Journal of the Neurological Sciences, 1978, 35:211-224 © Elsevier Scientific Publishing Company, Amsterdam - Printed in The Netherlands
211
T H E CERVICAL SOMATOSENSORY EVOKED P O T E N T I A L (SEP) IN T H E DIAGNOSIS OF M U L T I P L E SCLEROSIS
D. G. SMALL*, W. B. MATTHEWS** and MARIAN SMALL University Department of Neurology, Churchill Hospital, Oxford (Great Britain)
(Received 28 June, 1977)
SUMMARY Abnormalities of the potential evoked by stimulation of the median nerve and recorded over the cervical spine were found in 59 % of patients with multiple sclerosis (,MS) this proportion increasing to 69 % of those in the definite diagnostic category and to 100 % in the severely disabled. Abnormalities were often found in the absence of relevant clinical signs and the method appears to be capable of revealing clinically silent plaques. In patients with a single episode of neurological disease, including retrobulbar neuritis, and at least compatible with the onset of MS, the proportion of abnormalities did not rise above 18 %. Only prolonged follow-up will permit assessment of the value of this and of other evoked potential techniques in the detection of the early case of the disease.
INTRODUCTION Abnormalities of visual (Halliday, McDonald and Mushin 1973) and auditory (Robinson and Rudge 1975) evoked potentials can be demonstrated in patients with multiple sclerosis (MS), often in the absence of relevant symptoms or signs. This evidence of disordered conduction can be used to confirm the existence of multiple lesions within the central nervous system and is therefore of potential diagnostic value. The cervical spinal cord is one of the commonest sites at which MS plaques occur and it was therefore natural to examine the effects of this disease on the potentials recorded over the cervical spine evoked by stimulation of the median nerve that we described in the normal subject (Matthews, Beauchamp and Small 1974). Preliminary results (Small, Beauchamp and Matthews 1974, 1977) had indicated a high proportion of * Present address: The National Hospital, Queen Square, London WC1N 3BG, Great Britain.
** Requests for reprints.
212 abnormalities, again often in the absence of symptoms or signs attributable to disease of the spinal cord. We here present the results of a more extended experience. METHOD The method of stimulation and recording has already been described (Matthews et al. 1974). The stimulus was a square-wave current pulse of 0.3 msec duration applied 1/sec to the median nerve at the wrist, the stimulus strength being adjusted to 4 times the sensory threshold. This produced a slight twitch of the thenar muscles but was not unpleasant. Recordings were made from chlorided silver disc electrodes applied to the skin of the neck, the routine placements being between the 6th and 7th cervical spines (CV7) and immediately rostral to the 2nd cervical spine (CVI), with a common midfrontal reference electrode (FZ, 10-20 system). The response from the hand area of the contralateral parietal region was recorded simultaneously, the placement of the electrode being that described by Namerow (1968), again with FZ as reference. The amplifiers had a flat frequency response from 2 to 1000 Hz and a high frequency rolloff of 24 db/octave above 1500 Hz. The signals were sampled digitally at 10 points/ msec and averaged by summation of 256 responses. Arm length was measured from the 7th cervical spine to the wrist with the arm extended to 90 ° . RESULTS Normal values Attention was directed to the amplitude, latency and wave form of the main negative potential of the cervical response (wave II of NI4)* at the 2 recording sites (CVI and CV7), and to the latency of the initial potential recorded from the scalp (N20). Amplitude of N 14 was measured from the immediately preceding positive trough or from the point of take-off to the peak of the negative potential, as indicated in Fig. 2. Recordings were made from stimulation of 43 arms in 28 normal subjects (age range 18-50 years). The mean amplitude at CVI was 3.1 #V (n 43; range 1.7--4.2; SD 0.7) and at CV7, 2.8 #V (n 43; range 1.5-4.0; SD 0.8). A value of 1 #V or less at either site was taken as abnormal. Normal values of the latency of N14, measured from stimulus to peak, were established in 21 normal subjects and 11 patients without spinal, cerebral or peripheral nervous disease (age range 13-59 years), values for the 2 sides being averaged for each subject if both arms were stimulated. The mean latency at CV7 was 13.4 msec (n 32; SD 0.84). The latency at CV1 did not differ from that at CV7 by more than 0.2 msec in any of these subjects. Asymmetry of latency was present in all subjects in whom both
* While the moan iatencies of this response and of the initial response recorded from the scalp would suggest that these should be called N13 and N19 respectively, these responses have traditionally been designated as N I 4 and N20, a terminology which we retain.
213
:)2--~ 2O
t
14
12
I
I
I
I
I
70
75
80
85
90
ARM LENGTcHm .
Fig. 1. Relation of latency of the main peak of N14 at CV7 and of N20 to a r m length, with regression lines (r = 76; r = 71 respectively) and the upper limits of confidence 2.5 SD above the regression lines.
arms were stimulated but did not exceed 0.7 msec. Latency was correlated with arm length (r : 0.76) and abnormality was defined as a value in excess of 2.5 SD above the regression line of arm length plotted against latency (Fig. 1). The wave form of N14 is normally subject to minor variations but the 3 peaks shown in Fig. 2 can usually be identified. Possible abnormalities of waves I and III have not been considered in this investigation. Wave II is constantly present in the normal and absence or gross distortion of this peak has been taken as abnormal.
129
12,0
lpVI 5m| A
Fig. 2. In this and in subsequent figures CV7 and CVI indicate recordings from the lower and upper cervical electrode placements respectively, with a c o m m o n reference at FZ, evoked by stimulation of the right (R) or left (L) median nerve, 256 sweeps being averaged. The sweep begins 4 msec after the stimulus. Latency of significant peaks is indicated in msec. This illustrates normal results in a w o m a n of 35 with mild but definite MS. The 3 peaks I, II and III are best seen in RCV7. The arrow indicates the point from which the amplitude of wave II is measured. Wave 0 is referred to in the text as a possible point from which to measure latency.
214 The initial purpose of recording from 2 sites in the neck was the attempt to demonstrate slowing of conduction within the cervical spinal cord. NI4, however, does not appear to be a travelling wave and, although, when abnormalities were present, the latency of the main peak often differed widely between the 2 recording sites, no systematic alteration could be detected and these changes appeared to be merely the result of distortion. Consistency of the abnormalities recorded from the two sites was often helpful in clarifying their nature. The mean latency of N20 from stimulus to peak in 20 normal subjects and I 1 patients without relevant disease was 19.1 msec (n 31; SD 0.95). Latency was again correlated with arm length (r = 0.71). Abnormality was defined as values in excess of 2.5 SD above the regression line of arm length against latency (Fig. 1). Absence of N20 was also regarded as abnormal. When clinically relevant abnormalities due to peripheral nerve disease were excluded by recording the sensory potential from the median nerve. Patients
Between April 1973 and August 1976 we examined 126 patients in whom the diagnosis of MS was established or had been reasonably entertained. Many of these patients were examined on more than 1 occasion but the results of a second investigation are included only in 6 patients in whom the diagnostic category had changed between 2 recordings. The results of 132 examinations are therefore reported here. At the time of the recording 52 patients were classified as definite cases of MS, 24 as probable and 21 as possible cases according to the criteria of McAlpine (1972). Eleven patients had optic neuritis alone. Two further categories proved necessary. Eighteen patients were examined within 3 months of the onset of a single episode of neurological disease and are classified as "acute, not diagnosed (AN)". Of these 9 had sensory symptoms, 3 had isolated diplopia, 2 had clinical evidence of a brain stem lesion, 2 had weakness of 1 lower limb and 1 had paroxysmal tonic seizures. A further 6 patients with chronic neurological symptoms or signs in whom a diagnosis of MS was considered unlikely were classified as "chronic, not diagnosed (CN)". The results include those in 2 patients who were each examined at different times when classified in both the possible and definite categories of MS; in 2 patients when probable and later definite; and in 2 who were investigated soon after the onset of symptoms (AN) and were re-examined later when in the probable category. In these 132 recordings in 126 patients abnormalities of N I 4 were present on one or both sides in 63. Abnormalities were of different but inter-related types. Prolonged latency, that is to say, a normal wave form at a latency in excess of the defined normal (Fig. 3) was relatively uncommon, being found as the only abnormality in 15 patients (24 ~ of those with abnormalities). Absence of an evoked potential of greater than 1 #V amplitude at or near the expected latency from stimulation of one or both median nerves (Figs. 4 and 5) was observed in 29 patients (46 ~o of those with a b n o r m a lities). Sometimes this was followed by a late wave of abnormal form (Fig. 6). In 19 patients (30 ~ of those with abnormalities), wave II was absent or greatly diminished in amplitude, with apparent preservation of waves I and III (Figs. 7 and 8). Different
215
16.7 R C V ~
LCV7
14.8
lgV
Fig. 3. Recordings in a m a n of 55 with definite MS but without sensory abnormalities in the upper limbs. RCV7 is of normal form but prolonged latency.
