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Photic Driving in Amblyopia Ex Anopsia*
RETINAL VEIN OCCLUSION
463
29. Astrup, T.: Biological significance of fibrinolysin. Lancet, 2:564-568 (Sept.) 1956. 30. Remitiert, L. F., and Cohen, P. P.: Partial purification and properties of proteolytic enzyme of human serum. J. Biol. Chem., 181:431-448 (Nov.) 1949. 31. Clifton, E. E., and Cannamela, D, A.: Fibrinolytic and proteolytic activity of human plasminogen: Prepared from fraction III of human plasma. J. Appi. Physiol, 6:42-50 (July) 1953. 32. Clifton, E E., Grossi, C. E., and Cannamela, D. A.: Lysis of thrombi productd by sodium morrhuate in femoral vein of dogs by human plasmin. Ann. Surg., 139:52-62 (Jan.) 1954. 33. Grossi, C. E., and Clifton, E. E : Lysis of arterial thrombi in rabbits and dogs by use of activated human plasminogen. Surg., 37:794-802 (May) 1955 34. Villavivencio, J. L., and Warren, R.: Experience with the use of human fibrinolysin. Angiology, 10:263-267 (Aug.) 1959. 35. Sheffer, A. L.: The treatment of pulmonary embolism with fibrinolysin. Angiology, 10:292-298 (Aug.) 1959. 36. Carroll, B. J.: Clinical observation in the treatment of phlebothrombosis with fibrinolysin. Angiol ogy, 10:308-310 (Aug.) 1959. 37. Roberts, B., and Thompson, S.: Clinical experiences with fibrinolysin. Angiology, 10:302-307 (Aug.) 1959. 38. Boyles, P. W.: Sustemic reaction after intravenous fibrinolysin therapy. J.A.M.A., 170:1045-1047 (June) 1959. 39. Ziskin, D. E. : Personal communication. 40. Moser, K. M.: Clinical observation in thrombo-embolic disease treated with fibrinolysin. Angiology, 10:319-331 (Aug.) 1959. 41. Clifton, E. E.: Early experience with fibrinolysin. Angiology, 10:244-252 (Aug.) 1959. 42. Sussman, B. J., and Fitch, T. S.: Thrombolysis with fibrinolysin in cerebral arterial occlusion. J.A.M.A., 167:1705 (Aug.) 1958. 43. Harloe, J. P.: The treatment of some problem cases of thrombo-embolic disease with fibrinolysin. Angiology, 10:283-291 (Aug.) 1959. 44. Sheffer, A. L., and Israel, H. I. : The treatment of pulmonary embolism with fibrinolysin. Angiol ogy, 10:292-298 (Aug.) 1959. 45. Stewart, C. F.: Two cases of massive edema of the leg treated with fibrinolysin. Angiology, 10: 299-301 (Aug.) 1959. 46. Evans, J. A., and Smedal, M. I.: Clinical experiences with fibrinolysin therapy. Angiology, 10:311318 (Aug.) 1959. 47. Singher, H. O., and Chappie, R. V.: A therapeutic approach to thrombo-embolic disease. Clin. Med., 6:349-446,1959. 48. Fletcher, H. P., Alkjaersig, M. S., Sawyer, W. D., and Sherry, S. : Evaluation of human fibrinoly sin (Actase). J.A.M.A., 172:912-915 (Feb.) 1960. 49. Howden, G. D.: The successful treatment of a case of central retinal vein thrombosis with intra venous fibrinolysin. Canad. M.A.J., 81:382-384 (Sept.) 1959.
PHOTIC DRIVING IN AMBLYOPIA EX JAMES E.
M I L L E R , M.D.,
ANOPSIA*
L A V E R N E C. J O H N S O N ,
GEORGE A. U L E T T , M.D.,
AND J A C K H A R T S T E I N ,
PH.D., M.D.
Saint Louis, Missouri Various alterations in response to flicker ing light have been described in amblyopia ex anopsia. It has been suggested that criti cal flicker frequency determination, photic driving, and central cortical time may be used as methods to evaluate amblyopia, and
possibly to indicate the site or sites of origin. F o r example, changes in critical flicker fre quency determination have been used as a subjective method in evaluating the optic conduction system. A report by Lohmann 1 described a differ-
*From the Department of Ophthalmology, the Oscar Johnson Institute, the Department of Psychi atry, and the Research Laboratories of the Malcolm Bliss Mental Health Center, Washington Uni versity School of Medicine. This investigation was supported in part by a research grant, B-1349, from
the National Institute of Neurological Diseases and Blindness of the National Institutes of Health, Public Health Service. Presented in part at the Mid western Section of the Association for Research in Ophthalmology, Indianapolis, Indiana, April 23, 1960.
