither to the group of patients that developed SNHL nor to those who responded to intervention. Looking through the literature we could not find any difference between sexes. This study is still in progress. -:a
125
0
2%
5aa I
I
1000 I
/I
I
2000 I
,m,
I
1003 I
I
eaao i
r
Fig. 1. Audiogram of a young male, 13-years-old, DFO dose was 50 mg/kg x 5 days/week.
125
250
1-y
1”
/
with
bilateral
Fig. 2. Audiogram of the same patient 6 months after intervention. dose reduced to 30 mg/kg x 5 days/week. X, 1. ear; 0, r. ear.
5co I
I
I I
hearing
ZOO?
1aaa I
I
I
I
I
I I
loss exceeding
Almost
complete
I
:a00 I
BCOO
;a
I
I I
,,”
80 dB. Daily recovery.
DFO
G. Kontzoglou 12s
so0
et al. / Int. J. Pediatr. 1000
2000
4000
a000
Otorhinolaryngol. 125
250
3.5 (1996) 500
229
223-230
1000
2000
8000
4000
-1
39
,750
1500
3000
moo
750
(
!
I
3,
I
I
I
I
I
I
:;
;
1
)
'F-4 ! :*r ; ,*;I
/
/
/
1
/
1
a0
I 1
I 1
! I
i I
I I
I I
,i ,,*
1500
3000
1
6000
Fig. 3. Audiogram of a female patient, 7-years-old, with normal hearing checked in February 1989. Daily DFO dose: 50 mg/kg x 5 days/week. Fig. 4. Audiogram of the same patient 3 years after the first audiogram, (February 1992), with bilateral hearing aggravation. Daily DFO dose: 55 mg/kg x 5 days/week.
5. Conclusions
The long-term systematic otologic follow-up in patients with thalassemia major led us to the following conclusions: (1) no patients had any specific otolaryngological problems before and during the study; (2) no one presented any auditory toxic effect during the first period of the study (1988-1990); and (3) 24/88 patients (27%) presented sensorineural hearing loss during the second period (199 1- 1993). SNHL was observed in older patients, which is probably related to the longitudinal systematic chelation therapy which has been used mainly for the last years. No statistically significant difference was found regarding serum ferritin levels and DFO dose. It must be noted that all patients were receiving a rather high DFO dose, according to the literature data. The improvement of hearing loss, after reduction or withdrawal of DFO indicates that SNHL bears a direct etiopathogenic relation to the drug. Hearing impairment was reversed by prompt intervention in 50% of the patients in a period of 3-6 months. Persisting hearing loss for more than 6-9 months indicates a non reversible lesion. Bibliographic updating and regular follow-up of thalassemic patients may prevent the complications, not only of the disease itself, but also of its treatment.
References [l] Biesalski, Phoniatrie and Radioaudiologie, Ein tiberblick, G. Thieme Verlag, Stuttgart, 1973 (278-279). [2] Burian, K., Fanta, H. and Reisner, H. (1980) Neurootologie Diagnostic.and Klinic, Ein Kompendium, G. Thieme Verlag, Stuttgart New York 1980 (80-88).
