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Retinal Changes in Human Cytomegalovirus Infection: An electron microscopic study
R E T I N A L C H A N G E S IN H U M A N C Y T O M E G A L O V I R U S I N F E C T I O N AN
E L E C T R O N M I ^ROSCOPIC STUDY
ISAMU TSUKAHARA, M . D . , ITSUYA U E N O , M.D., Kyoto, Japan
AND HIDENOKI K A W A N I S H I ,
M.D.
111 recent years, increasing interest in chamber were not remarkable. Both pupils were ocular involvement in cytomegalic inclusion round, four mm in size and did not react to light. The crystalline lens and vitreous were clear. The disease has been reflected in reports on the optic disc was rather hyperemic and its margin histologic changes in the retina and chor- was blurred. The retina was diffusely covered oid. 1- " The characteristic feature of the le witli a grayish-white exudate. Numerous yellow spots and small hemorrhages were scattered sions is the presence of large mononuclear throughout. The retina was slightly detached. After admission, diarrhea, vomiting and anorexia cells containing inclusions both in the nuclei and in the cytoplasm. According to Smith, 6 persisted and the patient gradually became de hydrated. Fluid therapy had no effect. On April the majority of these large cells range in 13, a fever of 38°C to 39°C and pulmonary symp toms developed. These persisted despite vigorous size from 20 [x-30 [A. The intranuclear inclu sions, from 5 i-i-10 [>■ in size, are surrounded antibiotic therapy. On April 21, various neurologic abnormalities developed. The patient died on April by clear haloes which separate the inclusions 25, 1964. The autopsy findings were those of congenital from the nuclear membrane. With hematoxylin and eosin the inclusions are baso- agamma-globulinemia and generalized cytomegal ic. inclusion disease. Inclusion cells were found in philic and the cytoplasmic inclusions are less the lungs, adrenals, posterior pituitary gland, in distinct. In the retina, these large mononu testines, heart, liver, spleen, pancreas, kidneys, clear cells are believed to be mesenchymal thyroid and salivary glands. A more detailed de scription of the physical and laboratory examina or glial/ 1,0 tions and the autopsy appears in another paper.' T h e present report describes the electron METHOD microscopic appearance of the retinal lesions T h e right eye was obtained at autopsy, of an infant with cytomegalic inclusion dis and fixed in formalin. W h e n microscopic ease. examination showed the type of chorioretinC A S E REPORT itis characteristic of cytomegalic inclusion A five-month-old male infant was admitted to disease, an electron microscopic study was Kyoto University Hospital on March 25, 1964, made of the retinal lesions. because of diarrhea and blindness. The infant was T h e remainder of the celloidin block was delivered without complication after a normal pregnancy on October 20, 1963, with a birth cut into small pieces, a few of which were weight of 3,700 gin. Eighteen days prior to ad immersed in an aceton-ether solution for mission mild diarrhea started. On March 15, the several days, then fixed in 2 % isotonic 0 S 0 4 mother noted that the baby could not recognize toys. On February 29, petechiae appeared on the solution with phosphate buffer, dehydrated face, the back of the right hand and both feet in a series of ethyl-alcohol solutions and but faded out within a few days. embedded in epon. Ultrathin sections were Physical and laboratory examination revealed cut with a glass knife in a J U M - 5 micro congenital agamma-globulinemia and asympto matic hyponatremia. There was no anemia or tome and examined with a Hitachi H U - 1 1 thrombocytopenia. An X-ray film of the skull electron microscope. showed no calcification. The liver was palpable three cm below the right costal margin but the spleen was not palpable. Bye examination. Both eyes showed similar findings. The conjunctiva, cornea and anterior From the Departments of Ophthalmology and Pathology, Faculty of Medicine, Kyoto Univer sity, Kyoto City, Japan. 1
RESULTS MICROSCOPIC E X A M I N A T I O N
T h e most striking changes were observed in the retina and choroid. The retina was comparatively normal only in a small area
1154
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1966
Fig. 1 (Tsukahara, Ueno and Kawanishi). Irregular thickening and destruction of the retina. (R) Retina, (CH) Choroid. (XlOO.)
