J. Neurol. 213, 17--32 (1976) © by Springer-Verlag 1976

Original Investigations Visual Pattern Evoked Responses and Blink Reflexes in Assessment of MS Diagnosis A Clinical Study of 135 Multiple Sclerosis Patients * K . L o w i t z s c h 1, U. K u h n t ~, Ch. S a k m a n n a, K . M a u r e r 1, H. C. H o p f ~, D. S c h o t t t, a n d K . T h ~ t e r 1 1Neurologisehe Universitiitsldinik GSttingen (Director: Prof. H. J. Bauer) 2Max-Planck-Institut ffir Biophysikalische Chemie, Abteilung ffir Neurobiologie (Director: Prof. O. Creutzfcldt) aUniversiti~ts-Augenklinik GSttingen (Director: Prof. W. Hallermann) Received March 11, 1976

~ummary. VEPs were measured after pattern reversal in 135 MS patients and 30 control subjects. Neurological findings were documented in a standard manner. An extensive ophthalmological examination of all subjects was part of the study. The latency of P2 was abnormally delayed in 82~/o of the "definite", in 60~o of the "probable" and in 65% of the "possible" MS groups respectively. The VEP was more often delayed in relation to ophthalmological disturbances. Changes in the MS classification had to be made in more than 10~o of the patients, due to delay of VEP latency. These were patients with a "spinal" form of MS, which is known to create diagnostic problems. Optically and electrically evoked blink reflexes were recorded in 107 MS patients. All patients with mesencephalic lesions had delayed responses of the optically evoked reflex. 74% of the patients with caudal brainstem lesions had delayed latencies of the components of the electrically evoked blink reflex. The blink reflex was delayed in 18 additional patients without brainstem signs. The possibility of delineating clinically silent brainstem lesions by investigating blink reflexes is discussed. _Key words: Multiple sclerosis - - Visual evoked potentials - - Blink reflex. Zusammen[aasung. Bei 135 MS-Patienten wurden visuell (,,Pattern reversal") evozierte corticale Potentiale (VEP) registriert. Der neurologische Befund wurde einheitlich dokumentiert. Patienten und Kontrollen wurden einer ausfiihrlichen ophthalmologischen Untersuchung unterzogen. Die Pa-Latenz des VEP war bei ,,eindeutiger" MS (n = 73) in 82~o (~ ~- 134 ± 36,1 ms), bei ,,wahrseheinlicher" MS (n ~ 42) in 60~/o (~ ----119,2 4- 20,4 ms) und bei ,,fraglicher" MS (n = 20) in 65~/o (~ = 117,6 4 - 1 7 , 4 ms) gegeniiber der Kontrollgruppe (n = 30; • -~ 104,8 4- 3,85 ms) eindeutig verz6gert. Im Vergleich zu den ophthalmologisch nachweisbaren St6rungen (ira Bereieh Visus: 24~/o, Farbsinn: 40~/o, Goldmann-Perimetrie: 44~/o, Friedmann-Analyse: 54~o, ,,partielle Opticusatrophie": 51%) lag die Verz6gerungsrate fiir das VEP mit 73% deutlich h6her, so daft in fiber 10~o eine Neuklassifiziernng der MSDiagnose notwendig wurde. Es handelt sich dabei vorwiegend um ,,spinale" Formen mit den bekannten differentialdiagnostischen Problemcn. Bei 107 MS-Patienten wurde zus~tzlich der optisch und elektrisch ansgel6ste B]in~reflex registriert. Dot optische Blint:reflex war bei Li~sionen des iHittelhirns in allen F~illen (n = 23), der elektrische Blinkreflex bei L~sionen des caudaleu Hirnstammes in 74% (n = 26) pathologisch verz6gert. Augcrdem fand sich bei 18 Patienten ohne klinische Ansfiille ein patho• Supported by the "Deutsche Forschungsgemeinschaft" (Dr. Fischer Bosch-Stiftung).