230
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
[3] Cohen, A., Martin, M., Mizanin, J., Konkle, D. and Schwartz, E. (1990) Vision and hearing during desferrioxamine therapy. J. Pediat., 117 (211) Aug. 326-330. [4] Freedman, M., Bentur, Y. and Koren, Y. (1989) Biological and Toxic Properties of Desferrioxamine, Xth Congress of the International Society of Haematology - Jerusalem, Israel 9:5, 5799600. [5] Hybels, R.L. (1979) Drug toxicity for the inner ear. Clinics North Am., 63, 309-319. [6] Olivieri, N.F., Buncic, J.R., Chew, E. et al. (1986) Visual and auditory neurotoxicity in patients receiving subcutaneous desferrioxamine infusions. N. Engl. J. Med., 314, 8699873. [7] Orton, R.B., Veber L.L. and Sulk, H.M.B. (1985) Ocular and auditory toxicity of long-term, high dose subcutaneous desferrioxamine therapy. Can. J. Ophalmol, 20, 153-156. [8] Porter, J.B., Jaswon, M.S., Huehns, E.R., East, C.A. and Hazell, J.W. (1988) Desferrioxamine ototoxicity: evaluation of risk factors in thalassemic patients and guidelines for safe dosage. Br. J. Haematol., 73, 4033409. [9] Porter, J.B. and Huehns, E.R. (1989) The toxic effects of desferrioxamine. Clinics in Haematology. Balliere’e Clinical Heamatology 2 (2) 459-474. [IO] Stura, M., Arigliani, R., Molinari, A. and Tarantino, V. (1986) Evaluation of auditory function in homozygous P-thalassemia, Pediatr. Med. Clin. 8 (5) 7033705. [ll] Vacalos, A., Athanassiou, M., Koussi, A., Fragakis, J., Tsatra, J., Terzi, V. and Preponis, H. (1989) Thalassemia and Hearing Loss, 4th Italian-Greek-Yugoslav Congress of Otorhinolaryngology, Head and Neck Surgery, Porto Caras, June 4-7. [12] Virgillis, D., Asgiolo, S., Sanna, F. et al. (1979) Auditory involvement in thalassemia major. Acta Haematologica, 51, 209-215. [13] Wonke, B., Ho&and, A., Aldouri, M., Wickens, D., Flynn, D., Stearns, M. and Warner P. (1989) Reversal of desferrioxamine induced auditory neurotoxicity during treatment with CaDTPA. Arch. Dis. Child., 64, 77-82.
ELSEVIER
35 (1996)
223-230
Sensorineural hearing loss in children with thalassemia major in Northern Greece G. Kontzoglou”,*, A. Koussib, J. Tsatrab, G. Noussios”, V. Vital”, G. Sagarakis”, M. Athanassioub “E.N.T. blst Department
Department, Hippokration Hospital, Thessaloniki, Greece qf Paediatrics of Aristotelian University, Thessaloniki, Greece
Received 5 July 1995; revised 26 October 1995; accepted 4 November 1995
Abstract Eighty eight (88) P-thalassemic patients undergoing regular transfusion- chelation therapy with desferrioxamine (DFO) were studied for ENT problems from 1988 to 1993, as DFO has been implicated for auditory neurotoxicity. The mean age of the patients was 9.66 f 3.1 years, their pre-transfusion haemoglobin level was 9 f 2 g/dl, serum ferritin level was 2065 f 898 rig/ml and the daily DFO dose was 50.7 + 9.5 mg/kg for 5 days/week. The ENT study included, ENT examination, pure tone audiometry, speech audiometry, tympanometry, tone decay test and ABR. During this 6-year study 24/88 (27%) patients developed bilateral or ipsilateral sensorineural hearing loss in high tone frequencies, sometimes exceeding 80 dB, which was attributed to DFO toxicity. Therefore, a reduction or temporary withdrawal of DFO followed. After this intervention 12/24 patients recovered almost completely, 7/24 remained stable and 5/24 presented aggravation of their hearing loss. This study confirms the DFO induced auditory neurotoxicity and the necessity of periodical audiology control of P-thalassemic patients for prompt diagnosis and management of this complication. Keywords:
p-Thalassemia;
Children;
Desferrioxamine;
Neurotoxicity;
Hearing
loss
1. Introduction
Desferrioxamine (DFO) is, to date, the only chelation reducing iron overload in thalassemic patients.
agent with the ability
* Corresponding author, Panorrnou 2, 544 54, Thessaloniki, Macedonia, Greece. 0165-5876/96/$15.00 0 1996 Elsevier Science Ireland Ltd. All rights reserved SSDI
0165-5876(95)01308-3
of
224
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
DFO has been implicated as having auditory neurotoxicity, causing sensorineural hearing loss (SNHL) in these patients [3,6,7,9]. SNHL has been the subject of many investigations and studies during the past years [3,6-131. The conclusions of these studies showed that auditory neurotoxicity was related to: 1. the high level of serum ferritin; 2. the high dose of DFO associated with low serum ferritin [4,6]; 3. the young age of the patients as well as [6]; 4. the length of the treatment. The purpose of this study is to evaluate damages of the acoustic organ in our thalassemic patients and to proceed to immediate interventions when these are found.
