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Microcirculatory Changes During the Evolution of Papilledema
MICROCIRCULATORY CHANGES DURING T H E EVOLUTION PAPILLEDEMA
OF
A FIVE-STAGE F L U O R E S C E I N A N G I O G R A P H I C S T U D Y OF PROGRESSIVE S W E L L I N G OF O P T I C D I S K I N INTRACTABLE I N T R A C R A N I A L H Y P E R T E N S I O N E N R I Q U E P I O V A N E T T I , M.D.,
AND RONALD E C K E L H O F F
San Francisco, California
Accumulation of edema fluid at the disk in papilledema is evidenced by extravascular leakage of dye in the angiograms of the optic disk, and is associated with a series of com plex changes in the circulation of the disk. The appearance of visible capillaries reflects one aspect of these pathophysiologic changes. The sequential changes in morphol ogy of the capillaries can only be studied and evaluated by means of multiple fluorescein angiograms of the optic disk in the same pa tient during the development of papilledema. This type of study was carried out, docu menting the evolution of papilledema from its earliest recognizable stages until it was fully developed in a patient undergoing che motherapy for an inoperable intracranial tu mor. CASE REPORT
A 27-year-old architect was referred to the Uni versity of California Medical Center for chemo therapy of a metastatic malignant melanoma in the parieto-occipital region. Over the next seven weeks (the period encompassed by this study), he re mained ambulatory, alert, and cooperative despite some dysphasia and a right honomymous hemianopsia. Recurring symptoms of headache and vomiting and increasing edema of his optic disks indicated that his intracranial pressure was elevated. Two months from the time of admission, his neurologic signs began to progress. He died a month later. Necropsy showed a large anaplastic amelanotic tumor in the left hemisphere that had caused edema From the Neuro-Ophthalmology Service of the Departments of Ophthalmology, Neurosurgery, and Neurology, University of California, San Fran cisco. This study was supported in part by Public Health Service, Grant 1-F11-NB-2122-01-VSN from the National Institute of Health. Mr. Eckel hoff is chief of the Ophthalmic Photography Labora tory at the University of California, San Francisco. Reprints to Enrique Piovanetti, M.D., Department of Ophthalmology, District Hospital, San Juan, Puerto Rico 00935.
of the surrounding brain, hippocampal herniation, and secondary hemorrhage into the midbrain. SERIAL OBSERVATIONS OF OPTIC DISKS
At the time of admission the patient's left optic disk showed early but definite signs of papilledema. The right disk appeared slightly blurred on its nasal margin, but was not ele vated and there were no hemorrhages or exudates. Slight dilatation of the retinal veins was present. Because of other signs of raised intracranial pressure and definite edema of the left optic disk, the changes in his right fundus seemed to represent an incipient stage of papilledema. Fluorescein angiography and stereo fundus photography were performed to evaluate the changes in the op tic disk in this eye; and these studies were repeated four times over the next seven weeks as the changes in his right disk evolved to fully developed papilledema (Ta ble 1). Analysis—The five fluorescein angio graphic studies depicting the evolution of pa pilledema in the right eye were analyzed for changes in the superficial network of capil laries, the deep network of capillaries of the disk, the major retinal vessels and the per meability of capillaries and veins. These changes were compared and correlated with ophthalmoscopic findings (in stereo fundus photographs) at corresponding stages of swelling of the disk. Assuming that in papilledema there is im pairment of venous outflow,1 we can explain all the observed changes easily. Superficial network of capillaries—Nor mally these capillaries are derived from the central retinal artery as a radial plexus of straight vessels over the disk and peripapillary retina.2"7 As papilledema develops, pro-
S10
VOL. 74, NO. 3
PAPILLEDEMA
