Brain (1975) 98,413-^26
ELECTRICALLY ELICITED BLINK REFLEX IN DIAGNOSIS OF MULTIPLE SCLEROSIS REVIEW OF 260 PATIENTS OVER A SEVEN-YEAR PERIOD
JUN KIMURA {From the Department of Neurology, College of Medicine, University of Iowa, Iowa City, Iowa)
INTRODUCTION
THE blink reflex elicited by tactile stimulation of the cornea is a part of the routine neurological examination. Although it is an important clinical test for evaluation of the integrity of brain-stem function, accurate quantitative analysis is impossible if the reflex is assessed by simple observation as is done in ordinary clinical practice. The electrically elicited blink reflex is more meaningful in that the recording of the evoked potential with an oscilloscope allows precise determination of the reflex latencies. The blink reflex elicited by electrical stimulation of the supraorbital nerve consists of two temporally separate components (Kugelberg, 1952), an early R x and a late R, reflex (fig. 1). Whereas Rlt evoked only on the side of stimulation, is a simple pontine reflex (Shahani and Young, 1972), R,, recorded bilaterally with unilateral stimulation, is relayed through a more complex route that includes the pons and lateral medulla. Afferent impulses of R 8 enter the pons through the trigeminal nerve, descend to the ipsilateral spinal tract and ascend to make eventual connexions with both ipsilateral and contralateral facial nuclei (Kimura and Lyon, 1972). Because slowed conduction is characteristic of demyelination (McDonald and Sears, 1970), it was felt appropriate to examine the incidence of delayed blink reflexes in multiple sclerosis. In our preliminary study (Kimura, 1970), it was shown that R x was indeed delayed in 17 of 21 patients with clinical pontine signs and that R a was affected most prominently in patients with medullary lesions. Although a few subsequent papers have appeared (Namerow and Etemadi, 1970; Lyon and Van Allen, 1972; Kimura, 1973; Namerow, 1973) confirming the original findings, a large-scale survey of the blink reflex as a diagnostic test in multiple sclerosis has not been published. The purpose of this paper is to report seven years' experience with
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BY
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JUN KTMURA
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Stimulus Itelttlon Unit
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Amplltud*
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l_
Average
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Fio. 1.—Top: Stimulation and recording arrangement for the blink reflex. The presumed pathway of Ri through the pons (1), and direct and consensual R, through the pons and lateral medulla (2 and 3) are schematically indicated. The primary afferents of Ri and R t are shown as one fibre in the illustration. This and other details of central connexions of these reflexes are not known. Bottom: A typical oscilloscope recording of the blink reflex after right-sided stimulation. Note an ipsilateral R t and bilaterally simultaneous R t responses. Modified with permission from Kimura, J., and Harada, O. (1972) Electroenceph. Clin. Neurophysiol, 33, 369-377.
the blink reflex in 260 patients with multiple sclerosis. It will be shown that the test may be used to document a clinically silent brain-stem lesion and help to establish the anatomical dissemination of pathology. METHODS
Subjects lay supine on a bed in a warm room with eyes gently closed. Surface electrodes were used for both stimulation of the nerve and recording of evoked muscle action potentials. For recording, the active electrode was placed on the lateral aspect of the orbicularis oculi muscle and a reference electrode on the lateral surface of the nose. A ground electrode was located under the chin. The supraorbital nerve was stimulated with the cathode placed over the supraorbital foramen on one side, and the reflex responses were recorded from the orbicularis oculi muscle on both sides simultaneously. Shocks were of such
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1. R,
Stlmulttor
415
ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
intensity that R x and R, were just maximum and nearly stable with repeated trials. Shocks of the same intensity were delivered to each side in each subject. The latencies of Rx, ipsilateral Rfc and contralateral R s were measured from the stimulus artifact to the initial deflection of the evoked potential. If R x was difficult to elicit with a single shock it was usually helpful to deliver paired shocks with an interstimulus interval of 5 ms. When this was done the latency of R x was measured from the stimulus artifact of the second shock of the pair. For each subject at least four responses of R x and R 2 were recorded and the mean latency was obtained.
Normal Values The normal ranges of the latency of R x and R, were established in 83 healthy subjects, 7 to 86 years of age (mean age 37). Normal variations among different subjects and between the two sides in individuals are summarized in Table I. There TABLE I.—NORMAL LATENCIES OF R X AND R, COMPONENTS OF THB BLINK REFLEX 83 SUBJECTS (166 RESPONSES CONSEDERINO BOTH SIDES TOGETHER) Ry
Component
Ri
Mean latency (ms) Standard deviation (ms)
M±3 SD (ms) Upper limit of normal (ms)
10-45 0-84
10-5±2•5 13
Difference between two sides in one subject 0-31 0-30 0-3 ±0-9 1-2
Rt Components Difference Difference between Direct Rt Consensual Rt between responses direct (ipsilateral (contralateral to the and to R- and to the L-sided consensual side of side of response stimulus stimulus) stimulus) 10 1-6 30-5 30-5 1-7 1-2 4-4 3-4
31±10 41
31±13 44
1±4
2±5
5
7
was no significant difference between responses on the right and the left side. Normal latencies of R x and R, were distributed on a bell curve. As shown in Table I, R x may be considered delayed if it exceeds 13 ms and R, delayed if it exceeds 41 ms directly and 44 ms consensually. Additionally, the difference in latency of Rx between the two sides in one subject should be less than 1*2 ms. For R, two types of comparison were possible. First, a latency difference between the ipsilateral and the contralateral R 2 simultaneously evoked by stimulation on one side should not exceed 5 ms. Secondly, a latency difference between R, evoked by
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In addition to the reflex responses, the conduction of the facial nerve was also routinely tested by stimulating the nerve with the cathode placed just anterior to the mastoid process and recording the direct muscle response from the ipsilateral orbicularis oculi muscle. Its latency was measured from the stimulus artifact to the beginning of the evoked potential.
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JUN KIMURA
right-sided stimulation and corresponding reflexes subsequently evoked by left-sided stimulation should be less than 7 ms. Multiple Sclerosis Of 260 patients included in this study, 138 were seen at the University of Iowa (1968-69,1972-74) and 122 at the University of Manitoba (1969-72). Approximately one-half of these patients were referred because of a suspected diagnosis of multiple sclerosis. Others were selected from a hospital file or a list provided by the local Multiple Sclerosis Society and were requested to return for the test There were 91 males and 169 females ranging in age from 15 to 73 (mean age 37).
