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Scleral Canal Size and Optic Nerve Head Drusen
Scleral Canal Size and Optic Nerve Head Drusen Marc A. Mullie, F.R.C.S.(C), and Michael D. Sanders, F.R.C.S.
From projected optic disk photographs we measured the size of the scleral canal in two samples of emmetropic patients: one of patients with unilateral pseudopapilledema and drusen and the other of the general normal population. Measurements on the non-drusen-containing optic disk of patients with unilateral drusen were taken to reflect the scleral canal size of the fellow, affected eye. For both trained (t 6.642) and untrained (t 4.274) observers, the average diameters of the non-drusencontaining optic disks of patients with unilateral drusen were significantly smaller than those of the optic disks of normal patients (P = .0005, one-tailed independent r-test). The association of a small scleral canal with vascular anomalies, frequently noted in optic disks of patients with drusen, indicates a mesodermal dysgenesis of the optic nerve head.
=
=
THE PATHOGENESIS of optic disk drusen is incompletely known. Spencer! believed that axoplasmic transport alteration is the anatomic substrate for formation of drusen of the optic disk. He stated, "In familial cases the cause ofaxoplasmic transport alteration may be related to the presence of a genetically determined, small, crowded optic nerve head .... " However, because of the patients' refractive errors, as well as the indistinct margins of optic disks with drusen, he was unable to corroborate this statement. His impression was that "the discs in patients with familial drusen are clinically smaller than normal. ... " In a review of 250 eyes with pseudopapilledema, Rosenberg, Savino, and Glaser" suggested that "hyaline bodies arise in congenitally dysplastic discs, and it is our distinct impression that many of these discs have small diameters as well. ... "
Accepted for publication Dec. 13, 1984. From the Department of Neuro-Ophthalmology, National Hospital for Nervous Diseases, London, England. Dr. MulIie is the R. S. McGlauglin Fellow, McGill University, Montreal, Quebec, Canada. Reprint requests to Michael D. Sanders, F.R.C.S., Consultant Ophthalmologist, The National Hospital for Nervous Diseases, Queen Square, London WC1N 3BG, England.
356
We attempted to determine whether the scleral canals of optic disks with drusen are smaller than those of optic disks without drusen.
Subjects
and Methods
We measured and compared the scleral canal sizes in two samples of emmetropic patients: one of a group of patients with unilateral optic disk drusen in whom reliable measurements could be performed on the fellow-, non-drusen-containing optic disk and the other of the general population without optic nerve abnormalities. We reviewed the charts of 33 consecutive patients with the diagnosis of optic disk drusen seen at the National Hospital for Nervous Diseases between 1970 and 1984. The criteria for this diagnosis were either visible, calcified drusen or "buried" drusen verified by autofluorescence, late nodular hyperfluorescence on fluorescein angiography, or computed tomographic scans of the orbits. Twelve patients had bilateral exposed or buried drusen with pseudopapilledema. Twenty-one patients had unilateral exposed or buried drusen with pseudopapilledema and a fellow optic disk without drusen or significant swelling. Of these 21 fellow optic disks, eight were rejected from the study on the basis of either refractive error or an indistinct optic disk border, leaving 13 emmetropic fellow eyes in which the scleral rim of the optic disk was clearly definable. These 13 optic disks were selected as the first sample. There were eight female and five male patients ranging in age from 14 to 53 years, with a mean age of 27 years. A second sample of 19 optic disks from ten consecutive emmetropic patients without optic nerve disease was randomly selected from the outpatient charts of the neuro-ophthalmology clinic. There were five women and five men ranging in age from 25 to 42 years, with a mean age of 32 years. All optic disk photographs were taken with the Zeiss fundus camera at the standard 2.5X magnification on 24 x 36-mm film. Slide transparencies of the 13 non-drusen-containing optic disks from the sam-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 99:35fr-359, MARCH, 1985
Vol. 99, No.3
Optic Nerve Head Drusen
pIe with unilateral drusen were randomly mixed with slides of the 19 optic disks from the ten normal emmetropic subjects. All 32 slides were projected onto a screen at a fixed magnification of 16x. From the projected image, direct measurements of the diameter of the scleral opening were obtained in four meridians on the optic disk: 12 to 6 o'clock, 1:30 to 7:30 o'clock, 3 to 9 o'clock, and 4:30 to 10:30 o'clock. The rim of the scleral canal of the optic nerve head was defined as the line of transition between the orange-brown color of the peripapillary retina and the white-pink color of the optic disk. The average optic disk diameter for each optic disk was recorded as the mean of the four meridional values. Measurements were obtained by one of us (M.A.M.) for all 32 optic disks at one session and repeated one week later. To eliminate observer bias, two sets of measurements were also obtained by an independent untrained observer without any knowledge of the purpose of the study. Measurements taken one week apart were highly reproducible; Pearson's product-moment correlation coefficient was r = .98 and r = .92 for trained and untrained observers respectively. Overall sample means were taken as the average of each sample's mean measurement on the two occasions.
