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Somatosensory response to stimulus trains in patients with multiple sclerosis
Electroencephalography and Chmcal Neurophysiology, 1974, 3 7 23 33 Elsevier Scientific Pubhshmg Company, Amsterdam -- Printed m The Netherlands
23
S O M A T O S E N S O R Y R E S P O N S E TO S T I M U L U S T R A I N S IN P A T I E N T S W I T H M U L T I P L E SCLEROSIS 1 ROBERT
J. SCLABASSI, NORMAN S. NAMEROW AND NELSON F. ENNS
Department o/ NeuHdoql'. School o/" Medicine, Llnwer~'ttv o/Califorma
Lo,~ Angele,~, Los Angeles, Calt]. 90024 ( L1.S A. )
(Acceptlon for pubhcation December 28, 1973)
Multiple sclerosis (MS) is a disease, unique to the human, that affects the brain and spinal cord. The underlying pathophysiological mechanism appears to be blocked or impaired neuronal conduction across demyelinated areas of the central nervous system (CNS). To assess neuronal conduction in this disease one must rely on indirect measures such as the use of evoked cortical activity following peripheral stimulation. Investigations utilizing both the visual and somatosensory evoked response (VER and SER) have been pursued with some success (Baker et al. 1966; Namerow 1968 a, b; Richey et al. 1971: Namerow and Enns 1972). While these studies have demonstrated alteration of the evoked response waveform as a function of the patient's impairment of vision and proprioception, several shortcomings have become apparent. Accurate latency determination was at times difficult and in some patients wave peaks were poorly defined or missing, leading to problems in quantification. These considerations led us to the development of the somatosensory evoked response to trains of stimuli (SERT), an experimental approach outlined in detail in the preceding paper (Namerow et al. 1974). The present paper examines the characteristics of the SERT in MS patients, and analyzes the differences in this experimental response between patients and normal subjects. In particular, the SERT, filtered SERT, and single cycle average are described for the patient group. In addition, ~This research is supported by National Multiple Sclerosis Grant 516-C-3 and U.S. Health Service Grants NS08711 and NS02501 Computing assistance was obtained from the Health Science Computing Facility, UCLA, sponsored by NIH Special Resources Grant FR-3
the patient average peak-to-peak voltage and phase angle measurements which characterize the single cycle average are compared to those from normal subjects. These values are then used to characterize quantitatively the differences between the two experimental groups. METHOD
Experimental The experimental techniques, including scalp electrode placement, patient positioning, method of peripheral nerve stimulation, stimulation parameters, and data recording and reduction methods are identical to those described in the previous report. However, a reduced set of stimulating frequencies, consisting of 40, 60, 80, 100 and 160 Hz were utilized in this study. Subjects Thirty-three patients, ranging in age from 21 to 56 years with a mean of 37 years, were selected for study from the MS clinic at the UCLA School of Medicine. The approximate mean duration of illness in these patients was estimated at 9 years, during which time they were followed in the clinic for an average of 3 years. Several additional subjects were studied. One, a 21-year-old male (MS 059) presented with a 7 month history of extremely mild MS symptoms. Six MS patients were evaluated who gave no history of sensory impairment in the pathways under study and who on several physical examinations showed no sensory deficits. The clinical status of each patient was determined by the usual neurological examination. Clinical assessment of vibration perception
24
R.J. SCLABASSIel et]
was determined by using a standard 128 Hz tuning fork, and position sense by the patient's ability to perceive fine passive movements of the distal phalanx of the finger. The patient's hands were categorized into three groups according to the clinical sensory examination at the time of study. Hands placed in Group I (MS I) demonstrated no vibration or position sense impairment at the time of testing. Group II (MS II) included hands that demonstrated mild to moderate vibration and/or position sense impairment, while Group III (MS III) consisted of hands that revealed severe vibration and/or position perception deficits on clinical testing. The control group included a total of 29 hands from 18 subjects. Each control subject gave a history negative for significant neurological disease and each had an unremarkable neurological examination. The control subjects ranged in age from 24 to 46 years with a mean of 32 years. Analytical
Peak-to-peak amplitude and phase angle measurements were obtained for all subjects at each stimulating frequency, and then differentially analyzed using techniques of multivariate SINGLE STIMULUS
statistical analysis, In particular, the analytical problem was formulated as that of classifying the observed set of data from an experimental subject into one of two populations, normal or MS. The objectives of this approach were twofold. First, we wished to obtain a single number for each subject which summarized the relationship of that particular subject's response to both groups. Second. we desired to make meaningful probabilistic statements concerning the degree of clinical deficits and group classification from a subject's response. Two groups, one representing the normal population in the large (GN)and the other the MS population in the large (GMs), were constructed using the data obtained from seventeen normal subjects and seventeen MS patients. The group of MS subjects was designed to represent a cross-section of observed clinical deficits and contained four subjects from the MS I group, seven subjects from the MS II group, and six subjects from the MS III group. Two complementary approaches were utilized to achieve the desired objectives. One of these, Fisher's linear discriminant analysis (Fisher 1936: Morrison 1967) provides a linear function of the observed data which assigns to
TRAIN--IOOHZ
FILTERED TRAIN
NORM ~AL
--T.A,N
T
OFF
Fig. 1. Upper sertes" A single stimulus SER from a normal subject (N 050) followed by the same subject's SERT at 100 Hz, and, m the last column, the filtered SERT for 64 presentations of the stimulus train. L o w e r serte~s. Data from a paUent (MS 118) with moderate symptoms. The first response is the SER in a single stimulus The middle response Is to a train of" stimuli at 100 Hz. The lack of cortical activity at this frequency is evident. This is further demonstrated in the last column where the filtered S E R T shows virtually no 100 Hz activity.
SOMATOSENSORY RESPONSE IN MS
each subject a single number (Z-score) in such a way as to enhance the physiological differences between the normal and MS populations. The second procedure utilized was a stepwise Bayesian procedure (Anderson 1958: Dixon 1973) with the assumptions of equal costs of misclassification and equal apriori probabilities that the indiwdual comes from either the normal or the MS group. This procedure permits the conditional probability PIGMs;.'v~,, that the subject comes from the MS group given his observed data, to be calculated RESU1.FS
SERT and filtered S E R T A typical single stimulus evoked response (SER) obtained from a normal subject (N 050) is shown in Fig. l. This same subject's SERT and filtered SERT, for a stimulating frequency of 100 Hz, are shown to the right of the SER. In MSI
25
contrast, the SER from a patient (MS 118) with moderate vibration and position sense loss is shown in the bottom row of Fig. 1. The absence of the initial negative peak is quite prominent as is the marked delay in both the onset of the response and the peak of the major positive wave. This same patient, when stimulated with a train frequency of 100 Hz, produced virtually the same response as for the single stimulus. There is an apparent inability for this patient to respond to these rapidly occurring peripheral stimulations and to produce the characteristic rhythmical activity seen in normal subjects. In the filtered SERT the effect is even more dramatic and essentially no response is noted. This particular patient did demonstrate a discernible rhythmical response in the SERT at lower stimulating frequencies. The ability of the afferent pathways and cortex to transmit and process volleys of impulses produced by stimulating trains of successively MS .E
M S .I~
,' ',,
SER I,;
SERT ,¢oH~
~L,, /
V
!"
