LONG-TERM RESULTS OF LASER TREATMENT FOR RETINAL ...art45-paediatric-studies-docs.ema.europa.eu/GROUP F/Fluroescein/L… · Conclusion: Laser treatment was successful. Early ophthalmological

February 28, 2000 EUROPEAN JOURNAL OF MEDICAL RESEARCH 47

Eur J Med Res (2000) 5: 47-58 © J. Holzapfel Publishers 2000

LONG-TERM RESULTS OF LASER TREATMENT FOR RETINAL ANGIOMATOSIS IN

VON HIPPEL-LINDAU DISEASE

D. Schmidtl, E. Nattz, H. P. H. Neumann 2

1 Department of Ophthalmology, 2Department of Internal Medicine, University of Freiburg, Germany

Abstract: Purpose: In von Hippel-Lindau disease (VHL), reti­nal detachment is often a real threat if the retinal angiomas are left untreated. The aim of this trial was to diagnose and treat capillary angiomas early at an asymptomatic stage. Methods: Since 1983, we have investigated pa­tients with key lesions and those who are at risk for VHL in a multidisciplinary study. Classical reti­nal angiomas and microangiomas were treated with the Argon laser. Checks during a follow-up of 15 years have provided us with long-term re­sults. Results: We detected 189 retinal angiomas i9 97 eyes of 69 patients (lOS classical angiomas, in­cluding 19 fibrotic angiomas in 15 eyes, 84 micro­angiomas). During the study, 20 patients (twenty­one symptomatic eyes) entered the study already with a visual impairment.

Sixty asymptomatic eyes from 49 patients with a total of 108 retinal angiomas (55 microangiomas and 53 classical angiomas) were treated by us with photocoagulation. Nineteen asymptomatic eyes with angiomas of fibrotic type were observed only.

During a mean follow-up of 5.1 years (range: 0.25 - 15; SO: 3.88) observed after treatment, no deterioration of vision occurred in 37 patients treated with photocoagulation.

Regular controls showed 5 relapsing angiomas and 9 new angiomas which were successfully co­agulated again. New angiomas occurred in those eyes with several angiomas as a predisposition. Patients with a tendency to multiple angiomas need to be seen more frequently because these eyes have a high risk of becoming blind, even in already coagulated angiomas. Conclusion: Laser treatment was successful. Early ophthalmological examination of patients with re­tinal angiomatosis is a great challenge, since these lesions can only be successfully treated at an early stage. Treatment is then effective and safe, but long-term follow-up is necessary. New angiomas occurred in those eyes with several angiomas as a predisposition.

Key words: hemangioblastomas; von Hippel-Lin­dau disease; pheochromocytoma; CNS involve­ment; retinal angiomas; Argon laser treatment; ret­inal detachment

INTRODUCTION

Capillary retinal angiomatosis, also called von Hipper s disease [1, 2] has two main characteristic features. The first is the risk of visual impairment, and the second is that it occurs as a part of the von Hippel-Lindau syndrome (VHL) [3], an autoso­mal dominant disorder with a high penetrance but variable expression, and a predisposition to devel­op other tumors, particularly hemangioblastomas of the central nervous system, renal cell carcino­ma, pheochromocytoma, pancreatic cysts, and epididymal cystadenomas [4].

The incidence of retinal angiomas among pa­tients with VHL disease in large series had been recorded as 38% [5] and 45.6% [6]. Many reports have emphaSized that the treatment of retinal an­giomatosis is a major challenge [4, 7 -11], and systemic investigations, treatment and follow-up in large series of patients are pending.

In this study we report the long-term results in a large series of retinal angiomas, including symp­tomatic patients admitted because of visual im­pairment, but a large proportion of the angiomas were also detected and treated at an asymptom­atic stage.

METHODS

RECRUITMENT OF SUBJECTS

The Freiburg VHL study was established in 1983. Since then, 69 patients have been taken into the study as follows: 20 patients were originally in­vestigated by an ophthalmologist because of im­pairment of vision. Fourty-nine patients had asymptomatic angiomas which were either found incidentally, following reference to an ophthal­mologist because of a key lesion of VHL, or as a result of screening patients registered as having VHL. In 11 patients with symptomatic eye le­sions angiomas were detected in the other eye (Table 1).

Patients with retinal angiomas underwent ex­tensive examination for all the lesions of VHL in accordance with the screening program. If a pa­tient with a retinal angioma revealed extraocular lesions pertaining to VHL, or had a positive family history of the disease, the first degree relatives were also investigated.

48 EUROPEAN JOURNAL OF MEDICAL RESEARCH February 28, 2000

Table 1. Patients with symptomatic and asymptomatic eyes, found by screening.

Patients found by screening

Angioma of the other eye found in patients with a symptomatic angioma of one eye

No. of patients

58 49 asymptomatic and

9 symptomatic patients

11

For ethical reasons it was not possible to estab­lish a control group of patients with angiomas, since withholding treatment would have been too dangerous.

