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Electrophysiological examinations of the visual system in multiple sclerosis
Journal of the neurological Sciences, 1973, 20:161-175
161
i ~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Electrophysiological Examinations of the Visual System in Multiple Sclerosis M. FEINSOD*, O. A B R A M S K Y * * AND E. AUERBACH The Vision Research Laboratory, The Wolfson OphthalmologicalResearch Laboratories, Hadassah University Hospital and Medical School, Jerusalem (Israel) (Received 21 March, 1973)
INTRODUCTION
In multiple sclerosis vision is often affected, yet only 3 electrophysiological studies of the visual system have been carried out. These studies deal either with the electroretinogram (Gills 1966a; Halliday, McDonald and Mushin 1972) or with the visual evoked potential (Richey, Kooi and Tourtellotte 1971; Halliday et al. 1972). In our opinion a combined examination of retinal and striate function appears more meaningful than either test alone. In a previous paper on optic nerve lesions (Feinsod, Rowe and Auerbach 1971) the electroretinogram (ERG) was recorded together with the visual evoked potential (VEP). Among the various optic nerve affections studied in this investigation were 9 cases of multiple sclerosis. The results in some of these differed from those in the patients studied by Gills (1966a) in that their retinal responses were enhanced. In the present study the results of ERG and VEP examinations in 35 patients suffering from multiple sclerosis, including the 9 from the former study, are reported. According to the case history these patients fell into 3 groups: one with continuing visual symptoms, another with previous and transitory visual disturbances and another group which never experienced visual disturbances during the course of the disease. The electrophysiological findings have been related to these groups.
METHODS
The examinations were carried out in an electrically shielded cage with the patient in a recumbent position. Mydriasis was achieved by instillation of Mydriaticum Roche ® to each eye. For ERG recordings a Henkes contact lens electrode was fixed to each eye and an indifferent silver disk electrode was fastened to the midsupraorbital This project was supported in part by the Israeli Center for Psychobiology. * From the Department of Neurosurgery. ** From the Department of Neurology.
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M. FEINSOD, O. ABRAMSKY, E. AUERBACH
rim above each eye. The VEP was derived bipolarly from the occipital scalp between 9 mm silver disk electrodes placed at the inion and 5 cm above. A ground electrode was attached to each ear lobe. A Grass PS-2 photostimulator activated a xenon discharge lamp. The flash duration was about 10/~sec. The light source was centered at 20 cm in front of the patient's eyes. For ERG recordings a condenser-coupled dual beam CRO (Tektronix 502) was used. The electrodes were connected to the CRO through AC preamplifiers (Grass PS-5) whose filters were set at 0.1 cycles/sec and 200 cycles/sec. The responses were recorded simultaneously from both eyes and photographed from the screen of the CRO by a Grass camera (C4). Sweeps and the camera shutter were synchronized to coincide with stimulus onset. For the recording of the VEP, responses of 70 or 140 flashes delivered at a frequency of about 1 per 1.5 sec were averaged on the Computer of Average Transients (CAT 400B) for 250 msec following the stimulus onset. The averaged responses were displayed on the screen of the CRO, which was set for X Y tracings, and then photographed. The ERGs referred to in this study were elicited by single flash stimuli, and are those measured at the steady state of dark adaptation, i.e. the period of time necessary for the retinal response to recover completely from a preliminary light adaptation of 5 min. The potentials of negative (a-wave) and positive polarity (b-wave) generally achieve their maximal amplitudes within 30 min in the dark. Those patients who did not permit us to do the complete test or did not co-operate satisfactorily were examined without light adaptation and the test began immediately after the dim light of the shielded room was switched off. Consequently, the steady state condition was achieved in these cases in a much shorter time (generally a few min up to 10 min) as verified by the constant size of the retinal responses. In all tests the interval between stimuli was at least half a min, later in the dark 1 min. The normal ranges for the overall amplitudes of the a- and b-wave under our test conditions were determined more than 12 years ago and were recently illustrated in the histograms of a previous study (Feinsod et al. 1971). The values range between 100 and 200/~V for the a-wave and between 420 and 550/~V for the b-wave. The data represented in these histograms are based on the steady state ERGs from the examination of 98 eyes in 54 normal persons. In each ERG the a-wave amplitude was measured from the baseline down to the negative peak and the b-wave amplitude was determined from the negative peak of the a-wave up to the positive peak of the b-wave. The data of both waves are presented for all cases examined in Tables 1 to 3. The criteria used can be found in greater detail in former studies of the normal and the clinical ERG by Auerbach (1967, 1968, 1970). In the normal VEP elicited by the same flash stimuli used for the E R G recordings, the initial (pre-synaptic) positivity has a latency of 15-30 msec and an amplitude of up to 5 /~V. It is followed by the primary (post-synaptic) wave, the peak-to-trough amplitude of which has a range of 5-15 #V and a secondary wave which is even more variable than the other waves (Ciganek 1961; Kooi and Bagchi 1964; Creutzfeldt, Rosina, Ito and Probst 1969). In Tables 1 to 3 we tabulate the latent period of the VEPs of all 35 cases examined and the peak-to-trough amplitudes of their primary waves.
F M F
16 17 18
33 49 48
42
23 26 20 26 23 40 22 31 30 34 34 34
25
32
Age (years)
13 years 13 years 22 years
12 years
1 month 3 mont hs 6 months 1 year 1.5 year 2 years 2 years 3 years 8 years 9 years 10 years 12 years
2 weeks
l week
13 years 13 years 3 years
8 years
1 month 1 day 6 mont hs 1 year 1.5 year 2 years 1 year 3 years 8 years 9 years 10 years 6 years
2 weeks
1 week
Duration of visual symptoms
OS OU OU OD OS
OU OD OU OS OS OU OD OU OU OU OS OD OS OD
OD
OS
large central scotoma large central scotoma central scotoma blind light perception central s c ot oma blurred yision central scotoma central scotoma blindness blurred vision finger count : 1 m blurred vision central scotoma finger count : 2 m constricted visual field blind blindness central scotoma blurred vision constriction of visual field
Main visual complaint or findin# at time of examination
+ + -
+
+ + + _ _ + + + +
OS
+ + -
+
+ + _ + + _
OD
Optic atrophy
109 190 83
109
93 90 280 117 82 207 120 89 220 217 50 90 111
189
OS
53 160 125
75
93 117 250 138 131 200 135 52 160 159 43 82 100
178
OD
a-wave
540 380 413
625
750
600 350 325
426 463 690 424 331 619 520 368 660 614 259 268 362
490
600
396 424 610 407 268 625 462 393 710 678 286 328 333
OD
OS
b-wave
ERG (ItV)
a-wave: 100 #V-200 #V b-wave: 420-#V-550ItV
ERG normal amplitudes:
latency (of initial positivity): 15 msec-30 msec amplitude (of pri ma ry wave): 5 # V - I 5 #V
VEP normal values:
50
60
25 90 45 50
30 60
40
60 50 65
50
VEP
4.7
OS
5.3
OD
Amplitude of primary wave (It V)
extinct extinct 65
35
9.4
2.8
7.0
17.1
70 2.1 1.4 45 8.5 5.0 65 3.8 2.1 practically absent 35 2.1 8.3 extinct 50 5.7 7.1 65 8.8 8.8 extinct 25 3.3/8.0 3.3/5.3 2.5 50 2.3 2.0 65 2.0 2.7
55
OD
Latency (msec) OS
Symbols used in Tables 1--4: OD : right eye ; OS : left eye; O U : bot h eyes ; - : n o r m a l fundus ; + : pallor of optic disc ; + : optic atrophy. Figures in centre of col um m refer to binocular recording. N o r m a l E R G and VE P values for Tables 1-4:
F
F F M M F M F F F M M F
3 4 5 6 7 8 9 I0 11 12 13 14
15
M
2
.
F
Sex
1
Patient No.
Duration of disease
GROUP I : PATIENTS WITH VISUAL SYMPTOMS
TABLE 1
t"
<
O
pp.
;~ r~ rn
~
O
0
F F F F
M
F F F
1 2 3 4
5
6 7 8
30 47 42
29
18 25 26 29
Age (years)
For abbreviations see Table 1.
Sex
Patient No.
8 years 10 years 19 years
5 years
1 year 2 years 2 years 5 years
of disease
Duration
OS OS OU OD
10 months 1 year 1 year 3 years O D blurred vision O U blurred vision O D transient loss of vision O U blurred vision
4 years 8 years 3 years 18 years
transient loss of vision blurring of vision blurred vision papillitis
Main previous complaint orfindin9
Last appearance of visual symptoms
+ + +
+
_+ -+
OS
+ ± +
+
---
OD
atrophy
Optic
69 111 140
222
170 72 160 83
83 154 165
254
150 108 100 83
397 440 400
415
610 616 480 407
370 473 500
492
580 580 480 410
b-wave OS OD
ERG (izV) a-wave OS OD
G R O U P I1 ." P A T I E N T S W I T H P R E V I O U S V I S U A L D I S T U R B A N C E S
TABLE 2
50 40
40
75 60
Amplitude of
not
measurable 35 2.7 30 12.1 practically absent
65
2.0 18,6
4.7
10.6 3.3
primarlY.wave(j!V OS OD practically extinct 60 10.6 50 6.0 practically extinct
(msec) OS OD
Latency
VEP ~
~,
~;~
.~ r~
© >
ELECTROPHYSIOLOGICALEXAMINATIONSOF THE VISUAL SYSTEM IN M . S .