SER T tooH~
~ '~
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i
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~ 2juV ~"
FJg 2. The SER and SERTs at 40 and 100 Hz are shown for three subjects drawn from the MS I (MS 033). MS II (MS I I0). and MS II1 (MS 039) groups respectively The abihty of the afferent pathways to transmit stimulating trams is a function of stmlulatmg frequency and the degree of underlying pathology Patients m the MS I group tend to show actlvlt~ for stHnulatmg frequencies above 100 Hz, those m the MS It group tend to have decreased activity at 100 Hz, as compared to the first group, while patients m the MS I11 group tend to show decreased actwity at all stimulating frequencw~
26
R, h SCI.ABASSIel a/.
higher frequencies appears to be closely correlated to the degree of clinical sensory impairment. 1 2.0. That is, the more pronounced the subject's clini/'1\ p/ / / " Jcal deficits the lower the stimulating frequency at 5 which the SERT ceases to demonstrate the 1.5anticipated periodic response. This concept is demonstrated in Fig. 2, which shows the SER "r .N. o t.o. and SERT responses at stimulating frequencies I-.D,. of 40 and 100 Hz for a subject taken from each of ov • .50. the three MS groups. The subject drawn from the ~.~ MS MS I group (MS 033) at the time of testing demonstrated no observable clinical deficits. His O.O 20 4'o 6'0 io ,;o ,io ,;.o ,;o SER was essentially normal in configuration. STIMULATING FREQUENCY (Hz) The SERT at both stimulating frequencies deFig 3 The average peak-to-peak voltage amphtudes for the monstrated a near normal rhythmic pattern. The peak-to-peak voltage amplitudes as measured baszc normal and MS groups of seventeen subjects each The bars indicate plus or minus one standard error The stimulatfrom the filtered single cycle average were 1.80 ing frequencnes used were 40, 61). 80, 100 and 160 H7 yV at 40 Hz and 1.18 pV at 100 Hz. This is in comparison to normal mean averages of 1.63 cycle peak-to-peak amplitude as a function of and 1.37 yV respectively. The subject drawn stimulating frequency for both the MS patients from the MS lI group (MS 110) at the time of and the normal subjects are presented in Fig. 3. testing demonstrated mild sensory loss. This Both groups show a significant decrease in this patient's SER also appears relatively normal, measure with increasing stimulating frequency: The rhythmical activity produced by the stimulat- however, there are significant amplitude difing train at 40 Hz has a deteriorated quality ferences between the two groups at all stimulating to its appearance, but has a filtered single cycle frequencies. The prominent amplitude peaking average amplitude of normal magnitude (1.65 present in the normal group at 60 Hz is not pre/~V). At a stimulating frequency of 100 Hz, sent in the patient data. The amplitude coefficients however, the periodic component of the response of variation were also investigated. The relative has essentially disappeared with a filtered single dispersion for the MS group as compared to the cycle average amplitude of 0.23 yV. In addition normal group is approximately twice as great at the SERT response is similar in appearance to all stimulating frequencies except 40 Hz, indicatthe SER. The subject from the MS III group (MS ing that the inter-individual variations in this 039), had severe deficits in vibration and posi- measure tend to be greater for the MS patients as tion sense at the time of testing. This patient a group than for the normal subjects. This could showed little evidence of a periodic component al be indicative of the wide range of functional imthe two stimulating frequencies or for that matter pairment in patients with this disease. at any stimulating frequency. The steady-state The mean phase angles, at all stimulating amplitudes, as estimated by the filtered single cy- frequencies, are given in Fig. 4. The phase angles cle average, were reduced to 0.25 /tV at 40 Hz tend to be distributed in similar fashion for the and 0,13 pV at 100 Hz, The SER for this patient two groups with one qualitative difference. The is also abnormal in appearance with marked maximum change in phase angle, which occurs changes in both latencies and composition of the for both groups between 60 and 80 Hz, is almost component waves. twice as great for the normal group as it is for the MS group. The coefficient of variation beSimjle cycle average haved almost identically for the two groups, The peak-to-peak amplitude and phase angle except at 160 Hz where the normal group displays measurements characterizing the single cycle 60°° more relative variability. The inter-indiaverage were investigated for the various stimu- vidual variability of the phase angle data for the lating frequencies. The mean values of the single MS group is essentially constant.
§
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27
SOMATOSENSORY RESPONSE IN MS TABLE 1
T
o,.0 -
1:---'-''~ °
~
3.0.
i
Ix~t~T
I
"~
MS
T.
\/
'"
Correct classification of test cases based on successwe variables as designated by the stepwise discrimlnant analysis procedure A summarizes the results for the first five variables picked when all ten variables are included. B is the change when the variables are restricted to amplitudes only Variables included
I0.
"o Cases correctly classified
D
d!
f
vtoo 82.5 Vtoo, V~,o 88.0 vao, v~oo, V~6o 91.5 V4o, v(,O. Vl0 O, v160 ]00.0 v~o,v~,o.~p~o,v~oo,vt~ n 100.0
5.45 8 30 9.80 19.30 2078
1,32 2, 31 3, 30 4, 29 5. 28
46 14 34.06 25.93 37.15 3084
v-~o, V6o, vso, V~o0, V16o 100.0
20.40 5, 28
v
2O
40
60
80
STIMULATING
I00
120
140
160
A
FREQUENCY (Hz)
Fig. 4 The average phase angle (in radmns) plus or minus one slandard error for the seventeen subject MS and normal groups as a function of stimulating frequency. There is no sigmficant difference m phase angles between the two groups.
A one-way analysis of variance was performed between the two groups for each of the ten variables to test the null hypothesis that the population means are identical. The null hypothesis was rejected at a 1°,5 significance level for all values of peak-to-peak amplitude, while it was not rejected at this same significance level for any of the phase angles.
Differential analysis Two basic groups of seventeen normal subjects and seventeen MS patients were used as training groups to construct a discriminant function. Originally, all 10 variables (i.e., an amplitude and phase angle at each of the five stimulating frequencies) were included in the analysis. The results of the first five iterations of the stepwise procedures utilized are summarized in Table 1A. The variable providing the most discriminating power is the peak-to-peak voltage amplitude at a stimulating frequency of 100 Hz, for which 82.5 o,, of the training subjects were correctly classified. By the fourth iteration the discriminant function included the voltage variables at stimulating frequencies of 40, 60, 100 and 160 Hz, with 100°o of the training subjects correctly classified. At the fifth iteration the phase angle at 80 Hz was included but with negligible improvement in the separation between the two groups as measured by the Mahalanobis distance squared. The effect of excluding the phase angles from the calculations is demonstrated in Table IB, where the change in the results of the fifth iteration due to replacing q~8o with Vso is noted. This change is
30.26
* D is the Mahalanobis distance squared between the normal and the MS groups calculated for the included variables d.f. is the degrees of freedom F is a test stahstic testing the difference between groups as measured by the Mahalanobls distance
minimal, and for this reason it was decided to utilize only the filtered single cycle peak-to-peak voltage amplitudes as the discriminant variables. In order to assess the reliability of this classification procedure, a testing group of 27 "unknown" subjects was constructed. This "unknown" group contained eleven normal subjects and sixteen MS patients. All subjects in this group were correctly classified using the derived discriminant function. The results of this analysis, for both the total normal group (including both training and testing subjects) and the total MS group, in terms of Z-score distributions are summarized in Fig. 5, a. The 28 normal hands had an average Zscore of 0.87 and a standard deviation of 0.12, while the thirty-three subjects in the total MS group had an average Z-score of 0.18 with a standard deviation of 0.16. The decision line separating the two groups was Z=0.52, corresponding to an a posteriori probability of 0.5 (Fig. 5, b). The distribution of filtered single cycle average amplitudes, as a function of the clinical assessment of sensory loss, was also of interest. The average
28
R . J . SC1.ABASSI e l it/.
7. TOTAL
"~'ms = IS
6.
MS
GROUP
4. 3. 2.
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o
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.3
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NORMAL ~n
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20.
i I-1
.3 .4 .5 .6 .7 8 Z (TEST STATISTIC)
i
9
1
I0 II
12
respect to the subgroups classified on the basis of severity of clinical signs. Thus the MS I group tends to have greater amplitude values at each stimulating frequency than does the MS II group, and the MS II group has greater amplitude values than does the MS IIl group. The amplitude coefficient of variation does not display as consistent a pattern of change as the average amplitudes. The MS II group shows greater inter-individual variability with respect to the MS I group, while the MS III group displays less inter-individual variability. The distributions of Z-scores were also investigated and found to behave in a manner consistent with the degree of clinical signs. The MS I group has an average Z-score of 0.22 with a standard deviation of 0.19. the MS II group has an average Z-score of0.15 with a standard deviation of0.13, while the MS III group has an average Z-score of 0.I 2 with a standard deviation of 0.14 (Fig. 7).