464
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN
enee in critical flicker frequency between the two eyes, with the amblyopic eye respondingto a higher frequency of 46 per second in the central area, while the normal eye responded only to 34 per second. Teraskeli2 has also observed that the central area in the ambly opic eye had a flicker frequency comparable to 10 degrees peripheral. These findings were confirmed by Miles3 and Feinberg,4 although the latter two authors differed in their results for normal individuals, and the methods used were not comparable. Electro-encephalographic studies during exposure of the patient to a flashing light re sult in a change in brain wave frequencies to the rate of flicker. This phenomenon is known as photic driving. In general it will be found that the brain waves from the occipital cortex will tend to follow a flashing light at the rate of eight to 13 per second. This range of frequencies is known as the alpha range and is clearly seen when the patient is at rest with his eyes closed. Although photic driving occurs in almost all individuals,5 it may be difficult to detect without the aid of an elec tronic analyzer as it is often obscured by other frequencies superimposed upon the re sponses. Patients with amblyopia have been de scribed by Burian and Watson 6 as having al terations in photic driving. In a series con sisting of 65 normal subjects and 23 with amblyopia ex anopsia it was noted that photic driving was less easily produced in the amblyopic eye, and if present was of lower voltage and irregular in appearance. Often times the driving was combined with alpha rhythm. These findings were not ob served by Parson-Smith,7 Chinaglia and Ba lestrieri.8 The electro-encephalographic pattern of subjects with amblyopia have tended to indi cate a higher percentage of deviant tracings with spikes, slow activity, and fast activity being described.9"11 These findings are not characteristic per se for amblyopia. In addition to photic driving, it has been observed by Monnier12 that a response to a single flash of light may be obtained from
the occipital cortex. Thus one may measure the electroretinogram and photic driving re sponses simultaneously. The duration of the electroretinogram was then subtracted from the total time and the remainder was called central cortical time. This method of investi gation has been proposed by Burian and Watson 6 for studies of amblyopia, although no results were available. More refined techniques have been de veloped to obtain consistency in photic driv ing. These involve a large area of stimulus so that the entire field is filled with light. The use of electronic analyzers for a detailed study of the electro-encephalogram has per mitted discrete frequencies to be quantified for comparison of results. These summa tions, in turn, may be subjected to statistical analysis for reliability. Driving that was ob scured by other frequencies would be recog nized using this technique. The following re port concerns the use of such an apparatus. I. METHOD
Thirty-three children from the eye serv ices of Washington University Clinics and St. Louis City Hospital, whose ages ranged from six to 14 years, were used. The visual acuity was 20/70 or less in the ambly opic eye, and no evidence of pathology was noted. All of the test group had strabismus. Sixteen nonamblyopic children were re ferred from the pediatrie services for con trols. An attempt was made to match the ages of the amblyopic group. Each child was examined in the EEG Research Laboratory of the Malcolm Bliss Mental Health Center, and both a standard resting electroencephalo gram and response to intermittent photic stimulation were obtained. The light source consisted of a 500-watt bulb in a movie projector. Interruption of the light source was produced by a disc episcotister which could be varied to produce from three to 33 interruptions per second. The illumination was projected on a 30 by 30-inch white flashed opal glass screen, and the subject was seated 12 inches behind this screen. The light intensity was normally 100
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA foot-candles, and the light-dark ratio throughout was one to one. Neutral density filters were introduced to obtain an illumina tion of 50 and 25 foot-candles. A Gilson eight-channel electro-encephalograph was used, and scalp to scalp record ings were employed. Records were obtained from both the left and right parieto-occipital area, but only activity from the left side of the head was electronically analyzed for this study. The analyzer yielded a profile of the amount of activity at each of 24 frequencies within a 10-second interval. The pen deflec tion at each frequency was proportional to the average microvoltage multiplied by its duration during the 10-second period. In the initial phase of the experiment 16 amblyopes and 10 nonamblyopic subjects participated. Photic stimulation was pro duced with both eyes open, right eye covered, and then left eye covered. In the second phase of the study, the intensity of the flick ering light was varied as previously de scribed. Twenty amblyopic and six nonam blyopic children participated. Because of an overlap in some procedures, the number of subjects in each determination varied. PART 1. SPECIFIC EEG
PROCEDURE
1. Eight artefact-free 10-second pages of eyes closed resting activity. 2. Six artefact-free pages of eyes open resting activity. 3. Photic driving survey (with both eyes open) consisting of a 40-second exposure with a 40-second interval between each ex posure to each of the following frequencies: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13.5, 15, 18, 20, 22. 4. Photic driving survey with right eye covered (similar to No. 3 ) . 5. Photic driving survey with left eye covered (similar to No. 3). PART 2. SPECIFIC EEG
PROCEDURE
1. Eight pages of eyes closed resting ac tivity. 2. Six pages of eyes open resting activity. 3. Photic driving survey with light inten
465
sity of 100 foot-candles with right eye cov ered, consisting of 20-second exposure with a 20-second interval between each exposure to each of the following frequencies: 3, 4, 5, 6 , 7 , 8 , 9 , 10, 11, 12. 4. Photic driving survey with light inten sity of 50 foot-candles with right eye covered at the following frequencies: 4, 6, 9, 11. 5. Photic driving survey with light inten sity of 25 foot-candles with right eye covered at the frequencies listed in No. 4. 6. The same photic driving procedures from No. 3 to No. 5 were then repeated with the left eye covered. A 20-second light on, off interval was used throughout Part 2. The "resting eyes closed activity" was the average of six analyzed pages of artefactfree record. The "resting eyes open activity" was the average of four artefact free pages of analyzed activity. This was used as a baseline against which the effect of photic stimulation was evaluated. The amplitude of each dis crete frequency in the "resting eyes open ac tivity" was subtracted from that obtained by photic driving. In this study photic driving was defined as the amount of cortical activity present during photic stimulation minus the spontaneous activity recorded during eyes open resting period. II. RESULTS A. EYES CLOSED RESTING ACTIVITY