gressive stasis in the capillary bed leads to distortion of the radial pattern by dilatation and tortuosity. Empty, pre-existing capil laries are seen to cross over major blood ves sels as dark streaks. These later become visi ble as they fill with blood.8 This is not a pro cess of neovascularization, as has been im plied in the past.9 Ophthalmoscopically they are seen within the edematous tissue over the major vessels. There is the appearance of microaneurysmal dilatations in the capil laries, which increase in number at the fully developed stage. Some of these can be seen with the ophthalmoscope. The bright spots over the arterioles are probably capillaries seen end-on. These changes occur initially in only a segment of the disk and retina, and later extend to involve the whole circumfer ence. "Fleck exudates" appear on the disk, seen angiographically as blurred areas where little capillaries are seen and with no leakage of dye, an appearance consistent with multi ple microinfarcts. Capillary arteriovenous shunts are identifiable in all studies and re main unaltered throughout the period of ob servation. They are barely recognizable oph thalmoscopically. Their significance, relative to papilledema, is not clear (Figs. 2 and 3). Deep vascular network—The normal optic disk receives a vascular contribution from the choroidal vessels,5 and this produces the deep glow of the disk seen in early fluorescein angiograms.10 In the fully established stage, there is loss of the glow, and ophthal moscopically this corresponds to a loss of transparency of the tissue of the disk caused by edema. Major retinal vessels—Slight venous con gestion is present during the early stages of papilledema. At the fully established stage, further impairment of venuous outflow pro duces an increase in the tortuosity of the veins. The arterioles remain basically unal tered (Fig. 3). Permeability—Venous stasis causes al terations in permeability of the capillary and vein walls, permitting the dye to leak out and produce the late glow of the disk, the fluorés-
511 TABLE 1
SEQUENTIAL FLUORESCEIN ANGIOGRAPHIC STUDIES OF OPTIC DISK (FIGS. 1-4)
Study
Time Interval
State of Papilledema
Study 1 (Figs. A) Study 2 (not shown) Study 3 (not shown) Study 4 (Figs. B) Study 5 (Figs. C)
Initial study
Incipient stage
3 days later 14 days later 33 days later 47 days later
Fully developed stage
cence of peripapillary retina (Fig. 4 ) , and the perivenous staining (Fig. 3 ) . The extent of leakage of dye is proportional to the stage of papilledema,11"12 but unpredictable from the ophthalmoscopic appearance.13 COMMENT
Numerous reports 8-31 describe the salient fluorescein angiographie changes in papil ledema—i.e., capillary congestion, venous distention, and late leakage—based upon findings in single studies in many patients. Serial fluorescein angiograms have been done in subsiding papilledema.28'29 Serial studies of developing papillitis have also been reported.32 The pathophysiology of pa pillitis is different from papilledema caused by increased intracranial pressure; to our knowledge, a sequential study of the devel oping changes of papilledema due to in creased intracranial pressure in a single pa tient have not been reported heretofore. This case offered us the opportunity to observe the evolution of the changes we have de scribed, and also enabled us to demonstrate exactly how the microvasculature is altered in this condition. SUMMARY
By using sequential fluorescein angiography in a patient with an inoperable brain tumor, it was possible to study and correlate
512
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 1 (Piovanetti and Eckelhoff). Plain photo graphs. Right optic disk, showing the evolution from (A) an early stage to (C) fully developed stage of papilledema.
SEPTEMBER, 1972
VOL. 74, NO. 3
PAPILLEDEMA
Fig. 2 (Piovanetti and Eckelhoff). Angiography, capillary phase. There is distortion of the capillary radial pattern, occurring, intially (A) in the nasal segment of the disk, then spreading over the whole disk. Arteriovenous shunts are present (thin arrows), and remain unchanged. Tiny and barely visible, pre-existing capillaries (wide ar rows) are seen over a major vein, these become progressively dilated until in the fully developed stage (C) they form a prominent network of capil laries over the vein.
513
S14
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 3 (Piovanetti and Eckelhoff). Angiography, venous phase. (A-C) Note the development of microaneurysms as the condition progresses. The veins become more tortuous and dilated at the fully de veloped stage of papiUedema, while the arterioles remain unchanged. (B) There is perivenous stain ing of the walls of the major veins, best seen in later venous phase angiograms (arrows). (C) Arteriovenous shunts are seen (arrow).