18

K. Lowitzsch et al.

logischer Blinkreflex. I)er Vorteil der Blinkreflexanalyse zum Nachweis ,,sLummer" Hirnstammherde und zur topographischen Differenzierung Mittelhirn--caudaler Hirnstamm wird diskutiert. Demyelinated plaques cause clinical symptoms in the visual system in 36--77 ~/o of patients (R. Mtiller, 1949; Carter et al., 1950; Abb et al., 1956; Kurtzke, 1970; Poser et al., 1973; Kuroiwa et al., 1975). A clinically apparent involvement of the brainstem has been found in 30---65~/o of MS patients (Kurtzke, 1970; McAlpine et al., 1972 ; Kahana et al., 1973). However, autopsy findings indicate a far higher rate for the visual system. For example, Lumsden (1970) reported on an autopsy series of 36 cases in which demyelinated plaques were found in the visual system without exception, whereas, in an earlier study Lehoczky (1954) saw involvement of the visual system in 55% of cases. Corresponding data for the brainstem area are not available. Neurophysiological methods have been developed to verify clinically latent visual defects. Low frequency light stimuli (up to 4/s), such as short flashes, induce cortical evoked potentials. The latency and form of these potentials lead to conclusions about the functional state of the visual system (Riehey et al., 1971). Another frequently used stimulus in the low frequency range is pattern reversal, introduced for clinical purposes by Regan and Heron (1970). High interand intrasubject stability of latency and form of the pattern-evoked response are found to be the main advantages in relation to flash-evoked responses (Halliday et al., 1972, 1973). Regan (1972) was able to demonstrate the usefulness of medium stimulus frequencies which lead to steady responses. Phase shifts and amplitude changes can be measured with this method and used as criteria for the functional state of the visual system. I t is not yet known how far these methods supplement one another and/or overlap. In addition to the neurophysiological investigation of the visual system, Kimura (1975) clearly showed in his work that exact latency measurements of the electrically induced blink reflex can give further information about the state of dissemination in MS patients. I f the latencies of the components of the electrically evoked blink reflex are abnormally long, involvement of the caudal brainstem in the disease has to be taken into account. A further possibility for a differentiation of the dissemination would be possible if the optically evoked blink reflex supplies us with as consistent data as does the electrically evoked reflex. Both reflexes use a common efferent pathway, whereas the afferent branches of the reflexes differ. There is some evidence that optic nerve fibres synapsing in the superior colliculus constitute one section of the afferent branch of the optical blink reflex, i.e. a mesencephalic station (Brodal, 1969). The sensory nucleus of the fifth cranial nerve, and therefore the caudal brainstem, represents the main station of the afferent branch of the electrically evoked blink reflex. Papers concerning the influence of MS on the visual system report similar conclusions but the data differ strikingly. The reasons for this may be due partly to minor differences in the techniques used but also to the restricted number of patients examined and to differences of clinical classification. Therefore we believe t h a t it is necessary to carry out a study on a larger, homogeneously documented group of MS patients, including electrically and optically evoked blink reflexes as well as visually evoked potentials. Our results support supplementation of the clinical criteria for MS classification with neurophysiological data.

Evoked Responses in Multiple Sclerosis

19

Patients 135 MS p a t i e n t s aged 1 5 - - 7 2 years (41 ~ 12 years) were e x a m i n e d . T h e case h i s t o r y a n d t h e clinical neurological d a t a h a v e b e e n listed i n two d o c u m e n t a t i o n sheets (Poser et al., 1973). T h e criteria devised b y B a u e r x (1972) served as a basis for a diagnostic classification. T h e group " d e f i n i t e " MS comprised 73 p a t i e n t s ; the group " p r o b a b l e " MS 42 p a t i e n t s a n d finally t h e group "possible" MS 20 patients. A n extensive ophthalmological e x a m i n a t i o n was performed i n a d d i t i o n to t h e clinical neurological e x a m i n a t i o n . This comprised a n assessment of subjective a n d objective vision (retinascopy), t h e visual fields ( G o l d m a n n p e r i m e t r y , F r i e d m a n n analyzer), colour s e n s i t i v i t y (Ishihara, Haitz), m o t i l i t y of t h e eyes (Lee screen), if i n d i c a t e d b i n o c u l a r s t a t u s (cover test), i n t r a o c u l a r pressure, refractive m e d i a (slit l a m p e x a m i n a t i o n ) a n d t h e f u n d u s (direct, i n d i r e c t o p h t h a l m o scopy a n d -photography). All p a t i e n t s a n d the control subjects were e x a m i n e d a t a p p r o x i m a t e l y t h e same t i m e of t h e d a y b y t h e same person (Chr. S.). P a t i e n t s with ophthalmological signs n o t connected w i t h MS have n o t b e e n i n c l u d e d i n this s t u d y (Glaucoma, r e t i n a l d e t a c h m e n t ) . The control group consisted of 30 clinically a n d ophthalmologieally n o r m a l subjects aged 21 t o 69 years (34 -t= 13 years).

Me~od Pattern-reversal was used as a stimulus to evoke visual evoked potentials (Cobb et al., 1967; HaUiday et al., 1972). A mirror system similar to that described by Halliday et al. (1973) was used to displace the checkerboard pattern. The pattern was changed every 614 ms and the mirror took 5 ms for one movement. Overswinging of the mirror was less than 5~. The subject (wearing spectacles if appropriate} was sitting comfortably in a darkened Faraday cage. The distance from the eyes to the projection screen was 145 cm. The field of vision stimulated was 30°, the single squares measuring 50r × 50t. The bright fields in the middle of the stimulated area had a luminosity of 55 cd/m s, the dark ones 5.5 cd/m s. ~rom this a brightness contrast of 0.90 may be calculated (Brown and Mueller, 1966). At the periphery of the stimulated field the luminosity decreased slightly. With the usual projection systems this cannot be avoided, but the contrast between bright and dark squares remained constant over the whole field. With a second lamp a fixation mark was projected in the middle of the stimulated area. The size of the fixation mark was 45 t and the luminosity 172 cd/m 2, if measured on a bright square. The EEG was recorded unipolarly over the occipital region, 5 cm above the inion in the midline. The combined ear electrodes served as reference. The resistance between skin and electrodes was always maintained below 10 KD. Silver chloride electrodes glued to the skin were used as active electrodes and silver chloride ear clips as reference electrodes. The EEG was amplified with a conventional EEG apparatus (Siemens 8 channel, Mingograf}. The time constant was set at 1.2 s, the frequency filter at 70 Hz. The amplified EEG signals were fed in a hardware averager (TSnnies, Freiburg), summated and stored. The analysis time for the VEP was set at 500 ms, giving an analysis interval of 0.5 ms. The averaged potential was photographed and latencies were determined later. The standard examination consisted of 4 sessions; each session comprised 128 stimuli. As a rule both eyes were stimulated first, then the left and then the right eye alone. After this a control session was performed in which the subject looked at the fixation mark, the checkerboard pattern being covered. Single sessions were repeated if the subject was too agitated or restless or if the components of the VEP were not unequivocal. The latency of the peak of the large positive wave (P2 according to Harding (1974)) was taken as a reference point (Fig. 1D). x See Appendix.