1.5 disc diameters which was 1.5 disc diam eters lateral to the disc. All the rest of the retina was detached and showed irregular thickening and complete disorganization, with areas of hemorrhage and necrosis (fig. 1). In the involved area there was a moder ate infiltration of lymphocytes. T h e most characteristic feature was the presence throughout the retina of numerous large cells, 20{/.-35pt, in diameter, containing in tranuclear inclusions (fig. 2 ) . T h e intranu clear inclusions were basophilic, stained dark blue with hematoxylin and appeared granular. They were 10(Jt-15(x in diameter and were separated from the nuclear mem brane by a clear halo (fig. 2 ) . T h e nuclear chromalin was marginated along the nuclear membrane. In the choroid large cells con taining intranuclear inclusions were found within the lumen of the larger veins.
7 ) . Characteristic intranuclear inclusions were lattice or sievelike in shape and from them numerous immature viruses, with empty or full cores and measuring 80 nifji,100 mj/, in diameter, were being formed (figs. 6, 7 and 8 ) . I n the cytoplasm were scattered mature viruses with a nucleoid of high electron density and two coats (figs. 9 and 10). These viruses measured 160 m\x180 mji. in diameter. I n addition, throughout the cytoplasm of the infected large cells, there were numerous homogeneous gran ules of various sizes surrounded by a lim iting membrane (figs. 9 and 10). Some of
ELECTRON MICROSCOPIC E X A M I N A T I O N
The structure of the retina was complete ly destroyed except for the pigment epitheli al layer and internal limiting membrane (figs. 3, 4 and 5 ) . Comparatively wellpreserved pigment epithelial cells, which were apparently not infected, contained scattered fuscin granules and the microvillilike processes on their free surfaces had dis appeared (fig. 5 ) . T h e infected large cells had prominent polar nucleoli (figs. 6 and
Fig. 2 (Tsukahara, Ueno and Kawanishi). Large mononuclear cells containing intranuclear inclusions in the retina (arrows) (X 1,000.)
VOL. 62, N O . 6
HUMAN CYTOMEGALOVIRUS INFECTION
1155
jEBffNh
Fig. 3 (T.snkahara, Ueno and Kawanishi). Low magnification electron micrograph of a cross section of inner part of the retina. (VIS) Vitreous body. ( I L M ) Internal limiting membrane. ( L ) Lymphocyte. (X3.200.)
the larger granules had mature virus particles on the surface, occasionally sepa rating small homogenous granules. A few mulberry-like organized bodies were also occasionally noted in the cytoplasm (fig. 11). Bruch's membrane and the choriocapillary layer of the choroid did not show any particular change but a few viruses with an
<-M
Fig. 4 (Tsnkahara, LTeno and Kawanishi). Middle part of the retina. ( C I ) Cells infected by cytomegalovirus (CID) Degenerated, infected cells. ( N p ) Pyknotic nucleus. ( L ) Lymphocyte. ( X 3,200.)
1156
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1966
c i S i r U S t p - 1 1 ' 1 1 ' V e n ° f ; l l r 1 K ™ ^ ) . Electron micrograph of pigment epithelium and chorio!' 7 - (Sf) Fnscn, granule, (ml,) Myeloid body. (ISM) Rruch's membrane. C Qiluififmei (L; LapilUuy of the chonocapillans with (E) erythrocyte and (VM) mature virus. (X18.W0.)