DIAGNOSIS OF VON HIPPEL-LINDAU DISEASE AND THE SCREENING PROGRAM

VHL was diagnosed if a patient with a retinal an­gioma had a first degree relative with at least one of the six major features of the syndrome, i.e. reti­nal angioma, hemangioblastoma of the CNS, renal cysts and/or carcinoma, pancreatic cysts, a pheo­chromocytoma or an epididymal cystadenoma [9]. The screening program for extraocular VHL le­sions included cranial and spinal MRI, CT or MRI of the abdomen, sonography of the testes, cate­cholamine assay of the 24 hour urine and pedi­gree evaluation.

The diagnosis of VHL was confirmed by a germline mutation in the VHL gene in 63 of the 69 patients (Table 2).

Table 2. Germline Mutation in the YHL gene in the 69 patients included in this study.

Mutation

407 C to A 434 T to G 475 T to A 479 T to C 505 T to C 529 ins GCG 553+1G to A 557 A to G 607 C to T 676 +1 G to C 676 +2 A to G 677-2 A to G 694 C to T 699 C to G 712 C to T 746 T to A 761 C to A 792 del AG 2-kb Deletion 10 kb Deletion not found

n

1

3 35

1 2

1 3

1 2 1 2 1

3 1 6

Mutation numbers refer to the YHL nucleotide C/A/T/G: cytosin, adenin, thymin, guanin; kb: kilobases

TECHNIQUES OF EYE EXAMINATION

Each patient was subjected to a complete ophthal­mological examination, including visual acuity, biomicroscopy of the anterior segment, direct and indirect ophthalmoscopy, and examination of the retina with a Goldmann three-mirror glass .

CLASSIFICATION OF ANGIOMAS

The classification by Lane et al. [12] is:

Grade 1: simple angioma without vessel dilata­tion: 25 of our patients (36.2%)

Grade 2: 1 +feeder vessel dilatation ± intra-retinal exudates including patients with juxtapapillary an­giomas: 35 of our patients (50.7%)

Grade 3: 2+serous retinal detachment: 9 of our patients 03.1 %)

Grade 4: 2/3+proliferative vitreoretinopathy, caus­ing rhegmatogenous or traction retinal detach­ment: -

We distinguished three types of angiomas:

Classical angioma (Fig. 1) is a prominent, well­defined pink-to-red tumor with at least one pair of tortuous dilated feeder vessels. This corresponds to Grade 2 [12]

Microangioma (Fig. 2) is a tiny red lesion with very small feeder vessels. Its size is less than or equal to the diameter of the large retinal vessels. This corresponds to Grade 1 [12].

Fibrotic angioma (Fig. 3) is white or gray and does not show dilatation of the feeder vessels. This corresponds to Grade 1 [12].

Fluorescein angiography showed a characteris­tic hyperfluorescence after intravenous injection of the dye. Fluorescein angiography was per­formed, using the standard procedures and a fun­dus camera (Zeiss, Oberkochem, Germany), which was replaced in 1988 by a GRC-WTZ fun­dus camera (Olympus, Japan). Fluorescein angio­graphy [12] was used in patients with suspected microangiomas in order to confirm the ophthal­moscopic diagnosis. Fluorescein angiography was performed in cases of classical angioma in order to observe the blood transit through the angioma and the blood supply around the tumor. All pa­tients investigated had VHL. No patients with spo­radic retinal angiomas were included in this study.

TREATMENT MODALITIES

For treatment, the Argon blue coagulator LPK 80 II, (Rodenstock, Cologne, Germany) - replaced in 1988 by the Argon green coagulator, Visulas Argon (Zeiss, Oberkochem, Germany) - was used. Photo-

February 2H. 2000

Status before

o sees

EUROPEAN JOURNAL OF MEDI - L RESEARCH . l)

30 sees

Final status

60 sees

Fig. Z. Classical angio­ma with several feed­er and draining ves­st.' ls in the left eye of a 23-year-okl woman (before and after laser treatment).

Fig. 2 . Microangioma Unmasking of a

nodule on a peripher- . al vessel as an micro­angioma hy fluoresce­in angiography (30 and 60 sec after fluo­rescein injection) in the right eyt.' of a 37-yeJr-old man.

Fig. 3. Fibrotic angioma with no enlargement of the ves­sel (left eye of a 21-year-old woman).

50 EUROPEAN JOURNAL OF MEDICAL RESEARCH February 28, 2000

coagulation lasted for 0.1 or 0.2 secs, at an average power of 0.2 to 0.8 watts and with a spot size of 300 or 600 microns. In angiomas the size of the pa­pilla or larger, a spot size of 500 or 600 microns was used with a power of 0.6 to 0.8 watts for 0.2 secs . In angiomas with superficial white mem­branes which covered the tumor, the power was increased up to 1.5 watts. In angiomas smaller than the papilla, the power of 0.4 for 0.12 secs was usu­ally sufficient to destroy the tumor. In microangio­mas, considerably reduced power (power: 0.2-0.4 watts) was sufficient to destroy the angioma.

For some angiomas several sessions were nec­essary. In most patients with a classical type of angioma three sessions were carried out. For mi­croangiomas one session was sufficient to destroy the small tumor. All subjects were treated as out­patients.