Results The average diameters of the non-drusencontaining optic disks of patients with unilateral optic disk drusen were found to be significantly smaller than those of the optic disks of patients from the general population (Table). For both trained (t = 6.642) and untrained (t = 4.274) observers the difference was significant (P = .0005, one-tailed indepen-
TABLE OPTIC DISK MEASUREMENTS IN EMMETROPIC PATIENTS WITH AND WITHOUT OPTIC NERVE DRUSEN OPTIC DISK MEASUREMENT (MM) RANGE
Patients with drusen (No. = 13) Trained observer Untrained observer
60 to 76 64 to 79
MEAN
67 73
S.D.
4.49 4.59
Normal patients (No. = 19) Trained observer Untrained observer
68 to 93 71 to 94
82 82
6.75 6.74
357
dent t-test). The overall means of average optic disk diameters for the sample with drusen were 67 mm and 73 mm for trained and untrained observers respectively. In the sample without drusen the overall mean was 82 mm for trained and 82 mm for untrained observers. Based on the difference between each observer's sample means (67 and 82 mm vs 73 and 82 mm) patients with optic nerve drusen had optic disk surface areas an average of 20% to 33% smaller than those of a population without drusen.
Discussion Several theoretical and practical problems make it difficult to obtain accurate absolute fundus measurements clirucally." Kennedy, Schwartz, and Takamoto! attempted direct measurements, whereas Bengtsson and Krakau! and Littman! used an indirect approach by introducing optical corrective factors in their calculations. To circumvent these problems, we compared relative sizes of optic disks in two samples of emmetropic eyes. This design eliminates refractive error as one source of variation in measurement of fundus photographs. However, since emmetropic eyes can vary in axial length, 6 they may also vary in total dioptric power, thus influencing the magnification of optic disks. We therefore assumed that any significant variation in dioptric power between emmetropic eyes in the sample with drusen approximated that in the sample without drusen. Since measurement of the scleral rim in an optic disk with drusen may be difficult, we measured the optic disk in the contralateral eye (Figure). Because optic disk size is inherited and bilaterally similar.I:" it seems reasonable that in patients with unilateral pseudopapilledema and drusen optic disk size in the contralateral eye reflects optic disk size in the eye with drusen. Furthermore, ten of the 13 contralateral optic disks without drusen showed vascular anomalies commonly associated with drusen, implying that abnormal development of the optic nerve head may occur bilaterally, even in a patient with unilateral drusen. We do not know why a single optic disk predominantly or exclusively develops drusen. The familial type of optic disk drusen is inherited as an irregular autosomal dominant trait." Other congenital anomalies of optic disks with drusen include an increased number of major vessels on the optic disk itself, tortuous vessels with abnormal branching, vascular loops, cilioretinal arteries, and patchy areas of delayed filling of the peripapillary choriocapillaris on fluorescein angiography. 8,9 Congenital abnormalities of these mesodermal-derived structures, in association with a small scleral canal in
358
March, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
Figure (Mullie and Sanders). Left, Fluorescein angiogram in late phase of right optic disk of a patient with right optic nerve drusen. Note nodular hyperfluorescence of the optic disk, giving a scalloped and indistinct border. Right, Fluorescein angiogram in late phase of the left optic disk of the same patient. The left optic disk shows a well defined edge. The optic disk vasculature in both eyes is congenitally anomalous.
