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Changes Around the Optic Nervehead: in presumed ocular histoplasmosis
AMERICAN
454
JOURNAL
OF OPHTHALMOLOGY
Symposium. Boston, Little-Brown, 1963, pp. 36-77. "15. Weiss, L. P., and Fawcett, D. W . : Cytochemical observations on chicken monocytes, macrophages and giant cells in tissue culture. J. Histochem. & Cytochem. 1:47, 1953.
SEPTEMBER,
1966
16. Weimar, V.: The sources of fibroblasts in corneal wound repair. Arch. Ophth. 60 :93, 1958. 17. Waardenburg, P . J., Franceschetti, A. and Klein, D . : Genetics and Ophthalmology. Springfield, Thomas, 1961, p. 456.
CHANGES AROUND THE OPTIC NERVEHEAD IN T.
F.
PRESUMED OCULAR
SCHLAEGEL, J R . , M.D.,
Indianapolis,
HISTOPLASMOSIS
AND DAVID K E N N E Y , M . D .
Indiana
1-11
Various investigators have accepted histoplasmosis as the cause of a type of dis seminated choroiditis resulting in small, yel low, randomly scattered atrophic areas with or without macular involvement. These atro phic areas are 0.10 to 0.5 disc diameters in size, located at the level of the choriocapillaris, and may be seen anywhere in the fundus including the posterior pole. Changes around the optic nervehead have been men tioned before but never described thorough ly. As suggested by Maumenee and by Gass, involvement of the macula and/or disc area by disci form detachment of the retina seems to be due to a serous or hemorrhagic leak from the choriocapillaris, perhaps at the site of a mild nodular choroiditis. In this study, a diagnosis of presumed histoplasmosis was made on the basis of this typical clinical picture plus a positive histoplasmin skin test or a positive complement fixation test. In 52 of our first 110 cases, fundus photographs were taken of both optic discs so that a study could be made of the changes around them. Thirty-six of our 52 cases (70%) had in volvement around both optic discs (table 1). Involvement about only one disc was much From the Department of Ophthalmology, Indiana University School of Medicine. This investigation was supported in part by Research to Prevent Blind ness, Inc., New York.
TABLE 1 FREQUENCY OF CIRCUMPAPILLARY
INVOLVEMENT
Cases
Percentage
Both discs One disc Neither disc
36 8 8
70% 15%, 15%
TOTAL
52
100%
TABLE 2 T Y P E S OF
CIRCUMPAPILLARY I N V O L V E M E N T
Types
Discs
Percentage
Diffuse Nodular Mixed Hemorrhagic
39 23 9 9
49% 29% 11% 11%
80
100%,
less common (eight cases, 15%). Our pho tographs failed to show evidence of choroid itis around either disc in only 15%. TYPES OF CHOROIDITIS AROUND THE DISC
(table 2) The most common type of involvement was diffuse without discernible nodules (49%). A nodular type with yellow spots similar to those seen scattered throughout the fundus was present in 29%. A combined or mixed type was seen in 11%, and a symptomatic or hemorrhagic type in 1 1 % . Since our uveitis service is referral in type,
Figs. 1-4 (Schlaegel and Kenney). Types of choroiditis around the disc presumed t o be due to histoplasmosis: Figure 1-A and B. diffuse. Figure 2-A and B, nodular. Figure 3-A and B, mixed. Figure 4-A, active hemorrhagic, and B, healed hemorrhagic.