indistinct nucleoid were detected within the capillary lumen (figs. 5, 12 and 13). The vitreous body near the internal limiting membrane disclosed nothing of particular interest (fig. 3 ) . COMMENT
Cytomegalic inclusion disease has particu lar interest for the ophthalmologist because it may be confused with toxoplasmosis. De scriptions of microscopic observations of retinal and choroid involvement in both in fant and adult cytomegalic inclusion disease have appeared in the literature. 1 •3>5>6 To date, however, electron microscopic exam ination of the retina in this disease has not been reported. Microscopic study of our pa tient's right eye revealed numerous large mononuclear cells containing intranuclear
inclusions throughout the retina. Electron microscopy showed characteristic intranu clear inclusions resembling latticelike or sievelike plates from which numerous vi ruses were developing. The clear halo sepa rating the inclusion bodies from the nuclear membrane was not conspicuous in the elec tron micrographs, suggesting that the halo is probably an artifact. 8 It is interesting to note that mature viruses were seen on the surface of homogenous granules in the cyto plasm of infected cells. T h e origin of the large cells in the retina could not be deter mined but they might have been mesenchymal or glial cells as other authors have pointed out.15'0 Christensen 1 and associates have stated that the orgin of inclusion-bear ing cells in the lumina of choroidal vessels was most easily explained by virus invasion
VOL. 62, NO. 6
HUMAN CYTOMEGALOVIRUS
INFECTION
1157
< * Fig. 6 (Tsukahara, Ueno and Kawanishi). P a r t of a large infected cell. ( P N ) Polar nucleolus ( N ) i larged nucleus. ( N l ) Intranuclear inclusion, (nni) Nuclear membrane. (cm) Cell memlirane. (Xl6,500).
Fig. 7 (Tsukahara, Ueno and Kawanishi). Intranuclear inclusion ( N l ) forming numerous immature virus particles ( V d ) . ( n m ) Nu clear membrane. ( X 17,900.)
1158
AMERICAN JOURNAL OF OPHTHALMOLOGY
D E C E M B E R , 1966
Fig. 8 (Tsukahara, Ucno and Kawanishi) Higher magnification of intranuclear inclusion (Vd) Developing virus particle. (x24,900.)
Fig. 10 (Tsukahara, Ucno and Kawanishi). An area of infected cytoplasm, ((ill) Homogenous granule. (Gf) Fuscin granule. ( V m ) Mature virus. (Original X28,600.)
>»>-> lug. 13 (Tsukahara, Ueno and Kawanishi). Higher magnification of mature viruses ( V m ) in a capillary lumen ( C ) of the choriocapiUary layer. ( B M ) Bruch's membrane. ( P E ) Pigment epithelium. (X-W.SOO.)
VOL. 62, NO. 6
HUMAN CYTOMEGALOVIRUS
Fig. 11 (Tsukahara, Ueno and Kawanishi). An area of infected cytoplasm. (Gh) Homogenous granule. (Bm) Mulberrylike organized body. Arrow indicates a small homogenous granule separated f ■ ■ ii i l i - ; , . i inn!.- . T u l i r - c l fn.-i y . U ' w n
INFECTION
1159
Fig. 12 (Tsukahara, Ueno and Kawanishi). Choriocapillary layer with a pigment cell and a capillary in which mature viruses ( V m ) are seen. ( P E ) Pigment epithelium. ( B M ) Bruch's mem brane. (X7.000)
idBfeSii ^
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1160
AMERICAN JOURNAL OF OPHTHALMOLOGY
of the endothelium. W e detected virus particles in the lumen of the choriocapillaris hut could not observe the fine structure of the infected cells in the lumen of the choroidal veins.