RCVI
LCVI
5
ms
Fig. 4. Bdateral absence of N 14 in a 49-year-old woman with progressive paraparesis, pale optic discs and paraesthesiae in the hands. VEP were also abnormal.
RCVI
14.4 lgV
[ 5ms
Fig. 5. Absence of N14 on stimulation of the left median nerve with a normal response from the right in a m a n of 45 with definite MS but without sensory abnormalities in the upper limbs.
216 RCVI 17.4
RCV7
II~V 12.4
Fig. 6. L o w amplitude, distorted and delayed potential at RCV1 and absence of wave I I at RCV7 in a w o m a n o f 33 with definite b u t mild MS. F o u r years previously she h a d lost postural sense in t h e right a r m b u t there was n o sensory loss at the time o f recording.
LCVI
II~V
LCV7
Fig. 7. A b s e n c e o f wave II with a p p a r e n t preservation o f waves I a n d III in a m a n o f 26 with definite MS. LCVI
14
LCV7
Fig. 8. Reduction in a m p l i t u d e o f wave II in a m a n of 32 with definite MS. Pin-prick s e n s a t i o n was slightly b l u n t e d over the tips of the fingers.
217 abnormalities were sometimes present on stimulation of the two sides, the patient then being allocated to the more severely abnormal category, usually that of absence of the potential. Abnormalities of N20, defined as an absent potential or prolonged latency, were less frequent. In 45 examinations in which N14 was abnormal, abnormalities of N20 were also present. Eighteen patients had abnormal N14 and normal N20 potentials, while only 2 patients had prolonged latency of N20 and normal cervical potentials. One of these was examined while suffering from an acute brain stem lesion, resulting in the locked-in syndrome. Subsequent partial recovery and multiple relapses established the diagnosis of MS. The other patient was a definite case of MS with a short history and clinical evidence of predominant involvement of the brain stem.
Diagnostic value The incidence and distribution of the abnormalities of N14 in the defined diagnostic categories are shown in Table 1 ; 59 ~ of those in the 3 grades of diagnostic certainty of MS had abnormal cervical SEP, the highest incidence of 69 ~ being in patients in the definite category. The relatively high incidence of 52 ~ of abnormality in the possible group is almost entirely accounted for by the inclusion in this category, by definition, of patients with chronic progressive paraplegia without signs of disease beyond the spinal cord and without demonstrable cause. Of the 9 patients with this clinical presentation 8 had abnormal cervical SEP. The incidence of abnormal results was related to the severity of the disease. The 52 patients accepted as definite cases of MS were graded as mild, moderate or severe, the groups corresponding to Kurtzke's (1961) grades 1 and 2, 3 and 4, and 5-7, respectively. The relation of severity to abnormality of the cervical SEP is shown in Table 2. In every severely disabled patient with definite MS N14 was abnormal. Ab-
TABLE 1 DIAGNOSTIC CATEGORIES AND ABNORMALITIES OF N14 IN 132 INVESTIGATIONS OF 126 PATIENTS WITH ESTABLISHED OR SUSPECTED MS Diagnostic category Definite
Probable Possible Optic
AN a
N14 Absent Absent II Delay Normal
18 1l 7 16
5 3 2 14
5 3 3 10
0 l 1 9
0 1 2 15
1 0 0 5
29 19 15 69
Total
52
24
21
I1
18
6
132
69
42 59
52
18
17
17
Abnormal
For meaning of abbreviations see text.
CN a
Total
218 TABLE 2 RELATION OF DEGREE OF DISABILITY TO ABNORMALITY OF N14 IN 52 PATIENTS WITH DEFINITE MS Disability
Mild Moderate Severe
N14 Abnormal
Normal
~ Abnormal
9 14 13
9 7 0
50 67 100
normalities were, however, present, although in a smaller proportion, in patients with less severe disease and could persist during complete clinical remission. Diagnostic assistance is of more importance in the early or dubious case of MS, that is to say, those in the possible or A N categories in this series. The predictive value of SEP recordings in these patients can only be assessed by follow-up, which in no case has exceeded 3.5 years. By the summer of 1976, of the 18 patients in the A N category 5 were lost to follow-up, 1 was known not to have MS but mononeuritis multiplex and 8 were known not to have developed further neurological symptoms. In all these patients N14 had been normal. Three patients developed MS, 2 being probable and 1 a definite case. In 2 of these patients, N14 was normal at the initial examination, while in the third abnormalities were already present within 3 months of the first symptom and became more prominent as the disease advanced. Of the 21 patients classified as possible cases of MS, the 9 with progressive paraplegia did not develop evidence of multiple lesions during the period of follow-up. Of the remaining 12, 3 developed definite MS during the period of follow-up and in all 3 the cervical SEP had been normal when the patient was in the possible category. Nine patients had developed no further symptoms and 3 of these had abnormal SEP. The single patient in the CN category shown in Table 1 to have had abnormal SEP had chronic neurological disease, involving but not confined to the spinal cord, but with sensory loss, wasting and reflex changes thought to be unlike those of MS. The 11 patients presenting with retrobulbar neuritis as an isolated symptom form too small a group to allow conclusions to be drawn on the important matter of the possible value of SEP examination in predicting those who will develop MS. These patients, with others examined subsequently, will be the subject of a later communication. The 18 % of abnormalities found is clearly far below the proportion of these patients who would be expected to develop MS.