Additional subjects • e-o-e
o-eoo-o-
e-e~
\ \1•
I
1. II ~ ,
Seven additional MS patients were investigated. Six of these were patients whose medical histories indicated that none had experienced
!
v
r-,.oo '¢ . 7 5 ,
Z (TEST STATISTIC) Fig 5 a Th~s shows the distributions of Z-scores for the total normal (28 hands) and the total MS (33 subjects) included m the study groups. The average value of the Z-score for the MS group Js 0.18, while that for the normal group is 087. The decision hne between the two groups is at Z = 0 52. h" This shows the a posteriors probabihty that a subject belongs to the MS group, as a function of Z-score, conditioned on the experimentally observed peak-to-peak amphtude values Z = 0 52 corresponds to the 0 50 probability line
peak-to-peak amplitude values for the 17 hands in the MS I group, the 11 hands in the MS |l group, and the 6 hands in the MS lII group are shown in Fig. 6. Just as there were consistent differences between the average values of the normal and MS data (Fig. 3) there were consistent differences within the total MS group with
~o . 5 0
~
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~> o.o
20
• 40
?'']"
MS-']I (N.II) ~ (N-S)
60
80
STIMULATING
I00
= 120
140
160
FREOUENCY (Hz)
Fig. 6. A plot of the average peak-to-peak voltages of the repetwlte response as a function of the stimulating frequency for the three MS subgroups. There is apparent good agreement between the patients" climcal condition and the average peak-to-peak voltages The flat response of the MS III group indicates that there was virtually no repetit=ve activity to stimulation frequencies above 40 Hz. There is a tendency for the response curve for the MS II group to flatten out above 100 Hz while the MS 1 group, m general, follows a normal slope above 60 Hz.
29
SOMATOSENSORY RESPONSE IN MS
i1
~ 5 = .iz
i
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6 SUBJECTS
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17 SUBJECTS
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6 MS SUBJECTS WITH
INO SYMPTOMS REFERRABLE ITO THE SOMATOSENSORY SYSTEM
:
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Z (TEST STATISTIC) Fig 7 The distribution of Z-scores for the patient subgroups are shown In ad&tlon the Z-scores for six patients who had never demonstrated symptoms referable to the system under study are shown
SER
RIGHT HAND
sensory symptoms referable to the hand under study. All six classified as normal (bottom graph, Fig. 7) by the analytical procedure with an average Z-score of 0.82 and a standard deviation of 0.23. These results suggest the high specificity of the technique; that is, demyelination must be present in the pathway under study. The relative sensitivity of this approach can be seen from the data in Fig. 8. Shown are the SER and SERT responses at stimulating frequencies of 12, 80 and 100 Hz respectively obtained by both left and right median nerve stimulation of a young MS patient (MS 059). This 21-year-old male had a 7 month history of brief and fluctuating symptoms of bramstem and spinal cord MS. Sensory symptoms were only left-sided. At the time of electrical testing he had a completely normal neurological examination, although a week earlier he had mild vibration sense impairment in the left fingertips. His single evoked responses were practically identical and normal appearing. However, when his SERT responses were analyzed, his right hand was given a score falling just within the MS region (Z=0.489), with a 71"o probability of belonging to the MS group and a 1 "o probability of error in classification, while his left hand was given a score well within the MS region (Z= 0.229) with a 100% probability of belonging to the MS group and a l °/, probability of error in assessment.
SERT
SERT
SERT
I2H~
80H2
IooH~
-\
'\
• '1 .
,v, d
LEFT HAND
,_1 / '
[2~uV
Fig. 8. The single SER and SERT obtamed at stimulating frequencies of 12, 80 and 100 Hz from pauent MS 059 The neurological examination at the u m e of testing was normal throughout, although earher he had mild vibration sense lmpmrment at the left fingertips. The analysis gave a Z-score of 0.489 for the right hand, with a 71°o probability of belonging to the MS group, and a 1"i, probability of error in the assessment. The left hand had a Z-score of 0.229, with a 100 '',, probability of belonging to the MS group, and a 1% probability of error m assessment.
30 Qualitatively it may be appreciated from the SERTs shown in Fig. 8 that the tested pathways differ in their ability to respond to the 80 and 100 Hz stimulating trains. The right hand shows a more normal appearing response at these frequencies than do the equivalent data from the left hand. DISCUSSION
This and the previous paper (Namerow et al. 1974) present an experimental approach currently under evaluation in our laboratory for pathophysiological studies of MS. The pathology ofdemyelination in MS is well recognized and the implication that this, in turn, in some manner affects neuronal conduction has been a clinical axiom since the first pathological description of this disease. The impetus for the development of this approach was the demonstration in experimental demyelination of impaired transmission of repetitive stimuli through regions of demyelination [Cragg and Thomas 1964; McDonald and Sears 1970; Davis 1972). It was demonstrated that transmission can be impaired in two ways : decreased conduction velocity and intermittent blockage. Our desire was to capitalize on these observations to obtain a more sensitive measure of neuronal function in humans with demyelinating disease. Our results show significant differences in the SERT between MS patients and normals. One must consider what part of the afferent system has produced the observed changes. Clearly a normal response would depend on the integrity of each of the component portions of the afferent pathway. This includes consideration of peripheral nerve, spinal cord and brainstem tracts, multiple synaptic transmissions, and cortex. Available evidence indicates that there are no significant lesions of peripheral nerve in MS patients (Hasson et al, 1958; Lumsden 1970). Demyelination is certainly present in the central afferent axons and this is the most probable cause for the observed changes. While there is some evidence of plaques extending into cortical gray matter (Lumsden 1970), this is usually at the margin of the cortical mantle with little neuronal damage. The influence of the synapse is not so clearly defined, however. Some evidence
R . J . SCLABASSI e l al.