SEPTEMBER, 1972
VOL. 74. NO. 3
PAPILLEDEMA
Fig. 4 (Piovanetti and Eckelhoff). Angiography, late phase. Late leakage of dye at the disk and peripapillary retina is proportional to the stage of papilledema.
515
516
AMERICAN JOURNAL OF OPHTHALMOLOGY
the progressive ophthalmoscopic and angio graphie changes at the optic disk as papilledema progressed from a very early to a fully established stage. Microcirculatory changes took place in the superficial capillary network of the disk and peripapillary retina, associated with al terations in the major veins. These seem to result from impairment of the venous out flow leading to congestion and edema around these vessels. ACKNOWLEDGMENT
We are deeply grateful for the help of Drs. Wil liam F. Hoyt and Dennis O'Day in the development of this paper. REFERENCES
1. Behrman, S. : Pathology of papilledema. Brain 89:1, 1966. 2. Henkind, P. : Radial peripapillary capillaries of the retina. I. Anatomy : Human and comparative. Brit. J. Ophth. 51:115,1967. 3. : New observations on the radial peri papillary capillaries. Invest Ophth. 6:103, 1967. 4. : Microcirculation of the peripapillary retina. Tr. Am. Acad. Ophth. Otolaryng. 73:890, 1969. 5. Hayreh, S. S. : Blood supply of the optic nerve head and its role in optic atrophy, glaucoma and oedema of the optic disc. Brit. J. Ophth. 53:721, 1969. 6. Henkind, P., and Levitzky, M. : Angioarchitecture of the optic nerve. I. The papilla. Am. J. Ophth. 68:979, 1969. 7. Levitzky, M. and Henkind, P. : Angioarchitecture of the optic nerve. II. Lamina cribrosa. Am. J. Ophth. 68:986,1969. 8. Oosterhuis, J. A., Boen-Tan, T. N. : Fluores cein angiography in papilledema and pseudo-papilloedema. Ophthalmologica 159:96, 1969. 9. David, N. J., Heyman, A., and Hart, I. M. : Fluorescence photography of retinal vessels and op tic disc in papilledema. Tr. Am. Neurol. Ass. 88: 155, 1963. 10. O'Day, D., Crock, G., and Galbraith, J. E. K. : Fluorescein angiography of normal and atrophie optic discs. Lancet 2:224, 1967. 11. Blair, C. J., and Walsh, F. B. : Papilledema, optic neuritis, and pseudo-papilledema. The use of fluorescein angiography in differential diagnosis. Tr. Am. Acad. Ophth. Otolaryng. 73:914, 1969. 12. Linhart, J. W., Mclntosh, H. D., Heyman, A., and Hart, I. M. : Clinical experience with fluorescence retinal cinematography. Circulation 29 : 577, 1964. 13. Dollery, C. T., Mailer, C. M., and Hodge,
SEPTEMBER, 1972
J. V. : Studies by fluorescence photography of papilloedema in malignant hypertension. J. Neurol. Neurosurg. Psychiat. 28:241, 1965. 14. Alezzandrini, A. A., and Nicoli, C. : Retinofluoreseino-grafia. Arch. Oftal. Buenos Airies 40: 363,1965. 15. Amalric, P., Bessou P., and Biau, C. : As pects fluoresceinique de la papille et de la region peri-papillaire. Bull. Opht. Soc. Franc 80:334, 1967. 16. Dollery, C. T., Hodge, J. V., and Engel, M. : Studies of the retinal circulation with fluorescein. Brit. Med. J. 2:1210, 1962. 17. : Retinal photography using fluores cein. Med. Biol. Illus. 13:4, 1963. 18. Hoyt, W. F., and Beeston, D. : The Ocular Fundus in Neurologic Disease. A Diagnostic Manual and Stereo Atlas. St. Louis, C. V. Mosby, 1966. 19. Miller, S. J. H., Sanders, M. D., and Ffytche, T. J. : Fluorescein fundus photography in the detec tion of early papilledema and its differentiation from pseudopapilledema. Lancet 2:651, 1965. 20. Rodriguez-Barrios, R.: Fluorescein angioretinography as a diagnostic method for papilledema. Acta Neurol. Lat. Am. 9:213, 1963. 21. Rosen, E. S., Ashworth, B., and Jarpe, S. : Fluorescence Photography of the Eye. A Manual of Dynamic Clinical Ocular Fundus Pathology. New York, Appleton-Century-Crofts, 1969. 