optic disks that develop drusen, is evidence of the phenotypic expression in utero of the underlying genetic defect. A brief review of the normal embryologic development of the optic nerve head may help elucidate the delicate interplay of ectodermal and mesodermal elements in this region.:" At the eighth week (22- to 3D-mm stage) of gestation the ganglion cells have differentiated and the entire optic stalk is occupied by nerve fibers. At the 11th week (65-mm stage) the glial framework of the optic nerve begins to differentiate and blood vessels and elastic tissue invade the periphery of the nerve from the surrounding mesoderm. The hyaloid system begins to atrophy, and by the fourth month (lOO-mm stage) the primordia of the upper and lower branches of the central retinal artery appear on the optic disk. The sclera develops from mesodermal cells surrounding the optic vesicle, beginning at the limbus and extending posteriorly to reach the edge of the optic stalk by the end of the fifth month. In this way the peripapillary sclera forms after the neural optic stalk is complete. Mesodermal elements from the sclera then invade the glial framework of the primitive lamina, reinforcing it with collagen. The genetic and developmental mechanisms responsible for the mesodermal dysgenesis of the optic nerve head in patients who develop drusen are unknown. An abnormal posterior extension of sclera, Bruch's membrane, or both in the fetal period after the neural optic stalk has formed could conceivably encroach on the exit space of the nerve fibers from the eye. The absence of a central cup observed
in the optic disks of many patients with drusen may reflect crowding of emergent cell axons in a small scleral opening. Similarly, drusen are first detected clinically and histopathologically at the margins of the optic disk, 1 which could implicate the rigid edge of a small scleral canal as the aggravating factor in a relative mechanical blockage ofaxoplasmic flow in the normal eye at the level of the lamina scleralis!' or Bruch's membrane. 12 Seitz and Kersting" were the first to suggest that drusen of the optic disk may be the product of chronic degenerative changes in retinal ganglion cell axons. Spencer! reiterated their conclusions and Tso" added histopathologic evidence that abnormal axonal metabolism leads to intracellular mitochondrial calcification, axonal rupture, and extrusion of mitochondria into the extracellular space with further calcium deposition. The finding of abnormally small scleral canals in optic disks of patients with drusen supports Spencer's view' that "the normal physiologic damming of orthograde axoplasmic flow anterior to the lamina cribrosa is aggravated by local factors. We suggest that one factor is the abnormally narrow aperture of the scleral canal. When this process exceeds survival limits, degenerative changes begin which in the course of many years cause axonal death...." ACKNOWLEDGMENT
Richard Dewhirst, of the Department of NeuroOphthalmology, National Hospital, acted as the in-
Vol. 99, No.3
Optic Nerve Head Drusen
dependent untrained observer in making optic disk measurements and provided the illustrations.
References 1. Spencer, W. H.: Drusen of the optic disk and aberrant axoplasmic transport. The XXXIVEdward Jackson Memorial Lecture. Am. J. Ophthalmol. 85:1, 1978. 2. Rosenberg, M. A., Savino, P. J., and Glaser, J. A.: A clinical analysis of pseudopapilloedema. I. Population, laterality, acuity, refractive error, ophthalmoscopic characteristics, and coincident disease. Arch. Ophthalmol. 97:65, 1979. 3. Kennedy, S. J., Schwartz, B., Takamoto, T., and Eu, J. K. T.: Interference fringe scale for absolute ocular fundus measurement. Invest. Ophthalmol. Vis. Sci. 24:169, 1983. 4. Bengtsson, B., and Krakau, C. E. T.: Some essential optical features of the Zeiss fundus camera. Acta Ophthalmol. 55:123, 1977. 5. Littman, H.: Zur Bestimmung der wahren Grobe eines Objektes auf dem Hintergrund des lebenden Aunges. Klin. Monatsbl, Augenheilkd. 180:286, 1982.
