Ocular Abnormalities in Patients with β Thalassemia
Transcript of Ocular Abnormalities in Patients with β Thalassemia
Ocular Abnormalities in Patients With PThalassemia
Sotiris Gartaganis, M.D., Konstantinos Ismiridis, M.D., Ourania Papageorgiou, M.D.,Nicholas G. Beratis, M.D., and Dimitris Papanastasiou, M.D.
We examined 29 patients with homozygous Pthalassemia. The mean age of the patients was15.6 ± 8.9 years. Twelve patients (mean age,02.0 ± 10.4 years) had one or more ocularabnormalities. Five patients had degenerationof the retinal pigment epithelium, one hadlens opacities, two had lens opacities and degeneration of the retinal pigment epithelium,one had vascular abnormalities and degeneration of the retinal pigment epithelium, onehad angioid streaks, lens opacities, and degeneration of the retinal pigment epithelium, andtwo had angioid streaks and degeneration ofthe retinal pigment epithelium. These abnormalities were observed in patients with bothforms of Pthalassemia, major and intermedia.The frequency of the ocular abnormalities increased with age. The youngest patient with anocular abnormality was 6 1/2 years old. Therewas no correlation between the abnormalitiesobserved and the serum ferritin level, themean hematocrit value, and the dose of deferoxamine given to the patients.
PATIENTS with homozygous 13 thalassemiahave a variety of complications that may affectvirtually all organs. Ocular abnormalities suchas optic neuropathy.P retinal pigmentary degeneration presenting with night blindness.v'visual field defects.! decreased visual acuityand color vision abnormalities," cataracts," andacute visual 10ss2 have been reported.
Angioid streaks, an abnormality associatedwith several systemic diseases, such as Paget's
Accepted for publication Aug. 21, 1989.From the Departments of Ophthalmology (Drs. Garta
ganis and Ismiridis) and Pediatrics (Drs. Papageorgiou,Beratis, and Papanastasiou), University of Patras Medical School, Patras, Greece.
Reprint requests to Sotiris Gartaganis, M.D., Department of Ophthalmology, University of Patras MedicalSchool, Regional University Hospital of Patras, 261 10Patras, Greece.
disease of the bone," pseudoxanthorna elasticum," and sickle cell disease,"?' have also beenreported in three isolated case reports of patients with 13 thalassemia.P"
We observed ocular abnormalities in randompatients with homozygous 13 thalassemia. Ofparticular interest was that three of the 29patients had angioid streaks.
Subjects and Methods
Twenty-nine random patients with homozygous 13 thalassemia, followed up between 1981and 1988 in the Thalassemia Unit of our institution, participated in the study. Fifteen of thepatients were male and 14 were female. Themean age ± S.D. of the patients was 15.6 ± 8.9years, with a range of 6.5 to 37 years. Sixteen ofthe patients had 13 thalassemia major and 13had 13 thalassemia intermedia. The mean age ±S.D. of the patients with the major and theintermedia form of the disease was 14.2 ± 5.8and 17.1 ± 11.5 years, respectively.
All patients were transfused with 10 to 15mllkg of body weight of leukocyte-poor,packed, red blood cells at intervals of 15 to 30days depending on the patient's hematocritvalue. The patients' mean hematocrit value ±S.D. during the seven-year follow-up periodwas 33% ± 2%.
All patients, except three, were treated during the follow-up period with subcutaneousinfusions of deferoxamine. The mean deferoxamine dose ± S.D. was 52.7 ± 11.6 mg/kg ofbody weight/day, infused subcutaneously fourto five days per week. The serum ferritin levelwas measured every six months. The patients'mean ferritin level ± S.D. during the follow-upperiod was 3.304 ± 1.983 ng/mI.
All patients studied had an ocular examination, which included visual acuity testing, refraction testing, slit-lamp examination, indirectophthalmoscopy, biomicroscopy, and fluorescein angiography.
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700 AMERICAN JOURNAL OF OPHTHALMOLOGY December, 1989
Results
The ophthalmologic examination identified12 patients, five males and seven females, withocular abnormalities (Table). Five of the patients had degeneration of the retinal pigmentepithelium, one had lens opacities, two hadlens opacities and degeneration of the retinalpigment epithelium, one had vascular abnormalities and degeneration of the retinal pigment epithelium, two had angioid streaks anddegeneration of the retinal pigment epithelium, and one had angioid streaks, lens opacities, and degeneration of the retinal pigmentepithelium. Ocular abnormalities were ob-
served in five of the 13 patients with ~ thalassemia intermedia and in seven of the 16 patientswith ~ thalassemia major. The age distributionof the thalassemic patients studied, with andwithout ocular abnormalities, is shown in Figure 1. All patients 20 years of age or older hadocular abnormalities, whereas patients youngerthan 20 years of age demonstrated such abnormalities less frequently. In the age group of 6 to19 years, only five (22.7%) of the patientsshowed ocular abnormalities. The difference inthe frequency of the occurrence of ocular abnormalities between patients older and younger than 20 years is significant (X2 = 10.71, P ~.01).
