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Snowflake Degeneration in Hereditary Vitreoretinal Degeneration
AMERICAN JOURNAL OF OPHTHALMOLOGY VOLUME 77
FEBRUARY, 1974
NUMBER 2
S N O W F L A K E DEGENERATION IN HEREDITARY V I T R E O R E T I N A L DEGENERATION TATSUO HIROSE, M.D., K I N G Y. LEE, M.D., AND CHARLES L. SCHEPENS, M.D.
Boston, Massachusetts
Recent progress in methods for examining the vitreous and the peripheral retina1'2 has greatly contributed to our understanding of vitreoretinal abnormalities leading to retinal detachment. In Wagner's hereditary vitreo retinal degeneration, for example, various types of retinal breaks were in close associa tion with the visible vitreous and retinal changes.3 Examining the relatives of pa tients with possible familial retinal detach ment is important, since examination may lead to detection of an early change which precedes retinal breaks. This paper describes the relatively longterm clinical observation of a peculiar type of vitreoretinal degeneration found in 15 member's of one family, five of whom showed retinal detachment.
RESULTS
MATERIALS AND METHODS
In the offices of the Retina Associates, we examined 15 patients of three successive generations from one family. Routine exam ination and binocular indirect ophthalmoscopy with scleral depression were followed by a full fundus drawing and slit-lamp mi croscopy with Goldmann's three-mirror lens. Seven patients had chromosome studies. From the Department of Retina Research of the Retina Foundation, and the Retina Service of the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. This study was supported by Public Health Service research grant EY-00227 and center grant EY-00292 of the National Eye Institute, Na tional Institutes of Health. Reprint requests to Manuscript Editor, Retina Foundation, 20 Staniford St., Boston, MA 02114.
The family consisted of 35 white persons. The affected members were five males and ten females, ranging in age from 9 to 70 years (Fig. 1). Although another man (II12, Fig. 1) reportedly was affected, we were unable to examine him because he died. No reliable information was obtained on the ocular condition of the first generation (1-1 and 1-2, Fig. 1), except that neither was blind. 1-2 had five brothers and one sister; the only ocular problem reported was a cata ract that developed in the sister at an ad vanced age. Absence of blindness in the first generation does not deny the presence of the disease in their fundi, such as was found in their immediate offspring, because the char acteristic changes in the affected members occurred in the peripheral retina, while cen tral vision was relatively good. There was no consanguinity in any couple, and no patient had been premature. None had a congenital physical deformity or a known systemic disease, except for a history of pulmonary tuberculosis in one patient, rheumatic fever in two, and systemic hyper tension in one. The abnormalities common to all 15 patients were limited to the retina and vitreous. Since the ocular changes occurred in patients of different ages in three succes sive generations, and more than half of the patients were observed for from 8 to 20 years, we were able to obtain an idea of the natural course of the disease. The main clini cal findings for each patient are listed in the Table. For patients observed for more than
143
144
AMERICAN JOURNAL OF OPHTHALMOLOGY
s
m nr
5 16466 13
14
27
t
15
28
16
29
17
30
FEBRUARY, 1974
ErrO.
18
19
M6^ 20
21
31
Deceased
22
23
[24
6
25
26
51i 34
Vitreoretinal
degeneration, left and right eyes.
■- Follow-up for 3yrs
Retinal detachment, left and right eyes.
j;
Bilateral retinal degeneration reported.
Follow up for 8-20yrs
L J ( ^ 3 Unaffected male, female
35
Dense cataract with vision of light perception for 40yrs after accident, right eye.
Fig. 1 (Hirose, Lee, and Schepens). Pedigree of family with snowflake degeneration (RS1463). eight years, the Table lists the findings at their first and latest examination. In the following description, see the Table for all references to specific patients. Refractive error and visual acuity—Most of the patients had myopia that progressed slightly with age. Five eyes of three patients showed hyperopia. Astigmatism greater than 1 diopter occurred in 11 eyes. Although corrected vision was relatively good in most patients not affected by cataract or retinal detachment, one eye in patient 111-26 had amblyopia with vision of 20/200. Anterior segment—The eyelids, conjunc tiva, and sclera were normal in all patients. The cornea was clear in every patient except for the right eye of II-5, who had diffuse stromal opacities as a result of long-standing glaucoma. The anterior chamber and iris showed no abnormalities, except in five aphakic eyes that had peripheral anterior synechiae and a few cells in the aqueous. The angle was open and intraocular pressure was below 20 mm Hg in all patients, except for the one with glaucoma. Lens—We observed cataract in all pa tients above 32 years old in the second gen eration, and in two patients aged 24 and 42 years (111-14 and 111-26) in the third gener ation. The cataract type was not uniform.
Nuclear sclerosis occurred in four eyes of three patients (II-4, II-7, and 11-10); cen tral and peripheral cortical cataract in four eyes of two patients (II-9 and 11-11) ; cen tral posterior subcapsular cataract in four eyes of two patients (111-14 and 111-26) ; white specks on the surface of the embryonic nucleus in two eyes of one patient (111-14) ; and mature cataract in one eye (II-8, R E ) . Cataract type was unknown for those pa tients whose lenses had been removed surgi cally before we first saw them. Ten eyes of seven patients underwent cataract extraction between the ages of 34 and 67. None of these ten aphakic eyes showed a drawn-up pupil or vitreous strands incarcerated in the corneal wound. Vitreous—The majority of patients had vitreous changes. In older subjects, vitreous strands were especially prominent and could be detected with the ophthalmoscope. In younger individuals, careful slit-lamp exam ination revealed relatively fine swirling vit reous strands and liquefaction of the gel. The strands were translucent and ran in all directions. With eye movement, they moved slowly, but relatively freely, in the liquefied vitreous. Some patients showed localized thickening of the cortical vitreous over de generated areas of the retina. Posterior vit-
Fig. 2. (Hirose, Lee, and Schepens). Fundus drawings at different stages of the disease. Top left, Stage I. Marked white-with-pressure (wwp) all around the extreme fundus periphery. Separate area of wwp is found between ora and equator. Top right, Stage II. Snowflake degeneration. Minute discrete yellow-white dots resembling snowflakes appear in the areas of wwp. Surface of affected retina is slightly elevated, and elevation is crater-like in some places. Snowflakes also appear along retinal vessels. Chalky white clusters of short needle-like structures are seen in an equatorial area at 2 o'clock. Faint vitreous opacity appears near the posterior pole. Bottom right, Stage HI. Sheathing of retinal vessels, chorioretinal pigmentation, and fibrillar vitreous condensation. Bottom left, Stage IV. Increased pigmentation and disappearance of retinal vessels. Retinal vessels cannot be traced as far as the equator. Note sheathing of vessels near disk and focal chorioretinal atrophy. The whole retina looks atrophic. Swirling vitreous strands float in vitreous cavity.
B
Fig. 3. (Hirose, Lee, and Schepens). A, Fundus photograph of right eye of patient 111-26 at 44 years of age. Retinal arteries and veins show sheathing near the optic disk (RS 1489). B, Fundus photograph of the same patient showing clumps of pigment near the equator. If scleral depressor is used, snowflakes are observed in this area. Most of the snowflakes were so tiny that they were not clearly visible as individual dots in this picture. Fundus changes represent Stages III and IV. C, Fundus photograph of equatorial region of left eye of patient II-4 at 70 years of age, showing round or irregularly shaped clumps of brown-black pigment and focal chorioretinal atrophy. Vessels seen are choroidal vessels located underneath the clumps of pigment. No retinal vessels are visible and the whole retina looks thin and atrophic. Fundus changes represent Stage IV (RS1514).