suggests a synaptic blocking effect in MS (Bornstein 1968 : Carels and Cerf 1969). However, this has only been shown by inference in the human (Sonninen et al. 1973), and the significance of this contribution to our results remains unclear. The normal appearing response, when patients have symptoms referable to pathways other than the somatosensory system, would suggest that if a general synaptic effect is present it is not a major contributor to our results. Our patients were static in their clinical course, however, so that this would not rule out the possibility of a more prominent synaptic influence during a natural exacerbation of this disease. A close qualitative correlation between the degree of SERT alteration and the degree of clinical involvement exists, in the pathways under consideration, as a function of train stimulating frequency. Patients having barely detectable clinical signs had a response at all frequencies which appeared to be nearly normal. Patients who had no clinical signs at the time of testing but who had a known history of deficits in position and vibration sense in the hand under study showed little deterioration in the quality of the SERT until the stimulating frequency was increased past 100 Hz. Patients who had mild to moderate sensory deficits showed a deterioration of the response for stimulating frequencies above 40 Hz, while patients who demonstrated severe sensory loss revealed an impaired response at all stimulating frequencies. As already discussed there does not appear to be a characteristic alteration of the evoked cortical responses for all MS patients. This was demonstrated by the group of six patients who were very early in the course of their illness and who had primarily.visual deficits with no sensory symptoms referable to their hands. Each of these patients demonstrated normal evoked responses. This lack of a characteristic change irrespective of patient symptoms or signs would be an argument against a generalized synaptic effect in the static or stable MS patient. However, this would not exclude the possibility of detecting such an effect if more specific and sensitive measures of human synaptic function could be developed. The peak-to-peak amplitude of the single cycle average can be considered to be related to the amount of evoked cortical activity. If one hypo-
31
SOMATOSENSORY RESPONSE IN MS
thesizes that the level of cortical activity is directly related to both the number of subcortical conducting axons and the degree of partial conduction blockage, then the amplitude of this response should give a rough index of conduction block in these pathways. This was borne out by our results, in that there was an apparent close correlation between amplitudes and severity of clinical deficits. In addition, the amplitude values seem to be well suited for discriminating between normal subjects and MS patients. By use of Hotelling's multivariate T test (Anderson 1958), the two test groups were significantly separated (P < 0.001). This separation was also reflected in the Z-scores calculated for each individual, which permitted subject classification into the appropriate group. It was anticipated that the response phase angles would be related to conduction time from the site of stimulation to the cortex and thus reflect decreased conduction velocity across demyelinated regions. The phase angle data, however, did not demonstrate a separation between the normal and patient groups. One hypothesis which can possibly account for both the observed amplitude and phase angle data is as follows. Due to the short interstimulus intervals used, insufficient recovery time was available following the first stimulus, leading to an intermittent blockage of the effected fibers. That is, the fibers conduct across the demyelinated regions for only a fraction of the time. This in turn produces an amplitude attenuation proportional to the percentage of time conduction is blocked. The decrease in conduction velocity, while being significant across the demyelinated regions, has an effect which is insignificant for the total pathways under consideration, thereby producing no significant change in the phase angles between normals and patients. The concept of conduction blockage was suggested in a previous study (Namerow 1970) where successive blocking of demyelinated axons could explain recovery function response as one decreased interstimulus intervals. It has already been shown that conduction blockage is a primary factor when experimentally demyelinated lesions are exposed to heat (Davis 1970), and it is not unreasonable to assume a similar mechanism in MS. Recent animal studies (Rasminsky 1973)
support the concept that chronic slowing of conduction in demyelinated nerve fibers may be of minor clinical significance in human demyelinating disease and that the significant factor may be intermittent blockage of afferent impulses to a degree proportional to the severity of the underlying pathology. If one accepts this hypothesis then the following clinical inference can be made : Signs and symptoms in MS may be produced in primary fashion by intermittent nerve conduction block with slowed conduction playing a less important role. CONCLUSIONS
The SERT appears to be an extremely sensitive measure of neuronal function and as such should have direct clinical and experimental application in studying demyelinating disease. It is apparent from these experiments that the afferent pathways in patients suffering from MS have an impaired ability to transmit trains of stimuli. This impaired ability can be quantitatively described by the filtered single cycle peak-topeak amplitudes over a range of stimulating frequencies. There is a direct correlation between these amplitudes and the severity of clinical sensory impairment in the hands under study. Based on these measured values, discriminant functions can be developed which permit the classification of subjects into either normal or patient populations, and which permit probabilistic statements to be made about the chances of a particular individual belonging to either group. The phase angle measurements did not separate normal subjects from patients. Additionally, this method of study has the advantage of testing the entire central pathway, including axonal and synaptic components. This assumes greater importance in view of the growing body of evidence and orientation of thinking that considers multiple sclerosis as a membrance disease. The question of a synaptic factor in MS has not been fully resolved (Bornstein 1968; Carels and Cerf 1969), and at least one recent human study raises this issue again (Sonninen e t a l. 1973). Although direct measurements cannot be made, the SERT may find usefulness in evaluating this aspect of neuronal function in man.
32
R . J . SCLABASSI ('1 al.
SUMMARY
The train somatosensory evoked response (SERT) was examined in a group of thirtythree MS patients. The filtered SERT and single cycle averaged are described for the patient group, with the single cycle average characterized by peak-to-peak voltage amplitude and phase angle measurements. The differences in the experimental response between patients and normal subjects are examined. The single cycle average amplitudes demonstrated significant differences at all stimulating frequencies between the normal subjects and the MS patients, while phase angles did not. A discriminant function, based on the single cycle average peak-to-peak voltages, was developed to aid in characterizing subjects. Additionally, a posteriori probabilities were obtained to permit probabilistic statements concerning subject classification. These results were verified using a normal and MS subject who were correctly identified in each case. The clinical significance of the above observations is discussed. RESUME REPONSE SOMATO-SENSORIELLE
A DES TRAINS DE
STIMULATIONS CHEZ DES MALADES ATTEINTS DE SCLEROSE MU ETIPLE
Les r6ponses 6voqu6es somato-sensorielles des trains de stimulation (SERT) sont 6tudi6es dans un groupe de 33 malades atteints de scl6rose multiple. La SERT filtr6e et la moyenne isol6e d'un cycle sont d6crits pour le groupe de patients, le cycle moyen isol6 ~tant caract~ris~ par l'amphtude pic-fi-pic et les mesures d'angle de phase. Les diff6rences de r6ponse exp6rimentale entre malades et sujets normaux sont examin6es. Les amplitudes moyennes des cycles isol6s montrent des diff6rences significatives fi toute leur s6quence de stimulation entre les sujets normaux et les patients atteints de scl6rose multiple alors que les angles de phase n'en montrent pas. Une fonction discriminante bas6e sur les voltages pic-fi-pic moyens du cycle isol6 a 6t6 d6velopp6e pour aider fit caract6riser les sujets. En outre, des probabilit6s a posteriort ont 6t6
obtenues pour permettre des calculs de probabilit6 concernant la classification des sujets. Ces r6sultats ont et6 v6rifi6s '5 l'aide d'un sujet normal et d'un sujet avec sclerose multiple qui 6tait correctement identifids dans chaque cas. La signification clinique de ces observations est discut6e. The authors would like to acknowledge valuable discussions with Professor Lawrence Kruger In addition the authors wish to express appreciation to Diane Hohn for technical assistance in the laboratory, and to Cynthia Masters for secretarial assistance
REFERENCES ANDERSON, T W An tnlroductton t~) multtrottate stalt.stlca[ anah'sts John Wiley and Sons, Inc. New York, 1958 BAKER, J B., SANCFS, A and LARSON, S J Neurophys~ologlcal evaluation of patients V,lth multiple ~clerosls Marquette reed. Ret' , 1966, 32 37 BORNSTEIN. M B In the centralnertou.s ~'~~tem WiIhams and Wllkins, Baltimore, Md., 1968 CARELS, G. and CERE, J. A Functional alterations produced m an ~solated nerve center by serum from patients with multiple sclerosis, bit. Arch. AllerLl.i, 1969, 36 608-620 CRAGG, B. G and Thomas, P. K Change~ in nerve conduction In experimental allergic neuritis J Veurol NetllO~u~q Psl'chtat . 1964, 4 537 544 DAVIS, F. A. Axonal conduction ~tudleS based on some considerations of temperature effects in multiple sclerosis. Eleetroenceph chn ,~'emophvs'u~l., 1970, 28 281. DAVIS. F. A Impairment of repetitive impulse conduction In experimentally demyehnated and plessure-mjured nerves J. Neurol Neurosurq Psvchtat., 1972, 35 537 DIXON, W. J B M D biomedical computer proqrams Unlv Callf Press, Los Angeles, Cahf, 1973 FISHER, R. A The use of multiple measurements in taxonomic problems. Ann. Eugen. ( Lond. ). 1936, 7 179-188 Hassor,~, J., TERR',, R. D. and ZIMr~tERMAY. H M. Peripheral neuropathy in multiple sclerosis. Nemoh~ql' ( Mmneap. ). 1958, 8 503. LU~,ISDEN, C. E. In P J. V|NKEN and G W BRUYN (Eds), Handbool, o! chnical neuroloqv, l'ol. l~', Multiple .st'/erosis and other demevlinatmq disease. North-Holland Publishing Co., Amsterdam, 1970 MCDONALD, W. I. and SEARS,T. A. The effects of experimental demyehnation on conduction in the central nervous system. Brain, 1970, 93:583 598 MORRISON, D. F Multwariate ~stau~tu'al methods. McGrawHill, New York, 1967 NAMEROW, N. S Somatosensory evoked responses in multiple sclerosis. Bull Los Angeles neurol. Sot., 1968a, 33, 2 74-81 NAMEROW, N. S. Somatosensory evoked responses m multiple sclerosis patients with varying sensory loss. Neuroh~.qy (Minneap.), 1968b, I8, 12 1197 1204.