Right Normal Control Case
Case 3
^ ;
Stimulation
|_0.5mv 5 msec
FIG. 2.—Delayed R t on both sides in multiple sclerosis. An electric shock (arrows) was delivered to the supraorbital nerve, and R^ (brackets) of the blink reflex was recorded from the ipsilateral orbicularis oculi muscle in a normal subject and in 8 patients with multiple sclerosis. With a sweep speed of 5 ms/cm used here, R, falls outside the face of the oscilloscope and is not recorded (cf. fig. 3). Two tracings were recorded on each side in each subject to show consistency of Rx response. The top tracings are from a normal control, with shaded areas indicating the normal range (mean ±3 S.D. in 83 subjects). In addition to obvious increases in latency, Rx obtained in these patients is temporally dispersed and very irregular in wave form when compared to that in the normal control. None of these patients had unequivocal pontine signs clinically, although mild horizontal nystagmus was present in Cases 1, 2, 5, 6 and 7.
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All patients were given careful neurological examination before the test On the basis of the history and neurological findings they were divided into three groups:
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ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
145 definite, 57 probable and 58 possible cases of multiple sclerosis. A definite diagnosis was obtained by a history of one or more relapses and clinical evidence of anatomical dissemination of lesions. The diagnosis was considered probable if multiple levels of the central nervous system were involved without historical evidence of a relapse, or alternatively if the findings could be explained by a single lesion despite clinical remissions and exacerbations. Patients presenting with signs and symptoms suggestive of the disease but with neither dissemination of lesions nor a relapsing course were generally considered possible cases. McAlpine's diagnostic criteria (1972) were also utilized in categorizing difficult cases.
Side of Stimulation tion
Afferent Delay
Normal l
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|0.5mv 10 msec Fia. 3.—Alteration of R, in multiple sclerosis. A stimulus was delivered to the supraorbital nerve, and reflex responses were simultaneously recorded from the ipsilateral (upper tracing in each frame) and the contralateral (lower tracing in each frame) orbicularis oculi muscle. From top to bottom, two right-sided and two left-sided stimulations were delivered in each case to show consistency. An electric shock of the same intensity was used on each side. Note R t (small arrows over the peaks) is recorded only in the upper tracings and R, (horizontal brackets), in both the upper and lower tracings in each frame when either side of face is stimulated (cf. fig. 1). In a normal subject there is no significant difference in latencies of Rx or R, between the two sides. In a patient having hypalgesia on the left side of the face, R t was normal bilaterally on right-sided stimulation but nearly absent bilaterally on left-sided stimulation. An afferent delay of Rs, when seen in the face of normal R t as in this case, suggests a lateral medullary lesion. In another patient who had both abducens and facial nerve paresis on the left, R, was delayed on the left and normal on the right regardless of the side of stimulation. This finding together with a delayed Rt on the left suggests a lesion involving the efferent arc of the reflex.
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In patients seen on more than one occasion, the diagnosis was made at the time of the first examination when the blink reflex was tested. Thus, patients diagnosed
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JUN HMURA
initially as having possible multiple sclerosis remained in this category even if the diagnosis became definite during the course of the study. However, 11 patients originally considered as possible cases were excluded because they proved to have other diseases including ischaemic vascular disease (3), brain-stem tumour (2), cerebellar degeneration (2), cervical spondylosis (2), and Bell's palsy (2).
Table II summarizes the incidence of abnormal R x and R, in each group of definite, probable and possible cases. These are further subdivided into six clinically TABLE n.—ALTERATION OF THE BLINK REFLEX AND CLINICAL LOCALIZATION OF LESIONS
IN
260 PATIENTS WITH MULTIPLE SCLEROSIS
Clinical localization ofluiom BAcscnceplulic liffiif Internuclear ophthmlntoplesU Other pontine tlgm Medullary dgnl Brmin-*Um »igni of undetermined level No bnln-ctem lignj Total
Deflnitt dTatnotii Probable dlafnotlt No. with No. wUh No. abnormal tut No. abnormal test tested Rt Rx Rx X, tilled 4 3 7 2 1 3 4 24 6 22 15 6 3 6 14 7 8 11 6 3 17 12 8 11 6 4 33 10 24 10
Possible (BagrtosU No. with No. abnormal tut tested Rx 0 0 0 1 1 0 10 3 1 7 3 0 2 2 12
No. luted 12 31 32 35 37
Ttal No. with abnormal teit Rx R. 6 3 29 19 20 13 21 13 32 16
48
23
8
17
4
2
28
8
3
93
37
15
145
96
30
37
32
23
58
17
8
260
143
81
recognized categories: (1) mesencephalic signs (third or fourth cranial nerve involvement); (2) internuclear ophthalmoplegia; (3) other pontine signs (fifth, sixth or seventh cranial nerve involvement); (4) medullary signs (eighth, ninth or tenth cranial nerve involvement); (5) brain-stem signs of undetermined level (horizontal or vertical nystagmus other than classical internuclear ophthalmoplegia); and (6) no brain-stem signs. Table III shows the results in each group subdivided according to the duration of disease at the time the blink reflex was tested. The latency distribution of R x in 145 patients with a definite diagnosis is compared to that in 83 normal subjects in fig. 4. The patients were subdivided into three
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The conduction of the facial nerve as measured by the latency of the direct muscle response to facial nerve stimulation was normal on both sides in all 260 patients tested. In contrast, R x of the reflex response was bilaterally delayed (fig. 2) in 50 and unilaterally delayed in 95, 59 on the left and 36 on the right. In 81 of the 260 patients a delay of either direct or consensual R, or both (fig. 3) was seen to right- or left-sided stimulation. In 21 of the 81 patients, the afferent arc of the reflex (trigeminal nerve, pons or lateral medulla) was implicated because both the direct and consensual R , were delayed when the supraorbital nerve on the presumed side of lesion was stimulated. In 19, the delay was more consistent with involvement of the efferent arc (facial nucleus or nerve) since the direct but not consensual R s was delayed when the affected side was stimulated. In 41 others, R s was abnormal but could not be categorized as of either afferent or efferent type, perhaps suggesting more diffuse involvement of the reflex pathways.
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ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
TABLE in.—ALTERATION OF THE BLINK REFLEX AND DURATION OF ILLNESS IN 260 PATIENTS WITH MULTIPLE SCLEROSIS
Duratiom ofilbua 6 months or Ien 6 monthj to 1 jrr 1 to 5 y n 5 to 10 y n More than 10 y n
145
96
50
Probable diagnosis No.wUh No. abnormal lest tested R, R, 12 7 23 9 5 4 15 8 7 4 2 2 6 5 3 57
32
Possible iBatnosis No.wUh No. abnormal test tested Rt R, 38 8 4 11 4 2 6 3 1 3 2 1 0 0 0
23
58
17
Total No. with No. abnormal test tested R, R, 69 24 14 33 14 8 66 37 22 36 26 15 44 56 22 260
145
81
Normal Controls 83 subjects (166 responses) Multiple Sclerosis 145 patients (290 responses) 48 patients with no brainstem signs (96 responses)
59 patients with other brainstem signs (118 responses)
38 patients with pontine signs (76 responses)
10
14
18
22
10
14
18
Latency (msec) Fio. 4.—Distribution of latency of Ri of the blink reflex in 83 normal subjects (166 responses, considering right and left sides in each) and 14S patients (290 responses) with definite diagnosis of multiple sclerosis divided into three categories on the basis of clinical signs. Delay of Ri is most frequent in patients with pontine signs (left side of figure), but not uncommon in those with other brain-stem signs (centre of figure) or those with no brain-stem signs (right side of figure). Delayed Rx in patients with no clinical pontine signs suggests the presence of clinically silent pontine lesion.