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SNOWFLAKE DEGENERATION
147
reous detachment with collapse was not rare. ular, poorly demarcated, and generally lo No abnormal cells suggested inflammation in cated a little anterior to the equator. When the snowflakes extended further posteriorly, the vitreous cavity. Ocular fundus—The findings in the fun- they were distributed radially along the reti dus were characteristic, involved both nal vessels. eyes equally, and showed slow but definite In addition to this rather diffuse change in progress in most patients. Fundus changes the extreme periphery, similar circumscribed in patients of the second generation were areas were observed near and slightly an generally more severe than those of the terior to the equator. They were oval or third, and those of the third more pronounced elongated with the long axis parallel to the than those of the fourth, probably indicating equator, and had relatively well-defined bor the progressive nature of the disease with ders. When these areas were viewed in pro age. Progression in the fundus changes has file with scleral depression the retinal surface been divided into four stages (Fig. 2). appeared slightly elevated at the edges with STAGE i—Extensive "white-with-pressure" an excavated center, like an elongated saucer (wwp) all around the extreme fundus pe or a shallow crater. These focal areas had riphery was characteristic of the patients of snowflakes similar to those observed in the the fourth generation less than 15 years old extreme fundus periphery. When isolated, 45 (IV-27 and IV-29). There were also local such patches resembled what some ' have areas of wwp between the equator and the described as early lattice degeneration. The ora serrata. A few minute yellow-white spots cortical vitreous was thickened over the cra were seen in some areas of wwp. At this ters. stage, vitreous degeneration was detected In some areas, the crater-like lesions were only by careful slit-lamp examination. fused with the diffuse and more peripheral STAGE II—Snowflake degeneration became degeneration. Sometimes the snowflakes in apparent at this stage, occurring in three pa the focal areas were chalky white and elon tients of the.third generation (111-15, III- gated, giving the impression of a cluster of 17, and 111-19) whose ages ranged from needles or bristles. This appearance may be about 15 to the early 20s. One patient of the real or caused by astigmatism, which is more second generation (II-9) showed changes marked in the periphery. We provisionally typical of this stage at 38 years; findings call both the localized and the diffuse type of were unchanged when he reached 58. changes "snowflake degeneration." Most pa In this stage, the areas of wwp showed tients had snowflake degeneration over the minute, snowflake-like, yellow-white spots, whole circumference of the peripheral ret some of them brilliant, as if crystalline. Fun ina. When the changes were less extensive, dus examination with the direct or indirect certain quadrants were affected more fre ophthalmoscope without scleral depression quently than the others. The incidence of often failed to reveal these spots, but they snowflake degeneration was highest in the were clearly observed when scleral depres superotemporal quadrant (95%) and lowest sion was used with the indirect ophthalmo in the inferonasal quadrant (68%). In Stage scope, or when the slit-lamp microscope and II, condensations in the vitreous gel were Goldmann's three-mirror lens were used. In conspicuous enough to be detected with the areas with snowflakes, the retina looked ophthalmoscope. slightly elevated and had lost its transpar STAGE in—Characterized by sheathing of ency. The snowflakes were located in the su retinal vessels and pigmentation, this stage perficial layers of the retina and extended as affected two patients in the third generation far anteriorly as the ora serrata. The poste (111-14 and 111-26) and five relatively rior border of the snowflake area was irreg young patients in the second generation (II-
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TABLE SUMMARY OF CLINICAL FINDINGS IN 15 PATIENTS OF THE SAME FAMILY
Patient
Age, Sex yr
Eye
II-3
59
F
RE LE
II-4
50
F
RE LE RE LE
70
II-S
49
M
67 43
F
RE LE
II-8
39
M
RE LE RE LE
II-9
38
M
58
11-10 II-ll 111-14
36 32 24
F F M
44
111-15
17
F
36
111-17
5
F
23
RE LE RE LE
NLP
20/25 20/15 20/15 20/25 20/20 20/20 1/200 20/20
RE LE RE LE
- 2.50 —2.00 —2.75 —3.75
20/30 20/30 20/40 20/30 20/40 20/40 20/30 20/25 20/30 20/30 20/200 20/20 20/200 20/25 20/20 20/20 20/30 20/30 20/30 20/30
RE LE RE LE
RE LE RE LE
F
—2.75 —3.75 3.25 —4.60 -
LP
20/25
20/70 20/30 20/200
M
9
+ 10.50
20/30 20/200
- 4.00 —5.00
24
IV-29
4.75 4.75
RE LE RE LE
111-26
13
-
+
RE LE
F
NLP LP? NLP NLP
RE LE
F
5
CF 20/20 20/20 20/300 20/40 20/30
+ 11.50
15
IV-27
+ 11.75 + 11.25
Vitreous Corrected Cataract DegeneraVision tionf
RE LE
in-19
44
+11.00
RE LE RE LE
II-7
58
Refractive Error*
RE LE RE LE RE LE
2.75
HM
HM
1.13 —2.50 —4.25 - 4.13 + 1.75 1.63 + 1.87 + 3.00 + + 0.50
+ 0.38 —3.00 - 3.12
Aphakia Aphakia Aphakia
+ Aphakia
Aphakia Aphakia Aphakia Aphakia Aphakia
+ + +
Aphakia
+ Aphakia + + + +
Aphakia
+ + + + + Aphakia
Aphakia
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ?
+ +
+ + ? ?
+ + + +
Vessels^
Retinal Pigmen tation
Retinal Snow- WWP§ Detach Stage flakes ment ||
+ O
+ + ++ ++
+ + + +
T.O.D + T.S.O.D + No fundus details (due to corneal opacity) No fundus details O
s,o s
+ + +
+ + +
+ ++
+
No fundus details (d:ue to cataract) No fundus details T,D
No
+ + ++ ++ + + +
Ill III IV IV
+ + +
O
s
s,o s s,o s,o
? IV III III
II-III IV II II II II
+ + + + + +
+ + + + + + + + + + fundus details (d'ue to membrane at pupil)
S
o s s o o T.S.O
? ?
+ + + +
+ +
+ +
+ + + +
III III III III III III
III-IV II II III III
Scleral depressor not used
+ + ++ ++
+ ++ ++ + +
II II I II III III
III-IV III-IV Scleral depressor not used
+ +
+ + + +
I I I I
* Refractive error expressed as the spherical equivalent. t Vitreous degeneration revealed as fibrillar condensation and liquefaction of the vitreous. % Retinal vessels. T signifies thin; S, sheathed; O, obstructed vessels appearing as white line without blood column; D, disappeared before reaching the equator. § WWP indicates white-with-pressure present 360 degrees. || + signifies the presence of each sign; blank signifies its absence.