SOMATOSENSORY RESPONSE IN MS
33
NAMEROW, N. S. Somatosensory recovery functions in multiple sclerosis patients. Neurology (Minneap.), 1970, 20, 8 813-817
RASMINSKY,M. The effects of temperature on conduction in demyelinated single nerve fibers. Arch. Neurol. (Chtc.), 1973, 28: 287-292.
NAMEROW, N. S. and ENNS, N. F. Visual evoked responses m patients with multiple sclerosis. J. Neurol. Neurosurg. Psychlat., 1972, 35. 829 833 NAMEROW,N S., SCLABASSI,R. J. and ENNS,N. F. Somatosensory responses to stimulus trains: normative data. Electroenceph clin. Neurophysiol., 1974, 37" ll-21.
RICHEY, E. T., KOOI, K. A. and TOURTELLOTTE, W. W. Visually evoked responses in multiple sclerosis. J. NeuroL Neurosurg. Psychiat., 1971, 34:275-280 SONNINEN, V., Riekkinen, P. and RINNE, U. K. Acid monoamine metabohtes m cerebrospinal fluid m multiple sclerosis. Neurology ( Mmneap.), 1973, 23: 760-763.
23
S O M A T O S E N S O R Y R E S P O N S E TO S T I M U L U S T R A I N S IN P A T I E N T S W I T H M U L T I P L E SCLEROSIS 1 ROBERT
J. SCLABASSI, NORMAN S. NAMEROW AND NELSON F. ENNS
Department o/ NeuHdoql'. School o/" Medicine, Llnwer~'ttv o/Califorma
Lo,~ Angele,~, Los Angeles, Calt]. 90024 ( L1.S A. )
(Acceptlon for pubhcation December 28, 1973)
Multiple sclerosis (MS) is a disease, unique to the human, that affects the brain and spinal cord. The underlying pathophysiological mechanism appears to be blocked or impaired neuronal conduction across demyelinated areas of the central nervous system (CNS). To assess neuronal conduction in this disease one must rely on indirect measures such as the use of evoked cortical activity following peripheral stimulation. Investigations utilizing both the visual and somatosensory evoked response (VER and SER) have been pursued with some success (Baker et al. 1966; Namerow 1968 a, b; Richey et al. 1971: Namerow and Enns 1972). While these studies have demonstrated alteration of the evoked response waveform as a function of the patient's impairment of vision and proprioception, several shortcomings have become apparent. Accurate latency determination was at times difficult and in some patients wave peaks were poorly defined or missing, leading to problems in quantification. These considerations led us to the development of the somatosensory evoked response to trains of stimuli (SERT), an experimental approach outlined in detail in the preceding paper (Namerow et al. 1974). The present paper examines the characteristics of the SERT in MS patients, and analyzes the differences in this experimental response between patients and normal subjects. In particular, the SERT, filtered SERT, and single cycle average are described for the patient group. In addition, ~This research is supported by National Multiple Sclerosis Grant 516-C-3 and U.S. Health Service Grants NS08711 and NS02501 Computing assistance was obtained from the Health Science Computing Facility, UCLA, sponsored by NIH Special Resources Grant FR-3
the patient average peak-to-peak voltage and phase angle measurements which characterize the single cycle average are compared to those from normal subjects. These values are then used to characterize quantitatively the differences between the two experimental groups. METHOD
Experimental The experimental techniques, including scalp electrode placement, patient positioning, method of peripheral nerve stimulation, stimulation parameters, and data recording and reduction methods are identical to those described in the previous report. However, a reduced set of stimulating frequencies, consisting of 40, 60, 80, 100 and 160 Hz were utilized in this study. Subjects Thirty-three patients, ranging in age from 21 to 56 years with a mean of 37 years, were selected for study from the MS clinic at the UCLA School of Medicine. The approximate mean duration of illness in these patients was estimated at 9 years, during which time they were followed in the clinic for an average of 3 years. Several additional subjects were studied. One, a 21-year-old male (MS 059) presented with a 7 month history of extremely mild MS symptoms. Six MS patients were evaluated who gave no history of sensory impairment in the pathways under study and who on several physical examinations showed no sensory deficits. The clinical status of each patient was determined by the usual neurological examination. Clinical assessment of vibration perception
24
R.J. SCLABASSIel et]
was determined by using a standard 128 Hz tuning fork, and position sense by the patient's ability to perceive fine passive movements of the distal phalanx of the finger. The patient's hands were categorized into three groups according to the clinical sensory examination at the time of study. Hands placed in Group I (MS I) demonstrated no vibration or position sense impairment at the time of testing. Group II (MS II) included hands that demonstrated mild to moderate vibration and/or position sense impairment, while Group III (MS III) consisted of hands that revealed severe vibration and/or position perception deficits on clinical testing. The control group included a total of 29 hands from 18 subjects. Each control subject gave a history negative for significant neurological disease and each had an unremarkable neurological examination. The control subjects ranged in age from 24 to 46 years with a mean of 32 years. Analytical
Peak-to-peak amplitude and phase angle measurements were obtained for all subjects at each stimulating frequency, and then differentially analyzed using techniques of multivariate SINGLE STIMULUS
statistical analysis, In particular, the analytical problem was formulated as that of classifying the observed set of data from an experimental subject into one of two populations, normal or MS. The objectives of this approach were twofold. First, we wished to obtain a single number for each subject which summarized the relationship of that particular subject's response to both groups. Second. we desired to make meaningful probabilistic statements concerning the degree of clinical deficits and group classification from a subject's response. Two groups, one representing the normal population in the large (GN)and the other the MS population in the large (GMs), were constructed using the data obtained from seventeen normal subjects and seventeen MS patients. The group of MS subjects was designed to represent a cross-section of observed clinical deficits and contained four subjects from the MS I group, seven subjects from the MS II group, and six subjects from the MS III group. Two complementary approaches were utilized to achieve the desired objectives. One of these, Fisher's linear discriminant analysis (Fisher 1936: Morrison 1967) provides a linear function of the observed data which assigns to
TRAIN--IOOHZ
FILTERED TRAIN
NORM ~AL
--T.A,N
T
OFF
Fig. 1. Upper sertes" A single stimulus SER from a normal subject (N 050) followed by the same subject's SERT at 100 Hz, and, m the last column, the filtered SERT for 64 presentations of the stimulus train. L o w e r serte~s. Data from a paUent (MS 118) with moderate symptoms. The first response is the SER in a single stimulus The middle response Is to a train of" stimuli at 100 Hz. The lack of cortical activity at this frequency is evident. This is further demonstrated in the last column where the filtered S E R T shows virtually no 100 Hz activity.
SOMATOSENSORY RESPONSE IN MS
each subject a single number (Z-score) in such a way as to enhance the physiological differences between the normal and MS populations. The second procedure utilized was a stepwise Bayesian procedure (Anderson 1958: Dixon 1973) with the assumptions of equal costs of misclassification and equal apriori probabilities that the indiwdual comes from either the normal or the MS group. This procedure permits the conditional probability PIGMs;.'v~,, that the subject comes from the MS group given his observed data, to be calculated RESU1.FS
SERT and filtered S E R T A typical single stimulus evoked response (SER) obtained from a normal subject (N 050) is shown in Fig. l. This same subject's SERT and filtered SERT, for a stimulating frequency of 100 Hz, are shown to the right of the SER. In MSI
25
contrast, the SER from a patient (MS 118) with moderate vibration and position sense loss is shown in the bottom row of Fig. 1. The absence of the initial negative peak is quite prominent as is the marked delay in both the onset of the response and the peak of the major positive wave. This same patient, when stimulated with a train frequency of 100 Hz, produced virtually the same response as for the single stimulus. There is an apparent inability for this patient to respond to these rapidly occurring peripheral stimulations and to produce the characteristic rhythmical activity seen in normal subjects. In the filtered SERT the effect is even more dramatic and essentially no response is noted. This particular patient did demonstrate a discernible rhythmical response in the SERT at lower stimulating frequencies. The ability of the afferent pathways and cortex to transmit and process volleys of impulses produced by stimulating trains of successively MS .E
M S .I~
,' ',,
SER I,;
SERT ,¢oH~
~L,, /
V
!"