DECEMBER, 1966
with indistinct nucleoids were detected in the capillary lumen of the choroid. Sakyo-ku, Kyoto City REFERENCES
1. Clirislcnsen, L., Beeman, H. W. and Allen, A.: SUMMARY Cvtomegalic inclusion disease. Arch. Ophth. 57:90, The right eye of a five-month-old male 1957. 2. Guyton, T. B., Ehrlich, P., Blance, W. A., and infant with congenital agamma-globuline- Becker, M. H.: Observations in generalized cyto mia, generalized cytoniegalic inclusion dis niegalic inclusion disease of the new born. New ease and asymptomatic hyponatremia was Engl. J. Mcil. 257 :803, 1957. 3. I Jvorak-Tlicobald, G.: Cytoniegalic inclusion studied histopathologically. Microscopic ex disease: Report of a case. Am. f. Opbth. 47:52, amination revealed almost complete destruc 1959. 4. Burns, R. P.: Cytoniegalic inclusion disease: tion of the retina and numerous large monoIsolation of virus from anterior chamber. Am. J. nuclear cells containing intranuclear inclu Ophth. 45:300, 1958. sions throughout the retina. Electron mi 5. Manshot, W. A., and Daanian, C. B. F.: A croscopy showed that the intranuclear inclu case of cytoniegalic inclusion disease with ocular sions resembled latticelike plates. Numerous involvement. Ophthalmologica, 143:137, 1962. 6. Smith, M. E.: Retinal involvement in adult immature viruses, with empty or full cores, cvtomegalic inclusion disease. Arch. Ophth. 72:44, were developing from the inclusions. Ma 1964. 7. Maruno, Y., Nishio, T„ Fuki, A., Tsukature viruses, 160 mn. to 180 m[>. in diameter hara, T., and Ueno, I.: Asymptomatic hypona and with a nucleoid and double capsule, tremia (sickle cell syndrome) observed in a case were observed in the cytoplasm. A clear of generalized cytoniegalic inclusion disease with halo between the inclusion and the nuclear congenital agamnia-globulinemia. Ann. Pediat. Ja pan, 10 :465, 1964. membrane was observed with light mi 8. Bucbner, B. H., Hirano, T., Slusser, R. J., croscopy but not with electron microscopy, and Medearis, D. N., Jr.: Human cytomegalovisuggesting that the halo is probably an arti rus infection: Electron microscopic and histofact caused by shrinkage. A few viruses chemical changes in cultures of human fibroblasts. Am. J. Path. 46 :477, 1965.
OPHTHALMIC
MINIATURE
Research is a venture into the unknown and therefore a risk. There is no guarantee that any particular medical research will ever be of any economic benefit to the community. When one finds a new biomedical fact, he is looking into the face of a newborn babe with no way of know ing whether the baby will grow up to be a pillar of the community or the town bum. The most likely possibility is usually that the new fact will turn out to be like a musician, adding a great deal of interest to the world but contributing no great wealth. Biomedical
Science and Its Administration A Report to the President, 1965
E L E C T R O N M I ^ROSCOPIC STUDY
ISAMU TSUKAHARA, M . D . , ITSUYA U E N O , M.D., Kyoto, Japan
AND HIDENOKI K A W A N I S H I ,
M.D.
111 recent years, increasing interest in chamber were not remarkable. Both pupils were ocular involvement in cytomegalic inclusion round, four mm in size and did not react to light. The crystalline lens and vitreous were clear. The disease has been reflected in reports on the optic disc was rather hyperemic and its margin histologic changes in the retina and chor- was blurred. The retina was diffusely covered oid. 1- " The characteristic feature of the le witli a grayish-white exudate. Numerous yellow spots and small hemorrhages were scattered sions is the presence of large mononuclear throughout. The retina was slightly detached. After admission, diarrhea, vomiting and anorexia cells containing inclusions both in the nuclei and in the cytoplasm. According to Smith, 6 persisted and the patient gradually became de hydrated. Fluid therapy had no effect. On April the majority of these large cells range in 13, a fever of 38°C to 39°C and pulmonary symp toms developed. These persisted despite vigorous size from 20 [x-30 [A. The intranuclear inclu sions, from 5 i-i-10 [>■ in size, are surrounded antibiotic therapy. On April 21, various neurologic abnormalities developed. The patient died on April by clear haloes which separate the inclusions 25, 1964. The autopsy findings were those of congenital from the nuclear membrane. With hematoxylin and eosin the inclusions are baso- agamma-globulinemia and generalized cytomegal ic. inclusion disease. Inclusion cells were found in philic and the cytoplasmic inclusions are less the