2. Materials
and methods
Eighty-eight patients with thalassemia major, a consecutive sample of subjects in regular transfusion-chelated therapy attended to by the same investigators, were entered in a prospective longitudinal audiology study in 1988. Forty-six were males (52.3%) and forty-two were females (47.7%). Their age ranged from 6 to 25 years, with a mean age of 9.66 f 3.1 years. Their pre-transfusion haemoglobin (Hb) level was 9-l 1 g/dl, while serum ferritin was 2065 + 898 rig/ml. The daily dose of DFO was 50.7 f 9.5 mg/kg for 5 consecutive days/week. All 88 patients had an ENT examination and audiology tests such as, pure tone audiometry, speech audiometry, tympanometry, tone decay test and ABR. In pure tone audiometry the frequencies 125, 250, 500, 1000, 1500, 2000, 3000, 4000, 6000 and 8000 Hz were checked. Special emphasis and care was given on high tone frequencies (3000-8000 Hz). All patients were being followed every 3-6 months (6 months for those with normal audiological findings and 3 months for those with abnormal) for 6 years, (1988-1993). The lo-20 international system of electrode placement was used in evoked potential study. Brainstem auditory evoked potentials were performed in all 24 patients, using the Medelec MS 92a machine in a soundproof and electrically shielded room at an ambient temperature of 23°C. The latencies of waves I, III and V as well as interpeak latencies of I-III-III-V and I-V were all analyzed. Thus, both peripheral and central lesions could be tested. In order to have a baseline hearing measurement an audiometric check, which included pure tone audiometry, speech audiometry and tympanometry, was performed in 29 young outpatients. These patients were subsequently admitted in the Pediatric and ENT department and were found to have no otologic problems. The above audiometric check defined exactly the subjects’ range of hearing frequencies (especially between 3000-8000 Hz) and the hearing level was always found to be < 20 dB. The findings of these 29 patients were used as a baseline.
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
225
3. Results The results of the examinations of 88 patients have been evaluated in the course of two periods, the first one from 1988- 1990 and the second from 1991 to 1993 (continued). During the first period none of 88 patient presented with SNHL [l 11. During the second period, 24 out of 88 (27%) patients presented with SNHL in high tone frequencies (3000-8000 Hz). Fourteen from twenty-four (58%) of the last group were males and lo/24 (42%) were females. For the purpose of the present investigation, normal hearing was classified as between 0 and 20 dB, similar to our baseline, moderate hearing loss between 20 and 45 dB and severe loss greater than 45 dB [1,2,8] (Table 1). SNHL was moderate in 15124 (62.5%) patients, of whom 9 were male and 6 female, (7 ipsilateral - 8 bilateral) and severe in 9/24 (32.5%) patients, of whom 5 were male and 4 female (2 ipsilateral - 7 bilateral). SNHL was bilateral in 15 patients and ipsilateral in 9 patients and sometimes exceeded 80 dB. All audiology tests confirmed the cochlear lesion [3,7-10,12,13]. As in pure tone audiometry hearing loss was present only in high tone frequencies (sign of baseocochlear lesion), tympanometry test was within normal limits and speech audiometry was also normal as the lesion involved high tone frequencies only. Tone decay test was negative in all patients, sign of cochlear lesion. ABR did not show any appreciable abnormality, indicating that the lesion was possibly located in the cochlea, rather than in any other part of the auditory pathway. 3.1. Intervention Due to the absence of other toxic agents and the normal audiological findings during the first period of this study, the presented sensorineural hearing loss was attributed to DFO toxicity. As it has already been stated DFO dose was 50.7 + 9.5 mg/kg 5 days a week (a rather high dose for update data). Thus a modification in DFO dose followed: (a) temporary withdrawal of the drug for approximately 3 months and re-introduction of DFO therapy using lower doses (20-40 mg/kg 5 days a week) in patients with severe hearing loss, and (b) temporary reduction of DFO dose in patients with moderate hearing loss. Table 1 Hearing results before intervention Hearing loss
Normal hearing Moderate loss Severe loss
Patient nos. 88
64 15 9
Sex Male
Female
32 9 5
32 6 4
Classification of 24/88 patients, before any intervention, according to the level of hearing loss and sex. Normal hearing was classified as being between 0 and 20 dB, moderate hearing loss between 20 and 45 dB and severe loss greater than 45 dB.
