Albrecht v. Graefes Arch. klin. exp. Ophthal.
202,275-283 (1977)
GraefesArchiv
fur klinische und experimentelle
Ophthalmologie 9 by Springer-Verlag 1977
Multivariate Analysis of Visual Evoked Response E. M a c c o l i n i 1 , R. M e d u r i 2 , S. Cavicchi 3 and G. Cristini 1.
1 Istituto di clinica oculistica (Direttore: Prof. G. Cristini), Universita de Bologna, Via Massarenti 9, Bologna, Italy 2 Cattedra di ottiea fisiopatologica (Direttore: Prof.R. Meduri), Universita di Bologna, Bologna, Italy 3 Istituto di genetica (Direttore: Prof.D.L. Palenzona), Universita di Bologna, Bologna, Italy Summary. The visual potentials evoked by flash are analyzed in healthy subjects in cases of retinal detachment, of optic nerve lesions, and of amblyopia by means of different statistical methods: 1. Analysis of the various features of the response, evaluated separately 2. Analysis of the interdependence between the measures of the various features The first method supplies information on the differences in 'size' of the curves in the various samples, the second method reveals differences of 'shape'. The second method has proved to be able to distinguish both normal conditions from pathologic impairment of optic structures and the different sites of the lesions. Z u s a m m e n f a s s u n g . Es werden die durch Lichtreiz hervorgerufenen Sehpotentiale
bei Gesunden, bei Patienten mit Netzhautabl6sung, mit Sehnervenl~isionen und bei Amblyopen durch Anwendung unterschiedlicher statistischer Methoden untersucht: 1. Analyse der verschiedenen Merkmale der Antwort mit separater Bewertung; 2. Analyse der Abhgngigkeit der verschiedenen Messmerkmale untereinander. Die erstere Methode gibt Aufschlug fiber die Grdflenunterschiede der Kurven in den einzelnen Gruppen, die letztere fiber die Formunterschiede. Mit der zweiten Methode war es nicht nur mSglich, normale Zust~nde von krankhaften Erscheinungen der optischen Strukturen zu unterscheiden, sondern auch die Lokalisation der L~tsionen aufzuzeigen. Introduction
The visual response evoked by flash analyzed with the common means used in clinical practice assumes a real significance - except in Cases of very severe alterations or of the extinction of the evoked potential - only when evident asymmetries in the curves * Corresponding author
276
E. Maccolini et al.
obtained through monocular stimulation or in the registrations of the two hemispheres are present (Ebe et al., 1964; Vaughan et al., 1964; Kooi et al., 1965; Crighel et al., 1968; Jacobson et al., 1968; Oosterhuis et al., 1969; Harmony et al., 1973). These limitations are due to the marked morphological individuality of the curve (Werre et al., 1964.; Callaway, 1966) which makes it practically difficult to compare the single responses with a physiologic curve having precise characteristics of amplitude, latency, and casualness. Our clinical experience has, however, allowed us to observe a certain similarity in the curves obtained from patients with the same ophthalmic or neuro-ophthalmic lesions. In order to detect the elements that many differentiate normal findings from pathologic findings, with specific features of the single topic lesions, methods of statistical analysis were used. The elaboration was performed in two principal directions: 1. Analysis of the various features of the response, evaluated separately 2. Analysis of the interdependence between the measures of the various features Two different types of statistical analysis were used: 1. Comparison between the groups for each feature 2. Comparison between the groups on the basis of a combination of the various features The first statistical method utilizes the mean values and the confidence limits of the dimensional characters of evoked responses in order to verify if the different groups are samples randomly drawn from,~the same population or not. When we know a sample mean (g = ~-~-), its standard error (Se = ~ ) where S is standard deviation and " t " value at a 0.05 probability, confidence limits are obtained by the formula l = ~ + " t " 0.05 9 Se and represent the interval where 95 % of the mean values concerning the population ]ie. Tbe second metbod provides an estimation of the differences among samples on the basis of a multivariate approach when significant correlations between the characters are assumed to exist. For this purpose, the 'Canonical Analysis of Variance' has been applied, which takes many characters into consideration contemporaneously. When we have k samples drawn from a universe, each forms a swarm of points in a p-variate cartesian space. The analysis produces transformed axes in order to provide uncorrelated charac'cers. Each character, therefore, gives its own amount of variation. The first axis produced is inclined towards the greatest variability between the (uncorrelated) means of the k samples. The second axis is perpendicular (independent) to the first and inclined towards the next greatest variability, and so on. For this purpose, canonical variates are calculated from the latent roots (Xi) and vectors of the determinantal equation IB-XWI = O where B is the 'among groups' variance-covariance matrix and W is the 'within groups' matrix.