B
Fig. I-A
Fig. 3-A
Fig. 4-A
DIFFUSE
Fig. I B
NODULAR
Fig. 2-B
MIXED
HEMORRHAGIC
Fig. 3-1
F i g . 4-B
456
AMERICAN JOURNAL OF OPHTHALMOLOGY
it tends to attract severe cases so this 1 1 % incidence of the severe or hemorrhagic type of juxtapapillar\ r choroiditis may be higher than would be found in an unselected group of patients with ocular histoplasmosis. The retina was not elevated except in the severe hemorrhagic variety when disciform detach ment of the retina next to the disc was rou tinely present. Diffuse. The diffuse pattern of choroiditis had a yellow or yellow-gray appearance (fig. 1-A and B ) . T h e smaller retinal blood ves sels passed over this area without being in volved. T h e outer margin was irregular and indistinct and extended outward from the disc from 0.125 to 0.5 disc diameters. Al though pigmentation is not a prominent fea ture of histoplasmic choroiditis, a line of pigment may be seen bordering the disc in side the area of circumpapillary involve ment. This pigment was located at the level of the pigment epithelium and apparently derived from this layer. In one case there was a punctate hemorrhage lying deep in the retina but not a single patient had any symptoms referrable to this diffuse type of circumpapillary involvement. Nodular. From one to 20 nodules were seen around the disc. These nodules were ap proximately the size of the peripheral le sions of presumed histoplasmic choroiditis (0.1 to 0.5 disc diameters) and the color about the same as the disseminated lesions which was somewhat more yellow than the diffuse type of involvement (fig. 2-A and B ) . There seemed to be no predilection for any certain portion of the disc circumfer ence and this nodular choroiditis produced no symptoms in any of our patients. W e as sume that a nodular choroiditis has ap peared and then rapidly flattened out. This assumption is based on the rare observation with the slitlamp of this same course of events occurring in one of the more periph eral disseminated yellow spots and on exam ples of the supposed pathology. Mixed (diffuse-nodular). Many cases of circumpapillary choroiditis showed both nod-
S E P T E M B E R , 1966
TABLE 3 VISUAL OUTCOME IN NINE CASES OF THE HEMORRHAGIC TYPE OF CIRCUMPAPILLARY CHOROIDITIS
Visual Acuity
No. of Eyes
20/15 20/20 20/30 20/50 20/200 20/400
2 1 1 1 3 1
ular and diffuse changes. W h e n they were about equally divided, they were designated as mixed (fig. 3-A and B ) . Again no symp toms were produced. Hemorrhagic. These cases had a severe and symptomatic course. The hemorrhages (fig. 4-A) were beneath the retina a n d / o r the pigment epithelium and were usually' moderately severe with 360 degrees of cir cumpapillary involvement, although occa sionally they were limited to one side of the disc. Unfortunately the hemorrhagic form was often bilateral but not at the same time. Disciform detachment of the retina a n d / o r pigment epithelium may extend into the macula and cause temporary or permanent loss of vision. Of the nine eyes with severe involvement around the discs, four re covered useful central vision and four were left with permanent macular damage and a vision of 20/200 or less (table 3 ) . A n ele vated and usually white scar remained at the site of the hemorrhage and most severe inflammation next to the disc (fig. 4 - B ) . T h e usual scotoma (fig. 5-A) is centrally located and results from macular scarring. W i t h the 1/1000 white isopter we were not able to outline an arcuate scotoma in any of our cases indicating that the nerve fiber layer is seldom involved in this type of pre sumed ocular histoplasmosis. D I F F E R E N T I A L DIAGNOSIS
The diffuse type of circumpapillary cho roiditis may occasionally be confused with the following: 1. Inferior crescent or Fuchs' coloboma. A rim of pigment surrounds a white cres-
VOL. 62, NO. 3
NERVEHEAD IN HISTOPLASMOSIS LEFT EYE
RIGHT EYE
1/1000
1/1000 Vision.
. Reliable .
457
Vision.
.Date. . Field No
1
Fig. 5 (Schlaegel and Kenney). ( A ) Left eye, showing usual type of central scotoma. ( B ) Right eye, showing cecocentral scotoma due to extensive old scars.
cent beyond which the choroid may be thinned. In diffuse circumpapillary choroiditis, in contrast, the rim of pigment when present lies on the inner edge and the outside border of the choroiditis is irregular (fig. 1-A and B ) . 2. Scleral ring. T h e so-called scleral ring is seldom a complete ring but is most often seen on the temporal border of the disc. It is easily confused with the diffuse type of circumpapillary change unless a thin rim of pigment is present. T h e rim of pigment in the case of the scleral ring is on its outside edge whereas when due to histoplasmosis, it is on the inside edge. 3. Myopic crescent. A myopic crescent lies outside the scleral ring usually on the temporal side, is whiter and has a thin rim of pigment on its outer edge; whereas, cir cumpapillary choroiditis often has a thin rim of pigment on its inner edge separating the involved area from the disc. A situation easily confused with presumed ocular histo plasmosis is that in which atrophic areas of myopic degeneration about one-third disc diameter in size are scattered about the pos
terior pole. In mypoic degeneration how ever, these spots are whiter and tend to have scalloped edges. The presence of high myopia is helpful in such an instance, al though the two conditions could conceivably occur together. 4. Senile halo. A senile halo is not dis tinct and usually forms a yellowish-red or pale-red crescent on the temporal side. It may have a thin rim of pigment on its outer edge, not its inner edge as in that due to his toplasmosis. T h e nodular type of circumpapillary cho roiditis could be confused with drusen of the optic disc. 5. Drusen. Drusen occur over the surface of the disc as well as at its margin. They may protrude and can give rise to a nervefiber bundle defect. The nodules seen in ocular histoplasmosis, although similar to drusen in color, occur only at the periphery of the disc, are not elevated, do not glisten, and do not cause a nerve-fiber bundle block. T h e hcnwrrhagic type of circumpapillary choroiditis is occasionally referred with a tentative diagnosis of malignant melanoma.