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Total
Defadu dwfnosis No. with No. abnormal test letted Ri R, 4 3 8 5 2 13 26 14 45 22 12 29 39 19 50
O Normal Controls 83 subjects • 32 28
Multiple Sclerosis 145 patients 48 patients with no brainstem signs
59 patientswith other brainstem signs
38 patients with pontine signs
24 ^
20
05 16
Latency difference between two sides (msec) FIG. 5.—Distribution of latency diflFerence of Ri between the two sides in the same normal subjects and the patients shown in fig. 4. When compared to the corresponding histograms infig.4, it is evident that the assessment of latency difference between the two sides in one subject reveals abnormalities not detected by, simple latency measurements of Rx alone. l~l Normal Controls 83 subjects (166 responses) • 70 60
Multiple Sclerosis 115 patients (230responses) 45 patients with no brainstem signs (90 responses)
45 patients with other brainstem signs (90 responses)
25 patients with pontine signs (50 responses)
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Latency (msec) Fio. 6.—Distribution of latency of Rx of the blink reflex in 83 normals (166 responses, right and left sides in each) and 115 patients (230 responses) with probable and possible diagnoses of multiple sclerosis divided into three categories on the basis of clinical signs. Compared to the histograms in fig. 4, delay is less frequent in patients with probable and possible diagnoses than in those with definite diagnosis.
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I"
Q Normal Controls 83 subjects •
32 28
Multiple Sclerosis 115 patients 45 patients with no brainstem signs
4 5 patients with other brainstem sfgns
25 patients with pontine signs
24
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Latency difference between two sides (msec)
FIG. 7.—Distribution of latency difference of Ri between the two sides in the same normal subjects and the patients shown in fig. 6. Comparison between the corresponding histograms in figs. 6 and 7 shows that latency difference between the two sides in one subject reveals more abnormalities than detectable by a delay of absolute latency of Ri itself.
Remission Side of Stimulation
Exacerbation
April 15
July 2
^-slightly delayed
^•slightly delayed
^-markedly delayed
normal
. . f 1 33I1E j \
Stimulation
•
• V..VJV.J"
li.Omv 5 msec
FIG. 8.—Delay of Kx associated with progression of clinical signs. An electric shock (open arrow) was delivered to the supraorbital nerve and Rx (closed arrow) of the blink reflex was recorded from the ipsilateral orbicularis oculi in a patient with multiple sclerosis in remission and exacerbation. Two tracings were recorded on each side to show consistency. On April 15, Rx on the right was slightly but significantly delayed when compared to the response on the left. On July 2 of the same year, while in exacerbation, delay of R t on the right was only slightly more than before but Rx on the left was markedly delayed and was much slower than the response on the right. This finding indicates a new left-sided pontine lesion that developed after the initial examination. The shaded areas indicate normal range (mean ± 3 S.D. in 83 subjects). 29
BRAIN—VOL. XCVm
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JUN KIMURA
groups: (1) pontine signs including internuclear ophthahnoplegia; (2) other brainstem signs implicating the mesencephalon, medulla or undetermined level; and (3) no brain-stem signs. Fig. 5 shows the distribution of latency difference of Rx between the two sides in the same 145 patients and 83 normal subjects. Similarly, latency of R.! (fig. 6) and its difference between the two sides in the individual subject (fig. 7) are shown for the remaining 115 patients with probable and possible diagnoses.
DISCUSSION
There has recently been an increasing trend to use various neurophysiological techniques in diagnostic testing for multiple sclerosis as well as in evaluation of its pathophysiology (McDonald, 1974a). Visual and somatosensory evoked responses (Halliday and Wakefield, 1963; Namerow, 1968; Desmedt and Noel, 1973) have been most extensively studied in this disease and standardized for clinical use. Despite proven value in detecting silent lesions in multiple sclerosis (Halliday et ah, 1973), practical application of these methods is somewhat limited because they deal with small cerebral evoked potentials which can be recorded only by means of relatively elaborate equipment For practical purposes, a simpler and more readily accessible method would be desirable. The electrically evoked blink reflex is a technique which can be performed in any ordinary electromyographic laboratory since it can easily be recorded without averaging procedures (fig. 1). As shown in Table II, R x was abnormal in 49 of 63 patients with clinical pontine signs (78 per cent) and in 59 of 104 with other brain-stem signs (57 per cent). More importantly, however, R x was also abnormal in 37 of the remaining 93 patients, who presented no clinical evidence of brain-stem signs (40 per cent). Since alteration of R x is relatively specific to pontine lesions (Kimura, 1973), these findings indicate that the incidence of pontine involvement is much higher than clinically suspected and that clinically silent plaques in the pons can be detected by this test (fig. 2). The high incidence of delayed R x in the absence of clinical pontine signs means that this test is of value in documenting anatomical dissemination of lesions, which is so crucial in the diagnosis of multiple sclerosis. In our preliminary study (Kimura, 1970), Rj was delayed on one or both sides in all 7 patients who had internuclear ophthalmoplegia. The very high frequency of delayed R x in this syndrome was also reported subsequently by Namerow and
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In 50 patients who were studied on more than one occasion the latencies of R^ at the first and last examination were compared. In 32 patients in whom the clinical course and brain-stem signs were relatively stable, R x was unchanged in 20, improved in 7, and worse in 5. In 6 others who showed progression of brain-stem signs clinically R x remained the same in 4 and became worse in 2 (fig. 8). In the remaining 12 patients who were in remission when last seen, Rx was unchanged in 6 and improved in 6 others.
ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
423
Etemadi (1970) and by Lyon and Van Allen (1972). This association was further documented in the present study, where 29 of 31 patients with internuclear ophthalmoplegia showed a delay of R x (94 per cent). This finding is consistent with the hypothesis that the reflex pathway of R x is located near the medial longitudinal fasciculus, although it is also possible that patients with this syndrome generally have advanced disease in the pons causing a high incidence of delayed Rv It should be noted in this regard that 22 of the 29 patients aforementioned had, in addition to internuclear ophthalmoplegia, various other pontine signs.