20

K. Lowitzsch et al.

C A

R

20

/,0

60

80

MS

D

8~0

2'o

~'o

..: ~o

8o

' MS'

Fig. 1. (A and B) Electrically evoked blink reflexes (control subject). Mean value and upper limit for normal values (Ra -t- 2 SD, R2 + 2 SD) indicated by the hatched area. Upper record: right side recorded; lower record:left side recorded. Filled arrows in (A) and (B): stimulated side. Rz: early homolateral component. R2: late, bilateral component. Time as indicated. (C) Optically evoked blink reflex. Mean value and upper limit for normal values (R ~- 2 SD) indicated by the hatched area. Arrow at the beginning: stimulated eye. Broken line: beginning of the reflex, measured latency. (D) Pattern evoked response after left eye (L.E.) and right eye (R.E.) stimulation. Stimulus onset (pattern reversal) indicated by the square wave below the record. Mean value and upper limit for normal values (I~2 + 2 SD) indicated by the hatched area. Broken lines: peak of P~. I n all records negativity upwards

Subjects adapted for 5 rain to a luminosity below 3 cd/m z before optical blink reflexes were elicited. Flashes, discharged by a stroboscope 30 cm in front of the eyes, were used as stimuli. The reflex was induced for each eye separately and for both eyes together. To avoid an interaction between the visual stimulus and the acoustic stimulus (click) due to the discharge of the lamp, subjects wore sound isolating earphones. The stimuli were triggered manually and there was a pause of at least 15 s before the following stimulus. The subjects looked at the flash lamp with open eyes. I f no reflex potential could be recorded, the subjects were asked to close the eyes slightly. For evaluation we always tried to register 5 clear responses. The evoked muscle activity was recorded with surface electrodes situated on the middle of the lower lid on both sides. The electrical signals were amplified and filtered (t.c. : 0.1 s, F = 1 KHz) with an E E G apparatus (Siemens 8 channel, Mingograf). The signals were then displayed on a storage oscillograph, photographed and the latency determined. As the

.s

Evoked Responses in Multiple Sclerosis

21

latency, the time between stimulus artefact and the beginning of the muscle mass potential (Fig. IC) was taken. The right and left supraorbital nerves were stimulated cathodically by means of bipolar surface electrodes. The stimulus duration was set at 0.1 ms; the stimulus strength was 2--4 times higher than the threshold. Amplification, registration and latency measurement for the first (homolateral) stimulus response R 1 and the bilateral response R 2 were performed in a manner similar to the optically evoked blink reflex (Fig. 1A and B).

Results

A. Control Subjects 1. Visual Evoked Response I t was possible to obtain visual evoked potentials (VEP) from all control subjects. The interindividual variability of the form of the V E P was high, but a positive wave with a peak latency around 100 ms could be recognized regularly. This positivity corresponds to P~ (Fig. 1D). With the experimental conditions described above a peak latency of 103.8 ± 4.3 ms was measured for the control group. This is the mean value from all VEPs derived by monocular stimulation, so that from each subject two latency measurements were used. Comparing the latencies of P~ after monocular stimulation in the same subject, a difference of 1.8 -~ 1.54 ms was obtained. I n our material there was a tendency for latencies to be slightly longer after stimulation of the right eye. A statistical test showed this difference to be not significant (P < 0.15). Probably the trend might be explained by the course of the experiment. As described in the methods, the right eye was always stimulated in the last session. Arrangement of the data, depending on age, shows an increase of the latency with increasing age. Here also, the age dependent changes proved to be not significant (P < 0.1) after statistical analysis. A separation of the patients into groups depending on age as well as on the side of the stimulus was discarded because of the small differences and the low significance level obtained. I n this investigation latencies of P2 and differences between right and left eye stimulation have been classified as abnormally delayed ff the 9 5 ~ confidence level for normal subjects (P~ ± 2 SD; L R ± 2 SD) was exceeded. A limiting value of 112 ms (Fig. 1D) was taken for the positive peak P2 and a limiting value of 5 ms for the right--left difference. 2. Optically Evoked Blink Reflex We tried to elicit the blink reflex 5 times monoeularly as well as binocularly. After dark adaptation, the flash was triggered first with open eyes. With most subjects and patients this was successful only two or three times. I f this failed, they were asked to close the eyes slightly. The manipulation very often led to a sufficient triggering of the reflex. The latencies did not change measurably under these conditions. The mean value was calculated from the single latencies of one subject. Since the number of stimuli was small, standard deviations have little value. Inspection of the records indicated a low intra-individual variability. The mean values and the standard deviations of the control group for the different stimulus conditions are recorded in Table 1. The difference of the latencies after

22

K. Lowitzsch et al.

Table 1. Lateneies (mean ~ 1 SD in ms) of the optically and electrically induced blink reflex in 30 control subjects. Number (N) of tested reflexes: 90 for the optic reflex (left eye, right eye, both eyes), 60 for the electric reflex (left and right side separately) Stimulated side