SER T tooH~
~ '~
poo msee
I
F'
5~W-';
i
2.~V
~ 2juV ~"
FJg 2. The SER and SERTs at 40 and 100 Hz are shown for three subjects drawn from the MS I (MS 033). MS II (MS I I0). and MS II1 (MS 039) groups respectively The abihty of the afferent pathways to transmit stimulating trams is a function of stmlulatmg frequency and the degree of underlying pathology Patients m the MS I group tend to show actlvlt~ for stHnulatmg frequencies above 100 Hz, those m the MS It group tend to have decreased activity at 100 Hz, as compared to the first group, while patients m the MS I11 group tend to show decreased actwity at all stimulating frequencw~
26
R, h SCI.ABASSIel a/.
higher frequencies appears to be closely correlated to the degree of clinical sensory impairment. 1 2.0. That is, the more pronounced the subject's clini/'1\ p/ / / " Jcal deficits the lower the stimulating frequency at 5 which the SERT ceases to demonstrate the 1.5anticipated periodic response. This concept is demonstrated in Fig. 2, which shows the SER "r .N. o t.o. and SERT responses at stimulating frequencies I-.D,. of 40 and 100 Hz for a subject taken from each of ov • .50. the three MS groups. The subject drawn from the ~.~ MS MS I group (MS 033) at the time of testing demonstrated no observable clinical deficits. His O.O 20 4'o 6'0 io ,;o ,io ,;.o ,;o SER was essentially normal in configuration. STIMULATING FREQUENCY (Hz) The SERT at both stimulating frequencies deFig 3 The average peak-to-peak voltage amphtudes for the monstrated a near normal rhythmic pattern. The peak-to-peak voltage amplitudes as measured baszc normal and MS groups of seventeen subjects each The bars indicate plus or minus one standard error The stimulatfrom the filtered single cycle average were 1.80 ing frequencnes used were 40, 61). 80, 100 and 160 H7 yV at 40 Hz and 1.18 pV at 100 Hz. This is in comparison to normal mean averages of 1.63 cycle peak-to-peak amplitude as a function of and 1.37 yV respectively. The subject drawn stimulating frequency for both the MS patients from the MS lI group (MS 110) at the time of and the normal subjects are presented in Fig. 3. testing demonstrated mild sensory loss. This Both groups show a significant decrease in this patient's SER also appears relatively normal, measure with increasing stimulating frequency: The rhythmical activity produced by the stimulat- however, there are significant amplitude difing train at 40 Hz has a deteriorated quality ferences between the two groups at all stimulating to its appearance, but has a filtered single cycle frequencies. The prominent amplitude peaking average amplitude of normal magnitude (1.65 present in the normal group at 60 Hz is not pre/~V). At a stimulating frequency of 100 Hz, sent in the patient data. The amplitude coefficients however, the periodic component of the response of variation were also investigated. The relative has essentially disappeared with a filtered single dispersion for the MS group as compared to the cycle average amplitude of 0.23 yV. In addition normal group is approximately twice as great at the SERT response is similar in appearance to all stimulating frequencies except 40 Hz, indicatthe SER. The subject from the MS III group (MS ing that the inter-individual variations in this 039), had severe deficits in vibration and posi- measure tend to be greater for the MS patients as tion sense at the time of testing. This patient a group than for the normal subjects. This could showed little evidence of a periodic component al be indicative of the wide range of functional imthe two stimulating frequencies or for that matter pairment in patients with this disease. at any stimulating frequency. The steady-state The mean phase angles, at all stimulating amplitudes, as estimated by the filtered single cy- frequencies, are given in Fig. 4. The phase angles cle average, were reduced to 0.25 /tV at 40 Hz tend to be distributed in similar fashion for the and 0,13 pV at 100 Hz, The SER for this patient two groups with one qualitative difference. The is also abnormal in appearance with marked maximum change in phase angle, which occurs changes in both latencies and composition of the for both groups between 60 and 80 Hz, is almost component waves. twice as great for the normal group as it is for the MS group. The coefficient of variation beSimjle cycle average haved almost identically for the two groups, The peak-to-peak amplitude and phase angle except at 160 Hz where the normal group displays measurements characterizing the single cycle 60°° more relative variability. The inter-indiaverage were investigated for the various stimu- vidual variability of the phase angle data for the lating frequencies. The mean values of the single MS group is essentially constant.
§
\\\\
""---..
27
SOMATOSENSORY RESPONSE IN MS TABLE 1
T
o,.0 -
1:---'-''~ °
~
3.0.
i
Ix~t~T
I
"~
MS
T.
\/
'"
Correct classification of test cases based on successwe variables as designated by the stepwise discrimlnant analysis procedure A summarizes the results for the first five variables picked when all ten variables are included. B is the change when the variables are restricted to amplitudes only Variables included
I0.
"o Cases correctly classified
D
d!
f
vtoo 82.5 Vtoo, V~,o 88.0 vao, v~oo, V~6o 91.5 V4o, v(,O. Vl0 O, v160 ]00.0 v~o,v~,o.~p~o,v~oo,vt~ n 100.0
5.45 8 30 9.80 19.30 2078
1,32 2, 31 3, 30 4, 29 5. 28
46 14 34.06 25.93 37.15 3084
v-~o, V6o, vso, V~o0, V16o 100.0
20.40 5, 28
v
2O
40
60
80
STIMULATING
I00
120
140
160
A
FREQUENCY (Hz)
Fig. 4 The average phase angle (in radmns) plus or minus one slandard error for the seventeen subject MS and normal groups as a function of stimulating frequency. There is no sigmficant difference m phase angles between the two groups.
A one-way analysis of variance was performed between the two groups for each of the ten variables to test the null hypothesis that the population means are identical. The null hypothesis was rejected at a 1°,5 significance level for all values of peak-to-peak amplitude, while it was not rejected at this same significance level for any of the phase angles.
Differential analysis Two basic groups of seventeen normal subjects and seventeen MS patients were used as training groups to construct a discriminant function. Originally, all 10 variables (i.e., an amplitude and phase angle at each of the five stimulating frequencies) were included in the analysis. The results of the first five iterations of the stepwise procedures utilized are summarized in Table 1A. The variable providing the most discriminating power is the peak-to-peak voltage amplitude at a stimulating frequency of 100 Hz, for which 82.5 o,, of the training subjects were correctly classified. By the fourth iteration the discriminant function included the voltage variables at stimulating frequencies of 40, 60, 100 and 160 Hz, with 100°o of the training subjects correctly classified. At the fifth iteration the phase angle at 80 Hz was included but with negligible improvement in the separation between the two groups as measured by the Mahalanobis distance squared. The effect of excluding the phase angles from the calculations is demonstrated in Table IB, where the change in the results of the fifth iteration due to replacing q~8o with Vso is noted. This change is
30.26
* D is the Mahalanobis distance squared between the normal and the MS groups calculated for the included variables d.f. is the degrees of freedom F is a test stahstic testing the difference between groups as measured by the Mahalanobls distance
minimal, and for this reason it was decided to utilize only the filtered single cycle peak-to-peak voltage amplitudes as the discriminant variables. In order to assess the reliability of this classification procedure, a testing group of 27 "unknown" subjects was constructed. This "unknown" group contained eleven normal subjects and sixteen MS patients. All subjects in this group were correctly classified using the derived discriminant function. The results of this analysis, for both the total normal group (including both training and testing subjects) and the total MS group, in terms of Z-score distributions are summarized in Fig. 5, a. The 28 normal hands had an average Zscore of 0.87 and a standard deviation of 0.12, while the thirty-three subjects in the total MS group had an average Z-score of 0.18 with a standard deviation of 0.16. The decision line separating the two groups was Z=0.52, corresponding to an a posteriori probability of 0.5 (Fig. 5, b). The distribution of filtered single cycle average amplitudes, as a function of the clinical assessment of sensory loss, was also of interest. The average
28
R . J . SC1.ABASSI e l it/.