The incidence of brain-stem plaques is likely to rise with increasing duration of illness. In a series of 295 patients reported by Kahana et al. (1973), clinical brain-stem signs were found in 14 per cent at the onset of the disease and 65 per cent during the course of illness covering an average of seventeen years. These values compare to our observation of delayed Rx in 24 of 69 patients seen within six months of onset (35 per cent) and in 44 of 56 seen after ten years (79 per cent). In our series there was a considerable difference in the frequency of delayed Rx between those seen before (45 per cent) and after (76 per cent) five years had elapsed after the onset of clinical symptoms. Incidence of abnormal Rt also increased with the duration of illness. Because it is experimentally well established that slowing of conduction is associated with demyelination (Rasminsky and Sears, 1972), it seems reasonable to assume that delay of R x or R 2 in patients with multiple sclerosis is, at least in part, secondary to plaques involving the reflex arc itself. If this is the case, the reflex response may be mediated by the smaller and slower conducting fibres because the more heavily myelinated and faster fibres are substantially blocked, or, alternatively, conduction may be generally slowed in all fibres in the demyelinated areas. (Edema or other indirect effects of lesions outside the primary reflex pathways may also contribute, but a delay of R x in some patients by as much as several milliseconds is difficult to explain on this basis alone. Apparent delays of the reflex response can also be explained by assuming that conduction over the primary reflex pathway is blocked at the point of demyelination and that a secondary, more indirect reflex
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Because of inherent latency variability from one trial to the next, R 2 is less reliable than Rj. Furthermore, R s is significantly affected by contralateral hemispheric lesions (Kimura, 1974) or by any pathology rendering the patient comatose even if the integrity of the brain-stem is preserved (Lyon et al., 1972). Thus, unlike Rlt R t is not a specific test of brain-stem function. None the less, analysis of direct and consensual R a (fig. 3) is essential in determining whether the afferent or efferent arc of the reflex pathway is primarily involved (Kimura, 1973). As shown in Table U, Rj was less effective than R x in detecting brain-stem lesions. Like R1( Rt was most frequently abnormal in patients with clinical pontine signs. When seen in the face of a normal R^ however, alteration of R a was usually associated with clinical signs suggesting lateral medullary lesions (Kimura and Lyon, 1972).
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Because it is non-invasive and easily available, the bhnk reflex has now found wide clinical applicability in diagnosing abnormalities of the brain-stem in various neurological disorders (Kimura, 1973). The test, however, seems to have special value in the evaluation of multiple sclerosis because it enables one not only to document clinical brain-stem signs but also to detect clinically silent lesions. This is especially true because the brain-stem is one of the most commonly affected parts of the central nervous system in this disorder (Lumsden, 1970). The test also provides a simple means to assess quantitatively the progression or remission of the demyelinating process in the brain-stem as a supplement to clinical observation.
SUMMARY
The bunk reflex obtained from 260 patients with suspected multiple sclerosis was analysed according to clinical criteria for diagnosis. The R x component was delayed on one or both sides in 96 of 145 patients with definite diagnosis (66 per cent), 32 of 57 with probable diagnosis (56 per cent), and 17 of 58 with possible diagnosis (29 per cent). The incidence of abnormal R x rose with increasing duration of illness in each category. When the reflex was analysed according to the clinical localization of the lesion in the 260 patients, R x was abnormal in 49 of 63 patients with pontine signs (78 per cent), 59 of 104 with other brain-stem signs (57 per cent), and 37 of 93 with no clinical brain-stem signs (40 per cent). Alteration of R s was less specific but, when seen in the face of a normal R lf was usually associated with clinical signs suggesting lateral medullary lesions. These findings offer direct evidence that conduction through demyelinated zones in the central nervous system is indeed slowed and that the degree of slowing can be measured objectively by means of this simple technique in man. The high incidence of delayed R x in patients with no clinical pontine signs suggests that the test may be used to document a clinically silent pontine lesion in multiple sclerosis and help to establish the anatomical dissemination of pathology.
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connexion has developed. Halliday et al. (1973), studying visual evoked responses in this disease, noted that delays persisted indefinitely after an attack of acute optic neuritis even after visual acuity had returned to normal. In contrast, we observed an unequivocal reduction of initially prolonged latencies of R x in several patients during remission or while the clinical course was relatively stable. Namerow (1968) reported a similar observation in somatosensory evoked potentials in multiple sclerosis. Whereas these findings may be taken as suggestive evidence of remyelination in the central nervous system in man (Suzuki et al, 1969; McDonald, 19746), an apparent shortening of previously very prolonged reflex latencies may also occur secondary to development of an alternate reflex pathway bypassing the area of demyelination.
ELECTRICALLY ELICITED BUNK REFLEX IN MULTIPLE SCLEROSIS
425
ACKNOWLEDGMENTS The author wishes to thank Dr. Maurice W. Van Allen for his advice, and Dr. Stephen S. Kennedy and Jean M. DeCoster for their assistance. This investigation was supported by a grant from the National Multiple Sclerosis Society. Part of this work was done when the author was associated with the Department of Internal Medicine (Neurology), College of Medicine, University of Manitoba, and was supported by a grant from the Multiple Sclerosis Society of Canada. Presented at the Fifth International Congress of Electromyography, Rochester, Minnesota, USA, September 21-24, 1975.
DESMEDT, G. E., and NOEL, P. (1973) Average cerebral evoked potentials in the evaluation of lesions of the sensory nerves and of the central somatosensory pathway. In: "New Developments in Electromyography and Clinical Neurophysiology." Edited by J. E. Desmedt. Basel: Kargcr, Vol. 2, p. 352. HALUDAY, A. M., and WAKEFIELD, G. S. (1963) Cerebral evoked potentials in patients with dissociated sensory loss. / . Neurol. Neurosurg. Psychiat., 26, 211-219. , MCDONALD, W. I., and MUSHIN, J. (1973) The visual evoked response in the diagnosis of multiple sclerosis. Br. med. J., 4, 661-664. KAHANA, E., LEraowiTZ, U., and ALTER, M. (1973) Brainstem and cranial nerve involvement in multiple sclerosis. Ada neurol. scand., 49, 269-279. KJMURA, J. (1970) Alteration of the orbicularis oculi reflex by pontine lesions: Study in multiple sclerosis. Archs Neurol., Chicago, 22, 156-161. (1973) The blink reflex as a test for brainstem and higher central nervous system function. In: "New Developments in Electromyography and Clinical Neurophysiology." Edited by J. E. Desmedt. Basel: Karger, Vol. 3, pp. 682-691. (1974) Effect of hemispheral lesions on the contralateral blink reflex: A clinical study. Neurology, Minneap., 24, 168-174. , and LYON, L. W. (1972) Orbicularis oculi reflex in the Wallenberg syndrome: Alteration of the late reflex by lesions of the spinal tract and nucleus of the trigeminal nerve. / . Neurol. Neurosurg. Psychiat., 35, 228-233. KUOELBERG, E. (1952) Facial reflexes. Brain, 75, 385-396. LUMSDEN, C. E. (1970) The neuropathology of multiple sclerosis. In: "Handbook of Clinical Neurology." Edited by P. J. Vinken and G. W. Bruyn. Amsterdam: North Holland, Vol. 9, pp. 217-309. LYON, L. W., and VAN ALLEN, M. W. (1972) Orbicularis oculi reflex: studies in internuclear ophthalmoplegia and pseudointernuclear ophthalmoplegia. Archs Ophthal., N.Y., 87, 148-154. , KIMURA, J., and MCCORMCK, W. F. (1972) Orbicularis oculi reflex in coma: Clinical, electrophysiological, and pathological correlations. / . Neurol. Neurosurg. Psychiat., 35, 582-588. MCALPINE, D. (1972) Course and prognosis. In: "Multiple Sclerosis: A Reappraisal." Edited by D. McAlpine, C. E. Lumsden and E. D. Acheson. Edinburgh and London: Livingstone, pp. 197-223. MCDONALD, W. I. (1974a) Pathophysiology in multiple sclerosis. Brain, 97, 179-196. (19746) Remyelination in relation to clinical lesions of the central nervous system. Br. med. Bull., 30, 186-189. , and SEARS, T. A. (1970) The effects of experimental demyelination on conduction in the central nervous system. Brain, 93, 583-598.