N

One side 60

Both sides

30

Optic blink reflex homolat, contralat, response response

Electric blink reflex early response R1 (diff. L/R)

52.32=}=4.08 52.13=f=4.01 11.65~1.4 response left

response right

52.1=1=4.6

53.5-4-4.8

0.6±0.7

late response homolat, eontralat. 35.5=[=3.5 36.2±3.6

left and right eye stimulation can be neglected, nor does a comparison between monocularly and binocularly derived reflex lateneies show a significant difference. As the upper normal limit the 95% confidence limit was determined (Fig. 1C), all monoeularly elicited reflex lateneies serving to calculate this value. This value is 62 ms. 3. Electrically Evoked Blink Reflex The latencies for the first component of the reflex R1, which occurs exclusively homolaterally, as well as the latency differences after stimulation of the right and left side, are given in Table 1. A consistent difference of side was not detected. I n the last two columns of Table 1 the bilaterally elicited responses R2 are registered. The component R~ recorded contralaterally to the stimulated side appeared later more often than on the homolateral side. The upper normal limit for the different components was determined as for the optically induced blink reflex. The value for R 1 is 14.5 ms and for R 2 44 ms. The mean values for the control group are higher than comparable values given in the literature (Namerow, 1973; Kimura, 1975), but it should also be pointed out that, in the papers cited, the values for the different components R1 and R 2 differ. These differences are of minor importance compared with the abnormally increased latencies of certain MS patients. The reliability of triggering the blink reflex electrically is evidently higher than with flash triggering. I t is assumed that for the electrically induced blink reflex the afferent branch of the reflex consists of fewer interconnected synapses than for the optically induced blink reflex, though up to now it has not been clearly proven that the fiber connections between the sensory part of the triteminus nucleus and the nucleus of the seventh cranial nerve represent one part of the reflex arc. Even more uncertainty exists about the afferent path of the optically induced blink reflex. One has to assume that the afferent path synapses in certain layers of the superior collieulus. Evidence exists as well for fibers originating in the superior colliculns and ending in the area of the nucleus of the seventh cranial nerve. Some layers of the superior eolliculus receive fibers from visual cortical areas, but nothing is known as to how far cortical activity influences the afferent part of the reflex arc.

Evoked Responses in Multiple Sclerosis

23

B. M S Patients 1. Visual Evoked Response In 131 of the 135 patients examined an evaluablo V E P could be recorded. I n 4 patients the amplitude-noise ratio was too bad to determine lateneies. The form of the recorded potentials changed strongly. Because of this variability it was often difficult to decide which of the positive waves is P~. The amplitude relations between the different components were less clear than in the control subjects and in some recordings new components were obtained or components dissociated, further confusing the situation. The critical VEPs have been categorized as abnormal only if the latency of P1 or the latency of the new positive component was longer than the limiting value of 112 ms for P~. Taking this into consideration, 98 patients had an abnormally delayed P~ latency. As described earlier, stimulation of left and right eye can lead to different latencies. This is confirmed in the present group of patients. An abno1~nal latency was found in 72 patients (73%) after stimulation of either eye. The remaining 26 patients (27°/O) showed an abnormal latency of P~ only after stimulation of one eye, whereas stimulation of the other eye led to latencies in the normal range. The longest P2 latencies measured were about 200 ms (Fig. 2}. I f one takes the clinical diagnostic criteria mentioned above as a basis for classification, the group "definite" MS shows, as expected, with 8 2 ~ abnormally delayed responses, the highest percentage (see Table 2 and Fig. 2). The mean value of this group is 134.0 4- 36.1 ms. The difference of the P~ lateneies after monocular stimulation comes to 13.4 ~= 13 ms. Both values lie far outside the upper normal limit. In the "probable" MS group 6 0 ~ show delayed responses and the mean value of the whole group is 119.2 ± 20.4 ms, whereas the difference between monocular stimulated responses increased to 8.3 4- 11.4 ms. Finally, in the "possible" MS group 65~o had delayed responses; the average of the group is 117.6 ± 17.4 ms and for the left--right difference, 15 ~ 15 ms. The values indicate that, with growing evidence for the diagnosis of MS and with a progression in the course of the disease, the latencies are increased more and more, pointing to an increased probability of involvement of the visual system. However, these are statements derived from statistical evaluations and they cannot replace careful inspection of the V E P from each single patient. The difference of the P~ latencies after monocular stimulation, in combination with the absolute lateneies, gives information about different involvement of both sides of the visual system. I n the present study we have not analyzed this aspect of the data intensively except under certain circumstances, i.e. if the latencies are not abnormally delayed but the difference is too large.