458
AMERICAN JOURNAL OF OPHTHALMOLOGY
6. Malignant melanoma. Hemorrhage is uncommon and edema residues absent. I n the case of the hematoma which results from the heniorrhagic type of severe juxtapapillary histoplasmic choroiditis, the clini cal picture changes within a few weeks so that the correct diagnosis becomes easy. T h e typical disseminated areas of atrophic cho roiditis in both eyes and the presence of circumpapillary choroiditis in the opposite eye also aid in establishing histoplasmic choroid itis as the etiology. Other types of choroidi tis, however, may give rise to a heniorrhagic disciform detachment of the retina adjacent to the disc. SUMMARY
A study of the photographs of the disc region of 52 cases of presumed ocular histo plasmosis revealed an 8 5 % incidence of juxtapapillary choroiditis, 7 0 % bilateral, and 1 5 % unilateral. Neither disc was in volved in the remaining 1 5 % . Because these changes around the disc are common they are of help in making the clinical diagnosis of ocular histoplasmosis. F o u r types of pre sumed choroiditis around the disc were seen: diffuse, nodular, mixed (diffuse-nodu lar) and heniorrhagic. N o symptoms were present in any of the first three types. Some patients with the hemorrhagic type were probably referred because of their serious nature, producing an artificially high inci dence ( 1 1 % ) . Such hemorrhagic choroiditis with its disciform detachment of the macula
SEPTEMBER, 1966
was accompanied by a serious loss of central acuity. Half of these patients made substan tial visual recoveries, whereas the other half were left with a central vision of 20/200 or worse. 1100 West Michigan Street (46207) REFERENCES
1. Woods, A. C , and Wahlen, H. E . : The prob able role of benign histoplasmosis in the etiology of granulomatous uveitis. Am. T- Opbth. 49:205, 1960. 2. Falls, H. F., and Giles, C. L.: The use of Amphotericin-B in selected cases of chorioretini tis. Am. T. Opbth. 49:1288, 1960. 3. Giles, C. L., and Falls, H. F . : Further evaluation of amphotericin-B therapy in presump tive histoplasmosis chorioretinitis. Am. T- Ophth. 51 :588, 1961. 4. McCulloch, C.: Histoplasmosis. T r . Can. Opbth. Soc. 26:107, 1963. 5. Tarvis, G. J. and McCulloch, C.: Ocular his toplasmosis. Canad. M. A. J. 89:1270, 1963. 6. Walma, D., and Scblaegel, T. F . : Presumed histoplasmic choroiditis. Am. T. Ophth. 57:107, 1964. 7. Van Metre, T. E., Jr., and Maumenee, A. E . : Specific ocular uveal lesions in patients with evidence of histoplasmosis. Arch. Ophth. 71:314 1964. 8. Makley, T. A., Long, J. W., Suie, T. and Stephan, J. D.: Presumed histoplasmic chorioretinitis with specific emphasis on the present modes of therapy. Tr. Am. Acad. Ophth. 61 :433, 1965. 9. Woods, A. C.: Endogenous Inflammations of the Uveal Tract. Baltimore, Williams & Wilkius, 1961, pp. 169-176. 10. Klien, B. A.: A symposium on differential diagnostic problems of posterior uveitis. Dec. 2-5, 1964, Univ. Calif. Mod. Center, San Francisco. 11. Maumenee, A. E . : A symposium on differential diagnostic problems of posterior uvei tis. Dec. 2-5, 1964, Univ. Calif. Med. Center, San Francisco.