359
6. Sorsby, A.: Topical aspects. The functional anomalies of the eye. In Sorsby, A. (ed.): Modern Ophthalmology, vol. 3. Washington, D.C., Butterworth, 1964, p. 9. 7. Bengtsson, B.: The inheritance and development of cup and disc diameters. Acta Ophthalmol. 58:733, 1980. 8. Armaly, M. F.: Genetic determination of cup/disc ratio of the optic nerve. Arch. Ophthalmol. 78:35, 1967. 9. Lorentzen, D. W.: Drusen of the optic disk. Acta Ophthalmol. l(suppl. 90):179, 1966. 10. Erkkila, H.: The central vascular pattern of the eyeground in children with drusen of the optic disk. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 199:1, 1976. 11. Friedman, A. H., Beckerman, B., Gold, D. H., Walsh, J. B., and Gartner, S.: Drusen of the optic disc. Surv. Ophthalmol. 21:375, 1977. 12. Duke-Elder, S., and Cook, c.: Normal and abnormal development. In Duke-Elder, S. (ed.): System of Ophthalmology, vol. 3, pt. 1. London, Henry Kimpton, 1963, pp. 109, 162, and 204. 13. Seitz, R., and Kersting, G.: Die Drusen der sehnerven PapiJIe und des Pigmentepithels. Klin. Monatsbl. Augenheilkd. 140:75, 1962. 14. Tso, M. O. M.: Pathology and pathogenesis of drusen of the optic nerve head. Ophthalmology 88:1066, 1981.
From projected optic disk photographs we measured the size of the scleral canal in two samples of emmetropic patients: one of patients with unilateral pseudopapilledema and drusen and the other of the general normal population. Measurements on the non-drusen-containing optic disk of patients with unilateral drusen were taken to reflect the scleral canal size of the fellow, affected eye. For both trained (t 6.642) and untrained (t 4.274) observers, the average diameters of the non-drusencontaining optic disks of patients with unilateral drusen were significantly smaller than those of the optic disks of normal patients (P = .0005, one-tailed independent r-test). The association of a small scleral canal with vascular anomalies, frequently noted in optic disks of patients with drusen, indicates a mesodermal dysgenesis of the optic nerve head.
=
=
THE PATHOGENESIS of optic disk drusen is incompletely known. Spencer! believed that axoplasmic transport alteration is the anatomic substrate for formation of drusen of the optic disk. He stated, "In familial cases the cause ofaxoplasmic transport alteration may be related to the presence of a genetically determined, small, crowded optic nerve head .... " However, because of the patients' refractive errors, as well as the indistinct margins of optic disks with drusen, he was unable to corroborate this statement. His impression was that "the discs in patients with familial drusen are clinically smaller than normal. ... " In a review of 250 eyes with pseudopapilledema, Rosenberg, Savino, and Glaser" suggested that "hyaline bodies arise in congenitally dysplastic discs, and it is our distinct impression that many of these discs have small diameters as well. ... "
Accepted for publication Dec. 13, 1984. From the Department of Neuro-Ophthalmology, National Hospital for Nervous Diseases, London, England. Dr. MulIie is the R. S. McGlauglin Fellow, McGill University, Montreal, Quebec, Canada. Reprint requests to Michael D. Sanders, F.R.C.S., Consultant Ophthalmologist, The National Hospital for Nervous Diseases, Queen Square, London WC1N 3BG, England.
356
We attempted to determine whether the scleral canals of optic disks with drusen are smaller than those of optic disks without drusen.