V E P and Opl~thalmolog~cal Findin~js. The diagram in Figure 3 shows the results of the ophthalmological examination and the respective amounts by which V E P responses were delayed (stippled area). The first column gives a summary of all patients examined. On the basis of their histories it was concluded that 95 patients suffered from visual disturbances either in the past or at the time of the examination (Column 2). The number with verified ophthalmological signs was slightly higher (Column 3). The results of single tests carried out during the ophthalmological examination are shown on the right side of Figure 3. The percentage of

24

K. Lowitzsch et al. 200 MS

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Fig. 2. P2 latencies of MS patients, separated according to clinical classification. Each triangle represents one measurement. Open triangle: latency longer than 200 ms. Hatched area: mean value ± 2 SD of the control group. Each patient is represented by two triangles (left a n d right eye stimulation), one patient had a glass eye. n: number of stimulated eyes in each group Table 2. Visual disturbances, optic atrophy and delayed VEPs according to the clinical classification; the number of patients is indicated in brackets Classification clinical signs

Number (patients)

Visual disturbances

Optic atrophy

Delayed VEP

Definite MS Probable MS PossibleMS

73 42 20

77~o (56) 62% (26) 65% (13)

62~/o (45) 38% (16) 40% (8)

82% (60) 60% (25) 65% (13)

70%

51%

73% (98)

Total

135

(95)

(69)

delayed P2 latencies in the groups varies between 92% in the group with visual a c u i t y deficits a n d 88 % in the group with deficits in Gold_mann perimetry. F r o m this diagram (Fig. 3) no conclusions regarding an interaction between individual ophthalmological defects and abnormal V E P latency can be drawn, since an individual patient m a y be represented more t h a n once. A few patients h a d only one pathological ophthalmological sign. The n u m b e r of patients with optic atrophy, based on the criteria of Ballantyne and Michelson (1970) as functional deficit in vision a n d field and possibly pallor of the disc, and the n u m b e r of delayed V E P s

Evoked Responses in Multiple Sclerosis

25

MS PATIENTS(n) -

150

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Fig. 3. Delayed visual evoked potentials L~ relation to ophthalmological signs. The columns show the number of patients with the indicated signs, stippled area indicates number of

patients with delayed responses

in this group are presented in the last column of Figure 3. 79 patients were thought to suffer from optic atrophy and 76 of these had delayed P2 values. The relation between vision, optic atrophy and V E P amongst the diagnostic groups is shown in Table 2. The correlation between delayed V E P and optic atrophy is nearly complete. Only 1 patient with optic atrophy had a normal VEP, but 16 patients of the "definite" MS group without optic atrophy displayed abnormal P~. latencies. The findings in the "probable" and "possible" MS groups are similar (Table 2). The ophthalmological assessment proved to be normal for both eyes in 33 patients, while in another 27 patients the tests showed pathological results for only one eye. Even so, 8 of the 33 patients had a delayed V E P after stimulation of either side and another 8 patients had delayed VEPs after stimulation of one side. Of the 27 patients l l had abnormally delayed P2 latencies if stimulated on the ophthalmologically intact side. 2. Blink Reflexes The optically and electrically evoked blink reflexes were studied in 107 patients. From this group 52 patients (49%) displayed an abnormally delayed optically evoked blink reflex and in 47 patients (44%) one or more components of the electrically evoked blink reflex were delayed. Both kinds of reflex triggering led to longer latencies in 37 patients than in the control group. Table 3 summarizes the results according to the different diagnostic groups. Similar to the results found with the V E P method, the participation in the "definite" MS group is highest; 65% of the patients of this group have abnormally delayed visual blink reflexes on one or both sides, and one or more components of the electrically evoked blink reflex are delayed in 60 ~/o- These percentages are lowered to 32 and

26

K. Lowitzseh et al.

Table 3. Optically and electrically evoked blink reflexes in 107 MS patients separated according to the clinical classification. R 1 early homolateral response, R 2 bilateral late response

Optically evoked blink reflex

Failure

Definite MS N~62 patients

Probable MS Possible MS N=31 N = 14 patients patients

Total N=107 patients

one side both sides no response

2 33 5

1 9 --

1 1 --

4 43 5

40 (65%)

10 (32%)

2 (14%)

52 (49%)

Total Electrically evoked blink reflex Total

R 1 one side both sides R 2 one side both sides

10 7 15 18

2 1 2 5

1 -1 1

13 8 18 24

37 (60%)

8 (26%)

2 (14%)

47 (44%)

2 6 % r e s p e c t i v e l y in t h e g r o u p " p r o b a b l e " MS a n d t o 14 a n d 14% in t h e g r o u p " p o s s i b l e " MS (Table 3). A p a r t from d i v i d i n g t h e p a t i e n t s w i t h r e g a r d t o diagnostic groups of MS it seems m o r e i m p o r t a n t t o r e l a t e t h e results o f t h e reflex m e a s u r e m e n t s to topog r a p h i c a l a r e a s o f t h e b r a i n s t e m lesions. A s u r v e y , including t h e s e v e r i t y o f t h e delay, is given in t h e h i s t o g r a m of F i g u r e 4. Latencies o f all p a t i e n t s suffering from m e s e n c e p h a l i c d i s t u r b a n c e s are pooled in t h e first column. These include p a t i e n t s w i t h d i s t u r b a n c e s o f t h e t h i r d a n d f o u r t h cranial nerves, p a r a l y s i s o f v e r t i c a l gaze a n d e x t r a p y r a m i d M d i s t u r b a n c e s , m o s t l y c o m b i n e d w i t h long t r a c t signs. All p a t i e n t s w i t h such s y m p t o m s h a d a b n o r m a l l y d e l a y e d o p t i c b l i n k reflexes or even a loss of t h e m (Fig. 4). I n 5 p a t i e n t s of t h i s g r o u p one or m o r e c o m p o n e n t s o f t h e electrically e v o k e d b l i n k reflexes were d e l a y e d as well. This finding is i n t e r p r e t e d b y K i m u r a (1975) as being due t o a lesion in t h e c a u d a l b r a i n s t e m , which is clinically silent. I n t h e t h i r d column latencies are registered from p a t i e n t s w i t h clinical signs i n d i c a t i n g lesions in t h e pons or in t h e o b l o n g a t a . I t includes d i s t u r b a n c e s of t h e fifth, sixth, s e v e n t h a n d t w e l f t h cranial nerves, i n t e r n u c l e a r o p h t h a l m o p l e g i a , p a r a l y s i s o f h o r i z o n t a l gaze, s t r o n g dissociated or p e n d u l a r n y s t a g m u s , c e n t r a l H o m e r s y n d r o m e , as well as b u l b a r d y s p h a g i a a n d d y s a r t h r i a . These signs were often c o m b i n e d w i t h d i s t u r b a n c e s o f t h e long t r a c t s . D e l a y s of b o t h k i n d s o f reflexes h a v e been r e c o r d e d in these p a t i e n t s . I n a d d i t i o n t o t h e 21 p a t i e n t s showing d e l a y e d reflexes or reflex components, 5 p a t i e n t s w i t h