Relation of SEP to physical signs An elaborate investigation that merely confirmed the results of clinical sensory examination would be of little diagnostic value. Apart from acute rdapse, sensory loss in the upper limbs in MS is usually confined to slight and often variable blunting of cutaneous sensation in the fingers or similar minor disturbances of postural and vibration sense. We did not, in this series, have the opportunity to examine a patient
219 TABLE 3 RELATION OF SENSORY SYMPTOMS AND SIGNS AT THE TIME OF EXAMINATION TO ABNORMALITIES OF N14 263 arms were stimulated in 132 investigations of 126 patients with established or suspected MS. Sensory symptoms
Present Absent
NI4 Abnormal
Normal
~Abnormal
41 53
29 140
59 27
with acute severe loss o f p o s t u r a l sense o f p r e s u m e d spinal c o r d origin, the "useless h a n d " o f MS. It was n o t possible to correlate a b n o r m a l i t y o f e v o k e d p o t e n t i a l s with any specific f o r m o f sensory loss at the time o f e x a m i n a t i o n . A history o f r e l e v a n t sensory s y m p t o m s in the p a s t often p r o v e d impossible to distinguish with certainty f r o m paraesthesiae o f b a n a l p e r i p h e r a l causation. The c o r r e l a t i o n eventually e x a m i n e d was t h a t with sensory s y m p t o m s or sensory loss detectable on routine clinical e x a m i n a t i o n at the time o f the investigation. T h e results are shown in Table 3. The cervical SEP are clearly m o r e likely to be a b n o r m a l if there are sensory s y m p t o m s or signs in the a r m stimulated. A m o r e i m p o r t a n t finding in the present context is t h a t m o r e t h a n half the a b n o r m a l i t i e s (56 ~ ) f o u n d were f r o m stimulation o f the m e d i a n nerve in a r m s in which such s y m p t o m s and signs were absent. T h e r e was a stronger c o r r e l a t i o n o f a b n o r m a l results with signs o f spinal cord disease, defined as extensor p l a n t a r reflexes or sensory loss in the lower limbs due to long t r a c t i n v o l v e m e n t (Table 4). O f the 43 patients in all d i a g n o s t i c categories w h o h a d no sensory loss in the u p p e r limbs a n d no signs o f spinal c o r d disease 9 (21 ~ ) had a b n o r m a l cervical SEP.
Diagnostic specificity I n v e s t i g a t i o n o f the cervical SEP in forms of spinal c o r d disease other t h a n M S is incomplete. N14 has been n o r m a l in 1 case o f cervical s p o n d y l o t i c m y e l o p a t h y and a b n o r m a l in 2 : n o r m a l in 4 cases o f m o t o r n e u r o n e disease; n o r m a l in 2 patients with s y r i n g o m y e l i a a n d a b n o r m a l in 1 ; a n d n o r m a l in 1 p a t i e n t with an intrinsic cervical TABLE 4 RELATION OF SIGNS OF SPINAL CORD DISEASE, AS DEFINED IN THE TEXT, TO ABNORMALITIES OF NI4 IN 132 INVESTIGATIONS OF 126 PATIENTS WITH ESTABLISHED OR SUSPECTED MS Spinal cord signs
Present Absent
N14 Abnormal
Normal
~ Abnormal
47 16
24 45
66 26
220 TABLE 5 RESULTS OF CERVICAL SEP AND PATTERN REVERSAL VEP IN 74 PATIENTS WITH MS .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Definite Abnormal S and VEP Abnormal S and normal VEP Normal S and abnormal VEP Normal S and VEP Abnormal
.
.
.
.
.
Probable
.
.
.
.
.
.
.
.
Possible
23 6 12 2
6 I 5 3
5 2 4 5
95
80
69
86~
spinal cord tumour. Entirely normal potentials can be recorded from both the neck and scalp in the presence of profound loss of pain and thermal sensation in the stimulated arm. In a single patient with severe dissociated loss of postural sense in the upper limb of presumed spinal origin but of unknown cause, N I 4 was absent. It is, however, clear that abnormalities are not specific for MS. Relation to visual evoked potentials In 102 patients pattern-reversal visual-evoked potentials (VEP) were recorded at the same examination (Matthews, Small, Small and Pountney 1977). The results in the 74 patients in the 3 diagnostic categories of MS are shown in Table 5, and demonstrate the superior diagnostic capability of the combined techniques. DISCUSSION Evidence for the neural origin of N14 and for its probable generation at some site between the lower cervical spine and the brain stem has already been presented (Small et al. 1974; Small 1976). The present investigation throws no further light on the origin of the normal cervical potential except that the results in patients with syringomyelia and severe dissociated loss of pain and thermal sensibility indicate that, in c o m m o n with the scalp recorded SEP (Halliday and Wakefield 1963), N14 does not depend on the integrity of the spinothalamic tract but more probably on that of the posterior columns. We also confirmed our previous observation (Matthews et al_ 1974) that in normal subjects latency of the main peak of N14 was not increased at the more rostral recording site in the neck. This is in contrast to the potential evoked by peripheral nerve stimulation and recorded over the spinal column by Cracco (1973) and by Cracco, Cracco and Graziani (1975), who found prolongation of latency with increasing distance from the site of stimulation. With our recording electrodes approximately 8 cm apart and an assumed conduction velocity within the spinal cord of 55 m/sec (Dorfman 1977), the difference in latency of a travelling wave of this nature between CV7 and CV1 would be of the order o f 1.5 msec. No such difference was found and N14 appears to have characteristics different from those of the potential investigated by Cracco.
221 It was not, therefore, possible to pursue our original intention of investigating the effects of demyelination on conduction velocity within the spinal cord, calculated from the difference in latency between 2 recording sites. Abnormality had to be defined in different terms, presenting difficulties encountered in the clinical use of other forms of evoked potentials. Both the pattern-reversal VEP and the auditory evoked potential are complex wave forms containing several components that can be detected in the normal subject with variable consistency. In order to make any comparison with the results in patients with MS or other diseases it has been necessary to select one or more components that occur in normal subjects with latency, amplitude and wave form predictable within definable limits. With the VEP the P100 is used, although it is not the earliest component, because it is sufficiently consistent for measurements of latency and amplitude to be compared between patients and normal subjects. The auditory potential is more complex but here again it is possible to select certain peaks which allow reasonable comparison of these measurements (Robinson and Rudge 1975). The origins of these different components can be conjectured but are not known with certainty. We applied similar considerations to the cervical SEP. The source is unknown but the main peak of the response has predictable characteristics in the normal subject. A disadvantage of using the latency of the cervical SEP as a criterion of normality is that it is dependent on conduction through a considerable length of peripheral nervous system. We applied a correction based on the correlation between arm length and latency in the normal subject. Mastaglia, Black and Collins (1976), in the only other published account of the use of N14 in diagnosis, made no allowance for arm length but regarded any value in excess of 15.4 msec as abnormal. It is not possible to judge whether this greatly affected their conclusions, but in patients with long arms this value could not be accepted as abnormal (Fig. 1). It may be possible to overcome the difficulty of having to allow for arm length by measuring latency, not from the stimulus, but from the small negative peak that often precedes the main deflection (Fig. 2) and which may originate from the brachial plexus or dorsal roots. We have not consistently used this method as the electrode placement from which this peak can be reliably recorded was only determined at a late stage of the investigation. Prolonged latency of an otherwise normal wave form was a relatively infrequent finding in patients with MS, and reduction of amplitude was usually the major abnormality. Absence of a recognisable potential or a low amplitude peak that could not with certainty be distinguished from background noise was clearly abnormal. When a potential of higher amplitude but much prolonged latency and abnormal wave form was present (Fig. 6), it was sometimes difficult to define whether this was a distorted and delayed NI4 or whether N14 was absent. The other form of abnormality that we recognised as a distinctive pattern was absence of the main peak of N14, leaving the 2 subsidiary peaks at normal latency and amplitude. This is possibly an early stage of complete loss of the potential. Lesser distortions of the characteristic wave form, although commonly seen, were not regarded as abnormal. The proportion of patients in the 3 grades of diagnostic certainty of MS with abnormalities of the cervical SEP was somewhat lower than we reported after examina-