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REFERENCES
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NAMEROW, N. S. (1968) Somatosensory evoked responses in multiple sclerosis patients with varying sensory loss. Neurology, Mtnneap., 18, 1197-1204. (1973) Observations of the blink reflex in multiple sclerosis. In: "New Developments in Hectromyography and Clinical Neurophysiology." Edited by J. E. Desmedt. Basel: Karger, Vol. 3, pp. 692-696. , and ETEMADI, A. (1970) The orbicularis oculi reflex in multiple sclerosis. Neurology, Minntap., 20, 1200-1203. RASMINSKY, M., and SEARS, T. A. (1972) Internodal conduction in undissected demyelinated nerve fibres. J. PhysioL, 227, 323-350. SHAHANI, B. T., and YOUNO, R. R. (1972) Human orbicularis oculi reflexes. Neurology, Minneap., 22, 149-154.
(Received March 5, 1975)
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Suzun, K., ANDREWS, J. M., WALTZ, J. M., and TERRY, R. D. (1969) Ultrastrucrural studies of multiple sclerosis. Lab. Invest., 20, 444-^54.
ELECTRICALLY ELICITED BLINK REFLEX IN DIAGNOSIS OF MULTIPLE SCLEROSIS REVIEW OF 260 PATIENTS OVER A SEVEN-YEAR PERIOD
JUN KIMURA {From the Department of Neurology, College of Medicine, University of Iowa, Iowa City, Iowa)
INTRODUCTION
THE blink reflex elicited by tactile stimulation of the cornea is a part of the routine neurological examination. Although it is an important clinical test for evaluation of the integrity of brain-stem function, accurate quantitative analysis is impossible if the reflex is assessed by simple observation as is done in ordinary clinical practice. The electrically elicited blink reflex is more meaningful in that the recording of the evoked potential with an oscilloscope allows precise determination of the reflex latencies. The blink reflex elicited by electrical stimulation of the supraorbital nerve consists of two temporally separate components (Kugelberg, 1952), an early R x and a late R, reflex (fig. 1). Whereas Rlt evoked only on the side of stimulation, is a simple pontine reflex (Shahani and Young, 1972), R,, recorded bilaterally with unilateral stimulation, is relayed through a more complex route that includes the pons and lateral medulla. Afferent impulses of R 8 enter the pons through the trigeminal nerve, descend to the ipsilateral spinal tract and ascend to make eventual connexions with both ipsilateral and contralateral facial nuclei (Kimura and Lyon, 1972). Because slowed conduction is characteristic of demyelination (McDonald and Sears, 1970), it was felt appropriate to examine the incidence of delayed blink reflexes in multiple sclerosis. In our preliminary study (Kimura, 1970), it was shown that R x was indeed delayed in 17 of 21 patients with clinical pontine signs and that R a was affected most prominently in patients with medullary lesions. Although a few subsequent papers have appeared (Namerow and Etemadi, 1970; Lyon and Van Allen, 1972; Kimura, 1973; Namerow, 1973) confirming the original findings, a large-scale survey of the blink reflex as a diagnostic test in multiple sclerosis has not been published. The purpose of this paper is to report seven years' experience with
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BY
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JUN KTMURA
Contttnt Currtnt Unit
Stimulus Itelttlon Unit
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2. Direct Rt Avtrto* Amplltud*
Amplltud*
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l_
Average
Ampllfgd*
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Fio. 1.—Top: Stimulation and recording arrangement for the blink reflex. The presumed pathway of Ri through the pons (1), and direct and consensual R, through the pons and lateral medulla (2 and 3) are schematically indicated. The primary afferents of Ri and R t are shown as one fibre in the illustration. This and other details of central connexions of these reflexes are not known. Bottom: A typical oscilloscope recording of the blink reflex after right-sided stimulation. Note an ipsilateral R t and bilaterally simultaneous R t responses. Modified with permission from Kimura, J., and Harada, O. (1972) Electroenceph. Clin. Neurophysiol, 33, 369-377.
the blink reflex in 260 patients with multiple sclerosis. It will be shown that the test may be used to document a clinically silent brain-stem lesion and help to establish the anatomical dissemination of pathology. METHODS
Subjects lay supine on a bed in a warm room with eyes gently closed. Surface electrodes were used for both stimulation of the nerve and recording of evoked muscle action potentials. For recording, the active electrode was placed on the lateral aspect of the orbicularis oculi muscle and a reference electrode on the lateral surface of the nose. A ground electrode was located under the chin. The supraorbital nerve was stimulated with the cathode placed over the supraorbital foramen on one side, and the reflex responses were recorded from the orbicularis oculi muscle on both sides simultaneously. Shocks were of such
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1. R,
Stlmulttor
415
ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
intensity that R x and R, were just maximum and nearly stable with repeated trials. Shocks of the same intensity were delivered to each side in each subject. The latencies of Rx, ipsilateral Rfc and contralateral R s were measured from the stimulus artifact to the initial deflection of the evoked potential. If R x was difficult to elicit with a single shock it was usually helpful to deliver paired shocks with an interstimulus interval of 5 ms. When this was done the latency of R x was measured from the stimulus artifact of the second shock of the pair. For each subject at least four responses of R x and R 2 were recorded and the mean latency was obtained.