Subjects
and Methods
We measured and compared the scleral canal sizes in two samples of emmetropic patients: one of a group of patients with unilateral optic disk drusen in whom reliable measurements could be performed on the fellow-, non-drusen-containing optic disk and the other of the general population without optic nerve abnormalities. We reviewed the charts of 33 consecutive patients with the diagnosis of optic disk drusen seen at the National Hospital for Nervous Diseases between 1970 and 1984. The criteria for this diagnosis were either visible, calcified drusen or "buried" drusen verified by autofluorescence, late nodular hyperfluorescence on fluorescein angiography, or computed tomographic scans of the orbits. Twelve patients had bilateral exposed or buried drusen with pseudopapilledema. Twenty-one patients had unilateral exposed or buried drusen with pseudopapilledema and a fellow optic disk without drusen or significant swelling. Of these 21 fellow optic disks, eight were rejected from the study on the basis of either refractive error or an indistinct optic disk border, leaving 13 emmetropic fellow eyes in which the scleral rim of the optic disk was clearly definable. These 13 optic disks were selected as the first sample. There were eight female and five male patients ranging in age from 14 to 53 years, with a mean age of 27 years. A second sample of 19 optic disks from ten consecutive emmetropic patients without optic nerve disease was randomly selected from the outpatient charts of the neuro-ophthalmology clinic. There were five women and five men ranging in age from 25 to 42 years, with a mean age of 32 years. All optic disk photographs were taken with the Zeiss fundus camera at the standard 2.5X magnification on 24 x 36-mm film. Slide transparencies of the 13 non-drusen-containing optic disks from the sam-
©AMERICAN JOURNAL OF OPHTHALMOLOGY 99:35fr-359, MARCH, 1985
Vol. 99, No.3
Optic Nerve Head Drusen
pIe with unilateral drusen were randomly mixed with slides of the 19 optic disks from the ten normal emmetropic subjects. All 32 slides were projected onto a screen at a fixed magnification of 16x. From the projected image, direct measurements of the diameter of the scleral opening were obtained in four meridians on the optic disk: 12 to 6 o'clock, 1:30 to 7:30 o'clock, 3 to 9 o'clock, and 4:30 to 10:30 o'clock. The rim of the scleral canal of the optic nerve head was defined as the line of transition between the orange-brown color of the peripapillary retina and the white-pink color of the optic disk. The average optic disk diameter for each optic disk was recorded as the mean of the four meridional values. Measurements were obtained by one of us (M.A.M.) for all 32 optic disks at one session and repeated one week later. To eliminate observer bias, two sets of measurements were also obtained by an independent untrained observer without any knowledge of the purpose of the study. Measurements taken one week apart were highly reproducible; Pearson's product-moment correlation coefficient was r = .98 and r = .92 for trained and untrained observers respectively. Overall sample means were taken as the average of each sample's mean measurement on the two occasions.
Results The average diameters of the non-drusencontaining optic disks of patients with unilateral optic disk drusen were found to be significantly smaller than those of the optic disks of patients from the general population (Table). For both trained (t = 6.642) and untrained (t = 4.274) observers the difference was significant (P = .0005, one-tailed indepen-
TABLE OPTIC DISK MEASUREMENTS IN EMMETROPIC PATIENTS WITH AND WITHOUT OPTIC NERVE DRUSEN OPTIC DISK MEASUREMENT (MM) RANGE
Patients with drusen (No. = 13) Trained observer Untrained observer
60 to 76 64 to 79
MEAN
67 73
S.D.
4.49 4.59
Normal patients (No. = 19) Trained observer Untrained observer
68 to 93 71 to 94
82 82
6.75 6.74
357
dent t-test). The overall means of average optic disk diameters for the sample with drusen were 67 mm and 73 mm for trained and untrained observers respectively. In the sample without drusen the overall mean was 82 mm for trained and 82 mm for untrained observers. Based on the difference between each observer's sample means (67 and 82 mm vs 73 and 82 mm) patients with optic nerve drusen had optic disk surface areas an average of 20% to 33% smaller than those of a population without drusen.