165
TABLE 3 G R O U P IIl : P A T I E N T S W I T H N O V I S U A L D I S T U R B A N C E S
VEP ERG.(#V) Patient No.
Sex
Age Duration (years) " of disease Main clinical picture
a-wave OS
b-wave
OD
OS
Latency (msec)
OD OS
*
1 2
M M
18 33
3
M
21
4 5 6
M F M
31 25 39
7
M
35
8
F
26
9
F
44
1week 3 weeks
paraparesis spastic right hemiparesis 5 months cerebeUarataxia, paraparesis 1 year paraparesis 3years paraparesis 5 years cerebellar ataxia, paraparesis 6 years bulbar signs, paraparesis 8 years cerebellar ataxia, paraparesis 12 years ataxia, transient nystagmus
Amplitude of primary wave (PV)
OD
OS
OD
72 103 470 464 35
35
7.8
6.8
114 115 293 296 40 114 183 366 383 80
50 70
2.1 0.6
2.8 0.9
124 110 300 304 55 197 182 600 550 60 55 300 290 590 500 35 35
1.0 5.1
?
?
?
?*
3.5 1.1 4.8
practically extinct
137 125 496 518 55
55
232 224 526 629 40
55
2.7/5.3 2.7/6.0 1.7
See text. For abbreviations see Table 1.
Thirty-five patients suffering from multiple sclerosis were examined at various stages of the disease. In some the diagnosis could only be m a d e after the examination. The criteria for the diagnosis of multiple sclerosis were based on those used by McAlpine, L u m s d e n and A c h e s o n (1965) in patients with characteristic histories of relapse and remission and findings of multiple lesions. N o t included in this study were cases of retrobulbar neuritis; even recurrent cases were eliminated f r o m this study if not followed by the appearance of other neurological signs.
RESULTS The patients examined could be divided into 3 groups : those with visual s y m p t o m s at the time of the examination, others with transient visual disturbances but no signs at the time of the examination, and still others without visual s y m p t o m s at any time. The electrophysiological findings were related to the duration of the disease,-the d u r a t i o n of visual s y m p t o m s and to the presence of optic nerve atrophy. The data are summarized in Tables 1, 2 and 3. Table 4 is supplementary to the other 3 in classifying the ERG. To do the same with the V E P proved impractical and not useful. Group I : patients with visual disturbances
The 18 patients in this g r o u p were suffering from visual s y m p t o m e s ranging from blurred vision or s c o t o m a t a to amaurosis (Table 1). In all patients the V E P s were
3.3
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M. FEINSOD, O. ABRAMSKY, E. AUERBACH
TABLE 4 C L A S S I F I C A T I O N OF E R G C H A N G E S
Group I
Group II
Group I I I
Patient No.
Patient No.
a-wave
b-wave
a-wave
b-wave
a-wave
b-wave
1
N
OU
E OS N OD
N OU
E OU
S OS (N) OD
N OU
1
2
S
OU
S OS (N) OD
S OS (N) OD
E OU
(N)OU
S OU
2
3
S OS NOD
(N) OS NOD
N OS (N)OD
N OU
(N)OS N OD
SOU
3
4
E
E
SOU
(S) OU
N OS (N) OD
S
OU
4
5
N OU
(S) OS (N) OD
E OU
(S) OS NOD
N OU
E OS (E) OD
5
6
S OS N OD
S
OU
S OU
S OU
E OU
E OS N OD
6
7
E OU
E OU
(N) OS
N OU
OU
OU
N OD OU
N OU
8
N
9
S OU
S
10
E OS N OD
E OU
11
E OS N OD
E OU
12 13
S OU S OU
S OU S OU
14
(N) O U
S
15
(N) OS S OD
E OU
16
(N) OS S OD
E OS (E) OD
N OU
OU
(S) OS N OD
no ERG at steady state N OU
YOU
E OU
N OS E OD
7 8
OU
17
N OU
S OU
18
S OS NOD
S OS (N)OD
N: normal amplitude (N): at lowest normal limit or close to normal but above S : subnormal amplitude (S): close to lowest normal limit but below E : enhanced amplitude (E): close to highest normal limit disturbed in that they displayed prolonged latencies and/or reduced amplitudes. In some patients no VEP was recordable. The ERGs recorded were normal or practically n o r m a l i n o n l y 2 c a s e s ( p a t i e n t s 3 a n d 8). T h e o t h e r s w e r e e i t h e r s u b n o r m a l o r e n h a n c e d
ELECTROPHYSIOLOGICAL EXAMINATIONSOF THE VISUAL SYSTEM IN M.S.
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(Table 4). The e n h a n c e m e n t f o u n d in p a t i e n t s 1 a n d 4 was t r a n s i t o r y . P a t i e n t s 1 a n d 2 will be d e s c r i b e d in d e t a i l below. T h e case r e p o r t s o f p a t i e n t s 4, 10, 15 a n d 16, all e x h i b i t i n g e n h a n c e d E R G s , were r e p o r t e d in detail by F e i n s o d et al. (1971) w h e r e they a p p e a r as Cases 8, 7, 5 a n d 6 respectively.
Group II: patients with previous visual disturbances The 8 p a t i e n t s in this g r o u p h a d visual d i s t u r b a n c e s d u r i n g the course of their disease b u t d i d n o t c o m p l a i n at t h e time of the e x a m i n a t i o n (Table 2). In 7 of t h e m the V E P was a b n o r m a l o r absent. O n l y 1 p a t i e n t (No. 7) h a d a n o r m a l E R G a n d a n a l m o s t n o r m a l V E P ; she su fered f r o m t r a n s i e n t visual s y m p t o m s 3 years p r i o r to the e l e c t r o p h y s i o l o g i c a l e x a m i n a t i o n . In the 2 p a t i e n t s with e n h a n c e d E R G s it was m o r e so in the eye w h i c h was affected in the past. F u r t h e r detail will be found in T a b l e 4. P a t i e n t 1 r e p r e s e n t i n g the residual e l e c t r o p h y s i o l o g i c a l a b n o r m a l i t i e s will be l a t e r d e s c r i b e d in detail. Group I I I : patients with no visual disturbances A l t h o u g h the 9 patients o f this g r o u p d i d n o t suffer from visual s y m p t o m s at a n y time, they h a d a b n o r m a l V E P s with the p o s s i b l e e x c e p t i o n of p a t i e n t s I a n d 6 (Table 3). It is interesting t h a t also in this g r o u p n o t only n o r m a l or n e a r l y n o r m a l E R G s b u t also s u b n o r m a l E R G s a n d even E R G s w i t h e n h a n c e d positive a m p l i t u d e s were f o u n d (Tables 3 a n d 4). T h e case of p a t i e n t 5 will be d e s c r i b e d in detail. P a t i e n t 7 p e r m i t t e d us to r e c o r d his E R G for o n l y 4 m i n in the d a r k . The positive a m p l i t u d e s achieved after 3.5 m i n in the d a r k were 415/~V in the right eye alad 400/~V in the left; t h e negative p o t e n t i a l s were 100 #V in b o t h eyes. This is in the n o r m a l range for this early p e r i o d of dark adaptation. CASE REPORTS
Patient 1 (No. I in #roup lj A 32-year-old woman awoke with a feeling of vertigo and blurred vision in the left eye a week before admission. Later on during that day she became aware of a relative central scotoma. Eye movements caused left retrobulbar pains. Her visual acuity was 6/7.5 in the right eye and 6/9 in the left eye. No pathological findings were noted on fundoscopy. She was referred to our laboratory and ERG and VEP examinations were carried out. At the steady state of dark adaptation the b-wave in the ERG of the fight eye reached an amplitude of 490/aV while that of the left eye attained the enhanced amplitude of 600/zV (Fig. 1). The VEP to stimulation of the left eye differed from that to stimulation of the right eye in that the initial positive response was very small. Six weeks after beginning of steroid treatment her condition had improved to the extent that only a small scotoma remained. However, the ERG did not show a substantial improvement in that the b-wave in the left ERG was still enhanced and higher (580/zV)than the normal right ERG (510 gV). On the other hand, the VEP to stimulation of the right eye was now practicallynormal in that the latency became shorter. However, the VEP evoked by stimulation of the left eye did not show changes despite improved visual function. During the following months transient motor phenomena appeared in her lower limbs and pyramidal signs were elicited. The diagnosis of multiple sclerosis was thus established. Patient 2 (No. 2 in group I) Two days before admission this 25-year-old man complained of temporal headache which was followed by loss of central vision in the right eye. On examination, a large central scotoma was found in the visual field of the fight eye. Visual acuity and visual field were normal in the left eye despite vague complaints of blurred vision. Both fundi were normal. There were no other neurological deficits. The ERGs of both eyes were slightly subnormal. However, the VEP displayed very small amplitudes and
168
M. FEINSOD, O. ABRAMSKY, E. AUERBACH
Fig. 1. ERGs of patient 1 in group I. Right eye: upper trace. Left eye : lower trace. In this and all other recordings the positive polarity is upward. Note the enhanced response from the left (affected) eye. Calibrations : 200/iV, 20 msec.