In one patient who showed 4 angiomas in the periphery of one eye, up to 7 sessions were nec­essary in order to destroy the two angiomas with the same size as the papilla. In the other two smaller angiomas, 2 to 4 sessions were sufficient for the treatment. In 7 patients xenon light coagu­lation (Zeiss, Oberkochem, Germany) was used to treat 9 peripheral angiomas of about the same size as the papilla - before the study began. In one pa­tient, one angioma was treated by cryocoagulation before the study began. During this study; only laser coagulations were used for treatment. All laser coagulations were carried out by one oph­thalmologist (DS).

RESULTS

NUMBER AND SITE OF ANGIOMAS IN 69 PATIENTS

We detected 189 angiomas in 98 eyes of 69 pa­tients C39 females and 30 males).

One angioma was found in 24 patients (34.80/0), 2 angiomas were detected in 19 (27.60/0), 3 angiomas in 13 08.80/0), and 4 and more angio­mas in 13 patients 08.80/0) (Table 3). Asymp­tomatic eyes with one lesion (290/0) occurred in more patients than symptomatic eyes with one lesion (5 .80/0). However, 2 and more angiomas occurred in 29 patients with asymptomatic le­sions (420/0) and in 16 (23.20/0) patients with symptomatic lesions.

Table 3. Number of angiomas in 69 patients.

No. of angiomas No. of in one or both eyes patients

1 angioma 24 (34.8%) asymptomatic: 20 (29%) symptomatic: 4 (5.8%)

2 angiomas 19 (27.6%) asymptomatic: 12 (17.4%) symptomatic: 7 (10.1%)

3 angiomas 13 (18.8%) asymptomatic: 10 (14.5%) symptomatic: 3 (4.3%)

~ 4 angiomas 13 (18.8%) asymptomatic: 7 (10.1%) symptomatic: 6 (8.7%)

total 69 patients asym ptoma tic : 49 (71%) symptomatic:: 20 (29%)

The frequency of angiomas per eye showed that 3 and more angiomas were found more often in symptomatic than in asymptomatic patients.

One hundred and five classical angiomas (in­cluding 19 fibrotic angiomas) and 84 microangio­mas were counted. The mean age of the 30 men was 30.87 (range: 12-62; SD: 11.99) years, the mean age of 39 women was 31.3 years (range 11-75; SD: 15.04). In 49 asymptomatic patients the mean age was 32.3 years (range: 11-75; SD: 13.90) and in 20 symptomatic patients the mean age was 28.1 years (range: 11 - 54; SD: 13.44). Statistical investigation (unpaired t-test) showed that there was no distinct difference between the age of 49 asymptomatic and the age of 20 symptomatic pa­tients (p: 0.257). Twenty-nine (42 0/0) patients had bilateral 00 symptomatic and 19 asymptomatic) and 40 patients (58 0/0) had unilateral angiomas 00 patients were symptomatic and 30 patients were asymptomatic).

The site of classical angiomas and microangio­mas (n: 152) were registered in eyes which did not show retinal detachment and/or were not blind when they entered the study. Most tumors were located in the upper periphery of the retina 09 angiomas; 520/0), 7 of these angiomas were symptomatic and 72 asymptomatic. Twenty-eight angiomas (18.40/0) were located in the inferior pe-

Table 4. Retinal site of 152 angiomas in 69 patients upper retinal

upper periphery horizontal periphery inferior periphery juxtapapillary macular- area

79 (52%) 30 (19.7%) 28 (18.4%) 10 classical 4 (2.6%) angiomas (6.6%); 1 fibrotic

7 symptomatic 4 symptomatic angioma (0.66%) 1 symptomatic and and angioma; 72 asymptomatic 24 asymptomatic 10 symptomatic 3 asymptomatic angiomas angiomas angiomas; angiomas

1 asymptomatic angioma

February 28, 2000 EUROPEAN JOURNAL OF MEDICAL RESEARCH 51

riphery, 4 of these angiomas were symptomatic and 24 asymptomatic. Thirty angiomas 09.7%) (all asymptomatic) were found in the horizontal pe­riphery and 4 angiomas (2.6%) close to the macu­la, 1 of them was symptomatic and 3 asymptomat­ic. 10 angiomas were detected on or close to the optic disc (6.6%) which were all symptomatic and in one eye a fibrotic juxtapapillary angioma was present (Table 4).

SYMPTOMATIC EYES

Twenty patients 02 females and 8 males), were admitted to our hospital because of visual impair­ment. None experienced pain, either beforehand, at the time of the visual loss, or on presentation. However, when this study was started in 1983, three eyes had already been enucleated because of secondary glaucoma (one additional blind painful eye was enucleated later during the study) . Ten out of the 20 patients had bilateral ret-

Table 5 . Comparison of the initial retinal findings to those at the end of the study.