4, 11-7, II-8, 11-10, and I I - l l ) . Their ages ranged from the middle 20s to early 50s. I n these patients, retinal arteries and veins were sheathed peripherally in the area of the snowflake degeneration or slightly posterior to it. I n some patients, all visible arteries and veins showed sheathing anterior to the equa tor. Some vessels became white threads in
the fundus periphery. However, the sheath ing visible with the ophthalmoscope was lim ited to the larger vascular branches. W e failed to find the criss-crossed white network so characteristic of lattice degeneration, ex cept in one patient (11-10). In patients II-4, I I - l l , and 111-26, sheathing was present in the vessels located on and near the optic disk
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(Fig. 3, A ) . We saw clumps of black, irreg ularly shaped pigment around the equator near the posterior margin of the snowflake degeneration (Figs. 2 and 3, B). Some fundi showed sheathing of vessels without appreci able pigmentation. Indirect ophthalmoscopy during Stage III easily detected swirling vitreous strands. A majority of the patients had some degree of cataract. STAGE iv—Increased pigmentation and disappearance of retinal vessels appeared in patients aged 58 and over (II-4, II-5, and II-8). The pigment clumps were round or ir regularly shaped and discrete; their distribu tion in the fundus was not related to visible retinal vessels, which became attenuated and invisible in the fundus periphery. In patient II-4, the lower retinal arteries were sheathed and could be traced only a few disk diame ters beyond the disk margin ; the lower veins, only a little more peripherally. Small areas of chorioretinal atrophy appeared scattered among the pigment spots. Snowflakes were still seen, but looked less apparent. The reti nal periphery no longer looked elevated, but rather as if its once elevated surface had col lapsed or become thinner. This gradual col lapse or thinning of the retina was actually observed in the lower peripheral fundus of patient 111-26 during 20 years of observa tion. The overall reddish color of the fundus became yellow-orange at this stage and the retina looked atrophic (Fig. 3, C). The vitreous changes were more pro nounced in Stage IV than in Stage III. All the eyes in this stage were aphakic, indicat ing that a cataract had become dense enough to necessitate its removal. We actually saw some gradual fundus changes developing from one stage to the next in patients II-4, II-8, 111-15, and III26 over more than 19 years of observation. One patient (II-9), however, showed very little progress beyond Stage II during 20 years of observation. No edema, exudate, or neovascularization occurred in the retina or vitreous of any pa tient. Only some patients with retinal detach
149
ment had retinal hemorrhage. The macula was normal in all patients, except in patient 111-15, whose macula showed a slightly granular appearance with good central vision in both eyes at the age of 36. No cystic macular change was observed. The optic disk was normal in all patients, except for three eyes that showed temporal conus (II-9 and 111-17). Retinal detachment—Rhegmatogenous ret inal detachment occurred in four eyes (II-3, II-5, II-8, and 11-11) and was present by anamnesis in one other eye (II-5, R E ) . Only patients with retinal detachment had retinal breaks. Three of five eyes with reti nal detachment had horseshoe tears and large punched-out holes located in the upper or lower temporal quadrants, at the equator. No retinal break was detected in two eyes with retinal detachment. One had massive preretinal retraction and cataract (11-11); the other, with a history of two unsuccessful ret inal detachment operations, had glaucoma and corneal opacities that made fundus ex amination impossible (II-5, R E ) . Retinal detachment surgery was not indicated in these two eyes. The left eye of patient II-5 showed long-standing retinal detachment with two large retinal holes, vitreous hemor rhage, obliterated retinal vessels, and marked retinal pigmentation with atrophy. This pa tient underwent unsuccessful retinal detach ment surgery 13 years before we saw him. Although the eye retained questionable light perception, the patient would not have bene fited from further surgery. The two remaining eyes with retinal de tachment (II-3 and II-8) were operated on. The retina of patient II-3 remained reattached for two years after surgery until her accidental death. Patient II-8 had four reti nal operations. After the fourth operation, a scleral buckling, the retina remained attached for 19 years. Subjective symptoms—The main symp tom of the patients was impaired vision, which could be attributed to cataract or reti nal detachment. No patient noted night blindness, but four complained of seeing
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spots. Most patients under 30 years of age had no ocular symptoms, and abnormalities were found only by ophthalmologic examina tion. Genetics—Based on our evaluation of 35 members of this family, the snowflake de generation of the retina is probably due to an autosomal dominant mutant gene. Evidence of dominant transmission was provided by instances of both parent and child being sim ilarly affected (Fig. 1). The indication that it is an autosomal gene rests on the instance of male-to-male transmission (11-12 to 111-26). Although we were unable to examine 11-12, another ophthalmologist found that he had retinal degeneration. We presume that either 1-1 or 1-2 was also affected and passed the mutant gene to nine of the ten offspring. As this retinal degeneration is probably due to a single mutant gene, it is not surprising that chromosome analyses on seven affected fam ily members showed no abnormalities. DIFFERENTIAL DIAGNOSIS
The discrete yellow-white spots character istic of snowflake degeneration may not be specific indicators of any particular disease. These dots are occasionally observed in the peripheral fundus of other patients. How ever, the patients in this study are unique be cause they show extensive snowflakes and a familial and hereditary trend. Absence of inflammatory signs, or of con sistent systemic disease, and presence of a familial tendency to ocular abnormalities leads us to believe that the patients had a de generative disease involving mainly the ret ina and vitreous. Although myopia was common in our pa tients, it was mild, and the retinal changes observed differ from those seen in high my opes.6 Furthermore, the retinal and vitreous changes characteristic of this family also oc curred in nonmyopic eyes. Three kinds of hereditary degeneration affect the retina and vitreous: congenital re tinoschisis,7'8 Wagner's hereditary vitreoretinal degeneration,9-10 and Goldmann-
FEBRUARY, 1974
Favre's vitreotapetoretinal degeneration.11'12 The differences among these three diseases have been clearly described.13-14 The slight elevation of the retina, sheath ing of retinal vessels, and increased pigmen tation in the later stages described in the present study may simulate congenital or ac quired retinoschisis. Snowflakes are seen in acquired retinoschisis where they are pre sumed to represent the attachment of Miiller's cells to the basement membrane of the retina.15 The snowflakes seen ophthalmoscopically in this family resembled those of retinoschisis. However, it is uncertain whether or not they have the same origin. The fundus changes seen in our patients were, however, sharply differentiated from either type of retinoschisis. Although the surface of the retina in the area of snowflake degeneration looks slightly elevated, it never balloons. On the contrary, its center may be excavated, a feature that distinguishes this condition from both types of retinoschisis. The posterior border of the area of snowflake degeneration is poorly delineated and ir regular, extends along the retinal vessels in some cases, and fades gradually into normal looking retina. In contrast, retinoschisis has a sharp convex posterior edge. While snowflake degeneration extends to the ora serrata, the anterior limit of congenital retinoschisis seldom does.8 The macula was not affected in our patients, but is usually involved in con genital retinoschisis.8 Senile retinoschisis usually starts with cystoid degeneration at the ora serrata,16 but our patients had no marked cystoid degeneration. Wagner's disease should be considered in differential diagnosis because of the presence of myopia, presenile cataract, retinal pig mentation, sheathed retinal vessels, vitreous degeneration,9'10 and minute yellow-white dots17 in the peripheral retina. In fact, at first we thought our patients were affected by Wagner's disease. However, examination of more patients with Wagner's disease3 in dicated that there are definite differences be tween the appearance of the vitreous and
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retina in this disease and in snowflake de generation. No vitreous membrane with a hole and no optically empty vitreous cavity, so characteristic of Wagner's disease, occur red in any patient in the present study. Vit reous degeneration in this series was fibrillar rather than membranous. In the early stage of Wagner's disease, a localized area of thinned pigment epithelium or atrophy of the choriocapillaris results in exposure of the large choroidal vessels.3'10 The earliest change in the fundus of our pa tients was either wwp or snowflakes, both presumably caused by alterations in the cor tical vitreous or inner retinal layers, or both, rather than in the pigment epithelium and the choroid. As a result, the choroidal pat tern was obscured in the early stages of our cases, in contrast to its exposure in Wagner's disease. Absence of central or peripheral retinoschisis in our patients excluded the possibility of Goldmann-Favre's disease.11"13 This is further supported by the presence of fairly good ERG responses in our patients (unpub lished observations), in contrast to complete loss of the b-wave with retention of the awave, or a nonrecordable ERG in GoldmannFavre's disease.13'18 The latter is transmitted by an autosomal recessive trait, while our pa tients transmitted the disease by autosomal dominant inheritance. Three additional familial vitreoretinal dis eases have been reported by Favre, 19 FeilerOfry and associates,20 and Criswick and Schepens.21 The vitreous changes in our cases were similar to those in Favre's cases,19 which Francois called macrofibrillar vi treoretinal degeneration.22 Favre 19 noted cystoid peripheral degeneration in one of his patients. The fundus changes in his other pa tients were described as peripheral retinal degeneration. He did not describe snowflakes, retinal pigmentation, or sheathing or disappearance of retinal vessels, so it re mains uncertain whether or not our cases are the same as Favre's. The absence of congeni tal night blindness in our patients (unpub