Visual Evoked Response
277
The latent vectors corresponding to the determinantal equation and thus to the latent roots, are found from (B-XW) t = 0 and are the p-component vectors, t. These vectors may be standardized to give the canonical axes, u:
u=(t ,
W
t)-1/2
Latent roots represent estimates of variance among groups; latent vectors represent sets of coefficients so that it is possible to obtain a function which defines all the individuals on the basis of the p component of variation: Yi = a i l xl + a i l x2 + . . . . . . . .
aipX p
These functions may be plotted to provide differences among groups in a cartesian space where the axes represent the. principal sources of variation. The differences between the two statistical methods may be summarized as follows: the first considers the variables as independent one from the other, the second takes into consideration their relationship. The first method thus provides information on the 'size' of the evoked response of different samples, the second on their 'shape'.
Casu ist ics Four groups of patients were examined and compared: Group A: 100 normal individuals between 2 and 78 years of age (average age 42; 60 females, 40 males) Group B: 22 patients with detachment of the retina (average age 47) Group C: 42 patients (average age 38) suffering from deficient optic nerve conduction due to different lesions (interstitial: 12 cases; toxic: 8 cases; ischemic: 8 cases; post-traumatic: 5 cases; compressive: 5 cases, congenital optic atrophy: 4 cases) Group D: 42 patients with strabismic amblyopia (average age 10), 34 of whom had esotropic and 8 exotropic amblyopia In the last group (D), the comparison was made with 18 normals of the same age to avoid errors due to excessive age differences. The above casuistics including pathologic pictures with retinal lesions, with lesions of the conducting pathways and of the cortex, allowed examination of the semiologic significance in disorders of reception, conduction, and elaboration.
Methods of Testing
Equipment 1. Signal analyser Hewlett and Packard rood. 5480 2. Preamplifier N. Zagnoni 3. Photostimulator with xenon lamp N. Zagnoni
278
E. Maccolini et al,
4. XY plotter recorder Hewlett and Packard mod. 7004 5. Plate electrodes in silver alloy (diameter 4 ram) 6. Oscilloscope Tectronix rood. 502
Pro cedure The patient sitting (in maximal mydriasis) was left for 15 minutes under mesopic illumination (8 lux). During this time the electrodes for the registration of the visual evoked potentials, in monopolar sagittal derivation, were applied to the skull, the exploring electrode fixed on the median line 3 cm above the inion, the reference electrode fixed to the right auricular lobe. The stimulation consisted of a series of 64 white light flashes (with a frequency of 1 Hz produced by a xenon lamp bearing a parabolic mirror of a diameter of 20 cm placed frontally at 1 m f r o m the patient's eyes) of 300 lux illumination. Three series of stimulations were carried out at intervals of 1 min each. The oscilloscopic monitor-ray of the single cortical responses allowed control of the absence of artifacts. Four curves were thus obtained for each patient: 1. Spontaneous cortical activity 2. Visual evoked potentials following binocular stimulation 3. and 4. Visual evoked potentials following monocular stimulation of the right and left eye respectively
Evaluation of Curves On the deflection of each curve, identified by simple inspection, denominated according to Ciganek's terminology (1961), the following measures were performed: 1. Amplitude (mierovolt) The amplitude of wave I was calculated measuring the gradient between the onset of the curve and the wave apex, the amplitude of the subsequent waves measuring the gradient between the examined wave and that of the preceding wave. 2. Bases (milliseconds) This measure corresponds to the difference between the latency of the examined wave and the latency of the preceding wave. For wave I the basis is not determinable and was, therefore, substituted by the latency of the apex. In this investigation the latency values of waves II, III, IV, and V were excluded, because they are often strictly correlated and thus do not represent a specific feature of each apex (in the same curve, in fact, the latency of a wave may be influenced by the latency of the preceding wave). Each curve is defined by the value of 10 parameters: amplitude and latency of wave I (AI and LI), amplitude and basis of waves II, III, IV, and V (All and BII, AIII and BIII, AIV and BIV, AV and BV). In normal subjects the average values of the single parameters resulting from the curves after monocular stimulation were taken into consideration; in pathologic subjects we considered only those values obtained through the stimulation of the affected eye.
279
Visual Evoked Response
Results The results of the two methods of statistical analysis are reported separately.