Fig. 4. Latency histogram for some components of optically and electrically evoked blink reflexes in 107 MS patients, related to brainstem signs. Upper part: optically evoked blink reflex. Lower part: electrically evoked blink reflex. • Contralateral recorded reflex latencies. A Homolateral recorded reflex latencies. • No response of one side. Hatched areas: mean values :]: 2 standard deviations of the different components of control subjects. Broken line in lower part: limit between early and late response. The different columns show the reflex responses of patients with the indicated clinical brainstem signs. Further explanation see text

LATENCY

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28

K. Lowitzsch et al. MS

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LATENCY OF THE OPTIC BLINK REFLEX

Fig. 5. Correlation between P~ latency and latency of the optic blink reflex. Ordinate: latency of P2. Abscissa: latency of the optic blink reflex. Hatched areas: mean values ± 2 SD of the control group clear clinical signs had normal reflex latencies. I t should be mentioned in this context t h a t differences between sides have not been evaluated. Therefore this nmnber might be lower ff side differences were included. The second column contains the latencies of the 9 patients with combined mesencephalie and pontomedullary signs. All of them had delayed responses for both reflexes. Finally, 58 patients did not show any brainstem signs, although some of t h e m had pronounced long tract signs, either spastic para- or tetraplegia, which theoretically can be caused b y brainstem lesions. 18 patients of this group had delayed blink reflexes, as shown in the right hand column of Figure 4. I n 6 patients only components of the electrically evoked reflex were delayed; in 4 patients the optically evoked reflex was disturbed. The latencies from both reflexes were delayed in a further 8 patients. I t is assumed t h a t these patients have clinically silent lesions in the mesencephalon, and/or the pons and oblongata. The patients with disturbed optically evoked blink reflexes are presumed to have mesencephalic lesions. The disturbed electrically evoked blink reflexes point to lower brainstem lesions. Combined lesions or lesions in the lower brainstem have to be assumed for the patients with disturbances of both reflexes. Discussion I n the MS group studied we found significantly delayed V E P latencies in 73 ~/o of the patients. This value corresponds remarkably well with the results reported

Evoked Responses in Multiple Sclerosis h/S-PATIENTS {n) 80

29

DIAGNOSTIC CRITERIA: CLINICAL &CSFDATA

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Fig. 6. Comparison between the classification according to clinical criteria and to clinical criteria including delayed VEPs. The arrows indicate the number of patients who had to be reclassified due to abnormal VEP latency

b y Asselman et al. (1975), who found 67% with delayed responses. On the other hand, Halliday et al. (1973) found a delayed response in 96% of patients. The group examined b y Halliday et al. (1973) is comparable in number and classification to the group studied b y Asselman et al. (1975) but differences exist in the techniques used and in the determination of the upper limit of normal values. Since, for classification, we combined the McAlpine criteria with findings of CSF, the diagnostic criteria in our group are stricter. We assume t h a t this should have little effect on the group of MS patients as a whole and the "definite" MS group should not be modified b y applying CSF findings as well. This indicates t h a t the criteria used for classification cannot alone explain the differences of the results. Slight differences in the technique are unavoidable. We tried to set up a technique similar to t h a t described b y t t a l h d a y et al. (1973). Regarding the control values, this was satisfactory in spite of differences of luminosity. A comparison of the contrasts used shows negligible differences. I t is known t h a t contrast is more important t h a n luminosity as long as one does not shift to the scotopie range. More important, in our opinion, is the relatively small number in the sub-groups. As long as only 6 and 5 patients ("probable" MS) or 14 and 20 patients ("possible" MS) are concerned, predictions from statistical evaluations cannot be made. I n all three studies the "definite" MS patients show the largest latency delays and the largest differences between left and right eye stimulation. At the same time nearly all patients in this category have abnormal latencies, independent of ophthalmological signs. E v e n if the V E P is not important for the classification "definite" MS, it is important to know the degree of dissemination. I n our view, delayed responses facilitate a decision for a classification of "probable" versus "possible". The V E P proved to be more sensitive and therefore more powerful