1S1
lished observations) suggested that the dis ease is not identical to that described by Feiler-Ofry and his associates as hereditary vitreoretinal degeneration and night blind ness.20 Absence of neovascularization and exudation excludes familial exudative vitreoretinopathy.21 Other diseases have similar clinical fea tures and should be considered in the differ ential diagnosis of snowflake degeneration. The yellow-white dots of snowflake degener ation look entirely different ophthalmoscopically from the white dots seen in retinitis punctata albescens or fundus albipunctatus cum hemeralopia. The dots we observed were smaller, more yellowish, more densely packed, and distributed more peripherally than those in retinitis punctata albescens and related diseases. Lack of congenital night blindness in our patients also excluded reti nitis punctata albescens.23 The slowly pro gressive nature of the disease observed ex cluded fundus albipunctatus cum hemeralo pia, which is stationary.23 The clumps of pigment and the disappear ance of retinal vessels found in our patients at a late stage of the disease might suggest retinitis pigmentosa and related diseases. Al though wide varieties of retinitis pigmentosa have been described, there are more dispari ties than similarities between the clinical picture of our cases and that of retinitis pig mentosa. In retinitis pigmentosa, clumps of jet-black pigment, often with a bone spicule arrangement, usually appear at the equator, while the retina in the extreme periphery re mains normal.23 This produces an annular scotoma. In our patients, however, the fun dus changes started in the. extreme periphery and the field defect observed was not a ring scotoma but a circular depression of the pe ripheral visual field (unpublished observa tions). The retinal pigment was brownishblack rather than jet-black, it formed round or irregular clumps, and it appeared only in the late stages. Initially, snowflake degenera tion seems localized in the inner retinal layers, whereas retinitis pigmentosa starts in the
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neuroepitheliiim. All our patients enjoyed relatively good vision until they were affected by cataract or retinal detachment. Even our oldest patient, aged 70, was far from blind. Most patients with retinitis pigmentosa lose useful vision by this age. 23 T h e crater-like retinal areas with snowflakes may be similar, but not identical, to those described as retinal erosion 24 and vitre ous base excavation. 25 Retinal erosion re veals white dots in the vitreous instead of in the retina, and white dots are not mentioned in discussions of vitreous base excavations. 2 5 Yellow-white dots have been described as one of the characteristic changes in the early stage of lattice degeneration. 4 ' 5 Typical lattice degeneration is sharply demarcated, has its long axis parallel to the equator, is located between the equator and the ora serrata, 4 ' 5 but it is not usually seen at the ora. 26 It is char acterized by a network of fine white lines, small discrete yellow-white particles, and ab normalities of the adjacent vitreous. 4 ' 5 ' 2 6 T h e lesion becomes pigmented in the late stages. T h e snowflake degeneration de scribed here is extensive and starts near the ora serrata. Its posterior border is irregular, ill-defined, and partly fused with crater-like areas, and it protrudes radially along the ret inal vessels. Its distribution in the peripheral fundus is so diffusely spread that it does not look like lattice degeneration. Relatively large retinal vessels are sheathed in the area of snowflake degeneration or near the optic disk, but we did not see the network of fine white lines so characteristic of lattice degen eration, except in one patient. Some of the patients with snowflake degeneration have been observed for 20 years, and none has de veloped lesions resembling lattice. Snowflake degeneration is obviously then not an early stage of lattice degeneration. O n e of the pa tients studied was 70 years old, and the snowflake area in her fundus was free of visible retinal vessels; it seems unlikely that this area will eventually develop the changes typical of lattice degeneration. T h e individual yellow-white spots seen in
FEBRUARY, 1974
our patients may suggest snail-track degen eration. However, the location of the frost like changes in the latter is similar to that in lattice degeneration. 27 T h e fundus changes in our patients cannot be identified as snailtrack degeneration for the reasons described above. SUMMARY
Long-term follow-up of 15 members of one family that produced five patients with retinal detachment disclosed a peculiar type of progressive vitreoretinal degeneration, probably of autosomal dominant inheritance. T h e fundus appearance evolved through four stages: ( 1 ) extensive white-with-press u r e ; ( 2 ) snowflake degeneration; ( 3 ) sheathing of retinal vessels and pigmenta tion; and ( 4 ) increased pigmentation and disappearance of retinal vessels. A swirling fibrillar vitreous degeneration, equally pro gressive in nature, accompanied these fun dus changes. T h e cases observed were com pared with other diseases affecting the vitre ous and retina, especially Wagner's disease, Favre's macrofibrillary vitreoretinal degen eration, and extensive lattice degeneration. ACKNOWLEDGMENTS
W e thank Richard J. Goduti, M.D., of Portland, Maine, for sending us his patients; Leonard Atkins, M.D., Massachusetts General Hospital, for chromo some studies; Lewis B. Holmes, M.D., Genetic Unit at Massachusetts General Hospital, for his opinions on the genetics of the disease; and David Tilden, the Retina Foundation's illustrator, for the fundus drawing. REFERENCES 1. Cockerham, W. D., and Schepens, C. L.: Tech nique of vitreous cavity examination. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 66. 2. Schepens, C. L . : Techniques of examination of the fundus periphery. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 39. 3. Hirose, T., Lee, K. Y., and Schepens, C. L . : Wagner's hereditary vitreoretinal degeneration and retinal detachment. Arch. Ophthalmol. 89:175, 1973.
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4. Straatsma, B. R.: Lattice degeneration of the retina. Clinical description and course. In Kimura, S. J., and Caygill, W. M. (eds.) : Retinal Diseases. Philadelphia, Lea and Febiger, 1966, p. 155. 5. Spencer, L. M., Straatsma, B. R., and Foos, R. Y.: Tractional degenerations of the peripheral retina. In Symposium on Retina and Retinal Surg ery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 103. 6. Duke-Elder, S., and Abrams, D.: Ophthalmic Optics and Refraction. In Duke-Elder, S. (ed.) : System of Ophthalmology, vol. 5. St. Louis, C. V. Mosby, 1970, p. 326. 7. Kleinert, H.: Eine recessiv-geschlechtsgebundene Form der idiopathischen Netzhautspaltung bei nichtmyopen Jugendlichen. Graefe's Arch. Ophthal mol. 154:295,1953. 8. Kraushar, M. F., Schepens, C. L., Kaplan, J. A., and Freeman, H. M.: Congenital retinoschisis. In Contemporary Ophthalmology. Honoring Sir Stew art Duke-Elder. Baltimore, Williams and Wilkins, 1972, p. 265. 9. Wagner, H.: Ein bisher unbekanntes Ergleiden des Auges (Degeneratio hyaloideo-retinalis hereditaria), beobachtet im Kanton Zurich. Klin. Monatsbl. Augenheilkd. 100:840, 1938. 10. Alexander, R. L., and Shea, M.: Wagner's disease. Arch. Ophthalmol. 74:310, 1965. 11. Busacca, A., Goldmann, H., and SchiffWertheimer, S.: Biomicroscopie du corps vitre et du fond de l'oeil. Rapports presentes a la Societe Francaise d'Ophthalmologie. Paris, Masson and Co., 1957, p. 164. 12. Favre, M.: A propos de deux cas de degenerescence hyaloideoretinienne. Ophthalmologica 135 : 604, 1958. 13. Ricci, A.: Clinique et transmission genetique des differentes formes de degenerescence vitreoretinienne. Ophthalmologica 139:338, 1960. 14. Jaffe, N. S.: The Vitreous in Clinical Ophthal mology. St. Louis, C. V. Mosby, 1969, p. 235. 15. Zimmerman, L. E., and Spencer, W. H.: The
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pathologic anatomy of retinoschisis. Arch. Ophthal mol. 63:10, 1960. 16. Shea, M., Schepens, C. L., and von Pirquet, S. R.: Retinoschisis. 1. Senile type: A clinical re port of 107 cases. Arch. Ophthalmol. 63:1, 1960. 17. Jansen, L. M. A. A.: Degeneration hyaloideoretinalis hereditaria. Ophthalmologica 144:458, 1962. 18. Carr, R. E., and Siegel, I. M.: The vitreotapeto-retinal degenerations. Arch. Ophthalmol. 84:436,1970. 19. Favre, M.: Degenerescence "myopique" du corps vitre et emmetropie. Ophthalmologica 141: 357, 1961. 20. Feiler-Ofry, V., Adam, A., Regenbogen, L., Godel, V., and Stein, R.: Hereditary vitreoretinal degeneration and night blindness. Am. J. Ophthalmol. 67:553, 1969. 21. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 22. Francois, J.: The role of heredity in retinal detachment. In McPherson, A. (ed.): New and Controversial Aspects of Retinal Detachment. New York, Harper and Row Hoeber Medical Division, 1968, p. 101. 23. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder, S. (ed.) : System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, p. 326. 24. Rutnin, U., and Schepens, C. L.: Fiindus ap pearance in normal eyes. 3. Peripheral degenerations. Am. J. Ophthalmol. 64:1040, 1967. 25. Foos, R. Y., Spencer, L. M., and Straatsma, B. R.: Trophic degenerations of the peripheral ret ina. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 90. 26. Schepens, C. L.: Subclinical retinal detach ments. Arch. Ophthalmol. 47:593, 1952. 27. Aaberg, T. M., and Stevens, T. R.: Snail track degeneration of the retina. Am. J. Ophthalmol. 73:370, 1972.