Normal Values The normal ranges of the latency of R x and R, were established in 83 healthy subjects, 7 to 86 years of age (mean age 37). Normal variations among different subjects and between the two sides in individuals are summarized in Table I. There TABLE I.—NORMAL LATENCIES OF R X AND R, COMPONENTS OF THB BLINK REFLEX 83 SUBJECTS (166 RESPONSES CONSEDERINO BOTH SIDES TOGETHER) Ry
Component
Ri
Mean latency (ms) Standard deviation (ms)
M±3 SD (ms) Upper limit of normal (ms)
10-45 0-84
10-5±2•5 13
Difference between two sides in one subject 0-31 0-30 0-3 ±0-9 1-2
Rt Components Difference Difference between Direct Rt Consensual Rt between responses direct (ipsilateral (contralateral to the and to R- and to the L-sided consensual side of side of response stimulus stimulus) stimulus) 10 1-6 30-5 30-5 1-7 1-2 4-4 3-4
31±10 41
31±13 44
1±4
2±5
5
7
was no significant difference between responses on the right and the left side. Normal latencies of R x and R, were distributed on a bell curve. As shown in Table I, R x may be considered delayed if it exceeds 13 ms and R, delayed if it exceeds 41 ms directly and 44 ms consensually. Additionally, the difference in latency of Rx between the two sides in one subject should be less than 1*2 ms. For R, two types of comparison were possible. First, a latency difference between the ipsilateral and the contralateral R 2 simultaneously evoked by stimulation on one side should not exceed 5 ms. Secondly, a latency difference between R, evoked by
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In addition to the reflex responses, the conduction of the facial nerve was also routinely tested by stimulating the nerve with the cathode placed just anterior to the mastoid process and recording the direct muscle response from the ipsilateral orbicularis oculi muscle. Its latency was measured from the stimulus artifact to the beginning of the evoked potential.
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right-sided stimulation and corresponding reflexes subsequently evoked by left-sided stimulation should be less than 7 ms. Multiple Sclerosis Of 260 patients included in this study, 138 were seen at the University of Iowa (1968-69,1972-74) and 122 at the University of Manitoba (1969-72). Approximately one-half of these patients were referred because of a suspected diagnosis of multiple sclerosis. Others were selected from a hospital file or a list provided by the local Multiple Sclerosis Society and were requested to return for the test There were 91 males and 169 females ranging in age from 15 to 73 (mean age 37).
Right Normal Control Case
Case 3
^ ;
Stimulation
|_0.5mv 5 msec
FIG. 2.—Delayed R t on both sides in multiple sclerosis. An electric shock (arrows) was delivered to the supraorbital nerve, and R^ (brackets) of the blink reflex was recorded from the ipsilateral orbicularis oculi muscle in a normal subject and in 8 patients with multiple sclerosis. With a sweep speed of 5 ms/cm used here, R, falls outside the face of the oscilloscope and is not recorded (cf. fig. 3). Two tracings were recorded on each side in each subject to show consistency of Rx response. The top tracings are from a normal control, with shaded areas indicating the normal range (mean ±3 S.D. in 83 subjects). In addition to obvious increases in latency, Rx obtained in these patients is temporally dispersed and very irregular in wave form when compared to that in the normal control. None of these patients had unequivocal pontine signs clinically, although mild horizontal nystagmus was present in Cases 1, 2, 5, 6 and 7.
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All patients were given careful neurological examination before the test On the basis of the history and neurological findings they were divided into three groups:
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ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
145 definite, 57 probable and 58 possible cases of multiple sclerosis. A definite diagnosis was obtained by a history of one or more relapses and clinical evidence of anatomical dissemination of lesions. The diagnosis was considered probable if multiple levels of the central nervous system were involved without historical evidence of a relapse, or alternatively if the findings could be explained by a single lesion despite clinical remissions and exacerbations. Patients presenting with signs and symptoms suggestive of the disease but with neither dissemination of lesions nor a relapsing course were generally considered possible cases. McAlpine's diagnostic criteria (1972) were also utilized in categorizing difficult cases.
Side of Stimulation tion
Afferent Delay
Normal l
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|0.5mv 10 msec Fia. 3.—Alteration of R, in multiple sclerosis. A stimulus was delivered to the supraorbital nerve, and reflex responses were simultaneously recorded from the ipsilateral (upper tracing in each frame) and the contralateral (lower tracing in each frame) orbicularis oculi muscle. From top to bottom, two right-sided and two left-sided stimulations were delivered in each case to show consistency. An electric shock of the same intensity was used on each side. Note R t (small arrows over the peaks) is recorded only in the upper tracings and R, (horizontal brackets), in both the upper and lower tracings in each frame when either side of face is stimulated (cf. fig. 1). In a normal subject there is no significant difference in latencies of Rx or R, between the two sides. In a patient having hypalgesia on the left side of the face, R t was normal bilaterally on right-sided stimulation but nearly absent bilaterally on left-sided stimulation. An afferent delay of Rs, when seen in the face of normal R t as in this case, suggests a lateral medullary lesion. In another patient who had both abducens and facial nerve paresis on the left, R, was delayed on the left and normal on the right regardless of the side of stimulation. This finding together with a delayed Rt on the left suggests a lesion involving the efferent arc of the reflex.
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In patients seen on more than one occasion, the diagnosis was made at the time of the first examination when the blink reflex was tested. Thus, patients diagnosed
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JUN HMURA
initially as having possible multiple sclerosis remained in this category even if the diagnosis became definite during the course of the study. However, 11 patients originally considered as possible cases were excluded because they proved to have other diseases including ischaemic vascular disease (3), brain-stem tumour (2), cerebellar degeneration (2), cervical spondylosis (2), and Bell's palsy (2).