lungs, adrenals, posterior pituitary gland, in distinct. In the retina, these large mononu testines, heart, liver, spleen, pancreas, kidneys, clear cells are believed to be mesenchymal thyroid and salivary glands. A more detailed de scription of the physical and laboratory examina or glial/ 1,0 tions and the autopsy appears in another paper.' T h e present report describes the electron METHOD microscopic appearance of the retinal lesions T h e right eye was obtained at autopsy, of an infant with cytomegalic inclusion dis and fixed in formalin. W h e n microscopic ease. examination showed the type of chorioretinC A S E REPORT itis characteristic of cytomegalic inclusion A five-month-old male infant was admitted to disease, an electron microscopic study was Kyoto University Hospital on March 25, 1964, made of the retinal lesions. because of diarrhea and blindness. The infant was T h e remainder of the celloidin block was delivered without complication after a normal pregnancy on October 20, 1963, with a birth cut into small pieces, a few of which were weight of 3,700 gin. Eighteen days prior to ad immersed in an aceton-ether solution for mission mild diarrhea started. On March 15, the several days, then fixed in 2 % isotonic 0 S 0 4 mother noted that the baby could not recognize toys. On February 29, petechiae appeared on the solution with phosphate buffer, dehydrated face, the back of the right hand and both feet in a series of ethyl-alcohol solutions and but faded out within a few days. embedded in epon. Ultrathin sections were Physical and laboratory examination revealed cut with a glass knife in a J U M - 5 micro congenital agamma-globulinemia and asympto matic hyponatremia. There was no anemia or tome and examined with a Hitachi H U - 1 1 thrombocytopenia. An X-ray film of the skull electron microscope. showed no calcification. The liver was palpable three cm below the right costal margin but the spleen was not palpable. Bye examination. Both eyes showed similar findings. The conjunctiva, cornea and anterior From the Departments of Ophthalmology and Pathology, Faculty of Medicine, Kyoto Univer sity, Kyoto City, Japan. 1
RESULTS MICROSCOPIC E X A M I N A T I O N
T h e most striking changes were observed in the retina and choroid. The retina was comparatively normal only in a small area
1154
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1966
Fig. 1 (Tsukahara, Ueno and Kawanishi). Irregular thickening and destruction of the retina. (R) Retina, (CH) Choroid. (XlOO.)
1.5 disc diameters which was 1.5 disc diam eters lateral to the disc. All the rest of the retina was detached and showed irregular thickening and complete disorganization, with areas of hemorrhage and necrosis (fig. 1). In the involved area there was a moder ate infiltration of lymphocytes. T h e most characteristic feature was the presence throughout the retina of numerous large cells, 20{/.-35pt, in diameter, containing in tranuclear inclusions (fig. 2 ) . T h e intranu clear inclusions were basophilic, stained dark blue with hematoxylin and appeared granular. They were 10(Jt-15(x in diameter and were separated from the nuclear mem brane by a clear halo (fig. 2 ) . T h e nuclear chromalin was marginated along the nuclear membrane. In the choroid large cells con taining intranuclear inclusions were found within the lumen of the larger veins.
7 ) . Characteristic intranuclear inclusions were lattice or sievelike in shape and from them numerous immature viruses, with empty or full cores and measuring 80 nifji,100 mj/, in diameter, were being formed (figs. 6, 7 and 8 ) . I n the cytoplasm were scattered mature viruses with a nucleoid of high electron density and two coats (figs. 9 and 10). These viruses measured 160 m\x180 mji. in diameter. I n addition, throughout the cytoplasm of the infected large cells, there were numerous homogeneous gran ules of various sizes surrounded by a lim iting membrane (figs. 9 and 10). Some of
ELECTRON MICROSCOPIC E X A M I N A T I O N
The structure of the retina was complete ly destroyed except for the pigment epitheli al layer and internal limiting membrane (figs. 3, 4 and 5 ) . Comparatively wellpreserved pigment epithelial cells, which were apparently not infected, contained scattered fuscin granules and the microvillilike processes on their free surfaces had dis appeared (fig. 5 ) . T h e infected large cells had prominent polar nucleoli (figs. 6 and
Fig. 2 (Tsukahara, Ueno and Kawanishi). Large mononuclear cells containing intranuclear inclusions in the retina (arrows) (X 1,000.)