1st Statistical Method (Comparison of the Groups for each Feature) Detachment of the Retina and Optic Nerve Disorders: I n
the distinction between
normals, cases of retinal detachment, and conduction deficiency (Fig. 1), the amplitudes of the various deflections reveal a certain possibility of differentiating the 'normal' from the 'pathology', but not of distinguishing retinal detachment from conduction deficiency. The time characteristics (latency of wave I and bases of the
subsequent waves), on the contrary, do not allow differentiation between the three groups.
Amblyopia: Between
amblyopics and normals of the same age (Fig. 2) none of the parameters considered is able to reveal a significative difference.
( mSec.; }iV.)
L= latencies B = bases ,~= a m p l i t u d e s
50-
45-B
40--
f
35-30--
25--
B
20-A
15--
A
A
10--
5--
0 wave
123
123
I
II
1
23 III
123 IV
123 V
Fig. 1. Mean values + confidence limits of different measures in retinal d e t a c h m e n t (1), lesions of optic nerve conduction (2), normal subjects (3). The m e a n values o f t h e bases o f different waves in t h e three groups are superimposed; on t h e contrary, differences between normal individuals and pathologic cases are detectable on the amplitude of the waves
280
E. Maccolini et al.
(mSec.;
L= latencies B = bases A= amplitudes
pV.)
B
50--
45--
l[
40--
,
i
B
35-30-A
B
25--
it
20--
!
15--
1 t
10--
A
~
A
5--
'0 wave
1 23 I
I
23 II
1 23 III
1 23 IV
123 V
Fig. 2. Mean values _+confidence limits of different measures considered in amblyopic esotropic (1), exotropic (2),and healthy subjects of the same age (3). Both t h e mean o f t h e bases and t h e amplitudes show an evident superimposition a m o n g the three groups. This analysis, therefore, does n o t differentiate normal individuals f r o m pathologic cases
Table 1. Discrimination estimate a m o n g normal individuals, retinal detachments, lesions of optic nerve conduction obtained f r o m canonical analysis of variance. The two latent roots (?q) obtained represent variance estimates a m o n g groups along two independent directions of variation. Chi-square tests show that t h e first is highly significant (P < 0.005), b u t scarcely the second (P < 0.50). Z 1 and Z 2 are the linear f u n c t i o n s (latent vectors) derived from t h e a m o u n t of variation imputable to each character (AI . . . . BV). On t h e basis of the linear combination of different characters, the discrimination a m o n g groups is, therefore, highly significant. 1 2 0.583 0.054 Discrimination (%) 91.5 8. 5 C H I Square 72.83 8.37 Liberty degrees 11 9 P 0.005 0.50 AIII Bill AIV BIV AV BV AI LI AII BII 0.123 --0.016 --0.069 --0.017 0.145 --0.014 Z1 0.140 --0.024 0.012 0.004 0.055 -0.012--0.104 0.039 0.116 --0.043 Z2 0.239 0.011 - 0 . 2 9 2 0.010
2nd Statistical Method (Comparison of the Groups on the Basis of a Combination of the Various Features) Detachment of the Retina.and Optic Nerve Disorders: T h e d i f f e r e n t i a t i o n b e t w e e n normals, cases of retinal detachment, s i g n i f i c a t i v e ( T a b l e 1).
and conduction deficiency appears to be highly
Visual Evoked Response
1,: v a r i a t i o n
281
axis
0
i
C
-1,5
0;5
-0,5
tA
-0,5
2 ~ variation axis
Fig. 3. Graphic representation o f t h e results o f t h e canonical analysis of variance: relative position of the three groups (A = normal individuals; B = retinal d e t a c h m e n t s ; C = lesions of optic nerve conduction) with their 95% confidence limits. The groups are clearly discriminated
2 ~variation axis
N f 5
7
1 ~t variation axis
Fig. 4. Graphic representation of t h e results of t h e canonical analysis of variance: relative position of the three groups (N = healthy subjects; AO+ = amblyopic esotropic patients; AO-- = amblyopic exotropic patients) with their 95% confidence limits. The groups are clearly discriminated Table 2. Discrimination estimate a m o n g healthy, amblyopic esotropic a n d exotropic subjects, obtained f r o m the canonical analysis of variance. The t w o latent r o o t s (?q) obtained represent variance estimates a m o n g groups along two independent directions of variation. Chi-square tests show that the first is highly significant (P < 0,050), b u t scarcely the second (P < 0,40). Z 1 a n d Z 2 are the linear functions (latent vectors) derived f r o m corresponding latent roots, a n d represent t h e a m o u n t of variation imputable to each character (AI . . . . BV). On t h e basis of the linear combination of different characters, the discrimination a m o n g groups is, therefore, highly significant 1