226
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
Table 2 Hearing results after intervention Evolution of hearing
Recovered Aggravated Stable
Patient (nos. 24)
12 5 I
Sex Male
Female
7 3 3
5 2 4
Results after the intervention, classified in categories (recovered, aggravated, stable) according to sex.
3.2. Results after intervention After the above intervention in DFO dose, in 12/24 patients (50%) 7 male and 5 female, audiological findings became normal and hearing loss recovered almost completely after 3-6 months. 5/24 patients (20,83%), 3 male and 2 female, presented with aggravation of their audiological findings (increase of hearing loss) while the rest 7/24 (29,17%), 3 male and 4 female remained stable (Table 2). Eleven out of the 12 patients who recovered had moderate hearing loss (5 bilateral and 6 ipsilateral) and one had severe (ipsilateral). Aggravation was seen in 5 patients, of whom one had moderate (ipsilateral) and 4 severe (one ipsilateral and 3 bilateral) hearing loss before the intervention. Hearing loss remained stable in 7 patients, 3 with moderate (3 bilateral) and 4 with severe (4 bilateral), initial hearing loss. 4. Discussion During the past years many studies have been published on DFO toxicity on different organs, such as the retina and inner ear [3,6-131. On this basis all patients with thalassemia major of our unit, 6-25 years of age, having been on a program of transfusion-chelation for 4-15 years, were being entered in a preventive audiometric check since 1988. Results have been evaluated during two periods of therapy. During the first period, 1988- 1990, no patient presented abnormal audiological findings. However, during the second period 1991- 1993, 24/88 patients presented sensorineural hearing loss especially in high tone frequencies (Table 3). According to Hybel [5] this type of hearing loss is consistent with drug-induced toxicity. Although our study group included young patients (mean age 9.66 + 3.1), SNHL developed in the older group of patients (mean age 10.8 + 2.7 years) in contrast to the subjects with normal findings (mean age 9.1 f 3.2) statistically significant difference (P < 0.05). DFO dose was 52 f 7.2 mg/kg x 5 days/week in the group with abnormal findings while in the other group it was 50 f 10.4 mg/kg/ x 5 days/week no statistically significant difference (P > 0.05). Serum ferritin was found to be relatively lower in patients with SNHL (1888 + 896 rig/ml) than in patients with normal findings (2134 f 896 rig/ml), although there was no statistically significant difference (P > 0.05).
M M F F F M M M M M M M F M M F M M M F M M F F
hearing
134’12 lo4 I2 9 13 II 6.5 6.5 6.5 I3
1.5 12 I2 ,()7’12
1,p* 135’12 g*11*
8””
13.5 13 13
I3 69,1 2
15 97.1z
cheek, mterventlon
55 63 50 64 44 59 57 57 54 46 61 50 53 50 45 50 64 46 47 54 46 45 46 36
check
loss 40 35 35 90 80 40 70 50 40 55 70 50 75 30 85 40 80 30 35 40 25 45 35 45
(dB)
patlents.