222 tion of the first 60 cases (Small et al. 1977). This is partly explained by the natural inclination to examine first those with indisputable disease, and partly by more rigorous standards of normality. A similar phenomenon can be observed in the results o1 VEP in MS. The 96 ~ of abnormalities first reported by Halliday et al. (1973) could not be confirmed by Asselman, Chadwick and Marsden (1975) whose figure of 67 °~I is comparable to the 62~o in our own series (Matthews et al. 1977). Mastaglia et al. (1976) found an even lower proportion of 50 ~o- These differences no doubt result from the accidents of selection from differing hospital populations and from differences in technique. The usefulness of a diagnostic test in MS must first be examined in those in whom the diagnosis is regarded as certain on other grounds. The criteria for the clinical diagnosis of definite MS described by McAlpine (1972) are imperfect but are used by most investigators. McDonald (1975) already includes the results of neurophysiological measurements in his diagnostic criteria, but this is scarcely permissible in a study of the validity of a neurophysiological technique. Our finding of 69 ~, of abnormalities in clinically definite cases of MS, while comparable with the results of other laboratory tests, such as VEP examination or IgG estimation in the cerebrospinal fluid (Tourtellotte 1970), clearly indicates that in such patients lesions of the ascending tracts of the cervical spinal cord are either not invariable present or are not always detectable by this method. If the patient is severely disabled the cervical SEP are always abnormal, but this important finding is of limited diagnostic value. In the probable and possible categories of MS the proportion of abnormalities falls to 42~o and 52 ~ respectively. The relatively high figure in the possible group is due to the inclusion, by definition, of patients with progressive paraplegia and no clinical evidence of disease beyond the spinal cord. It has long been known that, if spinal tumours are excluded, most such patients, if followed to autopsy, are found to have MS (Marshall 1955). The usefulness of the cervical SEP measurements is not, however, limited to the confirmation of an already established diagnosis, as the technique is capable of demonstrating abnormalities in the cervical spinal cord without clinical accompaniment and presumably resulting from clinically silent plaques. In the majority of arms (56 o/,;) from which abnormal results were obtained, there were no sensory symptoms or sensory signs detected on routine clinical examination. The presence of such signs did, however, influence the results as abnormal potentials were recorded from 59 % of arms so affected (Table 3). The recording of the cervical SEP can, therefore, be added to the methods of detecting subclinical or multiple lesions in those suspected of having MS. Its capability of detecting the early case must, as with other techniques, be assessed after a more prolonged follow-up than has so far been achieved. Initial results are not, however, encouraging, as the 3 patients with possible MS in whom the diagnosis has become definite all had normal cervical SEP when recorded in the early stages of the disease. Of the patients examined during an isolated acute episode of neurological disease other than optic neuritis, 2 have developed MS and 1 of these, with very mild symptoms, had an abnormal recording. Abnormalities may also persist in patients with probable
223 MS who are in complete clinical remission. More extensive observations are needed before any conclusions can be drawn on the prognostic value with regard to subsequent MS of cervical SEP examinations in patients with retrobulbar neuritis. Our analysis of the scalp recorded SEP was limited to the short latency initial negative potential N20, constantly present in normal subjects, although the later, more variable components that other investigators have also examined were recorded. Halliday and Wakefield 0963) described abnormal cerebral SEP in 2 patients with MS. Baker, Larson, Sances and White 0968) found abnormalities in 69 out of 91 patients with MS and comment on the close association with proprioceptive sensory loss, although they do not specifically state whether the sensory changes referred to were in the arm stimulated. Namerow 0968), who paid particular attention to N20, found abnormalities on stimulation of 43 of 58 arms in patients with MS and he also emphasised the association with abnormalities of vibration and postural sense. In our series detection of abnormalities of N20 was a much less sensitive indicator of disease than the cervical SEP N14. In only 2 patients, both with clinical evidence of a brain stem lesion, was the cerebral potential delayed when the cervical potential was normal, whereas N20 was often unaffected when N14 was abnormal or absent. Mastaglia et al. (1976) have reported on the combined use of SEP and VEP examination in the diagnosis of MS. Using the cervical response alone they found abnormalities in 16 out of 17 patients with definite MS, but do not state whether their patients were severely disabled. Of the 52 patients in the 3 diagnostic categories of MS, 57 ~ had abnormal cervical SEP, a figure close to our finding of 59 ~. Using both techniques, they found 69 ~ of abnormalities of either SEP, VEP or both in patients with MS, SEP being the more sensitive test. In patients with MS in our series in whom both methods were employed the proportion of abnormalities reached 86 ~. There are difficulties in using the cervical SEP alone in the differential diagnosis of MS from other forms of spinal cord pathology, particularly spondylotic myelopathy. Abnormal potentials recorded in the absence of abnormal signs in the arm stimulated at present appear to favour a diagnosis of MS. Otherwise the abnormalities are in no way specific but are indicative of spinal cord disease, presumably involving the posterior columns. For diagnostic purposes the recording of potentials evoked by several forms of stimulus has obvious advantages in the demonstration of multiple or subclinical lesions. The abnormalities of cervical SEP in MS differ in character from those of VEP in that reduction of amplitude or absence of the response or of its main component was much more common than prolonged latency of a normal or low voltage potential. It is, perhaps, difficult to compare the short latency electrically evoked cervical potential with the long latency P100 visual potential evoked by pattern reversal. In the latter Halliday and McDonald (1977) have suggested that prolongation of latency, which seldom recovers as vision improves, is the result of demyelination, while reduction in amplitude, often rapidly reversible, indicates the number of fibres affected by conduction block. The results of serial recording of the cervical SEP will be reported later, but so far do not suggest that a similar explanation can be applied. Interpretation is impeded by lack of knowledge of the origins of the potential and of its separate components.
224 ACKNOWLEDGEMENTS O u r t h a n k s are d u e to o u r c o l l e a g u e s w h o r e f e r r e d p a t i e n t s for investigat,o~,. T h e w o r k was s u p p o r t e d in p a r t by the M . R . C .