30

K. Lowitzsch et al.

than a very careful ophthalmological and neurological examination as far as the visual system is concerned. Since all reports point to the high reliability and power of the pattern reversal test, this should be considered as a criterion in MS classification. The main criteria for a classification of MS are the clinical course, dissemination and CSF 2. The degree of dissemination plays an important role for diagnosis as "probable" or "possible" MS. Figure 6 shows that, taking the delayed responses into account, and after critical analysis of the data of each patient, 9 patients of the "possible" group should be included in the "probable" group and from this group 5 patients should be transferred to the "definite" group. All these patients proved to have the "spinal" form and there were neither history nor clinical signs pointing to a participation of the optic nerves. However, not only does MS alone lead to a latency increase of VEPs, but also certain ophthalmological disturbances (Asselmann et al., 1975; Cappin et al., 1975), storage diseases (unpublished findings in adult metachromatic leukodystrophia), cerebral vascular lesions (Bayliss et al., 1975), tumors as well as granulomatosis and local inflammatory lesions of the anterior and middle cranial fossa, if chiasm or optic nerve are involved (Asselmann et al., 1975). Lesions of the optic tracts and the radiation of Gratiolet seem to be rare (Hawkins et al., 1975). They produce hemianopie disturbances of the visual field and the macula is usually only partly involved. Milner et al. (1972) in their investigation showed that latency results mainly from the fovca and therefore does not change with these disturbances. Before drawing conclusions due to latency delays, these other disturbances have to be excluded or taken into consideration. Optic neuritis causes permanent delays of the VEP, even ff the attack occurred some years previously (30 years, unpublished observations) (Halliday et al., 1973; Milner et al., 1974; Asselmann et al., 1975). A permanent latency delay therefore suggests a lesion of the optic nerve. The high reliability of the latency delays related to an acute or an old attack of optic neuritis, independent of verified visual disturbances and independent of the time, makes the VEP method important, especially if it is used in the early course of MS or if it is a brainstem or spinal form of MS. In our group this method clarified the diagnosis in more than 10% of the patients. Recently Kimura (1975) demonstrated the diagnostic value of the electrically evoked blink reflex. The abnormal reflex verifies lesions in the caudal brainstem, even if clinical methods fail. We expected a similar diagnostic value for the mesencephalic level from the optically induced blink reflex. The results supported this expectation: all patients with mesencephalic signs displayed a delayed optically evoked blink reflex. Only a few of them showed a simultaneously delayed latency if stimulated electrically. Contrary to this, three quarters of the patients with caudal brainstem signs had delays of the electrically evoked blink reflex. These relationships cannot be pushed too far since there is no way of telling in how many patients we derived normal values in spite of lesions and furthermore we do not have any indication of the spread of the lesions. The pathways of both reflexes are only partly known and there is still discussion about the late components of the electrically evoked reflex and about higher centers of the brain controlling these late components and the optically induced reflex, i.e. lesions of higher centers may also influence the latencies. See Appendix.

Evoked Responses in Multiple Sclerosis

31

I n 26 p a t i e n t s w i t h o u t mesencephalic signs a n d n o r m a l b l i n k reflexes t h e V E P was c o n s i d e r a b l y d e l a y e d (see h i s t o g r a m ) . Lesions in t h e optic n e r v e influence p r i m a r i l y fibers w i t h t h i c k e r m y e l i n shears. I t s t h i n fibers m a y well form a m a j o r p a r t of t h e afferent p a t h w a y o f t h e o p t i c a l l y e v o k e d b l i n k reflex. I n c a t a n d m o n k e y i t h a s been shown t h a t t h i n fibers r u n p r i m a r i l y t o t h e s u p e r i o r collieulus. This histological r e s u l t a n d o u r n e u r o p h y s i o l o g i c a l results fit well a n d s u p p o r t t h e h y p o t h e s i s t h a t t h e s u p e r i o r colliculus is a m a i n s t a t i o n for t h e o p t i c b l i n k reflex. T h e efferent p a t h o f b o t h reflexes is t h e s a m e a n d i m p e d e s l o c a l i z a t i o n o f t h e lesion. A m o r e i n t e n s i v e discussion o f t h e d i a g n o s t i c v a l u e o f b o t h reflexes a n d t h e p o s s i b i l i t y of d e l i n e a t i n g lesions w i t h t h e b l i n k reflexes will a p p e a r elsewhere.

Appendix C l i n i c a l Classification

I. " D e f i n i t e " A. Cases with bouts and remissions with at least two relapses. Cases with insidiously progressive onset: symptoms present for at least 1 year. B. Disseminated symptomatology. C. Characteristic CSF alterations: mononuclear pleoeytosis of up to 50 cells/mm3 (150/3 cells). Normal or slightly increased protein content (not 100 mg~o). Abnormal colloid curve. Gammaglobulin (JgG). II. "Probable" At least two of the criteria mentioned above must be present (A -~ B, B ~- C, A + C). I n cases with acute onset: IB and C definitely present, persistence of CSF alterations after disappearance of relapse symptoms. I ~ cases with insidious onset: IB and C definitely present, continuous progression of the disease for at least ~ year, persistence of typical CSF alterations. III. "Possible" No definite evidence to support an alternative diagnosis. Course and symptoms (IB and C), however, not sufficiently typical for MS. (Monosymptomatic retrobulbar neuritis is classified in this group.)