454
JOURNAL
OF OPHTHALMOLOGY
Symposium. Boston, Little-Brown, 1963, pp. 36-77. "15. Weiss, L. P., and Fawcett, D. W . : Cytochemical observations on chicken monocytes, macrophages and giant cells in tissue culture. J. Histochem. & Cytochem. 1:47, 1953.
SEPTEMBER,
1966
16. Weimar, V.: The sources of fibroblasts in corneal wound repair. Arch. Ophth. 60 :93, 1958. 17. Waardenburg, P . J., Franceschetti, A. and Klein, D . : Genetics and Ophthalmology. Springfield, Thomas, 1961, p. 456.
CHANGES AROUND THE OPTIC NERVEHEAD IN T.
F.
PRESUMED OCULAR
SCHLAEGEL, J R . , M.D.,
Indianapolis,
HISTOPLASMOSIS
AND DAVID K E N N E Y , M . D .
Indiana
1-11
Various investigators have accepted histoplasmosis as the cause of a type of dis seminated choroiditis resulting in small, yel low, randomly scattered atrophic areas with or without macular involvement. These atro phic areas are 0.10 to 0.5 disc diameters in size, located at the level of the choriocapillaris, and may be seen anywhere in the fundus including the posterior pole. Changes around the optic nervehead have been men tioned before but never described thorough ly. As suggested by Maumenee and by Gass, involvement of the macula and/or disc area by disci form detachment of the retina seems to be due to a serous or hemorrhagic leak from the choriocapillaris, perhaps at the site of a mild nodular choroiditis. In this study, a diagnosis of presumed histoplasmosis was made on the basis of this typical clinical picture plus a positive histoplasmin skin test or a positive complement fixation test. In 52 of our first 110 cases, fundus photographs were taken of both optic discs so that a study could be made of the changes around them. Thirty-six of our 52 cases (70%) had in volvement around both optic discs (table 1). Involvement about only one disc was much From the Department of Ophthalmology, Indiana University School of Medicine. This investigation was supported in part by Research to Prevent Blind ness, Inc., New York.
TABLE 1 FREQUENCY OF CIRCUMPAPILLARY
INVOLVEMENT
Cases
Percentage
Both discs One disc Neither disc
36 8 8
70% 15%, 15%
TOTAL
52
100%
TABLE 2 T Y P E S OF
CIRCUMPAPILLARY I N V O L V E M E N T
Types
Discs
Percentage
Diffuse Nodular Mixed Hemorrhagic
39 23 9 9
49% 29% 11% 11%
80
100%,
less common (eight cases, 15%). Our pho tographs failed to show evidence of choroid itis around either disc in only 15%. TYPES OF CHOROIDITIS AROUND THE DISC
(table 2) The most common type of involvement was diffuse without discernible nodules (49%). A nodular type with yellow spots similar to those seen scattered throughout the fundus was present in 29%. A combined or mixed type was seen in 11%, and a symptomatic or hemorrhagic type in 1 1 % . Since our uveitis service is referral in type,
Figs. 1-4 (Schlaegel and Kenney). Types of choroiditis around the disc presumed t o be due to histoplasmosis: Figure 1-A and B. diffuse. Figure 2-A and B, nodular. Figure 3-A and B, mixed. Figure 4-A, active hemorrhagic, and B, healed hemorrhagic.