The eyes closed resting potentials are illus trated in Figure 1. Upon comparison of 16 normal subjects to 33 amblyopes, it was noted that both curves tend to be similar, with the maximum activity occurring in the range of 6.5 to 12 cycles per second. The slight increase seen in the alpha range (eight to 13 cycles per second) of the amblyopic group was not statistically significant. B. MONOCULAR PHOTIC DRIVING
The similarity of driving response in the affected eye and nonaffected eye is illustrated by the two profiles in Figure 2. The curve for the affected eye tended to be higher than for the nonaffected eye, especially in the
466
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN second were almost identical to those found between the affected and nonaffected eyes in the amblyopic subjects. C. BINOCULAR PHOTIC DRIVING
•-^. 9. 39 4 A3 9 93 9 99 T
9
9
10 11 12 13 19 « S 19 20 32 249 2T 30 33
EEC FltEOUENCY
Fig. 1 (Miller, et al.). Eyes closed resting activity. eight to 10 cycle per second range. How ever, this difference was not statistically reli able. In fact, only 16 subjects had more eight to 10 cycles per second in their affected eye, while 14 of the subjects had more eight to 10 cycles per second driving in their nonaffected eye. Further evidence of the similarity in the two eyes was seen in the correlation of amount of driving between the affected and nonaffected eye. For driving in the three to seven cycles per second range, the rank order (Rho) correlation was 0.63, and for driving in the eight to 12 range it was 0.66. Both correlations were significant beyond the 0.001 level indicating that if a low or high amount of driving was seen in one eye, a similar driving response will most often be found in the other eye. The fact that the correlation was not nearer 1.0 indicates that the response in the two eyes was not always identical for all subjects. When the driving response in the right eye was compared with driving in the left eye for the 16 nonamblyopic subjects, no signi ficant difference was found. A further indi cation of the resemblance between the amblyopic and nonamblyopic group was the rank order correlation between the right and left eye in the normal group. The correlations of 0.63 for three to seven cycles per second driving and a 0.69 for eight to 12 cycles per
The results listed in Table 1 indicated that the amblyopic response was significantly greater in the three to seven cycles per sec ond range and significantly less in the eight to 18 cycles per second range. The two groups did not differ in the 15 to 22 cycles per second range. The results are shown in Figure 3. The peak driving response for the amblyopic group was seven cycles per second, while the peak response for the nonamblyopic subjects was 11 cycles per second. The most striking difference in the two curves, how ever, was the marked decrease of the ambly opic driving responses in the eight to 13 cycles per second range. The nonamblyopic subjects had a constantly higher driving re sponse over the eight to 13 cycles per second AMBLVOPIA-EACH EYE SEPARATELY Driving Non-Affected Eye Driving Affected Eye
5
s
S ki
% W o.
? k ft: tu
SI
3.0 4-0 50 6.0 7.0 SO SO 10.0 11.0 12.0 εεβ
FREQUENCY
Fig. 2 (Miller, et al). Comparison of photic driving from the amblyopic and nonamblyopic eye.
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA
467
TABLE 1 PHOTIC DRIVING RESPONSE, BOTH EYES OPEN, FOR AMBLYOPIC AND NONAMBLYOPIC CHILDREN
8-13
3-7 Frequency (cps) Amblyopic Nonamblyopic
Mean
g £
124.1 54.8 83.5 31.7 2.39*
N — 16 N = 10 t
Mean
15-22 ^
Mpan Mean
112.9 46.1 160.6 49.3 2.46*
Std
8-10 ·
Dev. 38.2 23.3 49.5 16.3 1.61
Mean g j ; 69.6 37.9 84.1 41.7 0.88
11-13 Mean
Dev.
44.3 21.0 79.9 27.5 3.56f
* Significant <0.05 level. t Significant 0.01 level.
range, while the amblyopic subjects decreased within this area. Dividing the eight to 13 cycles per second range into eight to 10 and 11 to 13 cycles per second, and comparing the two groups of subjects, revealed the difference in driv ing response. The mean and standard devia tion values are also listed in Table 1. The mean values for the two groups reflected the curves of Figure 3 and indicated the de crease in driving response for the amblyopic group. The difference in driving response between the amblyopic and nonamblyopic subjects in the 11 to 13 cycles per second range would be expected by chance only one time out of a hundred. These results indicated that the pattern of driving was different between the amblyopic and nonamblyopic patients. The amblyopic subjects drove more in the slower frequen-
OO
εεδ
»»
IOO
no
cies below eight cycles per second, while the nonamblyopic patients responded more in the alpha range and this difference was pres ent only under binocular conditions. D. EFFECT OF LIGHT INTENSITY ON PHOTIC DRIVING
The response for 100, 50, and 25 footcandles of the affected and nonaffected eyes in amblyopic subjects are presented in Fig ure 4. The resemblance of the driving pro files of both affected and nonaffected eyes indicated that there was no relationship be tween driving and light intensity. Compari son of the curves for the affected and non affected eyes suggested that the driving re sponse in the affected eyes was greater than the nonaffected eyes. However, statistical AFFECTED EVE Driving tOOff Condi*« · · N"30 Owing SOft Candii« f——f Ν·20 Driving 23ft. Candì» « « N*20
NON-AFFECTED ETE Driving 100 ft. Candì«» · · Driving 50 ft Condì«! »— — f Driving 25 ft Candi«! »-—..-A
N ' 30 N*20 N* 20
B.i
FREQUENCY
Fig. 3 (Miller, et al.). Results from driving both eyes simultaneously in subjects with and without amblyopia.
EEC
FftEOUEttCf
Fig. 4 (Miller, et al.). Responses from the (left) affected and (right) nonaffected eye under reduced illumination.
468
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN
analysis again indicated that these differ ences could occur by chance. E. COMPARISON OF THE BASIC
EEG
Clinical comparison of the electro-encephalographic records of the two groups indi cated no statistical difference in the degree of disorganization, though the amblyopic group did have a larger number of subjects who demonstrated high amplitude slow waves or bursts of paroxysmal activity. Three (18.7 percent) of the 16 nonamblyopic sub jects and nine (27.3 percent) of the ambly opic subjects were classified as being disor dered for age. One nonamblyopic subject and three amblyopic subjects were categor ized as having borderline disorder for age. Statistical tests indicated that this could arise 30 times out of 100 by chance. Examination of the analyzer scores for the subjects classified as disordered for age indicated that all had more analyzed activity in the three to seven cycles per second range than did those classified as having normal activity. These results also supported pre vious findings that evaluation of analyzed electro-encephalographic activity and clinical examination produce similar results. III.