Status at entry of the study Status at the end of the study (after 15 years)

No of patients

asymptomatic patients

symptomatic patients

No of eyes

unilateral angiomas (in patients) right eye left eye

bilateral angiomas (in patients)

No. of angiomas

unilat: 47A+25MA binok.: 58A+59MA total: 105 A+ 84 MA = 189:

Treated angiomas

No. of treated angiomas by laser

No. of not laser-treated angiomas

Amaurosis (eyes)

Mean follow-up (15 years)

Distinct decrease in visual acuity (~ 0.2) :

A: angioma; MA: microangioma

15

5

10

23

7 4 3

8 patients -~

49 Angiomas: 32 (fibrotic angioma: 1) Microangioma: 17 (Retinal detachment: 13 angiomas; 7 microangiomas)

Amaurosis: 6 (enucleation: 3)

mean: 11.05 years (2-15 years) (follow-up of all 15 patients)

5

69

49 (26 females, 23 males)

20 (12 females; 8 males)

unilateral angiomas: 40 eyes bilateral angiomas: 58 eyes total: 98 eyes with angiomas

40 patients (58 % of 69 patients) 23 17

29 patients (42.0% of 69 patients)

105 classical angiomas + 84 microangiomas: 189 Classical angiomas : 105 (fibrotic angiomas: 19 angiomas in 13 patients); Microangiomas: 84 (Angiomas in retinal detachment: 22 A Microangiomas in retinal detachment: = 12 MA)

laser: 108 ruthenium plaque brachytherapy (elsewhere): 2

108 (53 classical angiomas; 55 microangiomas) in 60 eyes of 49 patients (39 asymptomatic; 10 symptomatic) (Treatment of 5 angiomas in an eye with retinal detachment was not successful)

13 untreated (no follow-up) + 37 angiomas in eyes with retinal detachment + 10 juxtapapillary angiomas + 19 fibrotic angiomas

total: 79

Amaurosis : 7 (enucleation: 4)

mean: 6.4 years (0 .25 - 15) 61 (follow-up of 61 patients; 8 patients no follow-up)

15

52 EUROPEAN JOURNAL OF MEDICAL RESEARCH February 28, 2000

ina I angiomas. 21 out of 30 eyes of 20 symptomat­ic patients (one patient had bilateral retinal de­tachment) were symptomatic and 9 eyes were asymptomatic. Ten eyes of symptomatic patients had no tumors in the fellow-eye. In 9 patients with a symptomatic eye, the other eye revealed asymptomatic angiomas, only one patient had bi­lateral retinal detachment due to retinal angiomat­osis. The mean follow-up of the 20 patients was 6.6 years (SD: 5.77).

A retinal detachment had been present for sev­eral months in the nearly blind eye of a 17 -year­old woman who had 5 peripheral angiomas which were first treated by laser, and a short time later also by kryocoagulation, both without success. A vitrectomy and a detachment operation were re­fused by the patient.

Treatment in 15 out of 20 patients who entered the study with a blind or nearly blind eye had been per­formed elsewhere (the angiomas in most of these eyes were bigger than the papilla and the feeder vessels were distinctly enlarged), either by retinal detachment surgery (6 patients) or xenon coagulation (2 patients) or enucleation (4 patients) or Ruthenium plaque bra­chytherapy (2 patients) or proton therapy (1 patient). 3 additional patients were not treated On 3 patients a juxta papillary angioma was only observed) and in two additional patients retinal detachment was the cause for low vision or blindness.

Concerning all patients during follow-~p, 4 eyes had been removed and 3 additional eyes were amaurotic (Table 5).

Six patients had a blind eye when the study began. One additional patient, a 17-year-old woman who also showed a blind eye due to reti­nal detachment entered the study 13 years after the beginning of the study. The mean age of all 7 patients (3 males and 4 females) was 19.71 years (range: 11-36; SD: 9.99). The difference of the mean age of 19.7 years is statistical significant (i.e. much younger compared to that of the remainder group of 62 patients with a mean age of 32.38 years) (p: 0.0203) (unpaired t-test).

One of the male patients who had a blind right eye at the age of 32 years developed a retinal de­tachment due to retinal angiomatosis of his left eye at the age of 61 years. This was the only pa­tient who had symptomatic eye lesions in both eyes.

Visual acuity of 15 symptomatic patients: of the 21 symptomatic eyes, 8 had distinctly reduced vi­sion between finger counting and 20/400, 7 had less diminished vision between 20/200 and 20/50.

ASYMPTOMATIC EYES

Asymptomatic eyes with retinal angiomas were observed in a total of 49 patients, and in addition 9 symptomatic patients with contralateral asymp­tomatic angiomas. Asymptomatic eyes were found in 26 females and 23 males, mean age: 32.3 years, range: 11 - 75, SD: 13.90. None of the asympto­matic eyes had ever had visual symptoms.

Affected eyes, types and number of angiomas: the total of affected eyes was 68. Bilateral angio-

mas occurred not only in symptomatic patients 00 out of 20 symptomatic patients) but also in 20 out of 49 asymptomatic eyes of patients with VHL. The total number of angiomas in asymptomatic eyes was 106 (48 microangiomas and 58 classical angiomas). The mean follow-up of 41 asympto­matic patients was 6.1 years, SD: 4.57. Visual acuity: in 62 eyes vision was normal (20/20), whereas 6 eyes had visual impairment unrelated to the angiomas: anisometropic amblyo­pia, retinal-choroidal scars in three eyes due to ar­terial hypertension from a pheochromocytoma, cataract C75-year-old patient), macular hole.