B
Fig. I-A
Fig. 3-A
Fig. 4-A
DIFFUSE
Fig. I B
NODULAR
Fig. 2-B
MIXED
HEMORRHAGIC
Fig. 3-1
F i g . 4-B
456
AMERICAN JOURNAL OF OPHTHALMOLOGY
it tends to attract severe cases so this 1 1 % incidence of the severe or hemorrhagic type of juxtapapillar\ r choroiditis may be higher than would be found in an unselected group of patients with ocular histoplasmosis. The retina was not elevated except in the severe hemorrhagic variety when disciform detach ment of the retina next to the disc was rou tinely present. Diffuse. The diffuse pattern of choroiditis had a yellow or yellow-gray appearance (fig. 1-A and B ) . T h e smaller retinal blood ves sels passed over this area without being in volved. T h e outer margin was irregular and indistinct and extended outward from the disc from 0.125 to 0.5 disc diameters. Al though pigmentation is not a prominent fea ture of histoplasmic choroiditis, a line of pigment may be seen bordering the disc in side the area of circumpapillary involve ment. This pigment was located at the level of the pigment epithelium and apparently derived from this layer. In one case there was a punctate hemorrhage lying deep in the retina but not a single patient had any symptoms referrable to this diffuse type of circumpapillary involvement. Nodular. From one to 20 nodules were seen around the disc. These nodules were ap proximately the size of the peripheral le sions of presumed histoplasmic choroiditis (0.1 to 0.5 disc diameters) and the color about the same as the disseminated lesions which was somewhat more yellow than the diffuse type of involvement (fig. 2-A and B ) . There seemed to be no predilection for any certain portion of the disc circumfer ence and this nodular choroiditis produced no symptoms in any of our patients. W e as sume that a nodular choroiditis has ap peared and then rapidly flattened out. This assumption is based on the rare observation with the slitlamp of this same course of events occurring in one of the more periph eral disseminated yellow spots and on exam ples of the supposed pathology. Mixed (diffuse-nodular). Many cases of circumpapillary choroiditis showed both nod-
S E P T E M B E R , 1966
TABLE 3 VISUAL OUTCOME IN NINE CASES OF THE HEMORRHAGIC TYPE OF CIRCUMPAPILLARY CHOROIDITIS
Visual Acuity
No. of Eyes
20/15 20/20 20/30 20/50 20/200 20/400
2 1 1 1 3 1
ular and diffuse changes. W h e n they were about equally divided, they were designated as mixed (fig. 3-A and B ) . Again no symp toms were produced. Hemorrhagic. These cases had a severe and symptomatic course. The hemorrhages (fig. 4-A) were beneath the retina a n d / o r the pigment epithelium and were usually' moderately severe with 360 degrees of cir cumpapillary involvement, although occa sionally they were limited to one side of the disc. Unfortunately the hemorrhagic form was often bilateral but not at the same time. Disciform detachment of the retina a n d / o r pigment epithelium may extend into the macula and cause temporary or permanent loss of vision. Of the nine eyes with severe involvement around the discs, four re covered useful central vision and four were left with permanent macular damage and a vision of 20/200 or less (table 3 ) . A n ele vated and usually white scar remained at the site of the hemorrhage and most severe inflammation next to the disc (fig. 4 - B ) . T h e usual scotoma (fig. 5-A) is centrally located and results from macular scarring. W i t h the 1/1000 white isopter we were not able to outline an arcuate scotoma in any of our cases indicating that the nerve fiber layer is seldom involved in this type of pre sumed ocular histoplasmosis. D I F F E R E N T I A L DIAGNOSIS
The diffuse type of circumpapillary cho roiditis may occasionally be confused with the following: 1. Inferior crescent or Fuchs' coloboma. A rim of pigment surrounds a white cres-
VOL. 62, NO. 3
NERVEHEAD IN HISTOPLASMOSIS LEFT EYE
RIGHT EYE
1/1000
1/1000 Vision.
. Reliable .
457
Vision.
.Date. . Field No
1
Fig. 5 (Schlaegel and Kenney). ( A ) Left eye, showing usual type of central scotoma. ( B ) Right eye, showing cecocentral scotoma due to extensive old scars.
cent beyond which the choroid may be thinned. In diffuse circumpapillary choroiditis, in contrast, the rim of pigment when present lies on the inner edge and the outside border of the choroiditis is irregular (fig. 1-A and B ) . 2. Scleral ring. T h e so-called scleral ring is seldom a complete ring but is most often seen on the temporal border of the disc. It is easily confused with the diffuse type of circumpapillary change unless a thin rim of pigment is present. T h e rim of pigment in the case of the scleral ring is on its outside edge whereas when due to histoplasmosis, it is on the inside edge. 3. Myopic crescent. A myopic crescent lies outside the scleral ring usually on the temporal side, is whiter and has a thin rim of pigment on its outer edge; whereas, cir cumpapillary choroiditis often has a thin rim of pigment on its inner edge separating the involved area from the disc. A situation easily confused with presumed ocular histo plasmosis is that in which atrophic areas of myopic degeneration about one-third disc diameter in size are scattered about the pos
terior pole. In mypoic degeneration how ever, these spots are whiter and tend to have scalloped edges. The presence of high myopia is helpful in such an instance, al though the two conditions could conceivably occur together. 4. Senile halo. A senile halo is not dis tinct and usually forms a yellowish-red or pale-red crescent on the temporal side. It may have a thin rim of pigment on its outer edge, not its inner edge as in that due to his toplasmosis. T h e nodular type of circumpapillary cho roiditis could be confused with drusen of the optic disc. 5. Drusen. Drusen occur over the surface of the disc as well as at its margin. They may protrude and can give rise to a nervefiber bundle defect. The nodules seen in ocular histoplasmosis, although similar to drusen in color, occur only at the periphery of the disc, are not elevated, do not glisten, and do not cause a nerve-fiber bundle block. T h e hcnwrrhagic type of circumpapillary choroiditis is occasionally referred with a tentative diagnosis of malignant melanoma.