VOL. 62, N O . 6
HUMAN CYTOMEGALOVIRUS INFECTION
1155
jEBffNh
Fig. 3 (T.snkahara, Ueno and Kawanishi). Low magnification electron micrograph of a cross section of inner part of the retina. (VIS) Vitreous body. ( I L M ) Internal limiting membrane. ( L ) Lymphocyte. (X3.200.)
the larger granules had mature virus particles on the surface, occasionally sepa rating small homogenous granules. A few mulberry-like organized bodies were also occasionally noted in the cytoplasm (fig. 11). Bruch's membrane and the choriocapillary layer of the choroid did not show any particular change but a few viruses with an
<-M
Fig. 4 (Tsnkahara, LTeno and Kawanishi). Middle part of the retina. ( C I ) Cells infected by cytomegalovirus (CID) Degenerated, infected cells. ( N p ) Pyknotic nucleus. ( L ) Lymphocyte. ( X 3,200.)
1156
AMERICAN JOURNAL OF OPHTHALMOLOGY
DECEMBER, 1966
c i S i r U S t p - 1 1 ' 1 1 ' V e n ° f ; l l r 1 K ™ ^ ) . Electron micrograph of pigment epithelium and chorio!' 7 - (Sf) Fnscn, granule, (ml,) Myeloid body. (ISM) Rruch's membrane. C Qiluififmei (L; LapilUuy of the chonocapillans with (E) erythrocyte and (VM) mature virus. (X18.W0.)
indistinct nucleoid were detected within the capillary lumen (figs. 5, 12 and 13). The vitreous body near the internal limiting membrane disclosed nothing of particular interest (fig. 3 ) . COMMENT
Cytomegalic inclusion disease has particu lar interest for the ophthalmologist because it may be confused with toxoplasmosis. De scriptions of microscopic observations of retinal and choroid involvement in both in fant and adult cytomegalic inclusion disease have appeared in the literature. 1 •3>5>6 To date, however, electron microscopic exam ination of the retina in this disease has not been reported. Microscopic study of our pa tient's right eye revealed numerous large mononuclear cells containing intranuclear
inclusions throughout the retina. Electron microscopy showed characteristic intranu clear inclusions resembling latticelike or sievelike plates from which numerous vi ruses were developing. The clear halo sepa rating the inclusion bodies from the nuclear membrane was not conspicuous in the elec tron micrographs, suggesting that the halo is probably an artifact. 8 It is interesting to note that mature viruses were seen on the surface of homogenous granules in the cyto plasm of infected cells. T h e origin of the large cells in the retina could not be deter mined but they might have been mesenchymal or glial cells as other authors have pointed out.15'0 Christensen 1 and associates have stated that the orgin of inclusion-bear ing cells in the lumina of choroidal vessels was most easily explained by virus invasion
VOL. 62, NO. 6
HUMAN CYTOMEGALOVIRUS
INFECTION
1157
< * Fig. 6 (Tsukahara, Ueno and Kawanishi). P a r t of a large infected cell. ( P N ) Polar nucleolus ( N ) i larged nucleus. ( N l ) Intranuclear inclusion, (nni) Nuclear membrane. (cm) Cell memlirane. (Xl6,500).
Fig. 7 (Tsukahara, Ueno and Kawanishi). Intranuclear inclusion ( N l ) forming numerous immature virus particles ( V d ) . ( n m ) Nu clear membrane. ( X 17,900.)
1158
AMERICAN JOURNAL OF OPHTHALMOLOGY
D E C E M B E R , 1966
Fig. 8 (Tsukahara, Ucno and Kawanishi) Higher magnification of intranuclear inclusion (Vd) Developing virus particle. (x24,900.)
Fig. 10 (Tsukahara, Ucno and Kawanishi). An area of infected cytoplasm, ((ill) Homogenous granule. (Gf) Fuscin granule. ( V m ) Mature virus. (Original X28,600.)
>»>-> lug. 13 (Tsukahara, Ueno and Kawanishi). Higher magnification of mature viruses ( V m ) in a capillary lumen ( C ) of the choriocapiUary layer. ( B M ) Bruch's membrane. ( P E ) Pigment epithelium. (X-W.SOO.)