In 13 patients who showed fibrotic angiomas the mean age was 38.1 years (21-59). There was a significant age difference of patients with fibrotic angiomas compared to the remainder patient group (n: 56) (p: 0.042)(unpaired t-test). The mean folow-u p of patients with fibrotic angiomas was 4.9 years (0.75 - 13); SD: 4.76.

EXTRAOCULAR LESIONS

The extraocular lesions in our patients are listed in Table 6.

Table 6. Lesions of Other Organs in 69 VHL patients with RA.

Diagnosis total (patients)

eNS hemangioblastoma cerebellar hemangioblastoma 23 (33.3%) spinal hemangioblastoma 5 (7.8 %) Pheochromocytoma 21 (30.4%) Renal lesions Renal cysts 9 (14.1 %) Renal cancer 10 (14.5%) Pancreatic cysts 12 (17.4 %) Epidydimal cystadenoma 5 (7.2%) Islet cell tumor 2 (2.9%) Endolymhatic sac tumor 1(1.6%) Liver hemangioma 2(3.1%)

TREATMENT

The pre-treatment situation: 49 asymptomatic pa­tients had peripheral angiomas (mid periphery or outer periphery of the retina) which were the size of the optic disc or smaller without secondary reti­nal changes (i.e. circumscribed retinal detachment or signs of preretinal traction).

Size of the 53 classical angiomas treated by laser:

The size of 32 angiomas treated by laser was about 1/2 diameter of the papilla, 19 angiomas had the same diameter as the papilla, 1 angioma with 1 1/2 the diameter of the papilla, and 1 an­gioma with twice the diameter of the papilla.

In 3 patients microangiomas were found close to the macula area of asymptomatic eyes.

February 28, 2000 EUROPEAN JOURNAL OF MEDICAL RESEARCH 53

Asymptomatic eyes: We treated 60 eyes of 49 patients with a total of 108 angiomas including 53 classical angiomas and 55 microangiomas by photocoagulation. Mean fol­low-up of 68 eyes of 49 patients was 5.1 years (0.25-15) SD: 4.71. The time of observation before laser treatment was in 22 patients 4.7 years (0.75 -14.5) SD: 4.37 and after treatment in 27 patients 5.1 years (0.25-15); SD: 4.18.

Treatment of most of classical angiomas with the size of the diameter of the papilla required 3 sessions, treatment of all the microangiomas only one session. Minor side effects occurred in three patient, who developed a small hemorrhage in the vitreous following the direct photocoagulation of an angioma, but the blood was reabsorbed after about 4 weeks without visual deterioration. We did not observe major side effects such as total retinal detachment, massive hemorrhage or perifo­cal edema in these eyes. 59 eyes were treated suc­cessfully and all 103 angiomas were completely coagulated.

We did not treat 37 angiomas (25 classical an­giomas, 12 microangiomas) in 10 eyes of 9 pa­tients with retinal detachment. In one of the 10 eyes with retinal detachment 5 angiomas were treated by laser, but without success because the detachment was a very prominent. We alsQ did not treat i) 10 juxtapapillary angiomas in 8 eyes of 8 patients, ii) 19 fibrotic angiomas in 15 eyes of 13 patients and iii) 15 angiomas (4 classical and 11 microangiomas) of 8 patients who did not return to the hospital for laser treatment or died (2 patients) or if microangiomas showed a spon­taneous regression (2 patients) or patients who were treated by ruthenium plaque brachythera­py elsewhere (2 patients). Some patients with a fibrotic angioma had classical angiomas or micro­angiomas, in addition, which were treated by laser. Some patients with microangiomas with a spontaneous regression and patients who were treated by ruthenium plaque brachytherapy elsewhere, also showed additional angiomas of the retina of the same eye or the fellow eye which were treated, too.

Reasons for visual deterioration: An example of spontaneous irreversible deteriora­tion due to an angioma close to the macula: an 18-year-old man with spontaneous visual deteri­oration from 20/20 to 20/200 due to a macular cystoid edema caused by an angioma the size of the papilla which was inferior to the macula, and close to the inferior temporal retinal artery, was referred to the clinic. At first the patient refused laser coagulation. When he finally agreed to treat­ment after some years, a careful coagulation was carried out in three sessions. The tumor was de­stroyed completely, but there was no further im­provement in the visual acuity.

In 4 eyes transient visual deterioration followed laser coagulation. In a 21-year-old patient with two angiomas close to the macula (1 to 2 disc di­ameters temporal to the macula) a macular edema

occurred several hours after treatment, together with a distinct decrease in visual acuity from 20/20 to 20/30. However, within one to two weeks the edema disappeared completely, and spontaneously, and the visual acuity became nor­mal again. In 3 patients with angiomas of the size of the papilla, hemorrhages on the surface of the tumour, or an additional localized vitreous hemor­rhage above the angioma, were present. In such a situation, treatment was stopped, and it was only continued after the absorption of the blood, sever­al weeks later. In no case of laser treatment of a peripheral angioma did retinal detachment occur. However, after the treatment of angiomas located in the central retina, the risk of a macular edema is great. In one patient who had an angioma tem­poral to the macula, lipid exudates were present in the macula before the laser treatment was start­ed. After this treatment, the exudates slowly dis­appeared.