40+X-8000 400+80 400&8000 300+8000 300%8OCil 6CKlC-8000 300&8000 600&8000 600&8OM) 125~8ooO 500&8ooO [email protected] 4OOC~8000 6cKK-8000 4WO-8OOCl 4OOt~8000 600%8000 400%8OCil 6Oix-8000 400+8000 So00 600@8000 So00 4000~8tXJO
in 24/88 thallasemic
Moderate Moderate Moderate Moderate Moderate Moderate
SWUtY
Moderate
SWSK
Moderate
SERX
SWXe
SWeK
%WR
Moderate
SWZK
Moderate Severe
SWX
Moderate Moderate Moderate SWeIe
Hearmg
Frequency
Pure tone audiogram
Audiometry
Greece
dose and results
5 days
m Northern
@g/ml
major
Dose DFO per week)
with thalassemia
(“g/ml)
dose, audiometry
2650 1850 1300 1600 1750 1500 1170 1600 3750 2100 1600 1150 I IO0 2600 700 1600 1800 1500 1250 4800 1700 2500 2350 1400
Ferritm
loss m chddren
level, UFO
Age (years)
Sex, age. ferritm
I 2 3 4 5 6 1 8 9 10 II 12 13 I4 15 16 I7 I8 19 20 21 22 23 24
Sex
Table 3 Sensorincural
T.D. Test Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Nomxd Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
ABR 1 i 1 1 1 1 1 1 1 1 L 1 1 1 $ 1 s 1 1 1 1 I 1 1
45 40 30 45 3 months1 50 45 33 45 36 3 months1 25 30 40 6 months1 30 3 months1 40 40 42 35 40 40 20
Intervention bw/W
30
30
20
25
dose DFO
of follow-up
Improvement Improvement Improvement Aggravation Same condition Improvement Same condition Improvement Aggravation Improvement Improvement Same conditton Improvement Same conditmn Aggravation Same conddion Improvement Same condition
Improvement Improvement Same condition Aggravation Aggravation
Results month)
(6-U
2 c.
F
b 5 2 OS
G. Kontzoglou et al. / Int. J. Pediatr. Otorhinolaryngol. 35 (1996) 223-230
228
We postulate that hearing loss in our patients is due to DFO toxicity firstly because none of our patients had any hearing impairment during the first period of our research (1988- 1990) and secondly during the second period there was no other cause of ototoxicity such as infections, damage of acoustic organs, head injury or use of any known ototoxic drugs except DFO. The mechanism of DFO induced ototoxicity .is not yet completely understood [8]. It may be due to chelation of other trace minerals (Zn, Cu, Mn) or to direct toxic effect of unchelated DFO, which may interfere with iron-dependent enzymes [5,8]. Reports of ototoxicity in patients with /3-thalassemia due to high doses of DFO and low serum ferritin levels suggest that the relationship between the dose of the chelating agent and the measurable size of the iron stores may be a more important determinant factor of toxic effects than dosage alone [5,6,8]. Young age of the patient, route of drug administration and constitution of the patients, are parameters that have also been implicated [5,8]. We suppose that the development of SNHL is the result of a combination of various different factors such as, the level of serum ferritin, the dose of DFO, the age of the patients and probably the local conditions in the inner ear which, with time, contribute to the development of DFO toxicity. It is well known that sometimes cochlear lesions are reversible if the causative agent is promptly removed. In our patients hearing improved in 12/24 (50%) deteriorated in 5 (20.83%) and remained stable in the remaining 7/24 (Figs. l-4). We suggest that our good results are probably due to prompt diagnosis and to therapeutic intervention through modification of the chelation scheme. There was no statistically significant difference between males and females, neither to the group of patients that developed SNHL nor to those who responded to intervention. Looking through the literature we could not find any difference between sexes. This study is still in progress. -:a
125
0
2%
5aa I
I
1000 I
/I
I
2000 I
,m,
I
1003 I
I
eaao i
r
Fig. 1. Audiogram of a young male, 13-years-old, DFO dose was 50 mg/kg x 5 days/week.
125
250
1-y
1”
/
with
bilateral
Fig. 2. Audiogram of the same patient 6 months after intervention. dose reduced to 30 mg/kg x 5 days/week. X, 1. ear; 0, r. ear.
5co I
I
I I
hearing
ZOO?
1aaa I
I
I
I
I
I I
loss exceeding
Almost
complete
I
:a00 I
BCOO
;a
I
I I
,,”
80 dB. Daily recovery.
DFO
G. Kontzoglou 12s
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et al. / Int. J. Pediatr. 1000
2000
4000
a000
Otorhinolaryngol. 125
250
3.5 (1996) 500
229
223-230
1000
2000
8000
4000
-1
39
,750
1500
3000
moo
750
(
!
I
3,
I
I
I
I
I
I
:;
;
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/
/
1
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1
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I 1
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i I
I I
I I
,i ,,*
1500
3000
1
6000
Fig. 3. Audiogram of a female patient, 7-years-old, with normal hearing checked in February 1989. Daily DFO dose: 50 mg/kg x 5 days/week. Fig. 4. Audiogram of the same patient 3 years after the first audiogram, (February 1992), with bilateral hearing aggravation. Daily DFO dose: 55 mg/kg x 5 days/week.