FEBRUARY, 1974
NUMBER 2
S N O W F L A K E DEGENERATION IN HEREDITARY V I T R E O R E T I N A L DEGENERATION TATSUO HIROSE, M.D., K I N G Y. LEE, M.D., AND CHARLES L. SCHEPENS, M.D.
Boston, Massachusetts
Recent progress in methods for examining the vitreous and the peripheral retina1'2 has greatly contributed to our understanding of vitreoretinal abnormalities leading to retinal detachment. In Wagner's hereditary vitreo retinal degeneration, for example, various types of retinal breaks were in close associa tion with the visible vitreous and retinal changes.3 Examining the relatives of pa tients with possible familial retinal detach ment is important, since examination may lead to detection of an early change which precedes retinal breaks. This paper describes the relatively longterm clinical observation of a peculiar type of vitreoretinal degeneration found in 15 member's of one family, five of whom showed retinal detachment.
RESULTS
MATERIALS AND METHODS
In the offices of the Retina Associates, we examined 15 patients of three successive generations from one family. Routine exam ination and binocular indirect ophthalmoscopy with scleral depression were followed by a full fundus drawing and slit-lamp mi croscopy with Goldmann's three-mirror lens. Seven patients had chromosome studies. From the Department of Retina Research of the Retina Foundation, and the Retina Service of the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. This study was supported by Public Health Service research grant EY-00227 and center grant EY-00292 of the National Eye Institute, Na tional Institutes of Health. Reprint requests to Manuscript Editor, Retina Foundation, 20 Staniford St., Boston, MA 02114.
The family consisted of 35 white persons. The affected members were five males and ten females, ranging in age from 9 to 70 years (Fig. 1). Although another man (II12, Fig. 1) reportedly was affected, we were unable to examine him because he died. No reliable information was obtained on the ocular condition of the first generation (1-1 and 1-2, Fig. 1), except that neither was blind. 1-2 had five brothers and one sister; the only ocular problem reported was a cata ract that developed in the sister at an ad vanced age. Absence of blindness in the first generation does not deny the presence of the disease in their fundi, such as was found in their immediate offspring, because the char acteristic changes in the affected members occurred in the peripheral retina, while cen tral vision was relatively good. There was no consanguinity in any couple, and no patient had been premature. None had a congenital physical deformity or a known systemic disease, except for a history of pulmonary tuberculosis in one patient, rheumatic fever in two, and systemic hyper tension in one. The abnormalities common to all 15 patients were limited to the retina and vitreous. Since the ocular changes occurred in patients of different ages in three succes sive generations, and more than half of the patients were observed for from 8 to 20 years, we were able to obtain an idea of the natural course of the disease. The main clini cal findings for each patient are listed in the Table. For patients observed for more than
143
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AMERICAN JOURNAL OF OPHTHALMOLOGY
s
m nr
5 16466 13
14
27
t
15
28
16
29
17
30
FEBRUARY, 1974
ErrO.
18
19
M6^ 20
21
31
Deceased
22
23
[24
6
25
26
51i 34
Vitreoretinal
degeneration, left and right eyes.
■- Follow-up for 3yrs
Retinal detachment, left and right eyes.
j;
Bilateral retinal degeneration reported.
Follow up for 8-20yrs
L J ( ^ 3 Unaffected male, female
35
Dense cataract with vision of light perception for 40yrs after accident, right eye.
Fig. 1 (Hirose, Lee, and Schepens). Pedigree of family with snowflake degeneration (RS1463). eight years, the Table lists the findings at their first and latest examination. In the following description, see the Table for all references to specific patients. Refractive error and visual acuity—Most of the patients had myopia that progressed slightly with age. Five eyes of three patients showed hyperopia. Astigmatism greater than 1 diopter occurred in 11 eyes. Although corrected vision was relatively good in most patients not affected by cataract or retinal detachment, one eye in patient 111-26 had amblyopia with vision of 20/200. Anterior segment—The eyelids, conjunc tiva, and sclera were normal in all patients. The cornea was clear in every patient except for the right eye of II-5, who had diffuse stromal opacities as a result of long-standing glaucoma. The anterior chamber and iris showed no abnormalities, except in five aphakic eyes that had peripheral anterior synechiae and a few cells in the aqueous. The angle was open and intraocular pressure was below 20 mm Hg in all patients, except for the one with glaucoma. Lens—We observed cataract in all pa tients above 32 years old in the second gen eration, and in two patients aged 24 and 42 years (111-14 and 111-26) in the third gener ation. The cataract type was not uniform.
Nuclear sclerosis occurred in four eyes of three patients (II-4, II-7, and 11-10); cen tral and peripheral cortical cataract in four eyes of two patients (II-9 and 11-11) ; cen tral posterior subcapsular cataract in four eyes of two patients (111-14 and 111-26) ; white specks on the surface of the embryonic nucleus in two eyes of one patient (111-14) ; and mature cataract in one eye (II-8, R E ) . Cataract type was unknown for those pa tients whose lenses had been removed surgi cally before we first saw them. Ten eyes of seven patients underwent cataract extraction between the ages of 34 and 67. None of these ten aphakic eyes showed a drawn-up pupil or vitreous strands incarcerated in the corneal wound. Vitreous—The majority of patients had vitreous changes. In older subjects, vitreous strands were especially prominent and could be detected with the ophthalmoscope. In younger individuals, careful slit-lamp exam ination revealed relatively fine swirling vit reous strands and liquefaction of the gel. The strands were translucent and ran in all directions. With eye movement, they moved slowly, but relatively freely, in the liquefied vitreous. Some patients showed localized thickening of the cortical vitreous over de generated areas of the retina. Posterior vit-
Fig. 2. (Hirose, Lee, and Schepens). Fundus drawings at different stages of the disease. Top left, Stage I. Marked white-with-pressure (wwp) all around the extreme fundus periphery. Separate area of wwp is found between ora and equator. Top right, Stage II. Snowflake degeneration. Minute discrete yellow-white dots resembling snowflakes appear in the areas of wwp. Surface of affected retina is slightly elevated, and elevation is crater-like in some places. Snowflakes also appear along retinal vessels. Chalky white clusters of short needle-like structures are seen in an equatorial area at 2 o'clock. Faint vitreous opacity appears near the posterior pole. Bottom right, Stage HI. Sheathing of retinal vessels, chorioretinal pigmentation, and fibrillar vitreous condensation. Bottom left, Stage IV. Increased pigmentation and disappearance of retinal vessels. Retinal vessels cannot be traced as far as the equator. Note sheathing of vessels near disk and focal chorioretinal atrophy. The whole retina looks atrophic. Swirling vitreous strands float in vitreous cavity.
B
Fig. 3. (Hirose, Lee, and Schepens). A, Fundus photograph of right eye of patient 111-26 at 44 years of age. Retinal arteries and veins show sheathing near the optic disk (RS 1489). B, Fundus photograph of the same patient showing clumps of pigment near the equator. If scleral depressor is used, snowflakes are observed in this area. Most of the snowflakes were so tiny that they were not clearly visible as individual dots in this picture. Fundus changes represent Stages III and IV. C, Fundus photograph of equatorial region of left eye of patient II-4 at 70 years of age, showing round or irregularly shaped clumps of brown-black pigment and focal chorioretinal atrophy. Vessels seen are choroidal vessels located underneath the clumps of pigment. No retinal vessels are visible and the whole retina looks thin and atrophic. Fundus changes represent Stage IV (RS1514).