22. Sanders, M. D.: Papilledema. Lancet 1:977, 1969. 23. Shimoni-Spivak, K. : Fluoreszenretinographie zur differential-diagnose der stauungspapille. Schweiz. Med. Wschr. 98:1968, 1968. 24. Tenner, A., and Honegger, H. : Fluoreszenangiographie zur diagnose der stauungspapille. Med. Wschr. 23:213, 1969. 25. Wessing, A., and von Noorden, G. K. : Fluo rescein Angiography of the Retina. Textbook and Atlas. St. Louis, C. V. Mosby, 1969. 26. Witmer, R. : Zur differentialdiagnose des papillenoedems. Doc. Ophth. 26:359, 1969. 27. : Differentialdiagnostische aspekete bei retinalen gefäbstörungen und papillenoedem. Oph thalmologica 156:313, 1968. 28. Bettman, J. W., Daroff, R. B., Sanders, M. D., and Hoyt, W. F. : Papilledema and symptomatic intracranial hypertension in systemic lupus erythematosus: A fluorescein angiographie study of re solving papilledema. Arch. Ophth. 80:189, 1968. 29. : Edema of the optic disk in hyperthyroidism without exophthalmos. A fluorescein an giographie study of its resolution. Am. J. Ophth. 66:714,1968. 30. Sanders, M. D. : A classification of papilloedema based on a fluorescein angiographie study of 69 cases. Tr. Ophth. Soc. U.K. 89:177, 1970. 31. Bynke, H. G., and Aberg, L. : Differentiation of papilledema from pseudopapilledema by fluores cein angiography. Acta Ophth. 48:752, 1970. 32. Rosen, E. S., and Ashworth, B. : Serial fluo rescein photography in acute retrobulbar neuritis. J. Neurol. Neurosurg. Psych. 31:253, 1968.
OF
A FIVE-STAGE F L U O R E S C E I N A N G I O G R A P H I C S T U D Y OF PROGRESSIVE S W E L L I N G OF O P T I C D I S K I N INTRACTABLE I N T R A C R A N I A L H Y P E R T E N S I O N E N R I Q U E P I O V A N E T T I , M.D.,
AND RONALD E C K E L H O F F
San Francisco, California
Accumulation of edema fluid at the disk in papilledema is evidenced by extravascular leakage of dye in the angiograms of the optic disk, and is associated with a series of com plex changes in the circulation of the disk. The appearance of visible capillaries reflects one aspect of these pathophysiologic changes. The sequential changes in morphol ogy of the capillaries can only be studied and evaluated by means of multiple fluorescein angiograms of the optic disk in the same pa tient during the development of papilledema. This type of study was carried out, docu menting the evolution of papilledema from its earliest recognizable stages until it was fully developed in a patient undergoing che motherapy for an inoperable intracranial tu mor. CASE REPORT
A 27-year-old architect was referred to the Uni versity of California Medical Center for chemo therapy of a metastatic malignant melanoma in the parieto-occipital region. Over the next seven weeks (the period encompassed by this study), he re mained ambulatory, alert, and cooperative despite some dysphasia and a right honomymous hemianopsia. Recurring symptoms of headache and vomiting and increasing edema of his optic disks indicated that his intracranial pressure was elevated. Two months from the time of admission, his neurologic signs began to progress. He died a month later. Necropsy showed a large anaplastic amelanotic tumor in the left hemisphere that had caused edema From the Neuro-Ophthalmology Service of the Departments of Ophthalmology, Neurosurgery, and Neurology, University of California, San Fran cisco. This study was supported in part by Public Health Service, Grant 1-F11-NB-2122-01-VSN from the National Institute of Health. Mr. Eckel hoff is chief of the Ophthalmic Photography Labora tory at the University of California, San Francisco. Reprints to Enrique Piovanetti, M.D., Department of Ophthalmology, District Hospital, San Juan, Puerto Rico 00935.