Table II summarizes the incidence of abnormal R x and R, in each group of definite, probable and possible cases. These are further subdivided into six clinically TABLE n.—ALTERATION OF THE BLINK REFLEX AND CLINICAL LOCALIZATION OF LESIONS
IN
260 PATIENTS WITH MULTIPLE SCLEROSIS
Clinical localization ofluiom BAcscnceplulic liffiif Internuclear ophthmlntoplesU Other pontine tlgm Medullary dgnl Brmin-*Um »igni of undetermined level No bnln-ctem lignj Total
Deflnitt dTatnotii Probable dlafnotlt No. with No. wUh No. abnormal tut No. abnormal test tested Rt Rx Rx X, tilled 4 3 7 2 1 3 4 24 6 22 15 6 3 6 14 7 8 11 6 3 17 12 8 11 6 4 33 10 24 10
Possible (BagrtosU No. with No. abnormal tut tested Rx 0 0 0 1 1 0 10 3 1 7 3 0 2 2 12
No. luted 12 31 32 35 37
Ttal No. with abnormal teit Rx R. 6 3 29 19 20 13 21 13 32 16
48
23
8
17
4
2
28
8
3
93
37
15
145
96
30
37
32
23
58
17
8
260
143
81
recognized categories: (1) mesencephalic signs (third or fourth cranial nerve involvement); (2) internuclear ophthalmoplegia; (3) other pontine signs (fifth, sixth or seventh cranial nerve involvement); (4) medullary signs (eighth, ninth or tenth cranial nerve involvement); (5) brain-stem signs of undetermined level (horizontal or vertical nystagmus other than classical internuclear ophthalmoplegia); and (6) no brain-stem signs. Table III shows the results in each group subdivided according to the duration of disease at the time the blink reflex was tested. The latency distribution of R x in 145 patients with a definite diagnosis is compared to that in 83 normal subjects in fig. 4. The patients were subdivided into three
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The conduction of the facial nerve as measured by the latency of the direct muscle response to facial nerve stimulation was normal on both sides in all 260 patients tested. In contrast, R x of the reflex response was bilaterally delayed (fig. 2) in 50 and unilaterally delayed in 95, 59 on the left and 36 on the right. In 81 of the 260 patients a delay of either direct or consensual R, or both (fig. 3) was seen to right- or left-sided stimulation. In 21 of the 81 patients, the afferent arc of the reflex (trigeminal nerve, pons or lateral medulla) was implicated because both the direct and consensual R , were delayed when the supraorbital nerve on the presumed side of lesion was stimulated. In 19, the delay was more consistent with involvement of the efferent arc (facial nucleus or nerve) since the direct but not consensual R s was delayed when the affected side was stimulated. In 41 others, R s was abnormal but could not be categorized as of either afferent or efferent type, perhaps suggesting more diffuse involvement of the reflex pathways.
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ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
TABLE in.—ALTERATION OF THE BLINK REFLEX AND DURATION OF ILLNESS IN 260 PATIENTS WITH MULTIPLE SCLEROSIS
Duratiom ofilbua 6 months or Ien 6 monthj to 1 jrr 1 to 5 y n 5 to 10 y n More than 10 y n
145
96
50
Probable diagnosis No.wUh No. abnormal lest tested R, R, 12 7 23 9 5 4 15 8 7 4 2 2 6 5 3 57
32
Possible iBatnosis No.wUh No. abnormal test tested Rt R, 38 8 4 11 4 2 6 3 1 3 2 1 0 0 0
23
58
17
Total No. with No. abnormal test tested R, R, 69 24 14 33 14 8 66 37 22 36 26 15 44 56 22 260
145
81
Normal Controls 83 subjects (166 responses) Multiple Sclerosis 145 patients (290 responses) 48 patients with no brainstem signs (96 responses)
59 patients with other brainstem signs (118 responses)
38 patients with pontine signs (76 responses)
10
14
18
22
10
14
18
Latency (msec) Fio. 4.—Distribution of latency of Ri of the blink reflex in 83 normal subjects (166 responses, considering right and left sides in each) and 14S patients (290 responses) with definite diagnosis of multiple sclerosis divided into three categories on the basis of clinical signs. Delay of Ri is most frequent in patients with pontine signs (left side of figure), but not uncommon in those with other brain-stem signs (centre of figure) or those with no brain-stem signs (right side of figure). Delayed Rx in patients with no clinical pontine signs suggests the presence of clinically silent pontine lesion.
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Total
Defadu dwfnosis No. with No. abnormal test letted Ri R, 4 3 8 5 2 13 26 14 45 22 12 29 39 19 50
O Normal Controls 83 subjects • 32 28
Multiple Sclerosis 145 patients 48 patients with no brainstem signs
59 patientswith other brainstem signs
38 patients with pontine signs
24 ^
20
05 16
Latency difference between two sides (msec) FIG. 5.—Distribution of latency diflFerence of Ri between the two sides in the same normal subjects and the patients shown in fig. 4. When compared to the corresponding histograms infig.4, it is evident that the assessment of latency difference between the two sides in one subject reveals abnormalities not detected by, simple latency measurements of Rx alone. l~l Normal Controls 83 subjects (166 responses) • 70 60
Multiple Sclerosis 115 patients (230responses) 45 patients with no brainstem signs (90 responses)
45 patients with other brainstem signs (90 responses)
25 patients with pontine signs (50 responses)
o3 5 0
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14
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Latency (msec) Fio. 6.—Distribution of latency of Rx of the blink reflex in 83 normals (166 responses, right and left sides in each) and 115 patients (230 responses) with probable and possible diagnoses of multiple sclerosis divided into three categories on the basis of clinical signs. Compared to the histograms in fig. 4, delay is less frequent in patients with probable and possible diagnoses than in those with definite diagnosis.
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I"
Q Normal Controls 83 subjects •
32 28
Multiple Sclerosis 115 patients 45 patients with no brainstem signs
4 5 patients with other brainstem sfgns
25 patients with pontine signs
24
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4
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Latency difference between two sides (msec)
FIG. 7.—Distribution of latency difference of Ri between the two sides in the same normal subjects and the patients shown in fig. 6. Comparison between the corresponding histograms in figs. 6 and 7 shows that latency difference between the two sides in one subject reveals more abnormalities than detectable by a delay of absolute latency of Ri itself.
Remission Side of Stimulation
Exacerbation
April 15
July 2
^-slightly delayed
^•slightly delayed
^-markedly delayed
normal
. . f 1 33I1E j \
Stimulation
•
• V..VJV.J"
li.Omv 5 msec
FIG. 8.—Delay of Kx associated with progression of clinical signs. An electric shock (open arrow) was delivered to the supraorbital nerve and Rx (closed arrow) of the blink reflex was recorded from the ipsilateral orbicularis oculi in a patient with multiple sclerosis in remission and exacerbation. Two tracings were recorded on each side to show consistency. On April 15, Rx on the right was slightly but significantly delayed when compared to the response on the left. On July 2 of the same year, while in exacerbation, delay of R t on the right was only slightly more than before but Rx on the left was markedly delayed and was much slower than the response on the right. This finding indicates a new left-sided pontine lesion that developed after the initial examination. The shaded areas indicate normal range (mean ± 3 S.D. in 83 subjects). 29
BRAIN—VOL. XCVm
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I"
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JUN KIMURA
groups: (1) pontine signs including internuclear ophthahnoplegia; (2) other brainstem signs implicating the mesencephalon, medulla or undetermined level; and (3) no brain-stem signs. Fig. 5 shows the distribution of latency difference of Rx between the two sides in the same 145 patients and 83 normal subjects. Similarly, latency of R.! (fig. 6) and its difference between the two sides in the individual subject (fig. 7) are shown for the remaining 115 patients with probable and possible diagnoses.