hi Discrimination (%) C H I Square Liberty degrees P Z1 Z2
AI 0,191 - 0,024
LI 0,069 0,047
0.436 69.8 19.0 t1 0.050 AII 0,075 0,205
2
0.188 30.2 9.06 9 0.40 BII - 0,050 0,001
AII[ - 0,075 - 0,048
BIII 0,064 - 0,042
AIV 0,024 0,095
B IV 0,033 --0,036
AV 0,091 -0,017
BV - 0,014 0,003
282
E. Maccolini et al.
The relative position of the three groups, with the two obtained variation axes (Fig. 3) confirms the substantial difference between 'normals' and 'pathologic' cases already observed with the first method of investigation, limited to the amplitude, and allows further distinction between retinal detachment and deficient optic nerve conduction.
Amblyopia.. In the
comparison of normals with amblyopic patients the differences are significative, though in a smaller degree9 Further significative distinction was revealed between esotropic and exotropic amblyopic patients (Fig. 4, Table 2). Conclusions The second method of analysis proved to be able to distinguish not only the condition of normal function from that of impairment of the examined structures but also the different sites of the lesion. Particularly interesting are the different factors emerging in eso- and exotropic squint, thus confirming previous experimental studies (Hubel and Wiesel, 1965; yon Noorden and Dowling, 1970). From a clinical point of view the usefulness of the method is shown by Figure 5 where the relative positions of the single curves are reported (normal, retinal detachment, opticopathy) and where normal and pathologic cases are put in evidence. The possibility arises of obtaining evidence of the characteristics of cases with lesional disorders with a relatively low probability of errors.
2 - -
1 - -
9
."
.
,~
"
9 ,=,
-.,
2
9
- 1 - -
~~ -2
w
- 3 ~
--3
I
--2
I
--1
I
I
0
I
1
I
2
I
3
I
4
1
5
Fig. 5. Graphic representation of the results of the canonical analysis of variance: relative position of the single individuals. 9 Healthy subjects 9 Retinal detachments 9 Lesions of optic nerve conduction Normal individuals are clearly discriminated from pathologic ones
Visual Evoked Response
283
The reported criteria of statistical evaluation can obviously become operative in clinical appfication by transcribing the values of the electrocortical graphic and introducing them into a computer which will rapidly supply the answer.
References
Callaway, E.: Averaged evoked response in psychiatry. J. Nervous and Mental Disease 143, 80 (1960) Ciganek, L.: Die elektroencephalographische Lichtreizantwort der menschlichen Hirnrinden. Vidavatel' Slovenskey Akademie Vied, Bratislava, 1961 Criegel, E., Pollici, I.: Photic evoked responses in patients with thalamic and brain stem lesions. Confin. Neurol. (Basel), 30, 301 (1968) Ebe, M., Mikami, T., Ito, H.: Clinical evolution of electrical responses of retinal and visual cortex to photic stimulation in ophthalmic diseases. Tohoku Exper. Med., 84, 92 (1964) Harmony, T., Ricardo, J., Otero, G., Fernandez, G., Llorente, S., Valdes, P. : Symmetry of the visual evoked potential in normal subjects. Electroenceph. Clin. Neurophysiol., 35,237 (1973) Hubel, D.H., Wiesel, T.N.: Binocular interaction in striate cortex of kittens reared in artificial squint. J. Neurophysiol., 28, 1041 (1965) Jacobson, J.H., Hirose, T., Suzuki, T.A.: Simultaneous ERG and VER in lesions of the optic pathways. Invest. Ophth., 7, 279 (1968) Kooi, K.A., Guvener, A.M., Bagchi, B.K.: Visual evoked response in the higher optic pathways. Neurology, 15,841 (1965) Noorden, G.K. von, Dowling, J.E.: Experimental amblyopia in monkeys: II. Behavioral studies in strabismic amblyopia. Arch. Ophthal. 84, 215 (1970) Oosterhuis, G.H., Ponsen, L., Jonkman, E.J., Magnus, O.: The average visual response in patients with cerebrovascular disease. Electroenceph. Clin. Neurophysiol., 27, 23 (1969) Vaughan, H.G., Katzman, R.: Evoked response in visual disorders. Ann. N. Y. Acad. Sci., 112,305 (1964) Werre, P.F., Smith, C.J.: Variability of response evoked by flashes in man. Electroenceph. Clin. Neurophysiol., 17,644 (1964) Received December 12, 1976
202,275-283 (1977)
GraefesArchiv
fur klinische und experimentelle
Ophthalmologie 9 by Springer-Verlag 1977
Multivariate Analysis of Visual Evoked Response E. M a c c o l i n i 1 , R. M e d u r i 2 , S. Cavicchi 3 and G. Cristini 1.