DISCUSSION
A comparison between the affected eye and nonaffected eye in amblyopic subjects failed to reveal any significant difference as determined by photic driving. This compari son was naturally made under monocular conditions with the nontested eye occluded. Using this technique, it could also be stated that no difference was found in the conduc tion system between the two eyes. However, under binocular conditions a shift of photic driving was found in patients with amblyopia and strabismus. The normal individual did not change his basic driving pattern, whereas the amblyopic subject drove at lower frequencies when both eyes were open. Thus it could be stated that an alteration in the response of the occipital cortex was seen under a binocular situation. (These deter
minations cannot be used to state definitely the location of amblyopia. They do, however, show that changes occur in the occipital re gion under binocular conditions). The tend ency to respond to flashes of light at lower frequencies also was unusual. This finding was not previously noted by Parson-Smith, Chinaglia, and Balestrieri. Most probably this was due to the conditions of their determinations since driving was ob tained with eyes closed and the nontested eye was bandaged. Naturally binocularity would be lacking under this situation. One problem that was not resolved was the possibility that these findings may be a manifestation of suppression since all of the test subjects had strabismus as well as am blyopia ex anopsia. Further studies are being conducted in a series of alternators in an effort to establish this. While the greater response obtained from the amblyopic eye at lower light intensities was not significant, the direction of the dif ferences again highlighted the finding that the affected eye was as responsive to photic stimulation as the nonaffected eye. This sug gested that other explanations must be sought to explain the differences in visual acuity besides a loss of gross photic re sponse. A clinical comparison indicated that the amblyopic group had a larger number of subjects with high amplitude slow waves or bursts of paroxysmal activity, even though corrected for age. However, only nine out of 33 were classified as being disordered, whereas three out of 16 in the control group showed similar changes. The series is too small to conclude that amblyopic subjects have a greater tendency toward abnormal electro-encephalograms. IV.
SUMMARY
1. In patients with amblyopia significantly less photic driving in the range of eight to 18 flashes and greater in the three to seven binocular conditions.
ex anopsia was found per second, area under
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA
2. The nonamblyopic subjects responded greatest in the eight to 13 flashes per second range with both eyes open. 3. No difference in photic driving was found testing the amblyopic and nonambly opic eye separately. 4. Decreasing the light intensity did not
469
influence the response from the amblyopic or nonamblyopic eye. 5. There was no significant difference in the clinical evaluation of the electroencaphalograms in the amblyopic and nonamblyopic groups. 640 South Kingshighway (10).
REFERENCES
1. Lohmann, W.: Ueber die lokalen Unterschiede der Verschmelzungsfrequenz auf der Retina und ihr abweichendes Verhalten bei der Amblyopia congenita. Arch. f. Ophth., 68:395, 1908. 2. Teraskeli, H.: Untersuchungen ueber die Amblyopie ohne Spiegelbefund bei schielenden und nicht schielenden Augen mittelst der Flimmermethode. Acta. Soc. Med. Feun., Ser. B, 19:1, 1934. 3. Miles, P. W.: Flicker fusion frequency in amblyopia ex anopsia. Am. J. Ophth., 32:225, 1949. 4. Feinberg, I.: Critical flicker frequency in amblyopia ex anopsia. Am. J. Ophth., 42:473, 1956. 5. Johnson, L. C, Ulett, G. A., and Gleser, G.: Studies of the photically stimulated EEG: 1. Quantifica tion and stability of photic driving patterns. USAF Sch. Avia. Med. Rept, 57:54 (Jan.) 1957. 6. Burian, H. M., and Watson, C. W.: Cerebral electric response to intermittent photic stimulation in amblyopia ex anopsia. Arch. Ophth., 48:137, 1952. 7. Parson-Smith, G.: Flicker stimulation in amblyopia. Brit. J. Ophth., 37:424, 1953. 8. Chinaglia, V., and Balestrieri, A.: L'elettroencefalogramma quale contributo allo studio della araMiopia. Rev. oto-neuro-oftal., 30:305, 1955. 9. Dver, D., and Bierman, E. O.: Cortical potential changes in suppression amblyopia. Am. J. Ophth., 35:66,1952. 10. Parson-Smith, G.: Activity of the cerebral cortex in amblyopia. Brit. J. Ophth., 37:359, 1953. 11. Steiger, R. M., and Wuerth, A.: Die Fixationsphotographie und die Elektroencephalographie in der Beurteilung der Schielamblyopie. Ophthalmologica, 129:240, 1955. 12. Monnier, M.: L'electro-retinogramme de l'homme. EEG & Clin. Neurophysiol., 1:87, 1949.
T H E CO-OPERATION O F EXTRAOCULAR MUSCLES PAUL BOEDER, P H . D .