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SNOWFLAKE DEGENERATION
147
reous detachment with collapse was not rare. ular, poorly demarcated, and generally lo No abnormal cells suggested inflammation in cated a little anterior to the equator. When the snowflakes extended further posteriorly, the vitreous cavity. Ocular fundus—The findings in the fun- they were distributed radially along the reti dus were characteristic, involved both nal vessels. eyes equally, and showed slow but definite In addition to this rather diffuse change in progress in most patients. Fundus changes the extreme periphery, similar circumscribed in patients of the second generation were areas were observed near and slightly an generally more severe than those of the terior to the equator. They were oval or third, and those of the third more pronounced elongated with the long axis parallel to the than those of the fourth, probably indicating equator, and had relatively well-defined bor the progressive nature of the disease with ders. When these areas were viewed in pro age. Progression in the fundus changes has file with scleral depression the retinal surface been divided into four stages (Fig. 2). appeared slightly elevated at the edges with STAGE i—Extensive "white-with-pressure" an excavated center, like an elongated saucer (wwp) all around the extreme fundus pe or a shallow crater. These focal areas had riphery was characteristic of the patients of snowflakes similar to those observed in the the fourth generation less than 15 years old extreme fundus periphery. When isolated, 45 (IV-27 and IV-29). There were also local such patches resembled what some ' have areas of wwp between the equator and the described as early lattice degeneration. The ora serrata. A few minute yellow-white spots cortical vitreous was thickened over the cra were seen in some areas of wwp. At this ters. stage, vitreous degeneration was detected In some areas, the crater-like lesions were only by careful slit-lamp examination. fused with the diffuse and more peripheral STAGE II—Snowflake degeneration became degeneration. Sometimes the snowflakes in apparent at this stage, occurring in three pa the focal areas were chalky white and elon tients of the.third generation (111-15, III- gated, giving the impression of a cluster of 17, and 111-19) whose ages ranged from needles or bristles. This appearance may be about 15 to the early 20s. One patient of the real or caused by astigmatism, which is more second generation (II-9) showed changes marked in the periphery. We provisionally typical of this stage at 38 years; findings call both the localized and the diffuse type of were unchanged when he reached 58. changes "snowflake degeneration." Most pa In this stage, the areas of wwp showed tients had snowflake degeneration over the minute, snowflake-like, yellow-white spots, whole circumference of the peripheral ret some of them brilliant, as if crystalline. Fun ina. When the changes were less extensive, dus examination with the direct or indirect certain quadrants were affected more fre ophthalmoscope without scleral depression quently than the others. The incidence of often failed to reveal these spots, but they snowflake degeneration was highest in the were clearly observed when scleral depres superotemporal quadrant (95%) and lowest sion was used with the indirect ophthalmo in the inferonasal quadrant (68%). In Stage scope, or when the slit-lamp microscope and II, condensations in the vitreous gel were Goldmann's three-mirror lens were used. In conspicuous enough to be detected with the areas with snowflakes, the retina looked ophthalmoscope. slightly elevated and had lost its transpar STAGE in—Characterized by sheathing of ency. The snowflakes were located in the su retinal vessels and pigmentation, this stage perficial layers of the retina and extended as affected two patients in the third generation far anteriorly as the ora serrata. The poste (111-14 and 111-26) and five relatively rior border of the snowflake area was irreg young patients in the second generation (II-
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TABLE SUMMARY OF CLINICAL FINDINGS IN 15 PATIENTS OF THE SAME FAMILY
Patient
Age, Sex yr
Eye
II-3
59
F
RE LE
II-4
50
F
RE LE RE LE
70
II-S
49
M
67 43
F
RE LE
II-8
39
M
RE LE RE LE
II-9
38
M
58
11-10 II-ll 111-14
36 32 24
F F M
44
111-15
17
F
36
111-17
5
F
23
RE LE RE LE
NLP
20/25 20/15 20/15 20/25 20/20 20/20 1/200 20/20
RE LE RE LE
- 2.50 —2.00 —2.75 —3.75
20/30 20/30 20/40 20/30 20/40 20/40 20/30 20/25 20/30 20/30 20/200 20/20 20/200 20/25 20/20 20/20 20/30 20/30 20/30 20/30
RE LE RE LE
RE LE RE LE
F
—2.75 —3.75 3.25 —4.60 -
LP
20/25
20/70 20/30 20/200
M
9
+ 10.50
20/30 20/200
- 4.00 —5.00
24
IV-29
4.75 4.75
RE LE RE LE
111-26
13
-
+
RE LE
F
NLP LP? NLP NLP
RE LE
F
5
CF 20/20 20/20 20/300 20/40 20/30
+ 11.50
15
IV-27
+ 11.75 + 11.25
Vitreous Corrected Cataract DegeneraVision tionf
RE LE
in-19
44
+11.00
RE LE RE LE
II-7
58
Refractive Error*
RE LE RE LE RE LE
2.75
HM
HM
1.13 —2.50 —4.25 - 4.13 + 1.75 1.63 + 1.87 + 3.00 + + 0.50
+ 0.38 —3.00 - 3.12
Aphakia Aphakia Aphakia
+ Aphakia
Aphakia Aphakia Aphakia Aphakia Aphakia
+ + +
Aphakia
+ Aphakia + + + +
Aphakia
+ + + + + Aphakia
Aphakia
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + ?
+ +
+ + ? ?
+ + + +
Vessels^
Retinal Pigmen tation
Retinal Snow- WWP§ Detach Stage flakes ment ||
+ O
+ + ++ ++
+ + + +
T.O.D + T.S.O.D + No fundus details (due to corneal opacity) No fundus details O
s,o s
+ + +
+ + +
+ ++
+
No fundus details (d:ue to cataract) No fundus details T,D
No
+ + ++ ++ + + +
Ill III IV IV
+ + +
O
s
s,o s s,o s,o
? IV III III
II-III IV II II II II
+ + + + + +
+ + + + + + + + + + fundus details (d'ue to membrane at pupil)
S
o s s o o T.S.O
? ?
+ + + +
+ +
+ +
+ + + +
III III III III III III
III-IV II II III III
Scleral depressor not used
+ + ++ ++
+ ++ ++ + +
II II I II III III
III-IV III-IV Scleral depressor not used
+ +
+ + + +
I I I I
* Refractive error expressed as the spherical equivalent. t Vitreous degeneration revealed as fibrillar condensation and liquefaction of the vitreous. % Retinal vessels. T signifies thin; S, sheathed; O, obstructed vessels appearing as white line without blood column; D, disappeared before reaching the equator. § WWP indicates white-with-pressure present 360 degrees. || + signifies the presence of each sign; blank signifies its absence.
4, 11-7, II-8, 11-10, and I I - l l ) . Their ages ranged from the middle 20s to early 50s. I n these patients, retinal arteries and veins were sheathed peripherally in the area of the snowflake degeneration or slightly posterior to it. I n some patients, all visible arteries and veins showed sheathing anterior to the equa tor. Some vessels became white threads in
the fundus periphery. However, the sheath ing visible with the ophthalmoscope was lim ited to the larger vascular branches. W e failed to find the criss-crossed white network so characteristic of lattice degeneration, ex cept in one patient (11-10). In patients II-4, I I - l l , and 111-26, sheathing was present in the vessels located on and near the optic disk
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SNOWFLAKE DEGENERATION
(Fig. 3, A ) . We saw clumps of black, irreg ularly shaped pigment around the equator near the posterior margin of the snowflake degeneration (Figs. 2 and 3, B). Some fundi showed sheathing of vessels without appreci able pigmentation. Indirect ophthalmoscopy during Stage III easily detected swirling vitreous strands. A majority of the patients had some degree of cataract. STAGE iv—Increased pigmentation and disappearance of retinal vessels appeared in patients aged 58 and over (II-4, II-5, and II-8). The pigment clumps were round or ir regularly shaped and discrete; their distribu tion in the fundus was not related to visible retinal vessels, which became attenuated and invisible in the fundus periphery. In patient II-4, the lower retinal arteries were sheathed and could be traced only a few disk diame ters beyond the disk margin ; the lower veins, only a little more peripherally. Small areas of chorioretinal atrophy appeared scattered among the pigment spots. Snowflakes were still seen, but looked less apparent. The reti nal periphery no longer looked elevated, but rather as if its once elevated surface had col lapsed or become thinner. This gradual col lapse or thinning of the retina was actually observed in the lower peripheral fundus of patient 111-26 during 20 years of observa tion. The overall reddish color of the fundus became yellow-orange at this stage and the retina looked atrophic (Fig. 3, C). The vitreous changes were more pro nounced in Stage IV than in Stage III. All the eyes in this stage were aphakic, indicat ing that a cataract had become dense enough to necessitate its removal. We actually saw some gradual fundus changes developing from one stage to the next in patients II-4, II-8, 111-15, and III26 over more than 19 years of observation. One patient (II-9), however, showed very little progress beyond Stage II during 20 years of observation. No edema, exudate, or neovascularization occurred in the retina or vitreous of any pa tient. Only some patients with retinal detach