Fig. 2. The averaged VEP monocular stimulations of patient 2 in group I. During attack of right retrobulbar neuritis (upper traces), after recovery (middle traces), during an attack of left retrobulbar neuritis (lower traces). Calibrations : 5/~V, 25 msec.
ELECTROPHYSIOLOGICAL EXAMINATIONS OF THE VISUAL SYSTEM IN M.S.
169
lengthened latencies to stimulation of either eye; that to stimulation of the right eye was even smaller and more lengthened than the VEP following stimulation of the left eye (Fig. 2, upper traces). Under ACTH treatment vision in the right eye improved in that the sensation of blurring disappeared and the scotoma diminished. A week after the first examination, the VEP was recorded again and after stimulation of either eye, an increase in the amplitudes in both VEPs was noted although the latencies remained lengthened (Fig. 2, middle traces). Six months later the patient complained of transient visual disturbances this time in the left eye. On examination pallor of the right optic disc and a relative scotoma was found in that eye. Visual acuity was 6/9 in both eyes. The ERG was now normal in both eyes. However, the VEP to stimulation of the left eye was smaller in amplitude as compared to the previous examinations and the latency seemed lengthened even more. The VEP following stimulation of the right eye appeared improved (Fig. 2, lower traces). During the following 3 months the patient suffered from an episode of loss of vision in the left eye for 1 day. On examination pyramidal signs were elicited in both legs. Thus the diagnosis of multiple sclerosis could be established.
Patient 3 (No. 1 in group II) One year prior to examination of this 18-year-old girl a sudden loss of vision occurred in her left eye for a period of 1 week. Vision in the right eye was normal as to acuity and visual field. After ACTH treatment her vision returned to normal within a month. Three months later she experienced paraesthesiae in both lower limbs and Babinski's sign could be elicited bilaterally. After 2 further months the patient complained of blurred vision in her left eye but no objective finding was noticeable in the ophthalmological examination. Babinski's sign was still present. When the electrophysioiogical examination was carried out, there were no visual complaints. The fundi were normal. The b-wave of the ERG of the right eye was above the normal amplitude range (580 #V), that of the left eye was even more enhanced (610/~V). The negative amplitudes were normal. The VEPs of both eyes were extremely subnormal. They were considered to be practically extinct as they could not be measured.
Patient 4 (No. 5 in group III) This 25-year-old woman suffered from paraesthesiae and numbness in her lower limbs at the age of 22, and pyramidal signs could be elicited. A year later her gait became awkward and cerebellar signs were found. Her symptoms receded after ACTH treatment. No visual complaints were ever present. The electrophysiological examination was carried out when the patient was hospitalized because of recurrent numbness in both legs. The general physical examination did not reveal any abnormal finding. The neurological examination disclosed bilateral Babinski's signs, and hyperactive tendon reflexes in both lower limbs. There was slight cerebellar ataxia. The fundi were normal, visual fields, full and visual acuity 6/6 in both eyes. The ERG of the right eye was at the upper normal limit (550 #V) while that of the left eye was enhanced (600 #V) (Fig. 3). The negative amplitudes were normal. The VEP was of markedly low amplitude and prolonged latency (Fig. 4).
Fig. 3. The ERGs of patient 5 in group III are enhanced in both eyes. Calibrations: 200 #V, 20 msec.
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M. FEINSOD, O. ABRAMSKY, E. AUERBACH
Fig. 4. VEPs of patient 5 in group 1II are of very low amplitude. Note that there was no evidence of visual system involvement at any time. Upper trace: following binocular stimulation. Middle trace: following stimulation of the right eye. Lower trace: following stimulation of the left eye. Calibrations : 5 uV, 25 msec. DISCUSSION
The 35 patients examined represent 3 possible types of involvement of the visual system accompanying multiple sclerosis. We are aware that they do not represent a cross-section of patients afflicted by multiple sclerosis. They enabled us, however, to study possible characteristic electrophysiological patterns related to clinical symptomatology.
~1) E lectroretinographic findings The ERG is an evoked response which represents the summated electrical activity in the retina (Brindley 1957) of a large number of neuronal elements. A normal ERG
ELECTROPHYSIOLOGICAL EXAMINATIONS OF THE VISUAL SYSTEM IN M.S.
171
may be considered as evidence of functional integrity of the retinal elements comprising at least the first 2 neurons. A subnormal ERG suggests a retinal anatomical or functional abnormality. We assume that an enhanced retinal response in the presence of a disturbed VEP or in its absence, is an indication of optic nerve affection. A more detailed account and review of the literature of the ERG and its clinical application, dealing also with questions relevant here, has been given by one of the authors (Auerbach 1970). Recent results (Feinsod et al. 1971) make it likely that in such cases in which an enhanced ERG is recorded, the absence of an inhibitory influence via centrifugal fibres within the optic nerve is responsible, thus upsetting a rivalry with the increasing retinal sensitivity in the dark. This concept appears to be substantiated by previous clinical observations (Dieterle and Babel 1955; Jacobson and Gestring 1958; Straub and Rank 1959; Gills 1966b; Feinsod and Auerbach 1969, 1971). Recently Halliday et al. (1972) did not find in cases of acute, unilateral optic neuritis an effect on the amplitudes of the potentials of both polarities. This is in contrast to the finding of Gills (1966a) and others. It is also in contrast to our findings such as those in the great majority of the cases presented in this study, in a former investigation (Feinsod et al. 1971) and in unpublished examinations of patients sent to our laboratory. We agree, however, that latency and pattern are generally normal. The reason for this disagreement may be the marked differences in the methods and procedures employed. Brindley and Hamasaki (1962) were unable to demonstrate in cats any change in the ERGs as a result of severance of 1 optic nerve. Neither were they able to find histological evidence of the existence of efferent fibres (Brindley and Hamasaki 1966). For this reason, these authors denied the presence of efferent fibres in the optic nerve. However, these experiments were carried out at constant background illumination, i.e. under photopic conditions. In cases of unilateral optic atrophy Feinsod et al. (1971) were able to show that the human ERG increased practically equally in both eyes during the photopic phase of dark adaptation. Only thereafter was it found that the b-wave in the ERG of the eye with the atrophic optic nerve gradually became larger than that of the other eye with the intact optic nerve. Similarly, an enhanced ERG after severance of an optic nerve was found in cats and monkeys by Jacobson and Gestring (1958) in recordings made after 10 min of dark adaptation, i.e. at the beginning of scotopic dominance in the recovery of retinal activity. In order to substantiate the above findings in humans (Feinsod et al. 1971) experiments were carried out in cats (Auerbach and Feinsod 1973). The ERG recovery from a light adaptation was followed in both eyes for about 1 hr both before and after severance of 1 optic nerve. In almost all animals tested after the section of 1 optic nerve the amplitudes of both ERGs were found to increase about equally during the first few rain in the dark, which seems to correspond with the photopic phase of dark adaptation. However, later the b-wave became enhanced in the eye with the cut optic nerve. Although Brindley and Hamasaki (1966) did not identify centrifugal fibres within the optic nerve, their existence was described in man and in the cat by several authors (Brooke, Downer and Powell 1965; Wolter 1965; Wolter and Knoblich 1965;
172
M. FEINSOD, O. ABRAMSKY, E. AUERBACH
Honrubia and Elliott 1968; Sacks and Lindenberg 1969). However, in contrast to the avian retina (Cowan 1970), the synaptic connections of centrifugal fibres with retinal cells in mammals is unknown. The 18 patients of 9roup I may have in common with those presented by Gills (1966a) a variability in the duration of the visual symptoms. He showed that the degrec of ERG subnormality was likely to be a function of the duration and severity of optic nerve atrophy. However, in our cases no correlation between the duration of the disease and the clinical condition on the one hand, and E R G amplitudes on the other was found. In some cases optic nerve atrophy was not yet visible ophthalmoscopically. It appears that the ERGs were either normal or subnormal, some even were enhanced, no matter the period of time of the affliction. F o r example, subnormal ERGs were found in patient 6 with visual symptoms for a period o f 1 year as well as in patient 17 with visual symptoms of 13 years' duration. This contrasts only slightly with Gills' data. However, the same applies to enhanced retinal responses, which were found in 7 patients of this group (not to mention the 5 additional cases in the 2 other groups) (Table 4). These abnormalities, too, were related neither to the duration of the disease nor to the severity of the visual symptoms. An enhanced ERG was found in patient 1 in the first week after the visual symptoms appeared as well as in patient 16 with primary optic nerve atrophy who became blind 13 years previously. The enhancement was in 2 cases transient (patients 1 and 4); this may have been the result of a temporary affection of the centrifugal optic nerve fibres. The normal ERG's recorded from only 2 patients of this group suggest that in them retinal elements were not affected by the disease; the visual symptoms may then be assumed to result from lesions situated more proximally in the visual system. Gills (1966a), following the observations of Bornstein and Crain (1965) and Cerfand Carels (1966), suggested that subnormal ERGs, being in contrast to his own findings of enhanced ERGs in eyes with sectioned optic nerves (Gills 1966b), may be due to the effect of a serum factor present in multiple sclerosis patients. This interpretation, though agreeing with his results, does not agree with the findings presented here. Retrograde trans-synaptic degeneration of retinal elements following optic nerve lesions does not seem to explain subnormal ERGs, as patients with similar conditions had normal or enhanced ERGs. Thus it may not apply to the present material. However, among the 69 cases of optic nerve affliction reported recently, there was 1 clear-cut case developing after encephalitis (No. 3 in Table I in Feinsod et al. 1971) in which an enhanced E R G in both eyes became subnormal in the course of 1 year. The few normal ERGs obtained from the patients of 9roup I I imply that with the methods used no recordable damage to retinal elements can be detected. There may well be no damage. But these patients were not examined electrophysiologically prior "to, during, or a short time after the attacks. Their retinal responses may have been different from those at present. The enhanced ERGs suggest a former optic nerve lesion which did not leave a clinical stigma. It is surprising that among the patients of group I I I at least 6 of the 9 showed abnormal ERGs and 7 cases showed abnormal VEPs. This suggests in the case of patients who did not have visual symptoms during the course of their disease, that some subclinical events may have occurred in their visual system which gave rise to
ELECTROPHYSIOLOGICAL EXAMINATIONS OF THE VISUAL SYSTEM IN M.S.