458
AMERICAN JOURNAL OF OPHTHALMOLOGY
6. Malignant melanoma. Hemorrhage is uncommon and edema residues absent. I n the case of the hematoma which results from the heniorrhagic type of severe juxtapapillary histoplasmic choroiditis, the clini cal picture changes within a few weeks so that the correct diagnosis becomes easy. T h e typical disseminated areas of atrophic cho roiditis in both eyes and the presence of circumpapillary choroiditis in the opposite eye also aid in establishing histoplasmic choroid itis as the etiology. Other types of choroidi tis, however, may give rise to a heniorrhagic disciform detachment of the retina adjacent to the disc. SUMMARY
A study of the photographs of the disc region of 52 cases of presumed ocular histo plasmosis revealed an 8 5 % incidence of juxtapapillary choroiditis, 7 0 % bilateral, and 1 5 % unilateral. Neither disc was in volved in the remaining 1 5 % . Because these changes around the disc are common they are of help in making the clinical diagnosis of ocular histoplasmosis. F o u r types of pre sumed choroiditis around the disc were seen: diffuse, nodular, mixed (diffuse-nodu lar) and heniorrhagic. N o symptoms were present in any of the first three types. Some patients with the hemorrhagic type were probably referred because of their serious nature, producing an artificially high inci dence ( 1 1 % ) . Such hemorrhagic choroiditis with its disciform detachment of the macula
SEPTEMBER, 1966
was accompanied by a serious loss of central acuity. Half of these patients made substan tial visual recoveries, whereas the other half were left with a central vision of 20/200 or worse. 1100 West Michigan Street (46207) REFERENCES
1. Woods, A. C , and Wahlen, H. E . : The prob able role of benign histoplasmosis in the etiology of granulomatous uveitis. Am. T- Opbth. 49:205, 1960. 2. Falls, H. F., and Giles, C. L.: The use of Amphotericin-B in selected cases of chorioretini tis. Am. T. Opbth. 49:1288, 1960. 3. Giles, C. L., and Falls, H. F . : Further evaluation of amphotericin-B therapy in presump tive histoplasmosis chorioretinitis. Am. T- Ophth. 51 :588, 1961. 4. McCulloch, C.: Histoplasmosis. T r . Can. Opbth. Soc. 26:107, 1963. 5. Tarvis, G. J. and McCulloch, C.: Ocular his toplasmosis. Canad. M. A. J. 89:1270, 1963. 6. Walma, D., and Scblaegel, T. F . : Presumed histoplasmic choroiditis. Am. T. Ophth. 57:107, 1964. 7. Van Metre, T. E., Jr., and Maumenee, A. E . : Specific ocular uveal lesions in patients with evidence of histoplasmosis. Arch. Ophth. 71:314 1964. 8. Makley, T. A., Long, J. W., Suie, T. and Stephan, J. D.: Presumed histoplasmic chorioretinitis with specific emphasis on the present modes of therapy. Tr. Am. Acad. Ophth. 61 :433, 1965. 9. Woods, A. C.: Endogenous Inflammations of the Uveal Tract. Baltimore, Williams & Wilkius, 1961, pp. 169-176. 10. Klien, B. A.: A symposium on differential diagnostic problems of posterior uveitis. Dec. 2-5, 1964, Univ. Calif. Mod. Center, San Francisco. 11. Maumenee, A. E . : A symposium on differential diagnostic problems of posterior uvei tis. Dec. 2-5, 1964, Univ. Calif. Med. Center, San Francisco.