References

Abb, L., Sehaltenbrand, G. : Statistisehe Untersuehungen zum Problem der Multiplen Sklerose. II. Mitteilung. Dtseh. Z. Nervenheilk. 174, 199--218 (1956) Asselmann, P., Chadwick, D. W., Marsden, C. D.: Visual evoked responses in the diagnosis and management of patients suspected of multiple sclerosis. Brain 98, 261--282 (1975) Ballantyne, A. J., Miehaelson, J. C.: Textbook of the fundus of the eye, p. 671, E. & S. Livingstone 1970 Bauer, H. J.: Communication to: Judgement of the validity of a clinical MS-diagnosis. In: The International Symposium on Multiple Sclerosis, G6teborg 1972. Acta neurol, scand., Suppl. 58, Vol. 50 (1974) Bayliss, S. G., Simpson, C., Wright, E. A. : Visual evoked potentials and transient ischaemie attacks. Brit. med. J. 1975 I, 396--397 Brodal, A.: Neurological anatomy in relation to clinical medicine, 2nd ed. London: Oxford Univ. Press 1969 Brown, J. L., Mueller, C. G. : Brightness discrimination and brightness contrast. In: Vision and visual perception (eds. C. L. Graham et al.), pp. 208---250. New York: John Wiley 1966

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Cappin, J. M., Nissim, S.: Visual responses in the assessment of field defects in glaucoma. Arch. Ophthal. 93, 9--18 (1975) Carter, S., Sciarra, D., Merrit, H. H. : The course of multiple sclerosis as determined by autopsy proven cases. Proc. Ass. Res. Nerv. Ment. Dis. 28, 471--511 (1950) Cobb, W. A., Morton, H. B., Ettlinger, G. : Cerebral potentials evoked by pattern reversal and their suppression in visual rivalry. Nature (Lond.) 216, 1123--1125 (1967) Halliday, A. M., McDonald, W. I., Mushin, J. : Delayed visual evoked response in optic neuritis. Lancet 1972 I, 982--985 Halliday, A. M., McDonald, W. I., Mushin, J.: Visual evoked response in diagnosis of multiple sclerosis. Brit. med. J. 1973 IV, 661--664 Harding, G. F. A.: The visual evoked response. Adv. Ophthal., Vol. 28, pp. 2--28. Basel: Karger 1974 Hawkins, K., Behrens, M. M.: Homonymous hemianopia in multiple sclerosis, with report of bilateral case. Brit. J. Ophthal. 59, 334--337 (1975) Kahana, E., Leibowitz, U., Alter, M.: Brainstem and cranial nerve involvement in multiple sclerosis. Acta neurol, scand. 49, 269--279 (1973) Kimura, J. : Electrically elicited blink reflex in diagnosis of multiple sclerosis. Review of 260 patients over a seven-year period. Brain 98, 413--426 (1975) Kuroiwa, Y., Igata, A., Itahara, K., Koshijima, S., Tsubaki, T., Toyokura, Y., Shibasaki, H. : Nationwide survey of multiple sclerosis in Japan. Neurology 25, 845--851 (1975) Kurtzke, J. F. : Clinical manifestations of multiple sclerosis. In: Handbook of clinical neurology (eds. P. J. Vinken, G. W. Bruyn), Vol. 9, pp. 161--216. Amsterdam: North-Holland Publ. Co.; New York: American Elsevier 1970 Lehoczky, T.: Pathologic changes in the optic system in disseminated sclerosis. Acta morph. hung. 4, 395 (1954) Lumsden, C. E.: The neuropathology of multiple sclerosis. In: Handbook of clinical neurology (eds. P. J. Vinken, G. W. Bruyn), Vol. 9, pp. 217--309. Amsterdam: North-Holland Publ. Co. ; New York: American Elsevier 1970 MeAlpine, D., Lumsden, Ch.E., Acheson, E. D. : Multiple sclerosis. A reappraisal, 2nd ed. Edinburgh-London: Churchill Livingstone 1972 Milner, B. A., Regan, D., Heron, J. R.: Theoretical models of the generation of steady-state evoked potentials, their relation to neuroanatomy and their relevance to certain clinical problems. Advane. exp. Med. Biol. 24, 157--169 (1972) Milner, B. A., Regan, D., Heron, J. R. : Differential diagnosis of multiple sclerosis by visual evoked potential recording. Brain 97, 755---772 (1974) Mfiller, R.: Studies on disseminated sclerosis. With special reference to symptomatology, course and prognosis. Acta reed. scand., Suppl. 222, 1--214 (1949) Namerow, N. S. : Observations of the blink reflex in multiple sclerosis. In: New developments in eleetromyography and clinical neurophysiology (ed. J. E. Desmadt), Vol. 3, pp. 692--696. Basel: Karger 1973 Poser, S., Hauptvogel, H. : Clinical data from 418 MS patients in relation to the diagnosis. Acta neurol, scand. 49, 473--479 (1973) Poser, S., Hauptvogel, H., Bauer, H. J. : Methodik der maschinellen Erfassung yon Daten bei einer multizentrischen Studie fiber die Multiple Sklerose. Z. Neurol. 204, 301--308 (1973) Regan, D. : Evoked potentials in psychology, sensory physiology and clinical medicine. London: Chapman and Hall 1972 Regan, D., Heron, J. R. : In: Background to migraine. London: Heinemann 1970 Richey, E. T., Kooi, K. A., Tourtelotte, W. W. : Visually evoked responses in multiple sclerosis. J. Neurol. Neurosurg. Psychiat. 34, 275--280 (1971) Dr. U. Kuhnt Max-Planek-Institut ffir Biophysikalische Chemic Abteilung ffir Neurobiologie Postfach 698 D-3400 C~ttingen Federal Republic of Germany