173
changes reflected by the electrophysiological recordings. (2) The visual evoked potentials ( V E P ) The finding of an abnormal VEP in nearly all of our patients is in accordance with the findings ofRichey et al. (1971). It is only partially in agreement with the findings of Halliday et al. (1972). However, it is difficult to compare our data with theirs since they emphasized the pattern-evoked responses. We certainly do not deny the importance of this method but we do not share the opinion of these authors regarding the VEPs produced by flash stimuli. Also this method proved itself to be a useful tool in a number of cases of unilateral, acute optic neuritis which we examined before, during and after treatment (unpublished data; and Feinsod et al. 1971). Halliday et al. (1972) found lengthened latencies in VEPs produced by patterned stimuli in the affected eye but not in the unaffected eye where the VEP was normal. Regarding the VEP elicited by flash stimuli to the affected eye, they did not detect an increase in latency as compared with the VEPs produced to stimuli to the unaffected eye. They do not mention, however, a comparison with VEPs elicited by flashes in healthy persons. Moreover, the choice of the peak latency of the most prominent wave, the post-synaptic primary wave, as a criterion is not fully satisfactory but it shows, if lengthened, that a delay has occurred in the impulse propagation of the afferent striate input. We prefer as a criterion the latency of the pre-synaptic initial positivity of the VEP, i.e. before any processing of the incoming information could have taken place in the striate cortex. We also prefer as a criterion the amplitude of the post-synaptic primary wave, which necessarily should be lengthened if the former is increased, and which serves as an indication of the neural events in the striate cortex following the input via the afferent pathways. In our examinations, despite using flash stimuli, the latencies were prolonged and the amplitudes decreased sometimes to an extent that the components could not be clearly identified or were even completely absent. Alterations in the VEPs in the group I patients were expected since they were examined while suffering from visual symptoms. It is noticeable, however, that in patients with unilateral retrobulbar neuritis and without any previous visual symptoms, the striate response to stimulation of the "good" eye was abnormal in its latency, amplitude or shape as in the example illustrated in Fig. 2. The abnormal cerebral response to stimulation of the affected eye can be explained as reflecting an abnormality in the conduction from that eye. However, it is difficult to explain with some certainty the abnormal response to stimulation of the "good" eye which may well indicate a subclinical involvement of its pathways. Abnormal VEPs in at least 7 of the 8 cases in group II, despite functional recuperation of the visual system, suggest changes in the visual pathways. This assumption is strengthened by the very few normal ERGs; they are either enhanced or subnormal. As mentioned above, clinically occult sequelae of multiple sclerosis lesions occurring in the cortex or white matter may explain the large incidence of abnormal ERGs and VEPs found in group IlL The number of patients in this group is too small for statistical analysis. On the other hand, the number of abnormal cases seems too large to be simply a coincidence. This is all the more evident since similar pathological VEPs
174
M. FEINSOD, O. ABRAMSKY, E. AUERBACH
in patients with no evidence of visual pathway involvement at any time were also described by Richey et al. (1971). In this context it should be noted that the visual system is one of the longest cerebral pathways. Its chances of becoming involved in a case of multiple sclerosis may be considered to be great. It is known that numerous plaques can be found, even when there are few clinical findings (Alpers 1963 ; Grinker and Sahs 1966). The combined examination of the ERG and VEP, the latter elicited both by flash stimuli and probably even more so by patterned stimuli, may serve to detect even the presence of occult cerebral lesions involving the visual system, let alone lesions arising from previous or clinically overt disturbances. As for the retinal response, it is emphasized again that our findings do not suggest that enhancement or subnormality can be correlated either with the duration of the disease or with the presence of symptoms or their severity.
SUMMARY
Electroretinograms (ERG) and visual evoked potentials (VEP) were recorded from 35 patients suffering from multiple sclerosis. Of these, 18 suffered from visual deficits at the time of the examinations, 8 had had transient visual symptoms in the past and 9 had no visual symptoms at any time. In contrast to previous reports on cases of multiple sclerosis, enhanced retinal responses were found. Furthermore, there was no direct correlation between the severity of the visual deficit, the duration of the visual symptoms and the abnormality reflected by the ERG and VEP. The E R G and VEP were abnormal even in the absence of visual symptoms. Among the 35 patients examined 11 exhibited in 1 or in both eyes an enhanced b-wave of the ERG and 20 others displayed at least in 1 eye subnormal retinal responses: There were only 4 patients with normal ERGs in both eyes. However, the VEPs were nearly normal only in 1 patient of the 4. No matter whether or not vision was affected at the time of the examination, the averaged visual evoked potentials of nearly all patients examined were abnormal.
REFERENCES ALPERS, B. J. (1963) Clinical Neurology, 5th edition, Davis, Philadelphia, Pa. At~RBACH, E. (1967) The human electroretinogram in the light and during dark adaptation, Docum. ophthal. (Den Haag), 22: 1-71. AUERBACH, E. (1968) The value of the different components for clinical electroretinography. In: ISCERG Symposium Ghent 1966, Karger, Basel, New York, pp. 162-173. AUto,BACh, E. (1970) 1. Electrophysiological examination (electroretinography and electro-oculography). 2. Clinical application of biodeetrical tests. In: A. J. BALLANTYNEAND L C. MICHAI~,SON (Eds.), Textbook of the Fundus of the Eye, 2rid edition, Livingstone, Edinburgh, London, lap: 22-35, 49-50 and 512-542. AUto,BACH, E. AND M. FF.INSOO(1973) Centrifugal effects on the cat electroretinogram after section of one optic nerve, Docum. ophthal. (Den Haag), 34: 47-55. BORNS~IN, M. B. ANO S. M. CRA~ (t965) Functional studies of cultured brain tissues as related to "Demyelinative disorders", Science, 148: 1242-1244. BRINDLEY, G. S. 0957) Additivity in the electroretinogram, J. Physiol. (Lond.), 137: P51.
ELECTROPHYSIOLOGICAL EXAMINATIONS OF THE VISUAL SYSTEM IN M.S.