Iowa City, Iowa
The best experimental basis for studying analytically the action of extraocular muscles has been given by A. W. Volkmann 1 who, by means of careful and painstaking meas urements on 30 heads, determined the aver age co-ordinates of the effective origins and the effective insertions of the six extraocular muscles. His findings (in mm.) presented in Table 1, form the basis of the present study. The origin of the co-ordinate system used by Volkmann coincides with the center of rotation of the eye ; the positive x-axis points outward, the positive y-axis backward, and the positive z-axis upward. With the aid of these co-ordinates, one can study the action of an individual muscle as follows: The three points, (1) the center of rota-
tion of the eye, (2) the effective origin of the muscle, and (3) the effective insertion of the muscle, determine its muscle plane, and the perpendicular to this plane through the center of rotation is its axis of rotation. Volkmann's co-ordinates of the muscle insertions refer to the primary position. For any other position of the eye, these co-ordi nates assume different values because the in sertions participate, of course, in the eye's rotation to the position in question. This means that there is a different set of muscle planes and axes of rotation for every posi tion of the eye. However, the participation of the effective insertions in the eye's rotation is not complete. The effective insertions re sist, so to speak, being rotated out of their primary muscle planes. This was observed
463
29. Astrup, T.: Biological significance of fibrinolysin. Lancet, 2:564-568 (Sept.) 1956. 30. Remitiert, L. F., and Cohen, P. P.: Partial purification and properties of proteolytic enzyme of human serum. J. Biol. Chem., 181:431-448 (Nov.) 1949. 31. Clifton, E. E., and Cannamela, D, A.: Fibrinolytic and proteolytic activity of human plasminogen: Prepared from fraction III of human plasma. J. Appi. Physiol, 6:42-50 (July) 1953. 32. Clifton, E E., Grossi, C. E., and Cannamela, D. A.: Lysis of thrombi productd by sodium morrhuate in femoral vein of dogs by human plasmin. Ann. Surg., 139:52-62 (Jan.) 1954. 33. Grossi, C. E., and Clifton, E. E : Lysis of arterial thrombi in rabbits and dogs by use of activated human plasminogen. Surg., 37:794-802 (May) 1955 34. Villavivencio, J. L., and Warren, R.: Experience with the use of human fibrinolysin. Angiology, 10:263-267 (Aug.) 1959. 35. Sheffer, A. L.: The treatment of pulmonary embolism with fibrinolysin. Angiology, 10:292-298 (Aug.) 1959. 36. Carroll, B. J.: Clinical observation in the treatment of phlebothrombosis with fibrinolysin. Angiol ogy, 10:308-310 (Aug.) 1959. 37. Roberts, B., and Thompson, S.: Clinical experiences with fibrinolysin. Angiology, 10:302-307 (Aug.) 1959. 38. Boyles, P. W.: Sustemic reaction after intravenous fibrinolysin therapy. J.A.M.A., 170:1045-1047 (June) 1959. 39. Ziskin, D. E. : Personal communication. 40. Moser, K. M.: Clinical observation in thrombo-embolic disease treated with fibrinolysin. Angiology, 10:319-331 (Aug.) 1959. 41. Clifton, E. E.: Early experience with fibrinolysin. Angiology, 10:244-252 (Aug.) 1959. 42. Sussman, B. J., and Fitch, T. S.: Thrombolysis with fibrinolysin in cerebral arterial occlusion. J.A.M.A., 167:1705 (Aug.) 1958. 43. Harloe, J. P.: The treatment of some problem cases of thrombo-embolic disease with fibrinolysin. Angiology, 10:283-291 (Aug.) 1959. 44. Sheffer, A. L., and Israel, H. I. : The treatment of pulmonary embolism with fibrinolysin. Angiol ogy, 10:292-298 (Aug.) 1959. 45. Stewart, C. F.: Two cases of massive edema of the leg treated with fibrinolysin. Angiology, 10: 299-301 (Aug.) 1959. 46. Evans, J. A., and Smedal, M. I.: Clinical experiences with fibrinolysin therapy. Angiology, 10:311318 (Aug.) 1959. 47. Singher, H. O., and Chappie, R. V.: A therapeutic approach to thrombo-embolic disease. Clin. Med., 6:349-446,1959. 48. Fletcher, H. P., Alkjaersig, M. S., Sawyer, W. D., and Sherry, S. : Evaluation of human fibrinoly sin (Actase). J.A.M.A., 172:912-915 (Feb.) 1960. 49. Howden, G. D.: The successful treatment of a case of central retinal vein thrombosis with intra venous fibrinolysin. Canad. M.A.J., 81:382-384 (Sept.) 1959.
PHOTIC DRIVING IN AMBLYOPIA EX JAMES E.
M I L L E R , M.D.,
ANOPSIA*
L A V E R N E C. J O H N S O N ,
GEORGE A. U L E T T , M.D.,
AND J A C K H A R T S T E I N ,
PH.D., M.D.
Saint Louis, Missouri Various alterations in response to flicker ing light have been described in amblyopia ex anopsia. It has been suggested that criti cal flicker frequency determination, photic driving, and central cortical time may be used as methods to evaluate amblyopia, and
possibly to indicate the site or sites of origin. F o r example, changes in critical flicker fre quency determination have been used as a subjective method in evaluating the optic conduction system. A report by Lohmann 1 described a differ-
*From the Department of Ophthalmology, the Oscar Johnson Institute, the Department of Psychi atry, and the Research Laboratories of the Malcolm Bliss Mental Health Center, Washington Uni versity School of Medicine. This investigation was supported in part by a research grant, B-1349, from
the National Institute of Neurological Diseases and Blindness of the National Institutes of Health, Public Health Service. Presented in part at the Mid western Section of the Association for Research in Ophthalmology, Indianapolis, Indiana, April 23, 1960.