of the surrounding brain, hippocampal herniation, and secondary hemorrhage into the midbrain. SERIAL OBSERVATIONS OF OPTIC DISKS
At the time of admission the patient's left optic disk showed early but definite signs of papilledema. The right disk appeared slightly blurred on its nasal margin, but was not ele vated and there were no hemorrhages or exudates. Slight dilatation of the retinal veins was present. Because of other signs of raised intracranial pressure and definite edema of the left optic disk, the changes in his right fundus seemed to represent an incipient stage of papilledema. Fluorescein angiography and stereo fundus photography were performed to evaluate the changes in the op tic disk in this eye; and these studies were repeated four times over the next seven weeks as the changes in his right disk evolved to fully developed papilledema (Ta ble 1). Analysis—The five fluorescein angio graphic studies depicting the evolution of pa pilledema in the right eye were analyzed for changes in the superficial network of capil laries, the deep network of capillaries of the disk, the major retinal vessels and the per meability of capillaries and veins. These changes were compared and correlated with ophthalmoscopic findings (in stereo fundus photographs) at corresponding stages of swelling of the disk. Assuming that in papilledema there is im pairment of venous outflow,1 we can explain all the observed changes easily. Superficial network of capillaries—Nor mally these capillaries are derived from the central retinal artery as a radial plexus of straight vessels over the disk and peripapillary retina.2"7 As papilledema develops, pro-
S10
VOL. 74, NO. 3
PAPILLEDEMA
gressive stasis in the capillary bed leads to distortion of the radial pattern by dilatation and tortuosity. Empty, pre-existing capil laries are seen to cross over major blood ves sels as dark streaks. These later become visi ble as they fill with blood.8 This is not a pro cess of neovascularization, as has been im plied in the past.9 Ophthalmoscopically they are seen within the edematous tissue over the major vessels. There is the appearance of microaneurysmal dilatations in the capil laries, which increase in number at the fully developed stage. Some of these can be seen with the ophthalmoscope. The bright spots over the arterioles are probably capillaries seen end-on. These changes occur initially in only a segment of the disk and retina, and later extend to involve the whole circumfer ence. "Fleck exudates" appear on the disk, seen angiographically as blurred areas where little capillaries are seen and with no leakage of dye, an appearance consistent with multi ple microinfarcts. Capillary arteriovenous shunts are identifiable in all studies and re main unaltered throughout the period of ob servation. They are barely recognizable oph thalmoscopically. Their significance, relative to papilledema, is not clear (Figs. 2 and 3). Deep vascular network—The normal optic disk receives a vascular contribution from the choroidal vessels,5 and this produces the deep glow of the disk seen in early fluorescein angiograms.10 In the fully established stage, there is loss of the glow, and ophthal moscopically this corresponds to a loss of transparency of the tissue of the disk caused by edema. Major retinal vessels—Slight venous con gestion is present during the early stages of papilledema. At the fully established stage, further impairment of venuous outflow pro duces an increase in the tortuosity of the veins. The arterioles remain basically unal tered (Fig. 3). Permeability—Venous stasis causes al terations in permeability of the capillary and vein walls, permitting the dye to leak out and produce the late glow of the disk, the fluorés-
511 TABLE 1
SEQUENTIAL FLUORESCEIN ANGIOGRAPHIC STUDIES OF OPTIC DISK (FIGS. 1-4)
Study
Time Interval
State of Papilledema
Study 1 (Figs. A) Study 2 (not shown) Study 3 (not shown) Study 4 (Figs. B) Study 5 (Figs. C)
Initial study
Incipient stage
3 days later 14 days later 33 days later 47 days later
Fully developed stage
cence of peripapillary retina (Fig. 4 ) , and the perivenous staining (Fig. 3 ) . The extent of leakage of dye is proportional to the stage of papilledema,11"12 but unpredictable from the ophthalmoscopic appearance.13 COMMENT
Numerous reports 8-31 describe the salient fluorescein angiographie changes in papil ledema—i.e., capillary congestion, venous distention, and late leakage—based upon findings in single studies in many patients. Serial fluorescein angiograms have been done in subsiding papilledema.28'29 Serial studies of developing papillitis have also been reported.32 The pathophysiology of pa pillitis is different from papilledema caused by increased intracranial pressure; to our knowledge, a sequential study of the devel oping changes of papilledema due to in creased intracranial pressure in a single pa tient have not been reported heretofore. This case offered us the opportunity to observe the evolution of the changes we have de scribed, and also enabled us to demonstrate exactly how the microvasculature is altered in this condition. SUMMARY
By using sequential fluorescein angiography in a patient with an inoperable brain tumor, it was possible to study and correlate
512
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 1 (Piovanetti and Eckelhoff). Plain photo graphs. Right optic disk, showing the evolution from (A) an early stage to (C) fully developed stage of papilledema.
