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.

©AMERICAN JOURNAL OF OPHTHALMOLOGY 108:699-703, DECEMBER, 1989 699

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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10

~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).

702 AMERICAN JOURNAL OF OPHTHALMOLOGY December, 1989

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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