149
ment had retinal hemorrhage. The macula was normal in all patients, except in patient 111-15, whose macula showed a slightly granular appearance with good central vision in both eyes at the age of 36. No cystic macular change was observed. The optic disk was normal in all patients, except for three eyes that showed temporal conus (II-9 and 111-17). Retinal detachment—Rhegmatogenous ret inal detachment occurred in four eyes (II-3, II-5, II-8, and 11-11) and was present by anamnesis in one other eye (II-5, R E ) . Only patients with retinal detachment had retinal breaks. Three of five eyes with reti nal detachment had horseshoe tears and large punched-out holes located in the upper or lower temporal quadrants, at the equator. No retinal break was detected in two eyes with retinal detachment. One had massive preretinal retraction and cataract (11-11); the other, with a history of two unsuccessful ret inal detachment operations, had glaucoma and corneal opacities that made fundus ex amination impossible (II-5, R E ) . Retinal detachment surgery was not indicated in these two eyes. The left eye of patient II-5 showed long-standing retinal detachment with two large retinal holes, vitreous hemor rhage, obliterated retinal vessels, and marked retinal pigmentation with atrophy. This pa tient underwent unsuccessful retinal detach ment surgery 13 years before we saw him. Although the eye retained questionable light perception, the patient would not have bene fited from further surgery. The two remaining eyes with retinal de tachment (II-3 and II-8) were operated on. The retina of patient II-3 remained reattached for two years after surgery until her accidental death. Patient II-8 had four reti nal operations. After the fourth operation, a scleral buckling, the retina remained attached for 19 years. Subjective symptoms—The main symp tom of the patients was impaired vision, which could be attributed to cataract or reti nal detachment. No patient noted night blindness, but four complained of seeing
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spots. Most patients under 30 years of age had no ocular symptoms, and abnormalities were found only by ophthalmologic examina tion. Genetics—Based on our evaluation of 35 members of this family, the snowflake de generation of the retina is probably due to an autosomal dominant mutant gene. Evidence of dominant transmission was provided by instances of both parent and child being sim ilarly affected (Fig. 1). The indication that it is an autosomal gene rests on the instance of male-to-male transmission (11-12 to 111-26). Although we were unable to examine 11-12, another ophthalmologist found that he had retinal degeneration. We presume that either 1-1 or 1-2 was also affected and passed the mutant gene to nine of the ten offspring. As this retinal degeneration is probably due to a single mutant gene, it is not surprising that chromosome analyses on seven affected fam ily members showed no abnormalities. DIFFERENTIAL DIAGNOSIS
The discrete yellow-white spots character istic of snowflake degeneration may not be specific indicators of any particular disease. These dots are occasionally observed in the peripheral fundus of other patients. How ever, the patients in this study are unique be cause they show extensive snowflakes and a familial and hereditary trend. Absence of inflammatory signs, or of con sistent systemic disease, and presence of a familial tendency to ocular abnormalities leads us to believe that the patients had a de generative disease involving mainly the ret ina and vitreous. Although myopia was common in our pa tients, it was mild, and the retinal changes observed differ from those seen in high my opes.6 Furthermore, the retinal and vitreous changes characteristic of this family also oc curred in nonmyopic eyes. Three kinds of hereditary degeneration affect the retina and vitreous: congenital re tinoschisis,7'8 Wagner's hereditary vitreoretinal degeneration,9-10 and Goldmann-
FEBRUARY, 1974
Favre's vitreotapetoretinal degeneration.11'12 The differences among these three diseases have been clearly described.13-14 The slight elevation of the retina, sheath ing of retinal vessels, and increased pigmen tation in the later stages described in the present study may simulate congenital or ac quired retinoschisis. Snowflakes are seen in acquired retinoschisis where they are pre sumed to represent the attachment of Miiller's cells to the basement membrane of the retina.15 The snowflakes seen ophthalmoscopically in this family resembled those of retinoschisis. However, it is uncertain whether or not they have the same origin. The fundus changes seen in our patients were, however, sharply differentiated from either type of retinoschisis. Although the surface of the retina in the area of snowflake degeneration looks slightly elevated, it never balloons. On the contrary, its center may be excavated, a feature that distinguishes this condition from both types of retinoschisis. The posterior border of the area of snowflake degeneration is poorly delineated and ir regular, extends along the retinal vessels in some cases, and fades gradually into normal looking retina. In contrast, retinoschisis has a sharp convex posterior edge. While snowflake degeneration extends to the ora serrata, the anterior limit of congenital retinoschisis seldom does.8 The macula was not affected in our patients, but is usually involved in con genital retinoschisis.8 Senile retinoschisis usually starts with cystoid degeneration at the ora serrata,16 but our patients had no marked cystoid degeneration. Wagner's disease should be considered in differential diagnosis because of the presence of myopia, presenile cataract, retinal pig mentation, sheathed retinal vessels, vitreous degeneration,9'10 and minute yellow-white dots17 in the peripheral retina. In fact, at first we thought our patients were affected by Wagner's disease. However, examination of more patients with Wagner's disease3 in dicated that there are definite differences be tween the appearance of the vitreous and
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SNOWFLAKE DEGENERATION
retina in this disease and in snowflake de generation. No vitreous membrane with a hole and no optically empty vitreous cavity, so characteristic of Wagner's disease, occur red in any patient in the present study. Vit reous degeneration in this series was fibrillar rather than membranous. In the early stage of Wagner's disease, a localized area of thinned pigment epithelium or atrophy of the choriocapillaris results in exposure of the large choroidal vessels.3'10 The earliest change in the fundus of our pa tients was either wwp or snowflakes, both presumably caused by alterations in the cor tical vitreous or inner retinal layers, or both, rather than in the pigment epithelium and the choroid. As a result, the choroidal pat tern was obscured in the early stages of our cases, in contrast to its exposure in Wagner's disease. Absence of central or peripheral retinoschisis in our patients excluded the possibility of Goldmann-Favre's disease.11"13 This is further supported by the presence of fairly good ERG responses in our patients (unpub lished observations), in contrast to complete loss of the b-wave with retention of the awave, or a nonrecordable ERG in GoldmannFavre's disease.13'18 The latter is transmitted by an autosomal recessive trait, while our pa tients transmitted the disease by autosomal dominant inheritance. Three additional familial vitreoretinal dis eases have been reported by Favre, 19 FeilerOfry and associates,20 and Criswick and Schepens.21 The vitreous changes in our cases were similar to those in Favre's cases,19 which Francois called macrofibrillar vi treoretinal degeneration.22 Favre 19 noted cystoid peripheral degeneration in one of his patients. The fundus changes in his other pa tients were described as peripheral retinal degeneration. He did not describe snowflakes, retinal pigmentation, or sheathing or disappearance of retinal vessels, so it re mains uncertain whether or not our cases are the same as Favre's. The absence of congeni tal night blindness in our patients (unpub
1S1