464
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN
enee in critical flicker frequency between the two eyes, with the amblyopic eye respondingto a higher frequency of 46 per second in the central area, while the normal eye responded only to 34 per second. Teraskeli2 has also observed that the central area in the ambly opic eye had a flicker frequency comparable to 10 degrees peripheral. These findings were confirmed by Miles3 and Feinberg,4 although the latter two authors differed in their results for normal individuals, and the methods used were not comparable. Electro-encephalographic studies during exposure of the patient to a flashing light re sult in a change in brain wave frequencies to the rate of flicker. This phenomenon is known as photic driving. In general it will be found that the brain waves from the occipital cortex will tend to follow a flashing light at the rate of eight to 13 per second. This range of frequencies is known as the alpha range and is clearly seen when the patient is at rest with his eyes closed. Although photic driving occurs in almost all individuals,5 it may be difficult to detect without the aid of an elec tronic analyzer as it is often obscured by other frequencies superimposed upon the re sponses. Patients with amblyopia have been de scribed by Burian and Watson 6 as having al terations in photic driving. In a series con sisting of 65 normal subjects and 23 with amblyopia ex anopsia it was noted that photic driving was less easily produced in the amblyopic eye, and if present was of lower voltage and irregular in appearance. Often times the driving was combined with alpha rhythm. These findings were not ob served by Parson-Smith,7 Chinaglia and Ba lestrieri.8 The electro-encephalographic pattern of subjects with amblyopia have tended to indi cate a higher percentage of deviant tracings with spikes, slow activity, and fast activity being described.9"11 These findings are not characteristic per se for amblyopia. In addition to photic driving, it has been observed by Monnier12 that a response to a single flash of light may be obtained from
the occipital cortex. Thus one may measure the electroretinogram and photic driving re sponses simultaneously. The duration of the electroretinogram was then subtracted from the total time and the remainder was called central cortical time. This method of investi gation has been proposed by Burian and Watson 6 for studies of amblyopia, although no results were available. More refined techniques have been de veloped to obtain consistency in photic driv ing. These involve a large area of stimulus so that the entire field is filled with light. The use of electronic analyzers for a detailed study of the electro-encephalogram has per mitted discrete frequencies to be quantified for comparison of results. These summa tions, in turn, may be subjected to statistical analysis for reliability. Driving that was ob scured by other frequencies would be recog nized using this technique. The following re port concerns the use of such an apparatus. I. METHOD
Thirty-three children from the eye serv ices of Washington University Clinics and St. Louis City Hospital, whose ages ranged from six to 14 years, were used. The visual acuity was 20/70 or less in the ambly opic eye, and no evidence of pathology was noted. All of the test group had strabismus. Sixteen nonamblyopic children were re ferred from the pediatrie services for con trols. An attempt was made to match the ages of the amblyopic group. Each child was examined in the EEG Research Laboratory of the Malcolm Bliss Mental Health Center, and both a standard resting electroencephalo gram and response to intermittent photic stimulation were obtained. The light source consisted of a 500-watt bulb in a movie projector. Interruption of the light source was produced by a disc episcotister which could be varied to produce from three to 33 interruptions per second. The illumination was projected on a 30 by 30-inch white flashed opal glass screen, and the subject was seated 12 inches behind this screen. The light intensity was normally 100
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA foot-candles, and the light-dark ratio throughout was one to one. Neutral density filters were introduced to obtain an illumina tion of 50 and 25 foot-candles. A Gilson eight-channel electro-encephalograph was used, and scalp to scalp record ings were employed. Records were obtained from both the left and right parieto-occipital area, but only activity from the left side of the head was electronically analyzed for this study. The analyzer yielded a profile of the amount of activity at each of 24 frequencies within a 10-second interval. The pen deflec tion at each frequency was proportional to the average microvoltage multiplied by its duration during the 10-second period. In the initial phase of the experiment 16 amblyopes and 10 nonamblyopic subjects participated. Photic stimulation was pro duced with both eyes open, right eye covered, and then left eye covered. In the second phase of the study, the intensity of the flick ering light was varied as previously de scribed. Twenty amblyopic and six nonam blyopic children participated. Because of an overlap in some procedures, the number of subjects in each determination varied. PART 1. SPECIFIC EEG
PROCEDURE
1. Eight artefact-free 10-second pages of eyes closed resting activity. 2. Six artefact-free pages of eyes open resting activity. 3. Photic driving survey (with both eyes open) consisting of a 40-second exposure with a 40-second interval between each ex posure to each of the following frequencies: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13.5, 15, 18, 20, 22. 4. Photic driving survey with right eye covered (similar to No. 3 ) . 5. Photic driving survey with left eye covered (similar to No. 3). PART 2. SPECIFIC EEG
PROCEDURE
1. Eight pages of eyes closed resting ac tivity. 2. Six pages of eyes open resting activity. 3. Photic driving survey with light inten
465
sity of 100 foot-candles with right eye cov ered, consisting of 20-second exposure with a 20-second interval between each exposure to each of the following frequencies: 3, 4, 5, 6 , 7 , 8 , 9 , 10, 11, 12. 4. Photic driving survey with light inten sity of 50 foot-candles with right eye covered at the following frequencies: 4, 6, 9, 11. 5. Photic driving survey with light inten sity of 25 foot-candles with right eye covered at the frequencies listed in No. 4. 6. The same photic driving procedures from No. 3 to No. 5 were then repeated with the left eye covered. A 20-second light on, off interval was used throughout Part 2. The "resting eyes closed activity" was the average of six analyzed pages of artefactfree record. The "resting eyes open activity" was the average of four artefact free pages of analyzed activity. This was used as a baseline against which the effect of photic stimulation was evaluated. The amplitude of each dis crete frequency in the "resting eyes open ac tivity" was subtracted from that obtained by photic driving. In this study photic driving was defined as the amount of cortical activity present during photic stimulation minus the spontaneous activity recorded during eyes open resting period. II. RESULTS A. EYES CLOSED RESTING ACTIVITY
The eyes closed resting potentials are illus trated in Figure 1. Upon comparison of 16 normal subjects to 33 amblyopes, it was noted that both curves tend to be similar, with the maximum activity occurring in the range of 6.5 to 12 cycles per second. The slight increase seen in the alpha range (eight to 13 cycles per second) of the amblyopic group was not statistically significant. B. MONOCULAR PHOTIC DRIVING
The similarity of driving response in the affected eye and nonaffected eye is illustrated by the two profiles in Figure 2. The curve for the affected eye tended to be higher than for the nonaffected eye, especially in the
466
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN second were almost identical to those found between the affected and nonaffected eyes in the amblyopic subjects. C. BINOCULAR PHOTIC DRIVING
•-^. 9. 39 4 A3 9 93 9 99 T
9
9
10 11 12 13 19 « S 19 20 32 249 2T 30 33
EEC FltEOUENCY
Fig. 1 (Miller, et al.). Eyes closed resting activity. eight to 10 cycle per second range. How ever, this difference was not statistically reli able. In fact, only 16 subjects had more eight to 10 cycles per second in their affected eye, while 14 of the subjects had more eight to 10 cycles per second driving in their nonaffected eye. Further evidence of the similarity in the two eyes was seen in the correlation of amount of driving between the affected and nonaffected eye. For driving in the three to seven cycles per second range, the rank order (Rho) correlation was 0.63, and for driving in the eight to 12 range it was 0.66. Both correlations were significant beyond the 0.001 level indicating that if a low or high amount of driving was seen in one eye, a similar driving response will most often be found in the other eye. The fact that the correlation was not nearer 1.0 indicates that the response in the two eyes was not always identical for all subjects. When the driving response in the right eye was compared with driving in the left eye for the 16 nonamblyopic subjects, no signi ficant difference was found. A further indi cation of the resemblance between the amblyopic and nonamblyopic group was the rank order correlation between the right and left eye in the normal group. The correlations of 0.63 for three to seven cycles per second driving and a 0.69 for eight to 12 cycles per
The results listed in Table 1 indicated that the amblyopic response was significantly greater in the three to seven cycles per sec ond range and significantly less in the eight to 18 cycles per second range. The two groups did not differ in the 15 to 22 cycles per second range. The results are shown in Figure 3. The peak driving response for the amblyopic group was seven cycles per second, while the peak response for the nonamblyopic subjects was 11 cycles per second. The most striking difference in the two curves, how ever, was the marked decrease of the ambly opic driving responses in the eight to 13 cycles per second range. The nonamblyopic subjects had a constantly higher driving re sponse over the eight to 13 cycles per second AMBLVOPIA-EACH EYE SEPARATELY Driving Non-Affected Eye Driving Affected Eye
5
s
S ki
% W o.