In a 29-year-old man who had an angioma the size of the papilla located about 2 disc diameters below the papilla, the first treatment was carried out in July 1993 and repeated in the following September. Because of an increase in the size of the angioma, a third photocoagulation was nec­essary. This was carried out in May 1994. The pa­tient returned in March 1997 with a circum­scribed flat retinal detachment around the slight­ly enlarged angioma. An intense photocoagula­tion of the angioma and of the whole area of the detached retina and the area around it was car­ried out. Laserpexy of the detached retina caused a stable condition adjacent to the angioma. The laser treatment was repeated in October 1997. The power had to be increased to 1,0 watts be­cause a white membrane on the surface of the tumor, prevented direct treatment of the angio­ma. The examination in December 1998 revealed a stabilization of the retinal findings with no tumor increase or deterioration of the detach­ment.

FOLLOW-UP

SYMPTOMATIC EYES

Seventeen of the 20 symptomatic patients had a regular follow-up investigation over a period of 6 months to 15 years, mean 6.5 years (SD: 5.86).

Three patients were not treated (in 2 patients an angioma of the optic disc was only observed for a short follow-up) and in two additional pa­tients retinal detachment was the cause for low vi­sion or blindness. Retinal detachment surgery was carried out in two eyes. These patients had a stable condition after operation, but with poor vi­sion. One patient with a juxtapapillary angioma developed a visual loss from 20/50 to 1/35 due to hemorrhages and edema of the macular region with secondary pucker. Vitrectomy and partial co­agulation of the angioma showed a scar formation of the central retina and papilla after surgery, but did not improve visual function.

54 EUROPEAN JOURNAL OF MEDICAL RESEARCH February 28, 2000

ASYMPTOMATIC EYES

Treated asymptomatic 49 eyes: Forty-nine patients had a mean follow-up of 5.1 years (0 - 15); SD: 4.71. In none of these eyes did any deterioration in vision occur. Eight asymptomatic patients had no follow-up.

In addition, 9 asymptomatic eyes of symptomat­ic patients were successfully treated by laser.

FREQUENCY OF RELAPSES

A relapse following the treatment of an angioma was seen in 5 patients after an interval after treat­ment of 6.6 years (mean); SD: 5.70). All these were microangiomas and were located at the co­agulated sites. In all 5 patients the relapses oc­curred in asymptomatic eyes (in 3 patients the fel­low eye was symptomatic) in which several angio­mas had been found which means that eyes with several angiomas were predisposed to new angio­mas. In a 31-year-old woman 3 and in a 20-year­old woman 2 recurrences occurred.

The mean age of the patients when the recur­rence occurred was 24.6 (range: 19-33) years; SD: 6.80. All 5 patients had a regular yearly follow-up. Photocoagulation of the angiomas was again ef­fective in all patients.

In a 15-year-old symptomatic patient who had had an enucleation of one eye because of a sec­ondary glaucoma after retinal detachment at the beginning of the study, the other eye showed an angioma half the size of the papilla and located temporal to the macula. This angioma had been treated by xenon coagulation several years be­fore the beginning of the study. However, a re­lapse of the angioma occurred 19 years later, making laser treatment necesary. One year later, new growth of the angioma was observed and an additional coagulation was carried out. 3 years after the last treatment, lipid exudates around the coagulated area were found, indicat­ing new activity of the remnants of this angioma in the retinal scar formation. A new photocoagu­lation was carried out. The lipid exudates de­creased again.

New angiomas were detected in 9 eyes during a mean follow-up interval of 4.2 years (1 1/4 to 8 years of observation; SD: 2.08). The mean age of the patients when the new microangiomas were detected was 27.7 (range: 19-37) years; SD: 7.18.

New angiomas occurred in those eyes with sev­eral angiomas as a predisposition. Patients with a tendency to multiple angiomas need to be seen more frequently because these eyes have a high risk of becoming blind, even in already coagulat­ed angiomas.

In one patient a juxtapapillary angioma devel­oped within 2 years. In the other eyes new devel­oped microangiomas were located in retinal areas other than the coagulated sites. An increase in size of a microangioma was found in a 16-year­old girl during a follow-up of 4 years. The angio­ma was destroyed by laser.

Two new angiomas had developed in the other eye of a 33-year-old man with a microangioma in one eye which had been treated by laser in March 1997. 1.5 years later an angioma of the optic disc and a peripheral angioma of the retina had devel­oped. Only the peripheral angiomas were treated.

Untreated asymptomatic eyes: Microangiomas: The mean follow-up of 25 micro­angiomas of 19 patients (21 eyes) did not show any growth during 4.3 years (0.25 - 14.5); SD: 3.71. The mean age of the 19 patients was 28 years (11-45); SD: 10.53.

DISCUSSION

We present here a study of VHL-associated retinal angiomatosis including 69 patients with 97 eyes in which 189 retinal angiomas were identified. This study lasted from 1983 to 1998 and provided us with long-term follow-up observations which can be used for a critical reevaluation of the manage­ment guide lines.