SEPTEMBER, 1972
VOL. 74, NO. 3
PAPILLEDEMA
Fig. 2 (Piovanetti and Eckelhoff). Angiography, capillary phase. There is distortion of the capillary radial pattern, occurring, intially (A) in the nasal segment of the disk, then spreading over the whole disk. Arteriovenous shunts are present (thin arrows), and remain unchanged. Tiny and barely visible, pre-existing capillaries (wide ar rows) are seen over a major vein, these become progressively dilated until in the fully developed stage (C) they form a prominent network of capil laries over the vein.
513
S14
AMERICAN JOURNAL OF OPHTHALMOLOGY
Fig. 3 (Piovanetti and Eckelhoff). Angiography, venous phase. (A-C) Note the development of microaneurysms as the condition progresses. The veins become more tortuous and dilated at the fully de veloped stage of papiUedema, while the arterioles remain unchanged. (B) There is perivenous stain ing of the walls of the major veins, best seen in later venous phase angiograms (arrows). (C) Arteriovenous shunts are seen (arrow).
SEPTEMBER, 1972
VOL. 74. NO. 3
PAPILLEDEMA
Fig. 4 (Piovanetti and Eckelhoff). Angiography, late phase. Late leakage of dye at the disk and peripapillary retina is proportional to the stage of papilledema.
515
516
AMERICAN JOURNAL OF OPHTHALMOLOGY
the progressive ophthalmoscopic and angio graphie changes at the optic disk as papilledema progressed from a very early to a fully established stage. Microcirculatory changes took place in the superficial capillary network of the disk and peripapillary retina, associated with al terations in the major veins. These seem to result from impairment of the venous out flow leading to congestion and edema around these vessels. ACKNOWLEDGMENT
We are deeply grateful for the help of Drs. Wil liam F. Hoyt and Dennis O'Day in the development of this paper. REFERENCES
1. Behrman, S. : Pathology of papilledema. Brain 89:1, 1966. 2. Henkind, P. : Radial peripapillary capillaries of the retina. I. Anatomy : Human and comparative. Brit. J. Ophth. 51:115,1967. 3. : New observations on the radial peri papillary capillaries. Invest Ophth. 6:103, 1967. 4. : Microcirculation of the peripapillary retina. Tr. Am. Acad. Ophth. Otolaryng. 73:890, 1969. 5. Hayreh, S. S. : Blood supply of the optic nerve head and its role in optic atrophy, glaucoma and oedema of the optic disc. Brit. J. Ophth. 53:721, 1969. 6. Henkind, P., and Levitzky, M. : Angioarchitecture of the optic nerve. I. The papilla. Am. J. Ophth. 68:979, 1969. 7. Levitzky, M. and Henkind, P. : Angioarchitecture of the optic nerve. II. Lamina cribrosa. Am. J. Ophth. 68:986,1969. 8. Oosterhuis, J. A., Boen-Tan, T. N. : Fluores cein angiography in papilledema and pseudo-papilloedema. Ophthalmologica 159:96, 1969. 9. David, N. J., Heyman, A., and Hart, I. M. : Fluorescence photography of retinal vessels and op tic disc in papilledema. Tr. Am. Neurol. Ass. 88: 155, 1963. 10. O'Day, D., Crock, G., and Galbraith, J. E. K. : Fluorescein angiography of normal and atrophie optic discs. Lancet 2:224, 1967. 11. Blair, C. J., and Walsh, F. B. : Papilledema, optic neuritis, and pseudo-papilledema. The use of fluorescein angiography in differential diagnosis. Tr. Am. Acad. Ophth. Otolaryng. 73:914, 1969. 12. Linhart, J. W., Mclntosh, H. D., Heyman, A., and Hart, I. M. : Clinical experience with fluorescence retinal cinematography. Circulation 29 : 577, 1964. 13. Dollery, C. T., Mailer, C. M., and Hodge,