VOL. 62, NO. 6
HUMAN CYTOMEGALOVIRUS
Fig. 11 (Tsukahara, Ueno and Kawanishi). An area of infected cytoplasm. (Gh) Homogenous granule. (Bm) Mulberrylike organized body. Arrow indicates a small homogenous granule separated f ■ ■ ii i l i - ; , . i inn!.- . T u l i r - c l fn.-i y . U ' w n
INFECTION
1159
Fig. 12 (Tsukahara, Ueno and Kawanishi). Choriocapillary layer with a pigment cell and a capillary in which mature viruses ( V m ) are seen. ( P E ) Pigment epithelium. ( B M ) Bruch's mem brane. (X7.000)
idBfeSii ^
.
■
^
- .
E|KL|*5p^^*
%&*'?"■
> * , # * *
"% / * >
' % " :"*
■ * V'
W**"""
i**
*'
1160
AMERICAN JOURNAL OF OPHTHALMOLOGY
of the endothelium. W e detected virus particles in the lumen of the choriocapillaris hut could not observe the fine structure of the infected cells in the lumen of the choroidal veins.
DECEMBER, 1966
with indistinct nucleoids were detected in the capillary lumen of the choroid. Sakyo-ku, Kyoto City REFERENCES
1. Clirislcnsen, L., Beeman, H. W. and Allen, A.: SUMMARY Cvtomegalic inclusion disease. Arch. Ophth. 57:90, The right eye of a five-month-old male 1957. 2. Guyton, T. B., Ehrlich, P., Blance, W. A., and infant with congenital agamma-globuline- Becker, M. H.: Observations in generalized cyto mia, generalized cytoniegalic inclusion dis niegalic inclusion disease of the new born. New ease and asymptomatic hyponatremia was Engl. J. Mcil. 257 :803, 1957. 3. I Jvorak-Tlicobald, G.: Cytoniegalic inclusion studied histopathologically. Microscopic ex disease: Report of a case. Am. f. Opbth. 47:52, amination revealed almost complete destruc 1959. 4. Burns, R. P.: Cytoniegalic inclusion disease: tion of the retina and numerous large monoIsolation of virus from anterior chamber. Am. J. nuclear cells containing intranuclear inclu Ophth. 45:300, 1958. sions throughout the retina. Electron mi 5. Manshot, W. A., and Daanian, C. B. F.: A croscopy showed that the intranuclear inclu case of cytoniegalic inclusion disease with ocular sions resembled latticelike plates. Numerous involvement. Ophthalmologica, 143:137, 1962. 6. Smith, M. E.: Retinal involvement in adult immature viruses, with empty or full cores, cvtomegalic inclusion disease. Arch. Ophth. 72:44, were developing from the inclusions. Ma 1964. 7. Maruno, Y., Nishio, T„ Fuki, A., Tsukature viruses, 160 mn. to 180 m[>. in diameter hara, T., and Ueno, I.: Asymptomatic hypona and with a nucleoid and double capsule, tremia (sickle cell syndrome) observed in a case were observed in the cytoplasm. A clear of generalized cytoniegalic inclusion disease with halo between the inclusion and the nuclear congenital agamnia-globulinemia. Ann. Pediat. Ja pan, 10 :465, 1964. membrane was observed with light mi 8. Bucbner, B. H., Hirano, T., Slusser, R. J., croscopy but not with electron microscopy, and Medearis, D. N., Jr.: Human cytomegalovisuggesting that the halo is probably an arti rus infection: Electron microscopic and histofact caused by shrinkage. A few viruses chemical changes in cultures of human fibroblasts. Am. J. Path. 46 :477, 1965.
OPHTHALMIC
MINIATURE
Research is a venture into the unknown and therefore a risk. There is no guarantee that any particular medical research will ever be of any economic benefit to the community. When one finds a new biomedical fact, he is looking into the face of a newborn babe with no way of know ing whether the baby will grow up to be a pillar of the community or the town bum. The most likely possibility is usually that the new fact will turn out to be like a musician, adding a great deal of interest to the world but contributing no great wealth. Biomedical
Science and Its Administration A Report to the President, 1965