REFERENCES Asselman, P., D. W. Chadwick and C_ E. Marsden (1975) Visual evoked responses in the diagnosis and management of patients suspected of multiple sclerosis, Brain, 98 : 261-282. Baker, J. B., S. J. Larson, A. Sances and P. T. White (1968) Evoked potentials as an aid to the diagnosis of multiple sclerosis, Neurology (Minneap.), 18:286 (abstract). Cracco, J. B., R. Q. Cracco and L. J. Graziani (1975) The spinal evoked response in infants and chddren, Neurology (Minneap.), 25: 31-36. Cracco, R. Q_ (1973) Spinal evoked response: peripheral nerve stimulation in man, Electroenceph. clin. Neurophysiol., 35: 379-386. Dorfman, L. J. (1977) Indirect estimation of spinal cord conduction velocity in man, Electroe~ceph. clin. Neurophysiol., 42: 26-34. Halliday, A. M. and W. I. McDonald (1977) Pathophysiology of demyelinating disease, Brit. reed. Bull., 33: 21-27. Halliday, A. M. and G. W. Wakefield (1963) Cerebral evoked potentials in patients with dissocmted sensory loss, J. Neurol. Neurosurg. Psychiat., 26: 211-219. Halliday, A. M., W. I. McDonald and J_ Mushin (1973) Visual evoked response in diagnosis of multiple sclerosis, Brit. reed. J., 4: 661-664. Kurtzke, J_ F. (1961) On the evaluation of disability in multiple sclerosis, Neurology (Minneap.), 11 : 686-694. McAlpine, D. (1972) In: Multiple Sclerosis: a Reappraisal, Churchill-Livingstone, Edinburgh, p. 202. McDonald, W. I. (1975) In: A. N. Davison, J. H. Humphrey, L. A. Liversedge, W. I. McDonald and J. S. Porterfield (Eds.), Multiple Sclerosis Research, H. M. Stationery Office, London, p. 8. Marshall, J. (1955) Spastic paraplegia of middle age. A clinico-pathological study, Lancet, l : 693-695. Mastaglia, F. L., J. I. Black and D. W_ K. Collins (1976) Visual and spinal evoked potentials in diagnosis of multiple sclerosis, Brit. reed. J., 3: 732. Matthews, W_ B., M. Beauchamp and D. G. Small (1974) Cervical somatosensory evoked responses in man, Nature (Lond.), 252: 230-232. Matthews, W. B., D. G. Small, M. Small and E. Pountney (1977) The pattern reversal evoked visual potential in the diagnosis of multiple sclerosis, J. NeuroL Neurosurg. Psychiat., in press. Namerow, N. S. (1968) Somatosensory evoked responses in multiple sclerosis patients with varying sensory loss, Neurology (Minneap.), 18: 1197-1204. Robinson, K. and P. Rudge (1975) Auditory evoked responses in multiple sclerosis, Lancet, 1 : 11641166_ Small, D. G. (1976) Peripherally evoked spinal cord potentials in neurological diagnosis. In: J. P. Nicholson tEd.), Scientific Aids in Hospital Diagnosis, Plenum Press, New York, pp. 155-163. Small, D. G., M. Beauchamp and W. B. Matthews (1974) Subcortical somatosensory evoked responses in man. In: J. E. Desmedt tEd.), Proceedings o] the International Symposium on Cerebral Evoked Potentials in Man, in press. Small, D. G., M. Beauchamp and W. B. Matthews (1977) Spinal evoked potentials m multiple sclerosis, Electroenceph. clin. Neurophysiol., 42: 141. Tourtellotte, W_ W. (1970) In: P. J. Vinken and G. W. Bruyn (Eds. ), Handbook oJ Clinical Neurology, Vol_ 9, North-Holland, Amsterdam, pp. 347-363.
211
T H E CERVICAL SOMATOSENSORY EVOKED P O T E N T I A L (SEP) IN T H E DIAGNOSIS OF M U L T I P L E SCLEROSIS
D. G. SMALL*, W. B. MATTHEWS** and MARIAN SMALL University Department of Neurology, Churchill Hospital, Oxford (Great Britain)
(Received 28 June, 1977)
SUMMARY Abnormalities of the potential evoked by stimulation of the median nerve and recorded over the cervical spine were found in 59 % of patients with multiple sclerosis (,MS) this proportion increasing to 69 % of those in the definite diagnostic category and to 100 % in the severely disabled. Abnormalities were often found in the absence of relevant clinical signs and the method appears to be capable of revealing clinically silent plaques. In patients with a single episode of neurological disease, including retrobulbar neuritis, and at least compatible with the onset of MS, the proportion of abnormalities did not rise above 18 %. Only prolonged follow-up will permit assessment of the value of this and of other evoked potential techniques in the detection of the early case of the disease.
INTRODUCTION Abnormalities of visual (Halliday, McDonald and Mushin 1973) and auditory (Robinson and Rudge 1975) evoked potentials can be demonstrated in patients with multiple sclerosis (MS), often in the absence of relevant symptoms or signs. This evidence of disordered conduction can be used to confirm the existence of multiple lesions within the central nervous system and is therefore of potential diagnostic value. The cervical spinal cord is one of the commonest sites at which MS plaques occur and it was therefore natural to examine the effects of this disease on the potentials recorded over the cervical spine evoked by stimulation of the median nerve that we described in the normal subject (Matthews, Beauchamp and Small 1974). Preliminary results (Small, Beauchamp and Matthews 1974, 1977) had indicated a high proportion of * Present address: The National Hospital, Queen Square, London WC1N 3BG, Great Britain.
** Requests for reprints.
212 abnormalities, again often in the absence of symptoms or signs attributable to disease of the spinal cord. We here present the results of a more extended experience. METHOD The method of stimulation and recording has already been described (Matthews et al. 1974). The stimulus was a square-wave current pulse of 0.3 msec duration applied 1/sec to the median nerve at the wrist, the stimulus strength being adjusted to 4 times the sensory threshold. This produced a slight twitch of the thenar muscles but was not unpleasant. Recordings were made from chlorided silver disc electrodes applied to the skin of the neck, the routine placements being between the 6th and 7th cervical spines (CV7) and immediately rostral to the 2nd cervical spine (CVI), with a common midfrontal reference electrode (FZ, 10-20 system). The response from the hand area of the contralateral parietal region was recorded simultaneously, the placement of the electrode being that described by Namerow (1968), again with FZ as reference. The amplifiers had a flat frequency response from 2 to 1000 Hz and a high frequency rolloff of 24 db/octave above 1500 Hz. The signals were sampled digitally at 10 points/ msec and averaged by summation of 256 responses. Arm length was measured from the 7th cervical spine to the wrist with the arm extended to 90 ° . RESULTS Normal values Attention was directed to the amplitude, latency and wave form of the main negative potential of the cervical response (wave II of NI4)* at the 2 recording sites (CVI and CV7), and to the latency of the initial potential recorded from the scalp (N20). Amplitude of N 14 was measured from the immediately preceding positive trough or from the point of take-off to the peak of the negative potential, as indicated in Fig. 2. Recordings were made from stimulation of 43 arms in 28 normal subjects (age range 18-50 years). The mean amplitude at CVI was 3.1 #V (n 43; range 1.7--4.2; SD 0.7) and at CV7, 2.8 #V (n 43; range 1.5-4.0; SD 0.8). A value of 1 #V or less at either site was taken as abnormal. Normal values of the latency of N14, measured from stimulus to peak, were established in 21 normal subjects and 11 patients without spinal, cerebral or peripheral nervous disease (age range 13-59 years), values for the 2 sides being averaged for each subject if both arms were stimulated. The mean latency at CV7 was 13.4 msec (n 32; SD 0.84). The latency at CV1 did not differ from that at CV7 by more than 0.2 msec in any of these subjects. Asymmetry of latency was present in all subjects in whom both
* While the moan iatencies of this response and of the initial response recorded from the scalp would suggest that these should be called N13 and N19 respectively, these responses have traditionally been designated as N I 4 and N20, a terminology which we retain.
213
:)2--~ 2O
t
14
12
I
I
I
I
I
70
75
80
85
90
ARM LENGTcHm .
Fig. 1. Relation of latency of the main peak of N14 at CV7 and of N20 to a r m length, with regression lines (r = 76; r = 71 respectively) and the upper limits of confidence 2.5 SD above the regression lines.
arms were stimulated but did not exceed 0.7 msec. Latency was correlated with arm length (r : 0.76) and abnormality was defined as a value in excess of 2.5 SD above the regression line of arm length plotted against latency (Fig. 1). The wave form of N14 is normally subject to minor variations but the 3 peaks shown in Fig. 2 can usually be identified. Possible abnormalities of waves I and III have not been considered in this investigation. Wave II is constantly present in the normal and absence or gross distortion of this peak has been taken as abnormal.
129
12,0
lpVI 5m| A
Fig. 2. In this and in subsequent figures CV7 and CVI indicate recordings from the lower and upper cervical electrode placements respectively, with a c o m m o n reference at FZ, evoked by stimulation of the right (R) or left (L) median nerve, 256 sweeps being averaged. The sweep begins 4 msec after the stimulus. Latency of significant peaks is indicated in msec. This illustrates normal results in a w o m a n of 35 with mild but definite MS. The 3 peaks I, II and III are best seen in RCV7. The arrow indicates the point from which the amplitude of wave II is measured. Wave 0 is referred to in the text as a possible point from which to measure latency.