1 Istituto di clinica oculistica (Direttore: Prof. G. Cristini), Universita de Bologna, Via Massarenti 9, Bologna, Italy 2 Cattedra di ottiea fisiopatologica (Direttore: Prof.R. Meduri), Universita di Bologna, Bologna, Italy 3 Istituto di genetica (Direttore: Prof.D.L. Palenzona), Universita di Bologna, Bologna, Italy Summary. The visual potentials evoked by flash are analyzed in healthy subjects in cases of retinal detachment, of optic nerve lesions, and of amblyopia by means of different statistical methods: 1. Analysis of the various features of the response, evaluated separately 2. Analysis of the interdependence between the measures of the various features The first method supplies information on the differences in 'size' of the curves in the various samples, the second method reveals differences of 'shape'. The second method has proved to be able to distinguish both normal conditions from pathologic impairment of optic structures and the different sites of the lesions. Z u s a m m e n f a s s u n g . Es werden die durch Lichtreiz hervorgerufenen Sehpotentiale
bei Gesunden, bei Patienten mit Netzhautabl6sung, mit Sehnervenl~isionen und bei Amblyopen durch Anwendung unterschiedlicher statistischer Methoden untersucht: 1. Analyse der verschiedenen Merkmale der Antwort mit separater Bewertung; 2. Analyse der Abhgngigkeit der verschiedenen Messmerkmale untereinander. Die erstere Methode gibt Aufschlug fiber die Grdflenunterschiede der Kurven in den einzelnen Gruppen, die letztere fiber die Formunterschiede. Mit der zweiten Methode war es nicht nur mSglich, normale Zust~nde von krankhaften Erscheinungen der optischen Strukturen zu unterscheiden, sondern auch die Lokalisation der L~tsionen aufzuzeigen. Introduction
The visual response evoked by flash analyzed with the common means used in clinical practice assumes a real significance - except in Cases of very severe alterations or of the extinction of the evoked potential - only when evident asymmetries in the curves * Corresponding author
276
E. Maccolini et al.
obtained through monocular stimulation or in the registrations of the two hemispheres are present (Ebe et al., 1964; Vaughan et al., 1964; Kooi et al., 1965; Crighel et al., 1968; Jacobson et al., 1968; Oosterhuis et al., 1969; Harmony et al., 1973). These limitations are due to the marked morphological individuality of the curve (Werre et al., 1964.; Callaway, 1966) which makes it practically difficult to compare the single responses with a physiologic curve having precise characteristics of amplitude, latency, and casualness. Our clinical experience has, however, allowed us to observe a certain similarity in the curves obtained from patients with the same ophthalmic or neuro-ophthalmic lesions. In order to detect the elements that many differentiate normal findings from pathologic findings, with specific features of the single topic lesions, methods of statistical analysis were used. The elaboration was performed in two principal directions: 1. Analysis of the various features of the response, evaluated separately 2. Analysis of the interdependence between the measures of the various features Two different types of statistical analysis were used: 1. Comparison between the groups for each feature 2. Comparison between the groups on the basis of a combination of the various features The first statistical method utilizes the mean values and the confidence limits of the dimensional characters of evoked responses in order to verify if the different groups are samples randomly drawn from,~the same population or not. When we know a sample mean (g = ~-~-), its standard error (Se = ~ ) where S is standard deviation and " t " value at a 0.05 probability, confidence limits are obtained by the formula l = ~ + " t " 0.05 9 Se and represent the interval where 95 % of the mean values concerning the population ]ie. Tbe second metbod provides an estimation of the differences among samples on the basis of a multivariate approach when significant correlations between the characters are assumed to exist. For this purpose, the 'Canonical Analysis of Variance' has been applied, which takes many characters into consideration contemporaneously. When we have k samples drawn from a universe, each forms a swarm of points in a p-variate cartesian space. The analysis produces transformed axes in order to provide uncorrelated charac'cers. Each character, therefore, gives its own amount of variation. The first axis produced is inclined towards the greatest variability between the (uncorrelated) means of the k samples. The second axis is perpendicular (independent) to the first and inclined towards the next greatest variability, and so on. For this purpose, canonical variates are calculated from the latent roots (Xi) and vectors of the determinantal equation IB-XWI = O where B is the 'among groups' variance-covariance matrix and W is the 'within groups' matrix.