lished observations) suggested that the dis ease is not identical to that described by Feiler-Ofry and his associates as hereditary vitreoretinal degeneration and night blind ness.20 Absence of neovascularization and exudation excludes familial exudative vitreoretinopathy.21 Other diseases have similar clinical fea tures and should be considered in the differ ential diagnosis of snowflake degeneration. The yellow-white dots of snowflake degener ation look entirely different ophthalmoscopically from the white dots seen in retinitis punctata albescens or fundus albipunctatus cum hemeralopia. The dots we observed were smaller, more yellowish, more densely packed, and distributed more peripherally than those in retinitis punctata albescens and related diseases. Lack of congenital night blindness in our patients also excluded reti nitis punctata albescens.23 The slowly pro gressive nature of the disease observed ex cluded fundus albipunctatus cum hemeralo pia, which is stationary.23 The clumps of pigment and the disappear ance of retinal vessels found in our patients at a late stage of the disease might suggest retinitis pigmentosa and related diseases. Al though wide varieties of retinitis pigmentosa have been described, there are more dispari ties than similarities between the clinical picture of our cases and that of retinitis pig mentosa. In retinitis pigmentosa, clumps of jet-black pigment, often with a bone spicule arrangement, usually appear at the equator, while the retina in the extreme periphery re mains normal.23 This produces an annular scotoma. In our patients, however, the fun dus changes started in the. extreme periphery and the field defect observed was not a ring scotoma but a circular depression of the pe ripheral visual field (unpublished observa tions). The retinal pigment was brownishblack rather than jet-black, it formed round or irregular clumps, and it appeared only in the late stages. Initially, snowflake degenera tion seems localized in the inner retinal layers, whereas retinitis pigmentosa starts in the
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neuroepitheliiim. All our patients enjoyed relatively good vision until they were affected by cataract or retinal detachment. Even our oldest patient, aged 70, was far from blind. Most patients with retinitis pigmentosa lose useful vision by this age. 23 T h e crater-like retinal areas with snowflakes may be similar, but not identical, to those described as retinal erosion 24 and vitre ous base excavation. 25 Retinal erosion re veals white dots in the vitreous instead of in the retina, and white dots are not mentioned in discussions of vitreous base excavations. 2 5 Yellow-white dots have been described as one of the characteristic changes in the early stage of lattice degeneration. 4 ' 5 Typical lattice degeneration is sharply demarcated, has its long axis parallel to the equator, is located between the equator and the ora serrata, 4 ' 5 but it is not usually seen at the ora. 26 It is char acterized by a network of fine white lines, small discrete yellow-white particles, and ab normalities of the adjacent vitreous. 4 ' 5 ' 2 6 T h e lesion becomes pigmented in the late stages. T h e snowflake degeneration de scribed here is extensive and starts near the ora serrata. Its posterior border is irregular, ill-defined, and partly fused with crater-like areas, and it protrudes radially along the ret inal vessels. Its distribution in the peripheral fundus is so diffusely spread that it does not look like lattice degeneration. Relatively large retinal vessels are sheathed in the area of snowflake degeneration or near the optic disk, but we did not see the network of fine white lines so characteristic of lattice degen eration, except in one patient. Some of the patients with snowflake degeneration have been observed for 20 years, and none has de veloped lesions resembling lattice. Snowflake degeneration is obviously then not an early stage of lattice degeneration. O n e of the pa tients studied was 70 years old, and the snowflake area in her fundus was free of visible retinal vessels; it seems unlikely that this area will eventually develop the changes typical of lattice degeneration. T h e individual yellow-white spots seen in
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our patients may suggest snail-track degen eration. However, the location of the frost like changes in the latter is similar to that in lattice degeneration. 27 T h e fundus changes in our patients cannot be identified as snailtrack degeneration for the reasons described above. SUMMARY
Long-term follow-up of 15 members of one family that produced five patients with retinal detachment disclosed a peculiar type of progressive vitreoretinal degeneration, probably of autosomal dominant inheritance. T h e fundus appearance evolved through four stages: ( 1 ) extensive white-with-press u r e ; ( 2 ) snowflake degeneration; ( 3 ) sheathing of retinal vessels and pigmenta tion; and ( 4 ) increased pigmentation and disappearance of retinal vessels. A swirling fibrillar vitreous degeneration, equally pro gressive in nature, accompanied these fun dus changes. T h e cases observed were com pared with other diseases affecting the vitre ous and retina, especially Wagner's disease, Favre's macrofibrillary vitreoretinal degen eration, and extensive lattice degeneration. ACKNOWLEDGMENTS
W e thank Richard J. Goduti, M.D., of Portland, Maine, for sending us his patients; Leonard Atkins, M.D., Massachusetts General Hospital, for chromo some studies; Lewis B. Holmes, M.D., Genetic Unit at Massachusetts General Hospital, for his opinions on the genetics of the disease; and David Tilden, the Retina Foundation's illustrator, for the fundus drawing. REFERENCES 1. Cockerham, W. D., and Schepens, C. L.: Tech nique of vitreous cavity examination. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 66. 2. Schepens, C. L . : Techniques of examination of the fundus periphery. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 39. 3. Hirose, T., Lee, K. Y., and Schepens, C. L . : Wagner's hereditary vitreoretinal degeneration and retinal detachment. Arch. Ophthalmol. 89:175, 1973.
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4. Straatsma, B. R.: Lattice degeneration of the retina. Clinical description and course. In Kimura, S. J., and Caygill, W. M. (eds.) : Retinal Diseases. Philadelphia, Lea and Febiger, 1966, p. 155. 5. Spencer, L. M., Straatsma, B. R., and Foos, R. Y.: Tractional degenerations of the peripheral retina. In Symposium on Retina and Retinal Surg ery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 103. 6. Duke-Elder, S., and Abrams, D.: Ophthalmic Optics and Refraction. In Duke-Elder, S. (ed.) : System of Ophthalmology, vol. 5. St. Louis, C. V. Mosby, 1970, p. 326. 7. Kleinert, H.: Eine recessiv-geschlechtsgebundene Form der idiopathischen Netzhautspaltung bei nichtmyopen Jugendlichen. Graefe's Arch. Ophthal mol. 154:295,1953. 8. Kraushar, M. F., Schepens, C. L., Kaplan, J. A., and Freeman, H. M.: Congenital retinoschisis. In Contemporary Ophthalmology. Honoring Sir Stew art Duke-Elder. Baltimore, Williams and Wilkins, 1972, p. 265. 9. Wagner, H.: Ein bisher unbekanntes Ergleiden des Auges (Degeneratio hyaloideo-retinalis hereditaria), beobachtet im Kanton Zurich. Klin. Monatsbl. Augenheilkd. 100:840, 1938. 10. Alexander, R. L., and Shea, M.: Wagner's disease. Arch. Ophthalmol. 74:310, 1965. 11. Busacca, A., Goldmann, H., and SchiffWertheimer, S.: Biomicroscopie du corps vitre et du fond de l'oeil. Rapports presentes a la Societe Francaise d'Ophthalmologie. Paris, Masson and Co., 1957, p. 164. 12. Favre, M.: A propos de deux cas de degenerescence hyaloideoretinienne. Ophthalmologica 135 : 604, 1958. 13. Ricci, A.: Clinique et transmission genetique des differentes formes de degenerescence vitreoretinienne. Ophthalmologica 139:338, 1960. 14. Jaffe, N. S.: The Vitreous in Clinical Ophthal mology. St. Louis, C. V. Mosby, 1969, p. 235. 15. Zimmerman, L. E., and Spencer, W. H.: The
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pathologic anatomy of retinoschisis. Arch. Ophthal mol. 63:10, 1960. 16. Shea, M., Schepens, C. L., and von Pirquet, S. R.: Retinoschisis. 1. Senile type: A clinical re port of 107 cases. Arch. Ophthalmol. 63:1, 1960. 17. Jansen, L. M. A. A.: Degeneration hyaloideoretinalis hereditaria. Ophthalmologica 144:458, 1962. 18. Carr, R. E., and Siegel, I. M.: The vitreotapeto-retinal degenerations. Arch. Ophthalmol. 84:436,1970. 19. Favre, M.: Degenerescence "myopique" du corps vitre et emmetropie. Ophthalmologica 141: 357, 1961. 20. Feiler-Ofry, V., Adam, A., Regenbogen, L., Godel, V., and Stein, R.: Hereditary vitreoretinal degeneration and night blindness. Am. J. Ophthalmol. 67:553, 1969. 21. Criswick, V. G., and Schepens, C. L.: Familial exudative vitreoretinopathy. Am. J. Ophthalmol. 68:578, 1969. 22. Francois, J.: The role of heredity in retinal detachment. In McPherson, A. (ed.): New and Controversial Aspects of Retinal Detachment. New York, Harper and Row Hoeber Medical Division, 1968, p. 101. 23. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder, S. (ed.) : System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, p. 326. 24. Rutnin, U., and Schepens, C. L.: Fiindus ap pearance in normal eyes. 3. Peripheral degenerations. Am. J. Ophthalmol. 64:1040, 1967. 25. Foos, R. Y., Spencer, L. M., and Straatsma, B. R.: Trophic degenerations of the peripheral ret ina. In Symposium on Retina and Retinal Surgery. Transactions of the New Orleans Academy of Ophthalmology. St. Louis, C. V. Mosby, 1969, p. 90. 26. Schepens, C. L.: Subclinical retinal detach ments. Arch. Ophthalmol. 47:593, 1952. 27. Aaberg, T. M., and Stevens, T. R.: Snail track degeneration of the retina. Am. J. Ophthalmol. 73:370, 1972.