Classical angiomas and microangiomas were treated by laser unless they were localized close to the optic disc, the macula or a major vessel ad­jacent to the macula. Fibrotic angiomas were not treated. For large angiomas, the procedure was begun with circular photocoagulation of the adja­cent retina. The rationale of treating the surround­ing retina first, is to prevent retinal detachment. Nicholson et ai. [13] described the rhegmatoge­nous retinal detachment caused by surface trac­tion on the angioma. The authors found tiny reti­nal breaks which had a characteristic location at the base of the angioma. The breaks are the cause of the detachment. Initial treatment of the sur­rounding retina reduces the likelihood of retinal detachment.

In the subsequent sessions, the top of the an­gioma itself was coagulated with laser.

The feeder vessels were not coagulated in our patients for two reasons: 1. the danger of recur­rence of the angioma, 2. the danger of vitreous hemorrhages. Goldberg and Koenig [14] found that it was impossible to obliterate the feeder ar­terioles by laser coagulation when the arteriole was markedly hypertrophied. In some relatively small angiomas recurrence occurred several months after argon laser photocoagulation of me­dium-sized arterioles. Wessing [15] mentioned the danger of treating the big feeder vessels by photo­coagulation, because massive vitreous hemorrhag­es can result from this procedure.

Asymptomatic retinal angiomatosis was identi­fied in 68 eyes of 49 patients whose VISIon was normal in all cases, except for 6 in whom the cause was not due to an angioma. A total of 53 classical and 55 microangiomas were destroyed by photocoagulation without any permanent side ef­fects, a procedure which has also been performed by others [10, 16, 17, 18, 19]. We can claim that the laser treatment in all our patients with asymp­tomatic angiomas was successful: in microangio-

February 28, 2000 EUROPEAN JOURNAL OF MEDICAL RESEARCH 55

mas and in small angiomas one or two sessions of treatment was sufficient to produce distinct scar­ring of the angioma. In angiomas bigger than the diameter of the papilla, several sessions were nec­essary. We preferred laser treatment to other pro­cedures (i.e. kryocoagulation or proton beam treatment) because it preserves the adjacent reti­na. With laser treatment, a more carefully directed destruction of the angioma is possible under di­rect observation of the lesion.

Fibrotic angiomas of the retina (Fig. 3) have only been mentioned occasionally in the literature [20]. Fibrotic angiomas in a young patient with VHL were first described by us in 1987 [21]. There was no change during follow-up of these angio­mas during more than 10 years. On the other hand, in this series 18 % of all affected eyes pre­sented with this type. Since the feeder vessels of these fibrotic angiomas are narrow, not much shunt of the blood in the angiomas is present, ex­cept in one patient, a 59-year-old woman, with a mixed type angioma who showed a fibrotic angio­ma with slightly dilated vessels. During follow-up of 11 years no growth of the angioma was no­ticed. We think that fibrotic angiomas can be re­garded as a final stage of scar formation. Therefore, we did not treat these lesions. According to our long-term results, this golicy seems to be adequate, since none of the patients showed any changes during a mean follow-up pe­riod of 4.9 years.

Our study also included angiomas in very deli­cate locations close to the macula (n = 4) (Fig. 5) involving the optic disc or in a juxtapapillary re­gion (n = 10) (Fig.4). Treatment itself may cause visual deterioration. The results of laser coagula­tion on or close to the optic disc reported in the literature are disappointing; some patients show relentless progression of their tumors or penetra­tion into the optic disc nerve fiber layer and papil­lo-macular bundle, with subsequent visual loss in spite of treatment [18, 22]. In this study, a total of 25 untreated asymptomatic microangiomas provid­ed us with insight into their natural course, and to our astonishment, these lesions - detected at any age from 11 to 45 years (mean 28 years) - pro­duced no complications and showed no signifi­cant growth within a mean follow-up period of 4.3 years.

It is most important to elucidate the long term expectations. Does effective treatment definitively destroy the lesions? Do new angiomas develop? Are there long-term risks of visual impairment?

Relapses of angiomas occurred in 5 patients (8%) of coagulated angiomas . Reevaluation of the initial findings and treatment revealed that all pri­mary coagulations of retinal angiomas produced distinct scar formation in every patient. Growth of relapsing angiomas seems to be slow, since all these were microangiomas. Permanent visual im­pairment did not occur. The figures for newly de­veloped angiomas are similar: in 9 patients new angiomas were detected (15% of the treated eyes) during follow-u p . All were microangiomas and did

not cause any decrease in visual acuity. We rec­ommend to treat microangiomas particularly in risky areas of the retina. Treatment is necessary in patients who are not reliable to return for control examination.

The figures for relapsing or newly developing angiomas suggest that one should consider the adequate intervals for follow-up investigations. The detection of new angiomas occurred after a mean observation period of 4.2 years in 15 % of all those eyes which had been followed-up, and the earliest was found after 1 1/4 year.