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BRINDLEY, G. S. AND D. I. HAMASAKI(1962) Evidence that the cat electroretinogram is not influenced by impulses to the eye along the optic nerve, J. Physiol. (Lond.), 163: 558-568. BRINDLEY, G. S. AND D. I. HAMASAKI (1966) Histological evidence against the view that the cat's optic nerve contains centrifugal fibers, J. Physiol. (Lond.), 184: g~g 499. BROOKE, R. N., J. C. DOWNER AND T. P. S. POWELL (1965) Centrifugal fibers to the retina in the monkey and cat, Nature ~Lond.), 207: 1365-1367. CERF, J. A. AND G. CARETS (1966) Multiple Sclerosis. Serum factor producing reversible alterations in bioelectric responses, Science, 152: 1066-1068. CIGANEK, C. (1961) The EEG response (evoked potential) to light stimulus in man, Electroenceph. clin. Neurophysiol., 13: 165-172. COWAN, W. M. (1970) Centrifugal fibers to the avian retina, Brit. med. Bull., 26: 112-118. CREUTZFELDT,O., A. ROSINA,M. ITO AND W. PROBST(1969) Visual evoked response of single cells and of the EEG in primary visual area of the cat, J. Neurophysiol., 32: 127-139. DIETERLE, P. AND J. BABEL(1955) L'inttr~t diagnostique de l'enregistrement simultan6 de l'61ectrorgtinogramme et de l'61ectroenctphalogramme (mesure du temps rgtino-cortical) dans les affections des voies optiques, Ophthalmologica, 129: 245-247. FEINSOD, M• AND E. AUERBACH (1969) Changes in the electroretinogram in lesions of the optic nerve, Electroenceph. clin. Neurophysiol., 27:217. FEINSOD, M. AND E. AtmRBACH (1971) The electroretinogram and the visual evoked potential in two patients with tuberculum sellae meningioma before and after decompression of the optic nerve, Ophthalmologica, 163: 360-368. FEINSOD, i . , H. ROWE AND E. AUERBACH(1971) Changes in the electroretinogram in patients with optic nerve lesions, Docum. ophthal. (Den Haag), 29: 169-200. GILLS, JR., J. P. (1966a) Electroretinographic abnormalities and advanced multiple sclerosis, Invest. Ophthalmol., 5 : 555-559. GILTS, JR., J. P. (1966b) The electroretinogram after section of the optic nerve in man, Amer. J. Ophthal., 62: 287-291. GRINKER, R. R. AND A. L. SAm (1966) Neurology, 6th edition, Thomas, Springfield. HALLIDAY, A. M., W. I. MCDONALD AND J. MUSHIN (1972) Delayed visual evoked response in optic neuritis, Lancet, 1 : 982-985. HONRUBIA, F. M. AND J. H. ELLIOTT (1968) Efferent innervation of the retina, Part 1 (Morphologic study of the human retina), Arch. Ophthal., 80: 98-103. JACOBSON, J. H. AND C. F. GESTRING (1958) Centrifugal influences upon the electroretinogram, Ann. N.Y. Acad. Sci., 74: 362-371. KooI, K. A. AND B. K. BAOCm (1964) Visual evoked responses in man: normative data, Ann. N. Y. Acad. Sci., 112: 254-269. McALPINE, D., C. E. LUMSDENAND E. D. ACHESON(1965) Multiple Sclerosis. A Reappraisal, Williams and Wilkins, Baltimore, Md. RICHEY, E. T., K. A. KOOIANDW. W. TOURTELLOTTE(1971) Visually evoked responses in multiple sclerosis, J. NeuroL Neurosurg. Psychiat., 34: 275-280• SACKS, J. G. AND R. LINDENBERG(1969) Efferent nerve fibers in bilateral congenital cystic eyeballs, Amer. J. Ophthal., 68: 691~i95. STRAUB, W. AND E. RANK (1959) Untersuchungen iiber den Nachweis einer Dunkeladaptation an blinden Augen, Dtsch. Ophthal. Ges. (Heidelberg), 62: 103-107. WOLTER, J. R. (1965) The reactions of the centrifugal nerves of the human eye. In: J. W. ROHEN (Ed.), The Structure of the Eye (II, Symposium), Schattauer, Stuttgart, pp. 85-95. WOLTER, J. R. AND R. R. KNOBLICH (1965) Pathway of centrifugal fibers in the human optic nerve, Brit. • J. Ophthal., 49: 246-250.
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i ~ Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
Electrophysiological Examinations of the Visual System in Multiple Sclerosis M. FEINSOD*, O. A B R A M S K Y * * AND E. AUERBACH The Vision Research Laboratory, The Wolfson OphthalmologicalResearch Laboratories, Hadassah University Hospital and Medical School, Jerusalem (Israel) (Received 21 March, 1973)
INTRODUCTION
In multiple sclerosis vision is often affected, yet only 3 electrophysiological studies of the visual system have been carried out. These studies deal either with the electroretinogram (Gills 1966a; Halliday, McDonald and Mushin 1972) or with the visual evoked potential (Richey, Kooi and Tourtellotte 1971; Halliday et al. 1972). In our opinion a combined examination of retinal and striate function appears more meaningful than either test alone. In a previous paper on optic nerve lesions (Feinsod, Rowe and Auerbach 1971) the electroretinogram (ERG) was recorded together with the visual evoked potential (VEP). Among the various optic nerve affections studied in this investigation were 9 cases of multiple sclerosis. The results in some of these differed from those in the patients studied by Gills (1966a) in that their retinal responses were enhanced. In the present study the results of ERG and VEP examinations in 35 patients suffering from multiple sclerosis, including the 9 from the former study, are reported. According to the case history these patients fell into 3 groups: one with continuing visual symptoms, another with previous and transitory visual disturbances and another group which never experienced visual disturbances during the course of the disease. The electrophysiological findings have been related to these groups.
METHODS
The examinations were carried out in an electrically shielded cage with the patient in a recumbent position. Mydriasis was achieved by instillation of Mydriaticum Roche ® to each eye. For ERG recordings a Henkes contact lens electrode was fixed to each eye and an indifferent silver disk electrode was fastened to the midsupraorbital This project was supported in part by the Israeli Center for Psychobiology. * From the Department of Neurosurgery. ** From the Department of Neurology.
162
M. FEINSOD, O. ABRAMSKY, E. AUERBACH
rim above each eye. The VEP was derived bipolarly from the occipital scalp between 9 mm silver disk electrodes placed at the inion and 5 cm above. A ground electrode was attached to each ear lobe. A Grass PS-2 photostimulator activated a xenon discharge lamp. The flash duration was about 10/~sec. The light source was centered at 20 cm in front of the patient's eyes. For ERG recordings a condenser-coupled dual beam CRO (Tektronix 502) was used. The electrodes were connected to the CRO through AC preamplifiers (Grass PS-5) whose filters were set at 0.1 cycles/sec and 200 cycles/sec. The responses were recorded simultaneously from both eyes and photographed from the screen of the CRO by a Grass camera (C4). Sweeps and the camera shutter were synchronized to coincide with stimulus onset. For the recording of the VEP, responses of 70 or 140 flashes delivered at a frequency of about 1 per 1.5 sec were averaged on the Computer of Average Transients (CAT 400B) for 250 msec following the stimulus onset. The averaged responses were displayed on the screen of the CRO, which was set for X Y tracings, and then photographed. The ERGs referred to in this study were elicited by single flash stimuli, and are those measured at the steady state of dark adaptation, i.e. the period of time necessary for the retinal response to recover completely from a preliminary light adaptation of 5 min. The potentials of negative (a-wave) and positive polarity (b-wave) generally achieve their maximal amplitudes within 30 min in the dark. Those patients who did not permit us to do the complete test or did not co-operate satisfactorily were examined without light adaptation and the test began immediately after the dim light of the shielded room was switched off. Consequently, the steady state condition was achieved in these cases in a much shorter time (generally a few min up to 10 min) as verified by the constant size of the retinal responses. In all tests the interval between stimuli was at least half a min, later in the dark 1 min. The normal ranges for the overall amplitudes of the a- and b-wave under our test conditions were determined more than 12 years ago and were recently illustrated in the histograms of a previous study (Feinsod et al. 1971). The values range between 100 and 200/~V for the a-wave and between 420 and 550/~V for the b-wave. The data represented in these histograms are based on the steady state ERGs from the examination of 98 eyes in 54 normal persons. In each ERG the a-wave amplitude was measured from the baseline down to the negative peak and the b-wave amplitude was determined from the negative peak of the a-wave up to the positive peak of the b-wave. The data of both waves are presented for all cases examined in Tables 1 to 3. The criteria used can be found in greater detail in former studies of the normal and the clinical ERG by Auerbach (1967, 1968, 1970). In the normal VEP elicited by the same flash stimuli used for the E R G recordings, the initial (pre-synaptic) positivity has a latency of 15-30 msec and an amplitude of up to 5 /~V. It is followed by the primary (post-synaptic) wave, the peak-to-trough amplitude of which has a range of 5-15 #V and a secondary wave which is even more variable than the other waves (Ciganek 1961; Kooi and Bagchi 1964; Creutzfeldt, Rosina, Ito and Probst 1969). In Tables 1 to 3 we tabulate the latent period of the VEPs of all 35 cases examined and the peak-to-trough amplitudes of their primary waves.