Visual Evoked Response
277
The latent vectors corresponding to the determinantal equation and thus to the latent roots, are found from (B-XW) t = 0 and are the p-component vectors, t. These vectors may be standardized to give the canonical axes, u:
u=(t ,
W
t)-1/2
Latent roots represent estimates of variance among groups; latent vectors represent sets of coefficients so that it is possible to obtain a function which defines all the individuals on the basis of the p component of variation: Yi = a i l xl + a i l x2 + . . . . . . . .
aipX p
These functions may be plotted to provide differences among groups in a cartesian space where the axes represent the. principal sources of variation. The differences between the two statistical methods may be summarized as follows: the first considers the variables as independent one from the other, the second takes into consideration their relationship. The first method thus provides information on the 'size' of the evoked response of different samples, the second on their 'shape'.
Casu ist ics Four groups of patients were examined and compared: Group A: 100 normal individuals between 2 and 78 years of age (average age 42; 60 females, 40 males) Group B: 22 patients with detachment of the retina (average age 47) Group C: 42 patients (average age 38) suffering from deficient optic nerve conduction due to different lesions (interstitial: 12 cases; toxic: 8 cases; ischemic: 8 cases; post-traumatic: 5 cases; compressive: 5 cases, congenital optic atrophy: 4 cases) Group D: 42 patients with strabismic amblyopia (average age 10), 34 of whom had esotropic and 8 exotropic amblyopia In the last group (D), the comparison was made with 18 normals of the same age to avoid errors due to excessive age differences. The above casuistics including pathologic pictures with retinal lesions, with lesions of the conducting pathways and of the cortex, allowed examination of the semiologic significance in disorders of reception, conduction, and elaboration.
Methods of Testing
Equipment 1. Signal analyser Hewlett and Packard rood. 5480 2. Preamplifier N. Zagnoni 3. Photostimulator with xenon lamp N. Zagnoni
278
E. Maccolini et al,
4. XY plotter recorder Hewlett and Packard mod. 7004 5. Plate electrodes in silver alloy (diameter 4 ram) 6. Oscilloscope Tectronix rood. 502
Pro cedure The patient sitting (in maximal mydriasis) was left for 15 minutes under mesopic illumination (8 lux). During this time the electrodes for the registration of the visual evoked potentials, in monopolar sagittal derivation, were applied to the skull, the exploring electrode fixed on the median line 3 cm above the inion, the reference electrode fixed to the right auricular lobe. The stimulation consisted of a series of 64 white light flashes (with a frequency of 1 Hz produced by a xenon lamp bearing a parabolic mirror of a diameter of 20 cm placed frontally at 1 m f r o m the patient's eyes) of 300 lux illumination. Three series of stimulations were carried out at intervals of 1 min each. The oscilloscopic monitor-ray of the single cortical responses allowed control of the absence of artifacts. Four curves were thus obtained for each patient: 1. Spontaneous cortical activity 2. Visual evoked potentials following binocular stimulation 3. and 4. Visual evoked potentials following monocular stimulation of the right and left eye respectively
Evaluation of Curves On the deflection of each curve, identified by simple inspection, denominated according to Ciganek's terminology (1961), the following measures were performed: 1. Amplitude (mierovolt) The amplitude of wave I was calculated measuring the gradient between the onset of the curve and the wave apex, the amplitude of the subsequent waves measuring the gradient between the examined wave and that of the preceding wave. 2. Bases (milliseconds) This measure corresponds to the difference between the latency of the examined wave and the latency of the preceding wave. For wave I the basis is not determinable and was, therefore, substituted by the latency of the apex. In this investigation the latency values of waves II, III, IV, and V were excluded, because they are often strictly correlated and thus do not represent a specific feature of each apex (in the same curve, in fact, the latency of a wave may be influenced by the latency of the preceding wave). Each curve is defined by the value of 10 parameters: amplitude and latency of wave I (AI and LI), amplitude and basis of waves II, III, IV, and V (All and BII, AIII and BIII, AIV and BIV, AV and BV). In normal subjects the average values of the single parameters resulting from the curves after monocular stimulation were taken into consideration; in pathologic subjects we considered only those values obtained through the stimulation of the affected eye.
279
Visual Evoked Response
Results The results of the two methods of statistical analysis are reported separately.