7. TOTAL
"~'ms = IS
6.
MS
GROUP
4. 3. 2.
o -.2 -.I
o
.2
.3
.4
.5
i
i
,
i
.6
.7
.8
.9
,
,
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i 1.2
1 TOTA L
6.
I
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I rI
4.
3.
NORMAL ~n
GROUP .87
I
2
I
I
....
0 -.2 - I
.2
I O.
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,~ n=-
-
40_
20.
i I-1
.3 .4 .5 .6 .7 8 Z (TEST STATISTIC)
i
9
1
I0 II
12
respect to the subgroups classified on the basis of severity of clinical signs. Thus the MS I group tends to have greater amplitude values at each stimulating frequency than does the MS II group, and the MS II group has greater amplitude values than does the MS IIl group. The amplitude coefficient of variation does not display as consistent a pattern of change as the average amplitudes. The MS II group shows greater inter-individual variability with respect to the MS I group, while the MS III group displays less inter-individual variability. The distributions of Z-scores were also investigated and found to behave in a manner consistent with the degree of clinical signs. The MS I group has an average Z-score of 0.22 with a standard deviation of 0.19. the MS II group has an average Z-score of0.15 with a standard deviation of0.13, while the MS III group has an average Z-score of 0.I 2 with a standard deviation of 0.14 (Fig. 7).
Additional subjects • e-o-e
o-eoo-o-
e-e~
\ \1•
I
1. II ~ ,
Seven additional MS patients were investigated. Six of these were patients whose medical histories indicated that none had experienced
!
v
r-,.oo '¢ . 7 5 ,
Z (TEST STATISTIC) Fig 5 a Th~s shows the distributions of Z-scores for the total normal (28 hands) and the total MS (33 subjects) included m the study groups. The average value of the Z-score for the MS group Js 0.18, while that for the normal group is 087. The decision hne between the two groups is at Z = 0 52. h" This shows the a posteriors probabihty that a subject belongs to the MS group, as a function of Z-score, conditioned on the experimentally observed peak-to-peak amphtude values Z = 0 52 corresponds to the 0 50 probability line
peak-to-peak amplitude values for the 17 hands in the MS I group, the 11 hands in the MS |l group, and the 6 hands in the MS lII group are shown in Fig. 6. Just as there were consistent differences between the average values of the normal and MS data (Fig. 3) there were consistent differences within the total MS group with
~o . 5 0
~
J'"'",.r
~> o.o
20
• 40
?'']"
MS-']I (N.II) ~ (N-S)
60
80
STIMULATING
I00
= 120
140
160
FREOUENCY (Hz)
Fig. 6. A plot of the average peak-to-peak voltages of the repetwlte response as a function of the stimulating frequency for the three MS subgroups. There is apparent good agreement between the patients" climcal condition and the average peak-to-peak voltages The flat response of the MS III group indicates that there was virtually no repetit=ve activity to stimulation frequencies above 40 Hz. There is a tendency for the response curve for the MS II group to flatten out above 100 Hz while the MS 1 group, m general, follows a normal slope above 60 Hz.
29
SOMATOSENSORY RESPONSE IN MS
i1
~ 5 = .iz
i
[
,
• .V-1 0.0 .I
-.2 -.I
.q
J
,,
I
.2
I.I :FI
0.0 .I
=
.
.
22
.2 .3 .4
i1
.
.
.
.
.7 .8 .9 1.0 II
12
MS-,,
I
.~ .4
4
.
.3 .4 .5 .6
-.2 -.; o.o I
-.2 -.I
MS - w r
6 SUBJECTS
I
II SUBJECTS
. . . . . . . .5
.6
.7
.B
.9
1.0 LI
1.2
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[
17 SUBJECTS
.5 .6
.7 .8 .9 1.0 I.I L2
6 MS SUBJECTS WITH
INO SYMPTOMS REFERRABLE ITO THE SOMATOSENSORY SYSTEM
:
o, ........ -.2-.I
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irl I]
.2
.:3 .4
.5
.6
.7
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Z (TEST STATISTIC) Fig 7 The distribution of Z-scores for the patient subgroups are shown In ad&tlon the Z-scores for six patients who had never demonstrated symptoms referable to the system under study are shown
SER
RIGHT HAND
sensory symptoms referable to the hand under study. All six classified as normal (bottom graph, Fig. 7) by the analytical procedure with an average Z-score of 0.82 and a standard deviation of 0.23. These results suggest the high specificity of the technique; that is, demyelination must be present in the pathway under study. The relative sensitivity of this approach can be seen from the data in Fig. 8. Shown are the SER and SERT responses at stimulating frequencies of 12, 80 and 100 Hz respectively obtained by both left and right median nerve stimulation of a young MS patient (MS 059). This 21-year-old male had a 7 month history of brief and fluctuating symptoms of bramstem and spinal cord MS. Sensory symptoms were only left-sided. At the time of electrical testing he had a completely normal neurological examination, although a week earlier he had mild vibration sense impairment in the left fingertips. His single evoked responses were practically identical and normal appearing. However, when his SERT responses were analyzed, his right hand was given a score falling just within the MS region (Z=0.489), with a 71"o probability of belonging to the MS group and a 1 "o probability of error in classification, while his left hand was given a score well within the MS region (Z= 0.229) with a 100% probability of belonging to the MS group and a l °/, probability of error in assessment.
SERT
SERT
SERT
I2H~
80H2
IooH~
-\
'\
• '1 .
,v, d
LEFT HAND
,_1 / '
[2~uV
Fig. 8. The single SER and SERT obtamed at stimulating frequencies of 12, 80 and 100 Hz from pauent MS 059 The neurological examination at the u m e of testing was normal throughout, although earher he had mild vibration sense lmpmrment at the left fingertips. The analysis gave a Z-score of 0.489 for the right hand, with a 71°o probability of belonging to the MS group, and a 1"i, probability of error in the assessment. The left hand had a Z-score of 0.229, with a 100 '',, probability of belonging to the MS group, and a 1% probability of error m assessment.
30 Qualitatively it may be appreciated from the SERTs shown in Fig. 8 that the tested pathways differ in their ability to respond to the 80 and 100 Hz stimulating trains. The right hand shows a more normal appearing response at these frequencies than do the equivalent data from the left hand. DISCUSSION
This and the previous paper (Namerow et al. 1974) present an experimental approach currently under evaluation in our laboratory for pathophysiological studies of MS. The pathology ofdemyelination in MS is well recognized and the implication that this, in turn, in some manner affects neuronal conduction has been a clinical axiom since the first pathological description of this disease. The impetus for the development of this approach was the demonstration in experimental demyelination of impaired transmission of repetitive stimuli through regions of demyelination [Cragg and Thomas 1964; McDonald and Sears 1970; Davis 1972). It was demonstrated that transmission can be impaired in two ways : decreased conduction velocity and intermittent blockage. Our desire was to capitalize on these observations to obtain a more sensitive measure of neuronal function in humans with demyelinating disease. Our results show significant differences in the SERT between MS patients and normals. One must consider what part of the afferent system has produced the observed changes. Clearly a normal response would depend on the integrity of each of the component portions of the afferent pathway. This includes consideration of peripheral nerve, spinal cord and brainstem tracts, multiple synaptic transmissions, and cortex. Available evidence indicates that there are no significant lesions of peripheral nerve in MS patients (Hasson et al, 1958; Lumsden 1970). Demyelination is certainly present in the central afferent axons and this is the most probable cause for the observed changes. While there is some evidence of plaques extending into cortical gray matter (Lumsden 1970), this is usually at the margin of the cortical mantle with little neuronal damage. The influence of the synapse is not so clearly defined, however. Some evidence
R . J . SCLABASSI e l al.