? k ft: tu
SI
3.0 4-0 50 6.0 7.0 SO SO 10.0 11.0 12.0 εεβ
FREQUENCY
Fig. 2 (Miller, et al). Comparison of photic driving from the amblyopic and nonamblyopic eye.
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA
467
TABLE 1 PHOTIC DRIVING RESPONSE, BOTH EYES OPEN, FOR AMBLYOPIC AND NONAMBLYOPIC CHILDREN
8-13
3-7 Frequency (cps) Amblyopic Nonamblyopic
Mean
g £
124.1 54.8 83.5 31.7 2.39*
N — 16 N = 10 t
Mean
15-22 ^
Mpan Mean
112.9 46.1 160.6 49.3 2.46*
Std
8-10 ·
Dev. 38.2 23.3 49.5 16.3 1.61
Mean g j ; 69.6 37.9 84.1 41.7 0.88
11-13 Mean
Dev.
44.3 21.0 79.9 27.5 3.56f
* Significant <0.05 level. t Significant 0.01 level.
range, while the amblyopic subjects decreased within this area. Dividing the eight to 13 cycles per second range into eight to 10 and 11 to 13 cycles per second, and comparing the two groups of subjects, revealed the difference in driv ing response. The mean and standard devia tion values are also listed in Table 1. The mean values for the two groups reflected the curves of Figure 3 and indicated the de crease in driving response for the amblyopic group. The difference in driving response between the amblyopic and nonamblyopic subjects in the 11 to 13 cycles per second range would be expected by chance only one time out of a hundred. These results indicated that the pattern of driving was different between the amblyopic and nonamblyopic patients. The amblyopic subjects drove more in the slower frequen-
OO
εεδ
»»
IOO
no
cies below eight cycles per second, while the nonamblyopic patients responded more in the alpha range and this difference was pres ent only under binocular conditions. D. EFFECT OF LIGHT INTENSITY ON PHOTIC DRIVING
The response for 100, 50, and 25 footcandles of the affected and nonaffected eyes in amblyopic subjects are presented in Fig ure 4. The resemblance of the driving pro files of both affected and nonaffected eyes indicated that there was no relationship be tween driving and light intensity. Compari son of the curves for the affected and non affected eyes suggested that the driving re sponse in the affected eyes was greater than the nonaffected eyes. However, statistical AFFECTED EVE Driving tOOff Condi*« · · N"30 Owing SOft Candii« f——f Ν·20 Driving 23ft. Candì» « « N*20
NON-AFFECTED ETE Driving 100 ft. Candì«» · · Driving 50 ft Condì«! »— — f Driving 25 ft Candi«! »-—..-A
N ' 30 N*20 N* 20
B.i
FREQUENCY
Fig. 3 (Miller, et al.). Results from driving both eyes simultaneously in subjects with and without amblyopia.
EEC
FftEOUEttCf
Fig. 4 (Miller, et al.). Responses from the (left) affected and (right) nonaffected eye under reduced illumination.
468
J. E. MILLER, L. C. JOHNSON, G. A. ULETT AND J. HARTSTEIN
analysis again indicated that these differ ences could occur by chance. E. COMPARISON OF THE BASIC
EEG
Clinical comparison of the electro-encephalographic records of the two groups indi cated no statistical difference in the degree of disorganization, though the amblyopic group did have a larger number of subjects who demonstrated high amplitude slow waves or bursts of paroxysmal activity. Three (18.7 percent) of the 16 nonamblyopic sub jects and nine (27.3 percent) of the ambly opic subjects were classified as being disor dered for age. One nonamblyopic subject and three amblyopic subjects were categor ized as having borderline disorder for age. Statistical tests indicated that this could arise 30 times out of 100 by chance. Examination of the analyzer scores for the subjects classified as disordered for age indicated that all had more analyzed activity in the three to seven cycles per second range than did those classified as having normal activity. These results also supported pre vious findings that evaluation of analyzed electro-encephalographic activity and clinical examination produce similar results. III.