1st Statistical Method (Comparison of the Groups for each Feature) Detachment of the Retina and Optic Nerve Disorders: I n
the distinction between
normals, cases of retinal detachment, and conduction deficiency (Fig. 1), the amplitudes of the various deflections reveal a certain possibility of differentiating the 'normal' from the 'pathology', but not of distinguishing retinal detachment from conduction deficiency. The time characteristics (latency of wave I and bases of the
subsequent waves), on the contrary, do not allow differentiation between the three groups.
Amblyopia: Between
amblyopics and normals of the same age (Fig. 2) none of the parameters considered is able to reveal a significative difference.
( mSec.; }iV.)
L= latencies B = bases ,~= a m p l i t u d e s
50-
45-B
40--
f
35-30--
25--
B
20-A
15--
A
A
10--
5--
0 wave
123
123
I
II
1
23 III
123 IV
123 V
Fig. 1. Mean values + confidence limits of different measures in retinal d e t a c h m e n t (1), lesions of optic nerve conduction (2), normal subjects (3). The m e a n values o f t h e bases o f different waves in t h e three groups are superimposed; on t h e contrary, differences between normal individuals and pathologic cases are detectable on the amplitude of the waves
280
E. Maccolini et al.
(mSec.;
L= latencies B = bases A= amplitudes
pV.)
B
50--
45--
l[
40--
,
i
B
35-30-A
B
25--
it
20--
!
15--
1 t
10--
A
~
A
5--
'0 wave
1 23 I
I
23 II
1 23 III
1 23 IV
123 V
Fig. 2. Mean values _+confidence limits of different measures considered in amblyopic esotropic (1), exotropic (2),and healthy subjects of the same age (3). Both t h e mean o f t h e bases and t h e amplitudes show an evident superimposition a m o n g the three groups. This analysis, therefore, does n o t differentiate normal individuals f r o m pathologic cases
Table 1. Discrimination estimate a m o n g normal individuals, retinal detachments, lesions of optic nerve conduction obtained f r o m canonical analysis of variance. The two latent roots (?q) obtained represent variance estimates a m o n g groups along two independent directions of variation. Chi-square tests show that t h e first is highly significant (P < 0.005), b u t scarcely the second (P < 0.50). Z 1 and Z 2 are the linear f u n c t i o n s (latent vectors) derived from t h e a m o u n t of variation imputable to each character (AI . . . . BV). On t h e basis of the linear combination of different characters, the discrimination a m o n g groups is, therefore, highly significant. 1 2 0.583 0.054 Discrimination (%) 91.5 8. 5 C H I Square 72.83 8.37 Liberty degrees 11 9 P 0.005 0.50 AIII Bill AIV BIV AV BV AI LI AII BII 0.123 --0.016 --0.069 --0.017 0.145 --0.014 Z1 0.140 --0.024 0.012 0.004 0.055 -0.012--0.104 0.039 0.116 --0.043 Z2 0.239 0.011 - 0 . 2 9 2 0.010
2nd Statistical Method (Comparison of the Groups on the Basis of a Combination of the Various Features) Detachment of the Retina.and Optic Nerve Disorders: T h e d i f f e r e n t i a t i o n b e t w e e n normals, cases of retinal detachment, s i g n i f i c a t i v e ( T a b l e 1).
and conduction deficiency appears to be highly
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1,: v a r i a t i o n
281
axis
0
i
C
-1,5
0;5
-0,5
tA
-0,5
2 ~ variation axis
Fig. 3. Graphic representation o f t h e results o f t h e canonical analysis of variance: relative position of the three groups (A = normal individuals; B = retinal d e t a c h m e n t s ; C = lesions of optic nerve conduction) with their 95% confidence limits. The groups are clearly discriminated
2 ~variation axis
N f 5
7
1 ~t variation axis
Fig. 4. Graphic representation of t h e results of t h e canonical analysis of variance: relative position of the three groups (N = healthy subjects; AO+ = amblyopic esotropic patients; AO-- = amblyopic exotropic patients) with their 95% confidence limits. The groups are clearly discriminated Table 2. Discrimination estimate a m o n g healthy, amblyopic esotropic a n d exotropic subjects, obtained f r o m the canonical analysis of variance. The t w o latent r o o t s (?q) obtained represent variance estimates a m o n g groups along two independent directions of variation. Chi-square tests show that the first is highly significant (P < 0,050), b u t scarcely the second (P < 0,40). Z 1 a n d Z 2 are the linear functions (latent vectors) derived f r o m corresponding latent roots, a n d represent t h e a m o u n t of variation imputable to each character (AI . . . . BV). On t h e basis of the linear combination of different characters, the discrimination a m o n g groups is, therefore, highly significant 1