Discussion Several theoretical and practical problems make it difficult to obtain accurate absolute fundus measurements clirucally." Kennedy, Schwartz, and Takamoto! attempted direct measurements, whereas Bengtsson and Krakau! and Littman! used an indirect approach by introducing optical corrective factors in their calculations. To circumvent these problems, we compared relative sizes of optic disks in two samples of emmetropic eyes. This design eliminates refractive error as one source of variation in measurement of fundus photographs. However, since emmetropic eyes can vary in axial length, 6 they may also vary in total dioptric power, thus influencing the magnification of optic disks. We therefore assumed that any significant variation in dioptric power between emmetropic eyes in the sample with drusen approximated that in the sample without drusen. Since measurement of the scleral rim in an optic disk with drusen may be difficult, we measured the optic disk in the contralateral eye (Figure). Because optic disk size is inherited and bilaterally similar.I:" it seems reasonable that in patients with unilateral pseudopapilledema and drusen optic disk size in the contralateral eye reflects optic disk size in the eye with drusen. Furthermore, ten of the 13 contralateral optic disks without drusen showed vascular anomalies commonly associated with drusen, implying that abnormal development of the optic nerve head may occur bilaterally, even in a patient with unilateral drusen. We do not know why a single optic disk predominantly or exclusively develops drusen. The familial type of optic disk drusen is inherited as an irregular autosomal dominant trait." Other congenital anomalies of optic disks with drusen include an increased number of major vessels on the optic disk itself, tortuous vessels with abnormal branching, vascular loops, cilioretinal arteries, and patchy areas of delayed filling of the peripapillary choriocapillaris on fluorescein angiography. 8,9 Congenital abnormalities of these mesodermal-derived structures, in association with a small scleral canal in
358
March, 1985
AMERICAN JOURNAL OF OPHTHALMOLOGY
Figure (Mullie and Sanders). Left, Fluorescein angiogram in late phase of right optic disk of a patient with right optic nerve drusen. Note nodular hyperfluorescence of the optic disk, giving a scalloped and indistinct border. Right, Fluorescein angiogram in late phase of the left optic disk of the same patient. The left optic disk shows a well defined edge. The optic disk vasculature in both eyes is congenitally anomalous.
optic disks that develop drusen, is evidence of the phenotypic expression in utero of the underlying genetic defect. A brief review of the normal embryologic development of the optic nerve head may help elucidate the delicate interplay of ectodermal and mesodermal elements in this region.:" At the eighth week (22- to 3D-mm stage) of gestation the ganglion cells have differentiated and the entire optic stalk is occupied by nerve fibers. At the 11th week (65-mm stage) the glial framework of the optic nerve begins to differentiate and blood vessels and elastic tissue invade the periphery of the nerve from the surrounding mesoderm. The hyaloid system begins to atrophy, and by the fourth month (lOO-mm stage) the primordia of the upper and lower branches of the central retinal artery appear on the optic disk. The sclera develops from mesodermal cells surrounding the optic vesicle, beginning at the limbus and extending posteriorly to reach the edge of the optic stalk by the end of the fifth month. In this way the peripapillary sclera forms after the neural optic stalk is complete. Mesodermal elements from the sclera then invade the glial framework of the primitive lamina, reinforcing it with collagen. The genetic and developmental mechanisms responsible for the mesodermal dysgenesis of the optic nerve head in patients who develop drusen are unknown. An abnormal posterior extension of sclera, Bruch's membrane, or both in the fetal period after the neural optic stalk has formed could conceivably encroach on the exit space of the nerve fibers from the eye. The absence of a central cup observed