Degeneration of the retinal pigment epitheli-
TABLECHARACTERISTICS OF AND OCULAR ABNORMALITIES IN 29 THALASSEMIC PATIENTS
OCULAR ABNORMALITIES
PATIENT NO.• THALASSEMIA DEGENERATION OF RETINAL LENS ANGIOID VASCULAR
SEX, AGE (VRS) TYPE' PIGMENT EPITHELIUM OPACITIES STREAKS ABNORMALITIES
1, M, 6Y2 I Present Absent Absent Absent
2, M, 7 I Absent Absent Absent Absent
3, F, 8 M Absent Absent Absent Absent
4, F, 83/4 M Absent Absent Absent Absent
5, F,9 I Absent Absent Absent Absent
6, M, 9Y4 I Absent Absent Absent Absent
7, M, 9% I Absent Absent Absent Absent
8, M, 10 M Absent Absent Absent Absent
9, F, 10 M Absent Absent Absent Absent
10, M, 10 I Absent Absent Absent Absent
11, M, 10% M Absent Absent Absent Absent
12, F, 11 I Absent Absent Absent Absent
13, M, 11 M Present Absent Absent Absent
14, M, 113/.1 M Absent Absent Absent Absent
15, F, 12 M Absent Present Absent Absent
16, M, 12 I Absent Absent Absent Absent
17, M, 12 M Present Absent Absent Absent
18, F, 13 M Absent Absent Absent Absent
19, M, 14% M Absent Absent Absent Absent
20, F, 15Y2 I Absent Absent Absent Absent
21, M, 17 M Absent Absent Absent Absent
22, F, 18 M Present Present Absent Absent
23, F,20 M Present Absent Present Absent
24, M, 22 M Present Absent Absent Absent
25, F,29 I Present Present Absent Absent
26, F,30 M Present Present Present Absent
27, M, 33 I Present Absent Absent Present
28, F, 34 I Present Absent Present Absent
29, F,37 I Present Absent Absent Absent
*1 indicates thalassemia intermedia; M, thalassemia major.
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~2 8Wi= 6ifu.. 4o02Z
o5-10 11 -15 16-20 21-25 as-oX> 31-35 36-40
PC£. GRaJPS(YEARS)Fig. 1 (Gartaganis and associates). Distribution of
the thalassemic patients by age. Hatched bars indicate 13 thalassemia major without ocular abnormalities; open bars, 13 thalassemia intermedia withoutocular abnormalities; cross-hatched bars, 13 thalassemia major with ophthalmologic abnormalities; dotted bars, 13 thalassemia intermedia with ocular abnormalities.
um was observed in 11 of the 29 13 thalassemicpatients studied (Table). On fluorescein angiography, these changes appeared by early hyperfluorescence, which occurred simultaneously with the choroidal fluorescence. Theselesions had the appearance of discrete smallrounded or oval areas located around the macula and especially the disk. All patients 20 yearsof age or older were affected, whereas only four(18.2%) of the patients younger than 20 years of
age had this abnormality. This difference issignificant (X2 = 11.82, P :s .01).
Punctate lens opacities located at the periphery of the cortex and not at the central portionof the lens were found in four female patients(Table). In three of the patients, only one eyewas affected, and in one patient both eyes wereaffected. The ages of the patients with lensopacities were 12, 18, 29, and 30 years. Therewas no correlation between the age of thepatients and the frequency of lens opacities.
As indicated in the Table, angioid streakswere detected in both eyes of three of the 29patients studied by both ophthalmoscopy andfluorescein angiography. The angioid streakshad a peripapillary distribution with an extension toward the macula. Their length was up tothree times the diameter of the disk. Therewere four to six angioid streaks in each eye ofthe patients. There were no macular changes ordrusen. All patients affected with this anomalywere female. Figure 2 illustrates the characteristic hyperfluorescence of the angioid streaksobserved in two of the patients. These lesionswere identified in two patients with 13 thalassemia major and in one patient with 13 thalassemia interrnedia. The two patients with the 13thalassemia major and angioid streaks were 20and 30 years old, whereas the patient with theintermedia form of the disease was 34 yearsold.
Fig. 2 (Gartaganis and associates). Left, Fluorescein angiogram during the arteriovenous phase in a20-year-old woman. Right, Fluorescein angiogram in a 30-year-old woman showing angioid streaks radiatingfrom the optic nerve (arrows).
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Vascular abnormalities were detected in botheyes of one patient. They consisted of tortuosity and an increase in the diameter of arteriolesand veins.
No correlation was shown between ocularabnormalities and the mean hematocrit values,the serum ferritin levels, and the dosage ofdeferoxamine given to the patients. However,it is noteworthy that two of the three patientswith angioid streaks had mean hematocrit values over 32%, and that one patient with angioidstreaks, two patients with degeneration of theretinal pigment epithelium, and one patientwith lens opacities had never received deferoxamine.