hi Discrimination (%) C H I Square Liberty degrees P Z1 Z2
AI 0,191 - 0,024
LI 0,069 0,047
0.436 69.8 19.0 t1 0.050 AII 0,075 0,205
2
0.188 30.2 9.06 9 0.40 BII - 0,050 0,001
AII[ - 0,075 - 0,048
BIII 0,064 - 0,042
AIV 0,024 0,095
B IV 0,033 --0,036
AV 0,091 -0,017
BV - 0,014 0,003
282
E. Maccolini et al.
The relative position of the three groups, with the two obtained variation axes (Fig. 3) confirms the substantial difference between 'normals' and 'pathologic' cases already observed with the first method of investigation, limited to the amplitude, and allows further distinction between retinal detachment and deficient optic nerve conduction.
Amblyopia.. In the
comparison of normals with amblyopic patients the differences are significative, though in a smaller degree9 Further significative distinction was revealed between esotropic and exotropic amblyopic patients (Fig. 4, Table 2). Conclusions The second method of analysis proved to be able to distinguish not only the condition of normal function from that of impairment of the examined structures but also the different sites of the lesion. Particularly interesting are the different factors emerging in eso- and exotropic squint, thus confirming previous experimental studies (Hubel and Wiesel, 1965; yon Noorden and Dowling, 1970). From a clinical point of view the usefulness of the method is shown by Figure 5 where the relative positions of the single curves are reported (normal, retinal detachment, opticopathy) and where normal and pathologic cases are put in evidence. The possibility arises of obtaining evidence of the characteristics of cases with lesional disorders with a relatively low probability of errors.
2 - -
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9
."
.
,~
"
9 ,=,
-.,
2
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I
--2
I
--1
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I
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1
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2
I
3
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4
1
5
Fig. 5. Graphic representation of the results of the canonical analysis of variance: relative position of the single individuals. 9 Healthy subjects 9 Retinal detachments 9 Lesions of optic nerve conduction Normal individuals are clearly discriminated from pathologic ones
Visual Evoked Response
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The reported criteria of statistical evaluation can obviously become operative in clinical appfication by transcribing the values of the electrocortical graphic and introducing them into a computer which will rapidly supply the answer.
References
Callaway, E.: Averaged evoked response in psychiatry. J. Nervous and Mental Disease 143, 80 (1960) Ciganek, L.: Die elektroencephalographische Lichtreizantwort der menschlichen Hirnrinden. Vidavatel' Slovenskey Akademie Vied, Bratislava, 1961 Criegel, E., Pollici, I.: Photic evoked responses in patients with thalamic and brain stem lesions. Confin. Neurol. (Basel), 30, 301 (1968) Ebe, M., Mikami, T., Ito, H.: Clinical evolution of electrical responses of retinal and visual cortex to photic stimulation in ophthalmic diseases. Tohoku Exper. Med., 84, 92 (1964) Harmony, T., Ricardo, J., Otero, G., Fernandez, G., Llorente, S., Valdes, P. : Symmetry of the visual evoked potential in normal subjects. Electroenceph. Clin. Neurophysiol., 35,237 (1973) Hubel, D.H., Wiesel, T.N.: Binocular interaction in striate cortex of kittens reared in artificial squint. J. Neurophysiol., 28, 1041 (1965) Jacobson, J.H., Hirose, T., Suzuki, T.A.: Simultaneous ERG and VER in lesions of the optic pathways. Invest. Ophth., 7, 279 (1968) Kooi, K.A., Guvener, A.M., Bagchi, B.K.: Visual evoked response in the higher optic pathways. Neurology, 15,841 (1965) Noorden, G.K. von, Dowling, J.E.: Experimental amblyopia in monkeys: II. Behavioral studies in strabismic amblyopia. Arch. Ophthal. 84, 215 (1970) Oosterhuis, G.H., Ponsen, L., Jonkman, E.J., Magnus, O.: The average visual response in patients with cerebrovascular disease. Electroenceph. Clin. Neurophysiol., 27, 23 (1969) Vaughan, H.G., Katzman, R.: Evoked response in visual disorders. Ann. N. Y. Acad. Sci., 112,305 (1964) Werre, P.F., Smith, C.J.: Variability of response evoked by flashes in man. Electroenceph. Clin. Neurophysiol., 17,644 (1964) Received December 12, 1976