DISCUSSION
A comparison between the affected eye and nonaffected eye in amblyopic subjects failed to reveal any significant difference as determined by photic driving. This compari son was naturally made under monocular conditions with the nontested eye occluded. Using this technique, it could also be stated that no difference was found in the conduc tion system between the two eyes. However, under binocular conditions a shift of photic driving was found in patients with amblyopia and strabismus. The normal individual did not change his basic driving pattern, whereas the amblyopic subject drove at lower frequencies when both eyes were open. Thus it could be stated that an alteration in the response of the occipital cortex was seen under a binocular situation. (These deter
minations cannot be used to state definitely the location of amblyopia. They do, however, show that changes occur in the occipital re gion under binocular conditions). The tend ency to respond to flashes of light at lower frequencies also was unusual. This finding was not previously noted by Parson-Smith, Chinaglia, and Balestrieri. Most probably this was due to the conditions of their determinations since driving was ob tained with eyes closed and the nontested eye was bandaged. Naturally binocularity would be lacking under this situation. One problem that was not resolved was the possibility that these findings may be a manifestation of suppression since all of the test subjects had strabismus as well as am blyopia ex anopsia. Further studies are being conducted in a series of alternators in an effort to establish this. While the greater response obtained from the amblyopic eye at lower light intensities was not significant, the direction of the dif ferences again highlighted the finding that the affected eye was as responsive to photic stimulation as the nonaffected eye. This sug gested that other explanations must be sought to explain the differences in visual acuity besides a loss of gross photic re sponse. A clinical comparison indicated that the amblyopic group had a larger number of subjects with high amplitude slow waves or bursts of paroxysmal activity, even though corrected for age. However, only nine out of 33 were classified as being disordered, whereas three out of 16 in the control group showed similar changes. The series is too small to conclude that amblyopic subjects have a greater tendency toward abnormal electro-encephalograms. IV.
SUMMARY
1. In patients with amblyopia significantly less photic driving in the range of eight to 18 flashes and greater in the three to seven binocular conditions.
ex anopsia was found per second, area under
PHOTIC DRIVING IN AMBLYOPIA EX ANOPSIA
2. The nonamblyopic subjects responded greatest in the eight to 13 flashes per second range with both eyes open. 3. No difference in photic driving was found testing the amblyopic and nonambly opic eye separately. 4. Decreasing the light intensity did not
469
influence the response from the amblyopic or nonamblyopic eye. 5. There was no significant difference in the clinical evaluation of the electroencaphalograms in the amblyopic and nonamblyopic groups. 640 South Kingshighway (10).
REFERENCES
1. Lohmann, W.: Ueber die lokalen Unterschiede der Verschmelzungsfrequenz auf der Retina und ihr abweichendes Verhalten bei der Amblyopia congenita. Arch. f. Ophth., 68:395, 1908. 2. Teraskeli, H.: Untersuchungen ueber die Amblyopie ohne Spiegelbefund bei schielenden und nicht schielenden Augen mittelst der Flimmermethode. Acta. Soc. Med. Feun., Ser. B, 19:1, 1934. 3. Miles, P. W.: Flicker fusion frequency in amblyopia ex anopsia. Am. J. Ophth., 32:225, 1949. 4. Feinberg, I.: Critical flicker frequency in amblyopia ex anopsia. Am. J. Ophth., 42:473, 1956. 5. Johnson, L. C, Ulett, G. A., and Gleser, G.: Studies of the photically stimulated EEG: 1. Quantifica tion and stability of photic driving patterns. USAF Sch. Avia. Med. Rept, 57:54 (Jan.) 1957. 6. Burian, H. M., and Watson, C. W.: Cerebral electric response to intermittent photic stimulation in amblyopia ex anopsia. Arch. Ophth., 48:137, 1952. 7. Parson-Smith, G.: Flicker stimulation in amblyopia. Brit. J. Ophth., 37:424, 1953. 8. Chinaglia, V., and Balestrieri, A.: L'elettroencefalogramma quale contributo allo studio della araMiopia. Rev. oto-neuro-oftal., 30:305, 1955. 9. Dver, D., and Bierman, E. O.: Cortical potential changes in suppression amblyopia. Am. J. Ophth., 35:66,1952. 10. Parson-Smith, G.: Activity of the cerebral cortex in amblyopia. Brit. J. Ophth., 37:359, 1953. 11. Steiger, R. M., and Wuerth, A.: Die Fixationsphotographie und die Elektroencephalographie in der Beurteilung der Schielamblyopie. Ophthalmologica, 129:240, 1955. 12. Monnier, M.: L'electro-retinogramme de l'homme. EEG & Clin. Neurophysiol., 1:87, 1949.
T H E CO-OPERATION O F EXTRAOCULAR MUSCLES PAUL BOEDER, P H . D .
Iowa City, Iowa
The best experimental basis for studying analytically the action of extraocular muscles has been given by A. W. Volkmann 1 who, by means of careful and painstaking meas urements on 30 heads, determined the aver age co-ordinates of the effective origins and the effective insertions of the six extraocular muscles. His findings (in mm.) presented in Table 1, form the basis of the present study. The origin of the co-ordinate system used by Volkmann coincides with the center of rotation of the eye ; the positive x-axis points outward, the positive y-axis backward, and the positive z-axis upward. With the aid of these co-ordinates, one can study the action of an individual muscle as follows: The three points, (1) the center of rota-
tion of the eye, (2) the effective origin of the muscle, and (3) the effective insertion of the muscle, determine its muscle plane, and the perpendicular to this plane through the center of rotation is its axis of rotation. Volkmann's co-ordinates of the muscle insertions refer to the primary position. For any other position of the eye, these co-ordi nates assume different values because the in sertions participate, of course, in the eye's rotation to the position in question. This means that there is a different set of muscle planes and axes of rotation for every posi tion of the eye. However, the participation of the effective insertions in the eye's rotation is not complete. The effective insertions re sist, so to speak, being rotated out of their primary muscle planes. This was observed