5. Conclusions
The long-term systematic otologic follow-up in patients with thalassemia major led us to the following conclusions: (1) no patients had any specific otolaryngological problems before and during the study; (2) no one presented any auditory toxic effect during the first period of the study (1988-1990); and (3) 24/88 patients (27%) presented sensorineural hearing loss during the second period (199 1- 1993). SNHL was observed in older patients, which is probably related to the longitudinal systematic chelation therapy which has been used mainly for the last years. No statistically significant difference was found regarding serum ferritin levels and DFO dose. It must be noted that all patients were receiving a rather high DFO dose, according to the literature data. The improvement of hearing loss, after reduction or withdrawal of DFO indicates that SNHL bears a direct etiopathogenic relation to the drug. Hearing impairment was reversed by prompt intervention in 50% of the patients in a period of 3-6 months. Persisting hearing loss for more than 6-9 months indicates a non reversible lesion. Bibliographic updating and regular follow-up of thalassemic patients may prevent the complications, not only of the disease itself, but also of its treatment.
References [l] Biesalski, Phoniatrie and Radioaudiologie, Ein tiberblick, G. Thieme Verlag, Stuttgart, 1973 (278-279). [2] Burian, K., Fanta, H. and Reisner, H. (1980) Neurootologie Diagnostic.and Klinic, Ein Kompendium, G. Thieme Verlag, Stuttgart New York 1980 (80-88).
230
G. Kontzoglou
et al. / Int. J. Pediatr.
Otorhinolaryngol.
35 (1996)
223-230
[3] Cohen, A., Martin, M., Mizanin, J., Konkle, D. and Schwartz, E. (1990) Vision and hearing during desferrioxamine therapy. J. Pediat., 117 (211) Aug. 326-330. [4] Freedman, M., Bentur, Y. and Koren, Y. (1989) Biological and Toxic Properties of Desferrioxamine, Xth Congress of the International Society of Haematology - Jerusalem, Israel 9:5, 5799600. [5] Hybels, R.L. (1979) Drug toxicity for the inner ear. Clinics North Am., 63, 309-319. [6] Olivieri, N.F., Buncic, J.R., Chew, E. et al. (1986) Visual and auditory neurotoxicity in patients receiving subcutaneous desferrioxamine infusions. N. Engl. J. Med., 314, 8699873. [7] Orton, R.B., Veber L.L. and Sulk, H.M.B. (1985) Ocular and auditory toxicity of long-term, high dose subcutaneous desferrioxamine therapy. Can. J. Ophalmol, 20, 153-156. [8] Porter, J.B., Jaswon, M.S., Huehns, E.R., East, C.A. and Hazell, J.W. (1988) Desferrioxamine ototoxicity: evaluation of risk factors in thalassemic patients and guidelines for safe dosage. Br. J. Haematol., 73, 4033409. [9] Porter, J.B. and Huehns, E.R. (1989) The toxic effects of desferrioxamine. Clinics in Haematology. Balliere’e Clinical Heamatology 2 (2) 459-474. [IO] Stura, M., Arigliani, R., Molinari, A. and Tarantino, V. (1986) Evaluation of auditory function in homozygous P-thalassemia, Pediatr. Med. Clin. 8 (5) 7033705. [ll] Vacalos, A., Athanassiou, M., Koussi, A., Fragakis, J., Tsatra, J., Terzi, V. and Preponis, H. (1989) Thalassemia and Hearing Loss, 4th Italian-Greek-Yugoslav Congress of Otorhinolaryngology, Head and Neck Surgery, Porto Caras, June 4-7. [12] Virgillis, D., Asgiolo, S., Sanna, F. et al. (1979) Auditory involvement in thalassemia major. Acta Haematologica, 51, 209-215. [13] Wonke, B., Ho&and, A., Aldouri, M., Wickens, D., Flynn, D., Stearns, M. and Warner P. (1989) Reversal of desferrioxamine induced auditory neurotoxicity during treatment with CaDTPA. Arch. Dis. Child., 64, 77-82.