214 The initial purpose of recording from 2 sites in the neck was the attempt to demonstrate slowing of conduction within the cervical spinal cord. NI4, however, does not appear to be a travelling wave and, although, when abnormalities were present, the latency of the main peak often differed widely between the 2 recording sites, no systematic alteration could be detected and these changes appeared to be merely the result of distortion. Consistency of the abnormalities recorded from the two sites was often helpful in clarifying their nature. The mean latency of N20 from stimulus to peak in 20 normal subjects and I 1 patients without relevant disease was 19.1 msec (n 31; SD 0.95). Latency was again correlated with arm length (r = 0.71). Abnormality was defined as values in excess of 2.5 SD above the regression line of arm length against latency (Fig. 1). Absence of N20 was also regarded as abnormal. When clinically relevant abnormalities due to peripheral nerve disease were excluded by recording the sensory potential from the median nerve. Patients
Between April 1973 and August 1976 we examined 126 patients in whom the diagnosis of MS was established or had been reasonably entertained. Many of these patients were examined on more than 1 occasion but the results of a second investigation are included only in 6 patients in whom the diagnostic category had changed between 2 recordings. The results of 132 examinations are therefore reported here. At the time of the recording 52 patients were classified as definite cases of MS, 24 as probable and 21 as possible cases according to the criteria of McAlpine (1972). Eleven patients had optic neuritis alone. Two further categories proved necessary. Eighteen patients were examined within 3 months of the onset of a single episode of neurological disease and are classified as "acute, not diagnosed (AN)". Of these 9 had sensory symptoms, 3 had isolated diplopia, 2 had clinical evidence of a brain stem lesion, 2 had weakness of 1 lower limb and 1 had paroxysmal tonic seizures. A further 6 patients with chronic neurological symptoms or signs in whom a diagnosis of MS was considered unlikely were classified as "chronic, not diagnosed (CN)". The results include those in 2 patients who were each examined at different times when classified in both the possible and definite categories of MS; in 2 patients when probable and later definite; and in 2 who were investigated soon after the onset of symptoms (AN) and were re-examined later when in the probable category. In these 132 recordings in 126 patients abnormalities of N I 4 were present on one or both sides in 63. Abnormalities were of different but inter-related types. Prolonged latency, that is to say, a normal wave form at a latency in excess of the defined normal (Fig. 3) was relatively uncommon, being found as the only abnormality in 15 patients (24 ~ of those with abnormalities). Absence of an evoked potential of greater than 1 #V amplitude at or near the expected latency from stimulation of one or both median nerves (Figs. 4 and 5) was observed in 29 patients (46 ~o of those with a b n o r m a lities). Sometimes this was followed by a late wave of abnormal form (Fig. 6). In 19 patients (30 ~ of those with abnormalities), wave II was absent or greatly diminished in amplitude, with apparent preservation of waves I and III (Figs. 7 and 8). Different
215
16.7 R C V ~
LCV7
14.8
lgV
Fig. 3. Recordings in a m a n of 55 with definite MS but without sensory abnormalities in the upper limbs. RCV7 is of normal form but prolonged latency.
RCVI
LCVI
5
ms
Fig. 4. Bdateral absence of N 14 in a 49-year-old woman with progressive paraparesis, pale optic discs and paraesthesiae in the hands. VEP were also abnormal.
RCVI
14.4 lgV
[ 5ms
Fig. 5. Absence of N14 on stimulation of the left median nerve with a normal response from the right in a m a n of 45 with definite MS but without sensory abnormalities in the upper limbs.
216 RCVI 17.4
RCV7
II~V 12.4
Fig. 6. L o w amplitude, distorted and delayed potential at RCV1 and absence of wave I I at RCV7 in a w o m a n o f 33 with definite b u t mild MS. F o u r years previously she h a d lost postural sense in t h e right a r m b u t there was n o sensory loss at the time o f recording.
LCVI
II~V
LCV7
Fig. 7. A b s e n c e o f wave II with a p p a r e n t preservation o f waves I a n d III in a m a n o f 26 with definite MS. LCVI
14
LCV7
Fig. 8. Reduction in a m p l i t u d e o f wave II in a m a n of 32 with definite MS. Pin-prick s e n s a t i o n was slightly b l u n t e d over the tips of the fingers.
217 abnormalities were sometimes present on stimulation of the two sides, the patient then being allocated to the more severely abnormal category, usually that of absence of the potential. Abnormalities of N20, defined as an absent potential or prolonged latency, were less frequent. In 45 examinations in which N14 was abnormal, abnormalities of N20 were also present. Eighteen patients had abnormal N14 and normal N20 potentials, while only 2 patients had prolonged latency of N20 and normal cervical potentials. One of these was examined while suffering from an acute brain stem lesion, resulting in the locked-in syndrome. Subsequent partial recovery and multiple relapses established the diagnosis of MS. The other patient was a definite case of MS with a short history and clinical evidence of predominant involvement of the brain stem.
Diagnostic value The incidence and distribution of the abnormalities of N14 in the defined diagnostic categories are shown in Table 1 ; 59 ~ of those in the 3 grades of diagnostic certainty of MS had abnormal cervical SEP, the highest incidence of 69 ~ being in patients in the definite category. The relatively high incidence of 52 ~ of abnormality in the possible group is almost entirely accounted for by the inclusion in this category, by definition, of patients with chronic progressive paraplegia without signs of disease beyond the spinal cord and without demonstrable cause. Of the 9 patients with this clinical presentation 8 had abnormal cervical SEP. The incidence of abnormal results was related to the severity of the disease. The 52 patients accepted as definite cases of MS were graded as mild, moderate or severe, the groups corresponding to Kurtzke's (1961) grades 1 and 2, 3 and 4, and 5-7, respectively. The relation of severity to abnormality of the cervical SEP is shown in Table 2. In every severely disabled patient with definite MS N14 was abnormal. Ab-
TABLE 1 DIAGNOSTIC CATEGORIES AND ABNORMALITIES OF N14 IN 132 INVESTIGATIONS OF 126 PATIENTS WITH ESTABLISHED OR SUSPECTED MS Diagnostic category Definite
Probable Possible Optic
AN a
N14 Absent Absent II Delay Normal
18 1l 7 16
5 3 2 14
5 3 3 10
0 l 1 9
0 1 2 15
1 0 0 5
29 19 15 69
Total
52
24
21
I1
18
6
132
69
42 59
52
18
17
17
Abnormal
For meaning of abbreviations see text.
CN a
Total
218 TABLE 2 RELATION OF DEGREE OF DISABILITY TO ABNORMALITY OF N14 IN 52 PATIENTS WITH DEFINITE MS Disability
Mild Moderate Severe
N14 Abnormal
Normal
~ Abnormal
9 14 13
9 7 0
50 67 100
normalities were, however, present, although in a smaller proportion, in patients with less severe disease and could persist during complete clinical remission. Diagnostic assistance is of more importance in the early or dubious case of MS, that is to say, those in the possible or A N categories in this series. The predictive value of SEP recordings in these patients can only be assessed by follow-up, which in no case has exceeded 3.5 years. By the summer of 1976, of the 18 patients in the A N category 5 were lost to follow-up, 1 was known not to have MS but mononeuritis multiplex and 8 were known not to have developed further neurological symptoms. In all these patients N14 had been normal. Three patients developed MS, 2 being probable and 1 a definite case. In 2 of these patients, N14 was normal at the initial examination, while in the third abnormalities were already present within 3 months of the first symptom and became more prominent as the disease advanced. Of the 21 patients classified as possible cases of MS, the 9 with progressive paraplegia did not develop evidence of multiple lesions during the period of follow-up. Of the remaining 12, 3 developed definite MS during the period of follow-up and in all 3 the cervical SEP had been normal when the patient was in the possible category. Nine patients had developed no further symptoms and 3 of these had abnormal SEP. The single patient in the CN category shown in Table 1 to have had abnormal SEP had chronic neurological disease, involving but not confined to the spinal cord, but with sensory loss, wasting and reflex changes thought to be unlike those of MS. The 11 patients presenting with retrobulbar neuritis as an isolated symptom form too small a group to allow conclusions to be drawn on the important matter of the possible value of SEP examination in predicting those who will develop MS. These patients, with others examined subsequently, will be the subject of a later communication. The 18 % of abnormalities found is clearly far below the proportion of these patients who would be expected to develop MS.