F M F
16 17 18
33 49 48
42
23 26 20 26 23 40 22 31 30 34 34 34
25
32
Age (years)
13 years 13 years 22 years
12 years
1 month 3 mont hs 6 months 1 year 1.5 year 2 years 2 years 3 years 8 years 9 years 10 years 12 years
2 weeks
l week
13 years 13 years 3 years
8 years
1 month 1 day 6 mont hs 1 year 1.5 year 2 years 1 year 3 years 8 years 9 years 10 years 6 years
2 weeks
1 week
Duration of visual symptoms
OS OU OU OD OS
OU OD OU OS OS OU OD OU OU OU OS OD OS OD
OD
OS
large central scotoma large central scotoma central scotoma blind light perception central s c ot oma blurred yision central scotoma central scotoma blindness blurred vision finger count : 1 m blurred vision central scotoma finger count : 2 m constricted visual field blind blindness central scotoma blurred vision constriction of visual field
Main visual complaint or findin# at time of examination
+ + -
+
+ + + _ _ + + + +
OS
+ + -
+
+ + _ + + _
OD
Optic atrophy
109 190 83
109
93 90 280 117 82 207 120 89 220 217 50 90 111
189
OS
53 160 125
75
93 117 250 138 131 200 135 52 160 159 43 82 100
178
OD
a-wave
540 380 413
625
750
600 350 325
426 463 690 424 331 619 520 368 660 614 259 268 362
490
600
396 424 610 407 268 625 462 393 710 678 286 328 333
OD
OS
b-wave
ERG (ItV)
a-wave: 100 #V-200 #V b-wave: 420-#V-550ItV
ERG normal amplitudes:
latency (of initial positivity): 15 msec-30 msec amplitude (of pri ma ry wave): 5 # V - I 5 #V
VEP normal values:
50
60
25 90 45 50
30 60
40
60 50 65
50
VEP
4.7
OS
5.3
OD
Amplitude of primary wave (It V)
extinct extinct 65
35
9.4
2.8
7.0
17.1
70 2.1 1.4 45 8.5 5.0 65 3.8 2.1 practically absent 35 2.1 8.3 extinct 50 5.7 7.1 65 8.8 8.8 extinct 25 3.3/8.0 3.3/5.3 2.5 50 2.3 2.0 65 2.0 2.7
55
OD
Latency (msec) OS
Symbols used in Tables 1--4: OD : right eye ; OS : left eye; O U : bot h eyes ; - : n o r m a l fundus ; + : pallor of optic disc ; + : optic atrophy. Figures in centre of col um m refer to binocular recording. N o r m a l E R G and VE P values for Tables 1-4:
F
F F M M F M F F F M M F
3 4 5 6 7 8 9 I0 11 12 13 14
15
M
2
.
F
Sex
1
Patient No.
Duration of disease
GROUP I : PATIENTS WITH VISUAL SYMPTOMS
TABLE 1
t"
<
O
pp.
;~ r~ rn
~
O
0
F F F F
M
F F F
1 2 3 4
5
6 7 8
30 47 42
29
18 25 26 29
Age (years)
For abbreviations see Table 1.
Sex
Patient No.
8 years 10 years 19 years
5 years
1 year 2 years 2 years 5 years
of disease
Duration
OS OS OU OD
10 months 1 year 1 year 3 years O D blurred vision O U blurred vision O D transient loss of vision O U blurred vision
4 years 8 years 3 years 18 years
transient loss of vision blurring of vision blurred vision papillitis
Main previous complaint orfindin9
Last appearance of visual symptoms
+ + +
+
_+ -+
OS
+ ± +
+
---
OD
atrophy
Optic
69 111 140
222
170 72 160 83
83 154 165
254
150 108 100 83
397 440 400
415
610 616 480 407
370 473 500
492
580 580 480 410
b-wave OS OD
ERG (izV) a-wave OS OD
G R O U P I1 ." P A T I E N T S W I T H P R E V I O U S V I S U A L D I S T U R B A N C E S
TABLE 2
50 40
40
75 60
Amplitude of
not
measurable 35 2.7 30 12.1 practically absent
65
2.0 18,6
4.7
10.6 3.3
primarlY.wave(j!V OS OD practically extinct 60 10.6 50 6.0 practically extinct
(msec) OS OD
Latency
VEP ~
~,
~;~
.~ r~
© >
ELECTROPHYSIOLOGICALEXAMINATIONSOF THE VISUAL SYSTEM IN M . S .
165
TABLE 3 G R O U P IIl : P A T I E N T S W I T H N O V I S U A L D I S T U R B A N C E S
VEP ERG.(#V) Patient No.
Sex
Age Duration (years) " of disease Main clinical picture
a-wave OS
b-wave
OD
OS
Latency (msec)
OD OS
*
1 2
M M
18 33
3
M
21
4 5 6
M F M
31 25 39
7
M
35
8
F
26
9
F
44
1week 3 weeks
paraparesis spastic right hemiparesis 5 months cerebeUarataxia, paraparesis 1 year paraparesis 3years paraparesis 5 years cerebellar ataxia, paraparesis 6 years bulbar signs, paraparesis 8 years cerebellar ataxia, paraparesis 12 years ataxia, transient nystagmus
Amplitude of primary wave (PV)
OD
OS
OD
72 103 470 464 35
35
7.8
6.8
114 115 293 296 40 114 183 366 383 80
50 70
2.1 0.6
2.8 0.9
124 110 300 304 55 197 182 600 550 60 55 300 290 590 500 35 35
1.0 5.1
?
?
?
?*
3.5 1.1 4.8
practically extinct
137 125 496 518 55
55
232 224 526 629 40
55
2.7/5.3 2.7/6.0 1.7
See text. For abbreviations see Table 1.
Thirty-five patients suffering from multiple sclerosis were examined at various stages of the disease. In some the diagnosis could only be m a d e after the examination. The criteria for the diagnosis of multiple sclerosis were based on those used by McAlpine, L u m s d e n and A c h e s o n (1965) in patients with characteristic histories of relapse and remission and findings of multiple lesions. N o t included in this study were cases of retrobulbar neuritis; even recurrent cases were eliminated f r o m this study if not followed by the appearance of other neurological signs.
RESULTS The patients examined could be divided into 3 groups : those with visual s y m p t o m s at the time of the examination, others with transient visual disturbances but no signs at the time of the examination, and still others without visual s y m p t o m s at any time. The electrophysiological findings were related to the duration of the disease,-the d u r a t i o n of visual s y m p t o m s and to the presence of optic nerve atrophy. The data are summarized in Tables 1, 2 and 3. Table 4 is supplementary to the other 3 in classifying the ERG. To do the same with the V E P proved impractical and not useful. Group I : patients with visual disturbances
The 18 patients in this g r o u p were suffering from visual s y m p t o m e s ranging from blurred vision or s c o t o m a t a to amaurosis (Table 1). In all patients the V E P s were
3.3
166
M. FEINSOD, O. ABRAMSKY, E. AUERBACH
TABLE 4 C L A S S I F I C A T I O N OF E R G C H A N G E S
Group I
Group II
Group I I I
Patient No.
Patient No.
a-wave
b-wave
a-wave
b-wave
a-wave
b-wave
1
N
OU
E OS N OD
N OU
E OU
S OS (N) OD
N OU
1
2
S
OU
S OS (N) OD
S OS (N) OD
E OU
(N)OU
S OU
2
3
S OS NOD
(N) OS NOD
N OS (N)OD
N OU
(N)OS N OD
SOU
3
4
E
E
SOU
(S) OU
N OS (N) OD
S
OU
4
5
N OU
(S) OS (N) OD
E OU
(S) OS NOD
N OU
E OS (E) OD
5
6
S OS N OD
S
OU
S OU
S OU
E OU
E OS N OD
6
7
E OU
E OU
(N) OS
N OU
OU
OU
N OD OU
N OU
8
N
9
S OU
S
10
E OS N OD
E OU
11
E OS N OD
E OU
12 13
S OU S OU
S OU S OU
14
(N) O U
S
15
(N) OS S OD
E OU
16
(N) OS S OD
E OS (E) OD
N OU
OU
(S) OS N OD
no ERG at steady state N OU
YOU
E OU
N OS E OD
7 8
OU
17
N OU
S OU
18
S OS NOD
S OS (N)OD
N: normal amplitude (N): at lowest normal limit or close to normal but above S : subnormal amplitude (S): close to lowest normal limit but below E : enhanced amplitude (E): close to highest normal limit disturbed in that they displayed prolonged latencies and/or reduced amplitudes. In some patients no VEP was recordable. The ERGs recorded were normal or practically n o r m a l i n o n l y 2 c a s e s ( p a t i e n t s 3 a n d 8). T h e o t h e r s w e r e e i t h e r s u b n o r m a l o r e n h a n c e d
ELECTROPHYSIOLOGICAL EXAMINATIONSOF THE VISUAL SYSTEM IN M.S.
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(Table 4). The e n h a n c e m e n t f o u n d in p a t i e n t s 1 a n d 4 was t r a n s i t o r y . P a t i e n t s 1 a n d 2 will be d e s c r i b e d in d e t a i l below. T h e case r e p o r t s o f p a t i e n t s 4, 10, 15 a n d 16, all e x h i b i t i n g e n h a n c e d E R G s , were r e p o r t e d in detail by F e i n s o d et al. (1971) w h e r e they a p p e a r as Cases 8, 7, 5 a n d 6 respectively.