in the optic disks of many patients with drusen may reflect crowding of emergent cell axons in a small scleral opening. Similarly, drusen are first detected clinically and histopathologically at the margins of the optic disk, 1 which could implicate the rigid edge of a small scleral canal as the aggravating factor in a relative mechanical blockage ofaxoplasmic flow in the normal eye at the level of the lamina scleralis!' or Bruch's membrane. 12 Seitz and Kersting" were the first to suggest that drusen of the optic disk may be the product of chronic degenerative changes in retinal ganglion cell axons. Spencer! reiterated their conclusions and Tso" added histopathologic evidence that abnormal axonal metabolism leads to intracellular mitochondrial calcification, axonal rupture, and extrusion of mitochondria into the extracellular space with further calcium deposition. The finding of abnormally small scleral canals in optic disks of patients with drusen supports Spencer's view' that "the normal physiologic damming of orthograde axoplasmic flow anterior to the lamina cribrosa is aggravated by local factors. We suggest that one factor is the abnormally narrow aperture of the scleral canal. When this process exceeds survival limits, degenerative changes begin which in the course of many years cause axonal death...." ACKNOWLEDGMENT
Richard Dewhirst, of the Department of NeuroOphthalmology, National Hospital, acted as the in-
Vol. 99, No.3
Optic Nerve Head Drusen
dependent untrained observer in making optic disk measurements and provided the illustrations.
References 1. Spencer, W. H.: Drusen of the optic disk and aberrant axoplasmic transport. The XXXIVEdward Jackson Memorial Lecture. Am. J. Ophthalmol. 85:1, 1978. 2. Rosenberg, M. A., Savino, P. J., and Glaser, J. A.: A clinical analysis of pseudopapilloedema. I. Population, laterality, acuity, refractive error, ophthalmoscopic characteristics, and coincident disease. Arch. Ophthalmol. 97:65, 1979. 3. Kennedy, S. J., Schwartz, B., Takamoto, T., and Eu, J. K. T.: Interference fringe scale for absolute ocular fundus measurement. Invest. Ophthalmol. Vis. Sci. 24:169, 1983. 4. Bengtsson, B., and Krakau, C. E. T.: Some essential optical features of the Zeiss fundus camera. Acta Ophthalmol. 55:123, 1977. 5. Littman, H.: Zur Bestimmung der wahren Grobe eines Objektes auf dem Hintergrund des lebenden Aunges. Klin. Monatsbl, Augenheilkd. 180:286, 1982.
359
6. Sorsby, A.: Topical aspects. The functional anomalies of the eye. In Sorsby, A. (ed.): Modern Ophthalmology, vol. 3. Washington, D.C., Butterworth, 1964, p. 9. 7. Bengtsson, B.: The inheritance and development of cup and disc diameters. Acta Ophthalmol. 58:733, 1980. 8. Armaly, M. F.: Genetic determination of cup/disc ratio of the optic nerve. Arch. Ophthalmol. 78:35, 1967. 9. Lorentzen, D. W.: Drusen of the optic disk. Acta Ophthalmol. l(suppl. 90):179, 1966. 10. Erkkila, H.: The central vascular pattern of the eyeground in children with drusen of the optic disk. Albrecht von Graefes Arch. Klin. Exp. Ophthalmol. 199:1, 1976. 11. Friedman, A. H., Beckerman, B., Gold, D. H., Walsh, J. B., and Gartner, S.: Drusen of the optic disc. Surv. Ophthalmol. 21:375, 1977. 12. Duke-Elder, S., and Cook, c.: Normal and abnormal development. In Duke-Elder, S. (ed.): System of Ophthalmology, vol. 3, pt. 1. London, Henry Kimpton, 1963, pp. 109, 162, and 204. 13. Seitz, R., and Kersting, G.: Die Drusen der sehnerven PapiJIe und des Pigmentepithels. Klin. Monatsbl. Augenheilkd. 140:75, 1962. 14. Tso, M. O. M.: Pathology and pathogenesis of drusen of the optic nerve head. Ophthalmology 88:1066, 1981.