Relation of SEP to physical signs An elaborate investigation that merely confirmed the results of clinical sensory examination would be of little diagnostic value. Apart from acute rdapse, sensory loss in the upper limbs in MS is usually confined to slight and often variable blunting of cutaneous sensation in the fingers or similar minor disturbances of postural and vibration sense. We did not, in this series, have the opportunity to examine a patient
219 TABLE 3 RELATION OF SENSORY SYMPTOMS AND SIGNS AT THE TIME OF EXAMINATION TO ABNORMALITIES OF N14 263 arms were stimulated in 132 investigations of 126 patients with established or suspected MS. Sensory symptoms
Present Absent
NI4 Abnormal
Normal
~Abnormal
41 53
29 140
59 27
with acute severe loss o f p o s t u r a l sense o f p r e s u m e d spinal c o r d origin, the "useless h a n d " o f MS. It was n o t possible to correlate a b n o r m a l i t y o f e v o k e d p o t e n t i a l s with any specific f o r m o f sensory loss at the time o f e x a m i n a t i o n . A history o f r e l e v a n t sensory s y m p t o m s in the p a s t often p r o v e d impossible to distinguish with certainty f r o m paraesthesiae o f b a n a l p e r i p h e r a l causation. The c o r r e l a t i o n eventually e x a m i n e d was t h a t with sensory s y m p t o m s or sensory loss detectable on routine clinical e x a m i n a t i o n at the time o f the investigation. T h e results are shown in Table 3. The cervical SEP are clearly m o r e likely to be a b n o r m a l if there are sensory s y m p t o m s or signs in the a r m stimulated. A m o r e i m p o r t a n t finding in the present context is t h a t m o r e t h a n half the a b n o r m a l i t i e s (56 ~ ) f o u n d were f r o m stimulation o f the m e d i a n nerve in a r m s in which such s y m p t o m s and signs were absent. T h e r e was a stronger c o r r e l a t i o n o f a b n o r m a l results with signs o f spinal cord disease, defined as extensor p l a n t a r reflexes or sensory loss in the lower limbs due to long t r a c t i n v o l v e m e n t (Table 4). O f the 43 patients in all d i a g n o s t i c categories w h o h a d no sensory loss in the u p p e r limbs a n d no signs o f spinal c o r d disease 9 (21 ~ ) had a b n o r m a l cervical SEP.
Diagnostic specificity I n v e s t i g a t i o n o f the cervical SEP in forms of spinal c o r d disease other t h a n M S is incomplete. N14 has been n o r m a l in 1 case o f cervical s p o n d y l o t i c m y e l o p a t h y and a b n o r m a l in 2 : n o r m a l in 4 cases o f m o t o r n e u r o n e disease; n o r m a l in 2 patients with s y r i n g o m y e l i a a n d a b n o r m a l in 1 ; a n d n o r m a l in 1 p a t i e n t with an intrinsic cervical TABLE 4 RELATION OF SIGNS OF SPINAL CORD DISEASE, AS DEFINED IN THE TEXT, TO ABNORMALITIES OF NI4 IN 132 INVESTIGATIONS OF 126 PATIENTS WITH ESTABLISHED OR SUSPECTED MS Spinal cord signs
Present Absent
N14 Abnormal
Normal
~ Abnormal
47 16
24 45
66 26
220 TABLE 5 RESULTS OF CERVICAL SEP AND PATTERN REVERSAL VEP IN 74 PATIENTS WITH MS .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Definite Abnormal S and VEP Abnormal S and normal VEP Normal S and abnormal VEP Normal S and VEP Abnormal
.
.
.
.
.
Probable
.
.
.
.
.
.
.
.
Possible
23 6 12 2
6 I 5 3
5 2 4 5
95
80
69
86~
spinal cord tumour. Entirely normal potentials can be recorded from both the neck and scalp in the presence of profound loss of pain and thermal sensation in the stimulated arm. In a single patient with severe dissociated loss of postural sense in the upper limb of presumed spinal origin but of unknown cause, N I 4 was absent. It is, however, clear that abnormalities are not specific for MS. Relation to visual evoked potentials In 102 patients pattern-reversal visual-evoked potentials (VEP) were recorded at the same examination (Matthews, Small, Small and Pountney 1977). The results in the 74 patients in the 3 diagnostic categories of MS are shown in Table 5, and demonstrate the superior diagnostic capability of the combined techniques. DISCUSSION Evidence for the neural origin of N14 and for its probable generation at some site between the lower cervical spine and the brain stem has already been presented (Small et al. 1974; Small 1976). The present investigation throws no further light on the origin of the normal cervical potential except that the results in patients with syringomyelia and severe dissociated loss of pain and thermal sensibility indicate that, in c o m m o n with the scalp recorded SEP (Halliday and Wakefield 1963), N14 does not depend on the integrity of the spinothalamic tract but more probably on that of the posterior columns. We also confirmed our previous observation (Matthews et al_ 1974) that in normal subjects latency of the main peak of N14 was not increased at the more rostral recording site in the neck. This is in contrast to the potential evoked by peripheral nerve stimulation and recorded over the spinal column by Cracco (1973) and by Cracco, Cracco and Graziani (1975), who found prolongation of latency with increasing distance from the site of stimulation. With our recording electrodes approximately 8 cm apart and an assumed conduction velocity within the spinal cord of 55 m/sec (Dorfman 1977), the difference in latency of a travelling wave of this nature between CV7 and CV1 would be of the order o f 1.5 msec. No such difference was found and N14 appears to have characteristics different from those of the potential investigated by Cracco.