SEPTEMBER, 1972
J. V. : Studies by fluorescence photography of papilloedema in malignant hypertension. J. Neurol. Neurosurg. Psychiat. 28:241, 1965. 14. Alezzandrini, A. A., and Nicoli, C. : Retinofluoreseino-grafia. Arch. Oftal. Buenos Airies 40: 363,1965. 15. Amalric, P., Bessou P., and Biau, C. : As pects fluoresceinique de la papille et de la region peri-papillaire. Bull. Opht. Soc. Franc 80:334, 1967. 16. Dollery, C. T., Hodge, J. V., and Engel, M. : Studies of the retinal circulation with fluorescein. Brit. Med. J. 2:1210, 1962. 17. : Retinal photography using fluores cein. Med. Biol. Illus. 13:4, 1963. 18. Hoyt, W. F., and Beeston, D. : The Ocular Fundus in Neurologic Disease. A Diagnostic Manual and Stereo Atlas. St. Louis, C. V. Mosby, 1966. 19. Miller, S. J. H., Sanders, M. D., and Ffytche, T. J. : Fluorescein fundus photography in the detec tion of early papilledema and its differentiation from pseudopapilledema. Lancet 2:651, 1965. 20. Rodriguez-Barrios, R.: Fluorescein angioretinography as a diagnostic method for papilledema. Acta Neurol. Lat. Am. 9:213, 1963. 21. Rosen, E. S., Ashworth, B., and Jarpe, S. : Fluorescence Photography of the Eye. A Manual of Dynamic Clinical Ocular Fundus Pathology. New York, Appleton-Century-Crofts, 1969. 22. Sanders, M. D.: Papilledema. Lancet 1:977, 1969. 23. Shimoni-Spivak, K. : Fluoreszenretinographie zur differential-diagnose der stauungspapille. Schweiz. Med. Wschr. 98:1968, 1968. 24. Tenner, A., and Honegger, H. : Fluoreszenangiographie zur diagnose der stauungspapille. Med. Wschr. 23:213, 1969. 25. Wessing, A., and von Noorden, G. K. : Fluo rescein Angiography of the Retina. Textbook and Atlas. St. Louis, C. V. Mosby, 1969. 26. Witmer, R. : Zur differentialdiagnose des papillenoedems. Doc. Ophth. 26:359, 1969. 27. : Differentialdiagnostische aspekete bei retinalen gefäbstörungen und papillenoedem. Oph thalmologica 156:313, 1968. 28. Bettman, J. W., Daroff, R. B., Sanders, M. D., and Hoyt, W. F. : Papilledema and symptomatic intracranial hypertension in systemic lupus erythematosus: A fluorescein angiographie study of re solving papilledema. Arch. Ophth. 80:189, 1968. 29. : Edema of the optic disk in hyperthyroidism without exophthalmos. A fluorescein an giographie study of its resolution. Am. J. Ophth. 66:714,1968. 30. Sanders, M. D. : A classification of papilloedema based on a fluorescein angiographie study of 69 cases. Tr. Ophth. Soc. U.K. 89:177, 1970. 31. Bynke, H. G., and Aberg, L. : Differentiation of papilledema from pseudopapilledema by fluores cein angiography. Acta Ophth. 48:752, 1970. 32. Rosen, E. S., and Ashworth, B. : Serial fluo rescein photography in acute retrobulbar neuritis. J. Neurol. Neurosurg. Psych. 31:253, 1968.