Discussion
Although patients with homozygous ~ thalassemia may develop a variety of ocular abnormalities, the literature lacks a systematic studyof the frequency of ophthalmologic abnormalities in such patients or the existence of associations between the ocular abnormalities andfactors relating to the treatment protocol andthe response of the patient.
We performed a complete ophthalmologicexamination in 29 random patients with homozygous ~ thalassemia and identified ocular abnormalities in 12 (41%) of them. The frequencyof ocular abnormalities increased with age;only the presence of lens opacities was notrelated to age. When patients of the same agewere compared, there was a similar rate ofocular abnormalities between the patients withthe major and the intermedia forms of ~ thalassemia (Fig. 1). Furthermore, there was not asignificant difference in the occurrence of ophthalmologic abnormalities between males andfemales, although lens opacities and angioidstreaks were detected only in females.
The most frequent abnormality identifiedwas degeneration of the retinal pigment epithelium, which was manifested by early hyperfluorescence on fluorescein angiography. Thisphenomenon probably resulted from a windowdefect caused by a thin and atrophic epitheliumpresent in the patients. This lesion was observed in both the intermedia and major formof ~ thalassemia. Of the factors examined (age,mean hematocrit value, serum ferritin levels,deferoxamine treatment) only advanced age(that is, age above 18 years) correlated positively with this abnormality. Patients treated withdeferoxamine as well as those patients who
were untreated demonstrated degeneration ofthe retinal pigment epithelium, which indicatesthat development of this lesion may be independent of the iron chelation therapy. Daviesand associates" and Lakhanpal, Schocket, andJijiS found degeneration of the retinal pigmentepithelium in patients with ~ thalassemia andattributed it to the administration of high dosesof deferoxamine.
Because lens opacities have been reported in~ thalassemic patients receiving high deferoxamine dosages, it was thought that the lensopacities resulted from deferoxamine intoxication." However, of the four patients with lensopacities identified in this study, one was nottreated with this chelating agent, and the otherthree had received dosages of deferoxaminelower than 55 mg/kg of body weight/day four tofive days per week. This finding indicates thatthe formation of lens opacities in thalassemicpatients cannot be attributed solely to deferoxamine intoxication.
Because the lens opacities were located at theperiphery of the lens, leaving the center intact,no reduction in visual acuity was present at thetime of examination. However, it is difficult todetermine the importance of this finding for thefuture, because with modern treatment regimens the life expectancy of ~ thalassemic patients is significantly increased. Follow-upstudies are necessary to evaluate possible progress of the lens opacities.
It is not clear whether or not the vascularabnormalities identified in the eyes of one ofthe thalassemic patients were related to thedisease.
Angioid streaks have been described in threeisolated patients with homozygous ~ thalassemia. 12•14 In this study, three of the 29 (10.3%)patients studied had angioid streaks. One ofthe patients was never treated with deferoxamine and the other two had received dosagesof deferoxamine lower than 43 mg/kg of bodyweight/day four to five days per week, whichshows that the formation of angioid streaks isindependent of the deferoxamine therapy. Because all patients with this anomaly were between 20 and 35 years of age, it appears thatolder patients are at risk for the development ofangioid streaks.
In addition to pseudoxanthoma elasticumand Paget disease, formation of angioid streakshas been described in hemoglobinopathies,such as sickle cell disease.v" sickle cell trait, 15
sickle cell thalassemia," sickle cell hemoglobinC disease." and hemoglobin H disease." Thepathogenic mechanism of this anomaly, how-
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ever, is poorly understood. Calcium depositionin Bruch's membrane has been implicated inthe formation of angioid streaks in pseudoxanthoma elasticum.P'" Paton" suggested thatchronic hemolysis results in iron deposition inBruch's membrane, whereas Hagedoorn" noted an increased iron staining in Bruch's membrane in patients with angioid streaks. Angioidstreaks in sickle cell disease are probably attributable to damage of the Bruch's membranecaused by intravascular thrornbosis.Pv The resulting nutritional disturbances make theBruch's membrane susceptible to the formationof cracks from the stress forces on the eyeballcaused by the pulling of the extraocular muscles."
That all 13 thalassemic patients who developed angioid streaks and lens opacities werefemale cannot be speculated on further at present because the number of the patients studiedis not sufficient for a reliable statistical analysis.
We failed to demonstrate a correlation between angioid streaks and the volume of bloodtransfused, the mean hematocrit value, thedeferoxamine dose, and the ferritin levels.However, it should be noted that the patientsstudied received appropriate treatment onlybetween 1981 and 1988. Previously, the patients were inadequately treated, and thereforeit is not known whether or not 13 thalassemicpatients who maintain hemoglobin levels within the normal range and a balanced iron equilibrium, with the application of frequent redblood cell transfusions and proper iron chelation therapy, will remain free of angioid streaksand the other ocular abnormalities described.
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