221 It was not, therefore, possible to pursue our original intention of investigating the effects of demyelination on conduction velocity within the spinal cord, calculated from the difference in latency between 2 recording sites. Abnormality had to be defined in different terms, presenting difficulties encountered in the clinical use of other forms of evoked potentials. Both the pattern-reversal VEP and the auditory evoked potential are complex wave forms containing several components that can be detected in the normal subject with variable consistency. In order to make any comparison with the results in patients with MS or other diseases it has been necessary to select one or more components that occur in normal subjects with latency, amplitude and wave form predictable within definable limits. With the VEP the P100 is used, although it is not the earliest component, because it is sufficiently consistent for measurements of latency and amplitude to be compared between patients and normal subjects. The auditory potential is more complex but here again it is possible to select certain peaks which allow reasonable comparison of these measurements (Robinson and Rudge 1975). The origins of these different components can be conjectured but are not known with certainty. We applied similar considerations to the cervical SEP. The source is unknown but the main peak of the response has predictable characteristics in the normal subject. A disadvantage of using the latency of the cervical SEP as a criterion of normality is that it is dependent on conduction through a considerable length of peripheral nervous system. We applied a correction based on the correlation between arm length and latency in the normal subject. Mastaglia, Black and Collins (1976), in the only other published account of the use of N14 in diagnosis, made no allowance for arm length but regarded any value in excess of 15.4 msec as abnormal. It is not possible to judge whether this greatly affected their conclusions, but in patients with long arms this value could not be accepted as abnormal (Fig. 1). It may be possible to overcome the difficulty of having to allow for arm length by measuring latency, not from the stimulus, but from the small negative peak that often precedes the main deflection (Fig. 2) and which may originate from the brachial plexus or dorsal roots. We have not consistently used this method as the electrode placement from which this peak can be reliably recorded was only determined at a late stage of the investigation. Prolonged latency of an otherwise normal wave form was a relatively infrequent finding in patients with MS, and reduction of amplitude was usually the major abnormality. Absence of a recognisable potential or a low amplitude peak that could not with certainty be distinguished from background noise was clearly abnormal. When a potential of higher amplitude but much prolonged latency and abnormal wave form was present (Fig. 6), it was sometimes difficult to define whether this was a distorted and delayed NI4 or whether N14 was absent. The other form of abnormality that we recognised as a distinctive pattern was absence of the main peak of N14, leaving the 2 subsidiary peaks at normal latency and amplitude. This is possibly an early stage of complete loss of the potential. Lesser distortions of the characteristic wave form, although commonly seen, were not regarded as abnormal. The proportion of patients in the 3 grades of diagnostic certainty of MS with abnormalities of the cervical SEP was somewhat lower than we reported after examina-
222 tion of the first 60 cases (Small et al. 1977). This is partly explained by the natural inclination to examine first those with indisputable disease, and partly by more rigorous standards of normality. A similar phenomenon can be observed in the results o1 VEP in MS. The 96 ~ of abnormalities first reported by Halliday et al. (1973) could not be confirmed by Asselman, Chadwick and Marsden (1975) whose figure of 67 °~I is comparable to the 62~o in our own series (Matthews et al. 1977). Mastaglia et al. (1976) found an even lower proportion of 50 ~o- These differences no doubt result from the accidents of selection from differing hospital populations and from differences in technique. The usefulness of a diagnostic test in MS must first be examined in those in whom the diagnosis is regarded as certain on other grounds. The criteria for the clinical diagnosis of definite MS described by McAlpine (1972) are imperfect but are used by most investigators. McDonald (1975) already includes the results of neurophysiological measurements in his diagnostic criteria, but this is scarcely permissible in a study of the validity of a neurophysiological technique. Our finding of 69 ~, of abnormalities in clinically definite cases of MS, while comparable with the results of other laboratory tests, such as VEP examination or IgG estimation in the cerebrospinal fluid (Tourtellotte 1970), clearly indicates that in such patients lesions of the ascending tracts of the cervical spinal cord are either not invariable present or are not always detectable by this method. If the patient is severely disabled the cervical SEP are always abnormal, but this important finding is of limited diagnostic value. In the probable and possible categories of MS the proportion of abnormalities falls to 42~o and 52 ~ respectively. The relatively high figure in the possible group is due to the inclusion, by definition, of patients with progressive paraplegia and no clinical evidence of disease beyond the spinal cord. It has long been known that, if spinal tumours are excluded, most such patients, if followed to autopsy, are found to have MS (Marshall 1955). The usefulness of the cervical SEP measurements is not, however, limited to the confirmation of an already established diagnosis, as the technique is capable of demonstrating abnormalities in the cervical spinal cord without clinical accompaniment and presumably resulting from clinically silent plaques. In the majority of arms (56 o/,;) from which abnormal results were obtained, there were no sensory symptoms or sensory signs detected on routine clinical examination. The presence of such signs did, however, influence the results as abnormal potentials were recorded from 59 % of arms so affected (Table 3). The recording of the cervical SEP can, therefore, be added to the methods of detecting subclinical or multiple lesions in those suspected of having MS. Its capability of detecting the early case must, as with other techniques, be assessed after a more prolonged follow-up than has so far been achieved. Initial results are not, however, encouraging, as the 3 patients with possible MS in whom the diagnosis has become definite all had normal cervical SEP when recorded in the early stages of the disease. Of the patients examined during an isolated acute episode of neurological disease other than optic neuritis, 2 have developed MS and 1 of these, with very mild symptoms, had an abnormal recording. Abnormalities may also persist in patients with probable
223 MS who are in complete clinical remission. More extensive observations are needed before any conclusions can be drawn on the prognostic value with regard to subsequent MS of cervical SEP examinations in patients with retrobulbar neuritis. Our analysis of the scalp recorded SEP was limited to the short latency initial negative potential N20, constantly present in normal subjects, although the later, more variable components that other investigators have also examined were recorded. Halliday and Wakefield 0963) described abnormal cerebral SEP in 2 patients with MS. Baker, Larson, Sances and White 0968) found abnormalities in 69 out of 91 patients with MS and comment on the close association with proprioceptive sensory loss, although they do not specifically state whether the sensory changes referred to were in the arm stimulated. Namerow 0968), who paid particular attention to N20, found abnormalities on stimulation of 43 of 58 arms in patients with MS and he also emphasised the association with abnormalities of vibration and postural sense. In our series detection of abnormalities of N20 was a much less sensitive indicator of disease than the cervical SEP N14. In only 2 patients, both with clinical evidence of a brain stem lesion, was the cerebral potential delayed when the cervical potential was normal, whereas N20 was often unaffected when N14 was abnormal or absent. Mastaglia et al. (1976) have reported on the combined use of SEP and VEP examination in the diagnosis of MS. Using the cervical response alone they found abnormalities in 16 out of 17 patients with definite MS, but do not state whether their patients were severely disabled. Of the 52 patients in the 3 diagnostic categories of MS, 57 ~ had abnormal cervical SEP, a figure close to our finding of 59 ~. Using both techniques, they found 69 ~ of abnormalities of either SEP, VEP or both in patients with MS, SEP being the more sensitive test. In patients with MS in our series in whom both methods were employed the proportion of abnormalities reached 86 ~. There are difficulties in using the cervical SEP alone in the differential diagnosis of MS from other forms of spinal cord pathology, particularly spondylotic myelopathy. Abnormal potentials recorded in the absence of abnormal signs in the arm stimulated at present appear to favour a diagnosis of MS. Otherwise the abnormalities are in no way specific but are indicative of spinal cord disease, presumably involving the posterior columns. For diagnostic purposes the recording of potentials evoked by several forms of stimulus has obvious advantages in the demonstration of multiple or subclinical lesions. The abnormalities of cervical SEP in MS differ in character from those of VEP in that reduction of amplitude or absence of the response or of its main component was much more common than prolonged latency of a normal or low voltage potential. It is, perhaps, difficult to compare the short latency electrically evoked cervical potential with the long latency P100 visual potential evoked by pattern reversal. In the latter Halliday and McDonald (1977) have suggested that prolongation of latency, which seldom recovers as vision improves, is the result of demyelination, while reduction in amplitude, often rapidly reversible, indicates the number of fibres affected by conduction block. The results of serial recording of the cervical SEP will be reported later, but so far do not suggest that a similar explanation can be applied. Interpretation is impeded by lack of knowledge of the origins of the potential and of its separate components.
224 ACKNOWLEDGEMENTS O u r t h a n k s are d u e to o u r c o l l e a g u e s w h o r e f e r r e d p a t i e n t s for investigat,o~,. T h e w o r k was s u p p o r t e d in p a r t by the M . R . C .
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