Group II: patients with previous visual disturbances The 8 p a t i e n t s in this g r o u p h a d visual d i s t u r b a n c e s d u r i n g the course of their disease b u t d i d n o t c o m p l a i n at t h e time of the e x a m i n a t i o n (Table 2). In 7 of t h e m the V E P was a b n o r m a l o r absent. O n l y 1 p a t i e n t (No. 7) h a d a n o r m a l E R G a n d a n a l m o s t n o r m a l V E P ; she su fered f r o m t r a n s i e n t visual s y m p t o m s 3 years p r i o r to the e l e c t r o p h y s i o l o g i c a l e x a m i n a t i o n . In the 2 p a t i e n t s with e n h a n c e d E R G s it was m o r e so in the eye w h i c h was affected in the past. F u r t h e r detail will be found in T a b l e 4. P a t i e n t 1 r e p r e s e n t i n g the residual e l e c t r o p h y s i o l o g i c a l a b n o r m a l i t i e s will be l a t e r d e s c r i b e d in detail. Group I I I : patients with no visual disturbances A l t h o u g h the 9 patients o f this g r o u p d i d n o t suffer from visual s y m p t o m s at a n y time, they h a d a b n o r m a l V E P s with the p o s s i b l e e x c e p t i o n of p a t i e n t s I a n d 6 (Table 3). It is interesting t h a t also in this g r o u p n o t only n o r m a l or n e a r l y n o r m a l E R G s b u t also s u b n o r m a l E R G s a n d even E R G s w i t h e n h a n c e d positive a m p l i t u d e s were f o u n d (Tables 3 a n d 4). T h e case of p a t i e n t 5 will be d e s c r i b e d in detail. P a t i e n t 7 p e r m i t t e d us to r e c o r d his E R G for o n l y 4 m i n in the d a r k . The positive a m p l i t u d e s achieved after 3.5 m i n in the d a r k were 415/~V in the right eye alad 400/~V in the left; t h e negative p o t e n t i a l s were 100 #V in b o t h eyes. This is in the n o r m a l range for this early p e r i o d of dark adaptation. CASE REPORTS
Patient 1 (No. I in #roup lj A 32-year-old woman awoke with a feeling of vertigo and blurred vision in the left eye a week before admission. Later on during that day she became aware of a relative central scotoma. Eye movements caused left retrobulbar pains. Her visual acuity was 6/7.5 in the right eye and 6/9 in the left eye. No pathological findings were noted on fundoscopy. She was referred to our laboratory and ERG and VEP examinations were carried out. At the steady state of dark adaptation the b-wave in the ERG of the fight eye reached an amplitude of 490/aV while that of the left eye attained the enhanced amplitude of 600/zV (Fig. 1). The VEP to stimulation of the left eye differed from that to stimulation of the right eye in that the initial positive response was very small. Six weeks after beginning of steroid treatment her condition had improved to the extent that only a small scotoma remained. However, the ERG did not show a substantial improvement in that the b-wave in the left ERG was still enhanced and higher (580/zV)than the normal right ERG (510 gV). On the other hand, the VEP to stimulation of the right eye was now practicallynormal in that the latency became shorter. However, the VEP evoked by stimulation of the left eye did not show changes despite improved visual function. During the following months transient motor phenomena appeared in her lower limbs and pyramidal signs were elicited. The diagnosis of multiple sclerosis was thus established. Patient 2 (No. 2 in group I) Two days before admission this 25-year-old man complained of temporal headache which was followed by loss of central vision in the right eye. On examination, a large central scotoma was found in the visual field of the fight eye. Visual acuity and visual field were normal in the left eye despite vague complaints of blurred vision. Both fundi were normal. There were no other neurological deficits. The ERGs of both eyes were slightly subnormal. However, the VEP displayed very small amplitudes and
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Fig. 1. ERGs of patient 1 in group I. Right eye: upper trace. Left eye : lower trace. In this and all other recordings the positive polarity is upward. Note the enhanced response from the left (affected) eye. Calibrations : 200/iV, 20 msec.
Fig. 2. The averaged VEP monocular stimulations of patient 2 in group I. During attack of right retrobulbar neuritis (upper traces), after recovery (middle traces), during an attack of left retrobulbar neuritis (lower traces). Calibrations : 5/~V, 25 msec.
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lengthened latencies to stimulation of either eye; that to stimulation of the right eye was even smaller and more lengthened than the VEP following stimulation of the left eye (Fig. 2, upper traces). Under ACTH treatment vision in the right eye improved in that the sensation of blurring disappeared and the scotoma diminished. A week after the first examination, the VEP was recorded again and after stimulation of either eye, an increase in the amplitudes in both VEPs was noted although the latencies remained lengthened (Fig. 2, middle traces). Six months later the patient complained of transient visual disturbances this time in the left eye. On examination pallor of the right optic disc and a relative scotoma was found in that eye. Visual acuity was 6/9 in both eyes. The ERG was now normal in both eyes. However, the VEP to stimulation of the left eye was smaller in amplitude as compared to the previous examinations and the latency seemed lengthened even more. The VEP following stimulation of the right eye appeared improved (Fig. 2, lower traces). During the following 3 months the patient suffered from an episode of loss of vision in the left eye for 1 day. On examination pyramidal signs were elicited in both legs. Thus the diagnosis of multiple sclerosis could be established.
Patient 3 (No. 1 in group II) One year prior to examination of this 18-year-old girl a sudden loss of vision occurred in her left eye for a period of 1 week. Vision in the right eye was normal as to acuity and visual field. After ACTH treatment her vision returned to normal within a month. Three months later she experienced paraesthesiae in both lower limbs and Babinski's sign could be elicited bilaterally. After 2 further months the patient complained of blurred vision in her left eye but no objective finding was noticeable in the ophthalmological examination. Babinski's sign was still present. When the electrophysioiogical examination was carried out, there were no visual complaints. The fundi were normal. The b-wave of the ERG of the right eye was above the normal amplitude range (580 #V), that of the left eye was even more enhanced (610/~V). The negative amplitudes were normal. The VEPs of both eyes were extremely subnormal. They were considered to be practically extinct as they could not be measured.
Patient 4 (No. 5 in group III) This 25-year-old woman suffered from paraesthesiae and numbness in her lower limbs at the age of 22, and pyramidal signs could be elicited. A year later her gait became awkward and cerebellar signs were found. Her symptoms receded after ACTH treatment. No visual complaints were ever present. The electrophysiological examination was carried out when the patient was hospitalized because of recurrent numbness in both legs. The general physical examination did not reveal any abnormal finding. The neurological examination disclosed bilateral Babinski's signs, and hyperactive tendon reflexes in both lower limbs. There was slight cerebellar ataxia. The fundi were normal, visual fields, full and visual acuity 6/6 in both eyes. The ERG of the right eye was at the upper normal limit (550 #V) while that of the left eye was enhanced (600 #V) (Fig. 3). The negative amplitudes were normal. The VEP was of markedly low amplitude and prolonged latency (Fig. 4).
Fig. 3. The ERGs of patient 5 in group III are enhanced in both eyes. Calibrations: 200 #V, 20 msec.
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Fig. 4. VEPs of patient 5 in group 1II are of very low amplitude. Note that there was no evidence of visual system involvement at any time. Upper trace: following binocular stimulation. Middle trace: following stimulation of the right eye. Lower trace: following stimulation of the left eye. Calibrations : 5 uV, 25 msec. DISCUSSION
The 35 patients examined represent 3 possible types of involvement of the visual system accompanying multiple sclerosis. We are aware that they do not represent a cross-section of patients afflicted by multiple sclerosis. They enabled us, however, to study possible characteristic electrophysiological patterns related to clinical symptomatology.