suggests a synaptic blocking effect in MS (Bornstein 1968 : Carels and Cerf 1969). However, this has only been shown by inference in the human (Sonninen et al. 1973), and the significance of this contribution to our results remains unclear. The normal appearing response, when patients have symptoms referable to pathways other than the somatosensory system, would suggest that if a general synaptic effect is present it is not a major contributor to our results. Our patients were static in their clinical course, however, so that this would not rule out the possibility of a more prominent synaptic influence during a natural exacerbation of this disease. A close qualitative correlation between the degree of SERT alteration and the degree of clinical involvement exists, in the pathways under consideration, as a function of train stimulating frequency. Patients having barely detectable clinical signs had a response at all frequencies which appeared to be nearly normal. Patients who had no clinical signs at the time of testing but who had a known history of deficits in position and vibration sense in the hand under study showed little deterioration in the quality of the SERT until the stimulating frequency was increased past 100 Hz. Patients who had mild to moderate sensory deficits showed a deterioration of the response for stimulating frequencies above 40 Hz, while patients who demonstrated severe sensory loss revealed an impaired response at all stimulating frequencies. As already discussed there does not appear to be a characteristic alteration of the evoked cortical responses for all MS patients. This was demonstrated by the group of six patients who were very early in the course of their illness and who had primarily.visual deficits with no sensory symptoms referable to their hands. Each of these patients demonstrated normal evoked responses. This lack of a characteristic change irrespective of patient symptoms or signs would be an argument against a generalized synaptic effect in the static or stable MS patient. However, this would not exclude the possibility of detecting such an effect if more specific and sensitive measures of human synaptic function could be developed. The peak-to-peak amplitude of the single cycle average can be considered to be related to the amount of evoked cortical activity. If one hypo-
31
SOMATOSENSORY RESPONSE IN MS
thesizes that the level of cortical activity is directly related to both the number of subcortical conducting axons and the degree of partial conduction blockage, then the amplitude of this response should give a rough index of conduction block in these pathways. This was borne out by our results, in that there was an apparent close correlation between amplitudes and severity of clinical deficits. In addition, the amplitude values seem to be well suited for discriminating between normal subjects and MS patients. By use of Hotelling's multivariate T test (Anderson 1958), the two test groups were significantly separated (P < 0.001). This separation was also reflected in the Z-scores calculated for each individual, which permitted subject classification into the appropriate group. It was anticipated that the response phase angles would be related to conduction time from the site of stimulation to the cortex and thus reflect decreased conduction velocity across demyelinated regions. The phase angle data, however, did not demonstrate a separation between the normal and patient groups. One hypothesis which can possibly account for both the observed amplitude and phase angle data is as follows. Due to the short interstimulus intervals used, insufficient recovery time was available following the first stimulus, leading to an intermittent blockage of the effected fibers. That is, the fibers conduct across the demyelinated regions for only a fraction of the time. This in turn produces an amplitude attenuation proportional to the percentage of time conduction is blocked. The decrease in conduction velocity, while being significant across the demyelinated regions, has an effect which is insignificant for the total pathways under consideration, thereby producing no significant change in the phase angles between normals and patients. The concept of conduction blockage was suggested in a previous study (Namerow 1970) where successive blocking of demyelinated axons could explain recovery function response as one decreased interstimulus intervals. It has already been shown that conduction blockage is a primary factor when experimentally demyelinated lesions are exposed to heat (Davis 1970), and it is not unreasonable to assume a similar mechanism in MS. Recent animal studies (Rasminsky 1973)
support the concept that chronic slowing of conduction in demyelinated nerve fibers may be of minor clinical significance in human demyelinating disease and that the significant factor may be intermittent blockage of afferent impulses to a degree proportional to the severity of the underlying pathology. If one accepts this hypothesis then the following clinical inference can be made : Signs and symptoms in MS may be produced in primary fashion by intermittent nerve conduction block with slowed conduction playing a less important role. CONCLUSIONS
The SERT appears to be an extremely sensitive measure of neuronal function and as such should have direct clinical and experimental application in studying demyelinating disease. It is apparent from these experiments that the afferent pathways in patients suffering from MS have an impaired ability to transmit trains of stimuli. This impaired ability can be quantitatively described by the filtered single cycle peak-topeak amplitudes over a range of stimulating frequencies. There is a direct correlation between these amplitudes and the severity of clinical sensory impairment in the hands under study. Based on these measured values, discriminant functions can be developed which permit the classification of subjects into either normal or patient populations, and which permit probabilistic statements to be made about the chances of a particular individual belonging to either group. The phase angle measurements did not separate normal subjects from patients. Additionally, this method of study has the advantage of testing the entire central pathway, including axonal and synaptic components. This assumes greater importance in view of the growing body of evidence and orientation of thinking that considers multiple sclerosis as a membrance disease. The question of a synaptic factor in MS has not been fully resolved (Bornstein 1968; Carels and Cerf 1969), and at least one recent human study raises this issue again (Sonninen e t a l. 1973). Although direct measurements cannot be made, the SERT may find usefulness in evaluating this aspect of neuronal function in man.
32
R . J . SCLABASSI ('1 al.
SUMMARY
The train somatosensory evoked response (SERT) was examined in a group of thirtythree MS patients. The filtered SERT and single cycle averaged are described for the patient group, with the single cycle average characterized by peak-to-peak voltage amplitude and phase angle measurements. The differences in the experimental response between patients and normal subjects are examined. The single cycle average amplitudes demonstrated significant differences at all stimulating frequencies between the normal subjects and the MS patients, while phase angles did not. A discriminant function, based on the single cycle average peak-to-peak voltages, was developed to aid in characterizing subjects. Additionally, a posteriori probabilities were obtained to permit probabilistic statements concerning subject classification. These results were verified using a normal and MS subject who were correctly identified in each case. The clinical significance of the above observations is discussed. RESUME REPONSE SOMATO-SENSORIELLE
A DES TRAINS DE
STIMULATIONS CHEZ DES MALADES ATTEINTS DE SCLEROSE MU ETIPLE
Les r6ponses 6voqu6es somato-sensorielles des trains de stimulation (SERT) sont 6tudi6es dans un groupe de 33 malades atteints de scl6rose multiple. La SERT filtr6e et la moyenne isol6e d'un cycle sont d6crits pour le groupe de patients, le cycle moyen isol6 ~tant caract~ris~ par l'amphtude pic-fi-pic et les mesures d'angle de phase. Les diff6rences de r6ponse exp6rimentale entre malades et sujets normaux sont examin6es. Les amplitudes moyennes des cycles isol6s montrent des diff6rences significatives fi toute leur s6quence de stimulation entre les sujets normaux et les patients atteints de scl6rose multiple alors que les angles de phase n'en montrent pas. Une fonction discriminante bas6e sur les voltages pic-fi-pic moyens du cycle isol6 a 6t6 d6velopp6e pour aider fit caract6riser les sujets. En outre, des probabilit6s a posteriort ont 6t6
obtenues pour permettre des calculs de probabilit6 concernant la classification des sujets. Ces r6sultats ont et6 v6rifi6s '5 l'aide d'un sujet normal et d'un sujet avec sclerose multiple qui 6tait correctement identifids dans chaque cas. La signification clinique de ces observations est discut6e. The authors would like to acknowledge valuable discussions with Professor Lawrence Kruger In addition the authors wish to express appreciation to Diane Hohn for technical assistance in the laboratory, and to Cynthia Masters for secretarial assistance
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RICHEY, E. T., KOOI, K. A. and TOURTELLOTTE, W. W. Visually evoked responses in multiple sclerosis. J. NeuroL Neurosurg. Psychiat., 1971, 34:275-280 SONNINEN, V., Riekkinen, P. and RINNE, U. K. Acid monoamine metabohtes m cerebrospinal fluid m multiple sclerosis. Neurology ( Mmneap.), 1973, 23: 760-763.