One may consider aggressive forms of angio­matosis. In fact, we have observed relapses in quite young people. Reviewing such families, we are currently unable to recognize specific germe­line mutations associated with a high risk of loss of vision.

According to the hereditary nature of VHL-asso­ciated retinal angiomatosis, visual impairment oc­curs early in life [8, 18, 19, 23, 24, 25, 26, 27, 28], and this has been confirmed by our study. The risk of retinal angioma before the age of 5 or lOis less than 1 percent and 5 per cent respectively (series by Maher et al., [29]). The mean age of our patients was 31.1 years. The actual age may even be considerably younger, since progression of the disease does not produce pain. However, blind­ness due to retinal angiomatosis is not restricted to the first decades of life, according to this study, since blindness was newly detected in a 61 year­old man.

The resources available and the possibilities of identifying retinal angiomatosis at an early stage have enormously improved during the last two decades. In the 1980's and subsequently the poli­cy has been to investigate all patients with key le­sions of the VHL complex ophthalmologically, and surgeons, neurosurgeons and internists have been invited to transfer patients with eNS hemangio­blastomas and pheochromocytomas. Furthermore, patients identified as suffering from VHL have been told about the autosomal dominant transmis­sion, and their relatives invited for screening. This regimen has been our policy for many years. Molecular genetic analysis of the VHL gene was introduced when - after identification of the VHL gene in 1993 [30] - the majority of VHL families were found to have germeline mutations within the VHL gene [31]. Screening for carrier status can be performed on a single blood sample, and it is most useful for the investigation of VHL families.

' Table 2 shows the mutations observed in this study. For ophthalmologists, the table also con­tains the important information that such muta­tions are currently found in the large majority of VHL families. In contrast to the mutation descrip­tion by Webster et al. [32] the majority of patients of our series have a mutation at nucleotide 505 .

Our conclusions are 1. Young patients who are thought to be in dan­ger of developing a retinal angioma within the near future should be investigated at least twice a

min, 51.9 sec

EUROPEAN jOI'W\JAL OF MEDIC,\[. I~ESEAl~CII February 21'3 , 2000

Fig 4. Fluorescein angiogram of a fibrotic angioma in a 29-year-old woman: distinct delay of contrast filling of the angioma and the retinal vein. Within 21.8 sec of the fluorescein injection only the artery, after 24 sec the angioma partially, and after 26.5 sec the whole angioma and the vein began to show fluorescein. After 29.6 sec the vein was completely filled with dye. There is hardly any hyperfluorescence around the angioma 1 min and 51.9 sec after in­jection of the dye, but slight hyperfluorescence was obvious 12 min and 3.5 sec after the fluorescein injection.

24 sec

29.6 sec

12 min, 3.5 sec

Fehruary 2H, 2000 EUI~OPEAN Jur if{ " \1. OF M ~DICAL H.ES f ·\RCH '57

Fill, ') . .JlIxlapapillary ~lngiol11;1 in the left eye of a 36-year-old woman.

year. However, in patients, of more than 30 years of ~lge, a follow-up of one year at the Iwgin.ning, and after 2 years a ,3-yearly examination s -ems to he sufficient. This is a general guideline, :tnd pa­tients with :1 tvndency to multiple ;lngiomas need to he seen ll1o['e frequcntly.

2. Recurrences rarely occurred (n: ') patients). If new angiomas (n: 9) appearecl or treated angio­m~IS recurrecl, new tTeatment was necess~lry ;ll1d

follow-up at regular interv:tls (ahout twicc a year) was l11Clnci;ltory . Tn young patients, in whom there is a risk th~lt the retinal angioma may develop rather rapidly , ;1 shorter follow-up interval is nec­ess:lry. New ~ll1gi(}l1wS occurred in those eyes with sever~tl ;ll1giomas as a predisposition. Patients with ~l tendency to multiple angiOl1l~IS n~:' t>d to he seen more frequently.

3. Long-term follow-up of 19 angiomas of the fi­brotic type in 13 patients showed no change in growth (mean follow-up: 4.9 ye~lrs; 0.75-'13; SD: 4.76) and no retinal complications.

4. Natural course of the untreated microangiomas: Long-term follow-up of 25 microangiomas of 19 patients did not usually show growth in 21 eyes (mean follow-up : 4.3 years; 0,25-14.5; SD: 3.71). However, in eyes with several angiomas, or if the other eye had become symptomatic, the risk of recurrence or of the development of new angio­mas was increased. In those eyes early treatment is necessary.

5. Early ophthalmological examination and the identificltion of patients with retinal angiomatosis is a great challenge, since these lesions can only be successfully treated at an early stage. Treatment

Fig. 6. Microangiollla Clrrm,v) close to the macLib in the left eye of a 20-y~'ar-old WOllwn. This angioma was later rre~lred hy 1~lser.

is then effecrive and S~ICc, but long-term follow-up is necessary.

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Received: December 29, 1999 / Accepted: January 26, 2000

Address for correspondence: Dieter Schmidt, M.D. Professor of Ophthalmology Univ.-Augenklinik Killianstr. 5 D-79106 Freiburg Germany Fax +49 7611270-4063 Phone +49 7611270-4001 e-mail [email protected]