~1) E lectroretinographic findings The ERG is an evoked response which represents the summated electrical activity in the retina (Brindley 1957) of a large number of neuronal elements. A normal ERG
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may be considered as evidence of functional integrity of the retinal elements comprising at least the first 2 neurons. A subnormal ERG suggests a retinal anatomical or functional abnormality. We assume that an enhanced retinal response in the presence of a disturbed VEP or in its absence, is an indication of optic nerve affection. A more detailed account and review of the literature of the ERG and its clinical application, dealing also with questions relevant here, has been given by one of the authors (Auerbach 1970). Recent results (Feinsod et al. 1971) make it likely that in such cases in which an enhanced ERG is recorded, the absence of an inhibitory influence via centrifugal fibres within the optic nerve is responsible, thus upsetting a rivalry with the increasing retinal sensitivity in the dark. This concept appears to be substantiated by previous clinical observations (Dieterle and Babel 1955; Jacobson and Gestring 1958; Straub and Rank 1959; Gills 1966b; Feinsod and Auerbach 1969, 1971). Recently Halliday et al. (1972) did not find in cases of acute, unilateral optic neuritis an effect on the amplitudes of the potentials of both polarities. This is in contrast to the finding of Gills (1966a) and others. It is also in contrast to our findings such as those in the great majority of the cases presented in this study, in a former investigation (Feinsod et al. 1971) and in unpublished examinations of patients sent to our laboratory. We agree, however, that latency and pattern are generally normal. The reason for this disagreement may be the marked differences in the methods and procedures employed. Brindley and Hamasaki (1962) were unable to demonstrate in cats any change in the ERGs as a result of severance of 1 optic nerve. Neither were they able to find histological evidence of the existence of efferent fibres (Brindley and Hamasaki 1966). For this reason, these authors denied the presence of efferent fibres in the optic nerve. However, these experiments were carried out at constant background illumination, i.e. under photopic conditions. In cases of unilateral optic atrophy Feinsod et al. (1971) were able to show that the human ERG increased practically equally in both eyes during the photopic phase of dark adaptation. Only thereafter was it found that the b-wave in the ERG of the eye with the atrophic optic nerve gradually became larger than that of the other eye with the intact optic nerve. Similarly, an enhanced ERG after severance of an optic nerve was found in cats and monkeys by Jacobson and Gestring (1958) in recordings made after 10 min of dark adaptation, i.e. at the beginning of scotopic dominance in the recovery of retinal activity. In order to substantiate the above findings in humans (Feinsod et al. 1971) experiments were carried out in cats (Auerbach and Feinsod 1973). The ERG recovery from a light adaptation was followed in both eyes for about 1 hr both before and after severance of 1 optic nerve. In almost all animals tested after the section of 1 optic nerve the amplitudes of both ERGs were found to increase about equally during the first few rain in the dark, which seems to correspond with the photopic phase of dark adaptation. However, later the b-wave became enhanced in the eye with the cut optic nerve. Although Brindley and Hamasaki (1966) did not identify centrifugal fibres within the optic nerve, their existence was described in man and in the cat by several authors (Brooke, Downer and Powell 1965; Wolter 1965; Wolter and Knoblich 1965;
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Honrubia and Elliott 1968; Sacks and Lindenberg 1969). However, in contrast to the avian retina (Cowan 1970), the synaptic connections of centrifugal fibres with retinal cells in mammals is unknown. The 18 patients of 9roup I may have in common with those presented by Gills (1966a) a variability in the duration of the visual symptoms. He showed that the degrec of ERG subnormality was likely to be a function of the duration and severity of optic nerve atrophy. However, in our cases no correlation between the duration of the disease and the clinical condition on the one hand, and E R G amplitudes on the other was found. In some cases optic nerve atrophy was not yet visible ophthalmoscopically. It appears that the ERGs were either normal or subnormal, some even were enhanced, no matter the period of time of the affliction. F o r example, subnormal ERGs were found in patient 6 with visual symptoms for a period o f 1 year as well as in patient 17 with visual symptoms of 13 years' duration. This contrasts only slightly with Gills' data. However, the same applies to enhanced retinal responses, which were found in 7 patients of this group (not to mention the 5 additional cases in the 2 other groups) (Table 4). These abnormalities, too, were related neither to the duration of the disease nor to the severity of the visual symptoms. An enhanced ERG was found in patient 1 in the first week after the visual symptoms appeared as well as in patient 16 with primary optic nerve atrophy who became blind 13 years previously. The enhancement was in 2 cases transient (patients 1 and 4); this may have been the result of a temporary affection of the centrifugal optic nerve fibres. The normal ERG's recorded from only 2 patients of this group suggest that in them retinal elements were not affected by the disease; the visual symptoms may then be assumed to result from lesions situated more proximally in the visual system. Gills (1966a), following the observations of Bornstein and Crain (1965) and Cerfand Carels (1966), suggested that subnormal ERGs, being in contrast to his own findings of enhanced ERGs in eyes with sectioned optic nerves (Gills 1966b), may be due to the effect of a serum factor present in multiple sclerosis patients. This interpretation, though agreeing with his results, does not agree with the findings presented here. Retrograde trans-synaptic degeneration of retinal elements following optic nerve lesions does not seem to explain subnormal ERGs, as patients with similar conditions had normal or enhanced ERGs. Thus it may not apply to the present material. However, among the 69 cases of optic nerve affliction reported recently, there was 1 clear-cut case developing after encephalitis (No. 3 in Table I in Feinsod et al. 1971) in which an enhanced E R G in both eyes became subnormal in the course of 1 year. The few normal ERGs obtained from the patients of 9roup I I imply that with the methods used no recordable damage to retinal elements can be detected. There may well be no damage. But these patients were not examined electrophysiologically prior "to, during, or a short time after the attacks. Their retinal responses may have been different from those at present. The enhanced ERGs suggest a former optic nerve lesion which did not leave a clinical stigma. It is surprising that among the patients of group I I I at least 6 of the 9 showed abnormal ERGs and 7 cases showed abnormal VEPs. This suggests in the case of patients who did not have visual symptoms during the course of their disease, that some subclinical events may have occurred in their visual system which gave rise to
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changes reflected by the electrophysiological recordings. (2) The visual evoked potentials ( V E P ) The finding of an abnormal VEP in nearly all of our patients is in accordance with the findings ofRichey et al. (1971). It is only partially in agreement with the findings of Halliday et al. (1972). However, it is difficult to compare our data with theirs since they emphasized the pattern-evoked responses. We certainly do not deny the importance of this method but we do not share the opinion of these authors regarding the VEPs produced by flash stimuli. Also this method proved itself to be a useful tool in a number of cases of unilateral, acute optic neuritis which we examined before, during and after treatment (unpublished data; and Feinsod et al. 1971). Halliday et al. (1972) found lengthened latencies in VEPs produced by patterned stimuli in the affected eye but not in the unaffected eye where the VEP was normal. Regarding the VEP elicited by flash stimuli to the affected eye, they did not detect an increase in latency as compared with the VEPs produced to stimuli to the unaffected eye. They do not mention, however, a comparison with VEPs elicited by flashes in healthy persons. Moreover, the choice of the peak latency of the most prominent wave, the post-synaptic primary wave, as a criterion is not fully satisfactory but it shows, if lengthened, that a delay has occurred in the impulse propagation of the afferent striate input. We prefer as a criterion the latency of the pre-synaptic initial positivity of the VEP, i.e. before any processing of the incoming information could have taken place in the striate cortex. We also prefer as a criterion the amplitude of the post-synaptic primary wave, which necessarily should be lengthened if the former is increased, and which serves as an indication of the neural events in the striate cortex following the input via the afferent pathways. In our examinations, despite using flash stimuli, the latencies were prolonged and the amplitudes decreased sometimes to an extent that the components could not be clearly identified or were even completely absent. Alterations in the VEPs in the group I patients were expected since they were examined while suffering from visual symptoms. It is noticeable, however, that in patients with unilateral retrobulbar neuritis and without any previous visual symptoms, the striate response to stimulation of the "good" eye was abnormal in its latency, amplitude or shape as in the example illustrated in Fig. 2. The abnormal cerebral response to stimulation of the affected eye can be explained as reflecting an abnormality in the conduction from that eye. However, it is difficult to explain with some certainty the abnormal response to stimulation of the "good" eye which may well indicate a subclinical involvement of its pathways. Abnormal VEPs in at least 7 of the 8 cases in group II, despite functional recuperation of the visual system, suggest changes in the visual pathways. This assumption is strengthened by the very few normal ERGs; they are either enhanced or subnormal. As mentioned above, clinically occult sequelae of multiple sclerosis lesions occurring in the cortex or white matter may explain the large incidence of abnormal ERGs and VEPs found in group IlL The number of patients in this group is too small for statistical analysis. On the other hand, the number of abnormal cases seems too large to be simply a coincidence. This is all the more evident since similar pathological VEPs
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in patients with no evidence of visual pathway involvement at any time were also described by Richey et al. (1971). In this context it should be noted that the visual system is one of the longest cerebral pathways. Its chances of becoming involved in a case of multiple sclerosis may be considered to be great. It is known that numerous plaques can be found, even when there are few clinical findings (Alpers 1963 ; Grinker and Sahs 1966). The combined examination of the ERG and VEP, the latter elicited both by flash stimuli and probably even more so by patterned stimuli, may serve to detect even the presence of occult cerebral lesions involving the visual system, let alone lesions arising from previous or clinically overt disturbances. As for the retinal response, it is emphasized again that our findings do not suggest that enhancement or subnormality can be correlated either with the duration of the disease or with the presence of symptoms or their severity.
SUMMARY
Electroretinograms (ERG) and visual evoked potentials (VEP) were recorded from 35 patients suffering from multiple sclerosis. Of these, 18 suffered from visual deficits at the time of the examinations, 8 had had transient visual symptoms in the past and 9 had no visual symptoms at any time. In contrast to previous reports on cases of multiple sclerosis, enhanced retinal responses were found. Furthermore, there was no direct correlation between the severity of the visual deficit, the duration of the visual symptoms and the abnormality reflected by the ERG and VEP. The E R G and VEP were abnormal even in the absence of visual symptoms. Among the 35 patients examined 11 exhibited in 1 or in both eyes an enhanced b-wave of the ERG and 20 others displayed at least in 1 eye subnormal retinal responses: There were only 4 patients with normal ERGs in both eyes. However, the VEPs were nearly normal only in 1 patient of the 4. No matter whether or not vision was affected at the time of the examination, the averaged visual evoked potentials of nearly all patients examined were abnormal.
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