DISCUSSION
There has recently been an increasing trend to use various neurophysiological techniques in diagnostic testing for multiple sclerosis as well as in evaluation of its pathophysiology (McDonald, 1974a). Visual and somatosensory evoked responses (Halliday and Wakefield, 1963; Namerow, 1968; Desmedt and Noel, 1973) have been most extensively studied in this disease and standardized for clinical use. Despite proven value in detecting silent lesions in multiple sclerosis (Halliday et ah, 1973), practical application of these methods is somewhat limited because they deal with small cerebral evoked potentials which can be recorded only by means of relatively elaborate equipment For practical purposes, a simpler and more readily accessible method would be desirable. The electrically evoked blink reflex is a technique which can be performed in any ordinary electromyographic laboratory since it can easily be recorded without averaging procedures (fig. 1). As shown in Table II, R x was abnormal in 49 of 63 patients with clinical pontine signs (78 per cent) and in 59 of 104 with other brain-stem signs (57 per cent). More importantly, however, R x was also abnormal in 37 of the remaining 93 patients, who presented no clinical evidence of brain-stem signs (40 per cent). Since alteration of R x is relatively specific to pontine lesions (Kimura, 1973), these findings indicate that the incidence of pontine involvement is much higher than clinically suspected and that clinically silent plaques in the pons can be detected by this test (fig. 2). The high incidence of delayed R x in the absence of clinical pontine signs means that this test is of value in documenting anatomical dissemination of lesions, which is so crucial in the diagnosis of multiple sclerosis. In our preliminary study (Kimura, 1970), Rj was delayed on one or both sides in all 7 patients who had internuclear ophthalmoplegia. The very high frequency of delayed R x in this syndrome was also reported subsequently by Namerow and
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In 50 patients who were studied on more than one occasion the latencies of R^ at the first and last examination were compared. In 32 patients in whom the clinical course and brain-stem signs were relatively stable, R x was unchanged in 20, improved in 7, and worse in 5. In 6 others who showed progression of brain-stem signs clinically R x remained the same in 4 and became worse in 2 (fig. 8). In the remaining 12 patients who were in remission when last seen, Rx was unchanged in 6 and improved in 6 others.
ELECTRICALLY ELICITED BLINK REFLEX IN MULTIPLE SCLEROSIS
423
Etemadi (1970) and by Lyon and Van Allen (1972). This association was further documented in the present study, where 29 of 31 patients with internuclear ophthalmoplegia showed a delay of R x (94 per cent). This finding is consistent with the hypothesis that the reflex pathway of R x is located near the medial longitudinal fasciculus, although it is also possible that patients with this syndrome generally have advanced disease in the pons causing a high incidence of delayed Rv It should be noted in this regard that 22 of the 29 patients aforementioned had, in addition to internuclear ophthalmoplegia, various other pontine signs.
The incidence of brain-stem plaques is likely to rise with increasing duration of illness. In a series of 295 patients reported by Kahana et al. (1973), clinical brain-stem signs were found in 14 per cent at the onset of the disease and 65 per cent during the course of illness covering an average of seventeen years. These values compare to our observation of delayed Rx in 24 of 69 patients seen within six months of onset (35 per cent) and in 44 of 56 seen after ten years (79 per cent). In our series there was a considerable difference in the frequency of delayed Rx between those seen before (45 per cent) and after (76 per cent) five years had elapsed after the onset of clinical symptoms. Incidence of abnormal Rt also increased with the duration of illness. Because it is experimentally well established that slowing of conduction is associated with demyelination (Rasminsky and Sears, 1972), it seems reasonable to assume that delay of R x or R 2 in patients with multiple sclerosis is, at least in part, secondary to plaques involving the reflex arc itself. If this is the case, the reflex response may be mediated by the smaller and slower conducting fibres because the more heavily myelinated and faster fibres are substantially blocked, or, alternatively, conduction may be generally slowed in all fibres in the demyelinated areas. (Edema or other indirect effects of lesions outside the primary reflex pathways may also contribute, but a delay of R x in some patients by as much as several milliseconds is difficult to explain on this basis alone. Apparent delays of the reflex response can also be explained by assuming that conduction over the primary reflex pathway is blocked at the point of demyelination and that a secondary, more indirect reflex
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Because of inherent latency variability from one trial to the next, R 2 is less reliable than Rj. Furthermore, R s is significantly affected by contralateral hemispheric lesions (Kimura, 1974) or by any pathology rendering the patient comatose even if the integrity of the brain-stem is preserved (Lyon et al., 1972). Thus, unlike Rlt R t is not a specific test of brain-stem function. None the less, analysis of direct and consensual R a (fig. 3) is essential in determining whether the afferent or efferent arc of the reflex pathway is primarily involved (Kimura, 1973). As shown in Table U, Rj was less effective than R x in detecting brain-stem lesions. Like R1( Rt was most frequently abnormal in patients with clinical pontine signs. When seen in the face of a normal R^ however, alteration of R a was usually associated with clinical signs suggesting lateral medullary lesions (Kimura and Lyon, 1972).
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Because it is non-invasive and easily available, the bhnk reflex has now found wide clinical applicability in diagnosing abnormalities of the brain-stem in various neurological disorders (Kimura, 1973). The test, however, seems to have special value in the evaluation of multiple sclerosis because it enables one not only to document clinical brain-stem signs but also to detect clinically silent lesions. This is especially true because the brain-stem is one of the most commonly affected parts of the central nervous system in this disorder (Lumsden, 1970). The test also provides a simple means to assess quantitatively the progression or remission of the demyelinating process in the brain-stem as a supplement to clinical observation.
SUMMARY
The bunk reflex obtained from 260 patients with suspected multiple sclerosis was analysed according to clinical criteria for diagnosis. The R x component was delayed on one or both sides in 96 of 145 patients with definite diagnosis (66 per cent), 32 of 57 with probable diagnosis (56 per cent), and 17 of 58 with possible diagnosis (29 per cent). The incidence of abnormal R x rose with increasing duration of illness in each category. When the reflex was analysed according to the clinical localization of the lesion in the 260 patients, R x was abnormal in 49 of 63 patients with pontine signs (78 per cent), 59 of 104 with other brain-stem signs (57 per cent), and 37 of 93 with no clinical brain-stem signs (40 per cent). Alteration of R s was less specific but, when seen in the face of a normal R lf was usually associated with clinical signs suggesting lateral medullary lesions. These findings offer direct evidence that conduction through demyelinated zones in the central nervous system is indeed slowed and that the degree of slowing can be measured objectively by means of this simple technique in man. The high incidence of delayed R x in patients with no clinical pontine signs suggests that the test may be used to document a clinically silent pontine lesion in multiple sclerosis and help to establish the anatomical dissemination of pathology.
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connexion has developed. Halliday et al. (1973), studying visual evoked responses in this disease, noted that delays persisted indefinitely after an attack of acute optic neuritis even after visual acuity had returned to normal. In contrast, we observed an unequivocal reduction of initially prolonged latencies of R x in several patients during remission or while the clinical course was relatively stable. Namerow (1968) reported a similar observation in somatosensory evoked potentials in multiple sclerosis. Whereas these findings may be taken as suggestive evidence of remyelination in the central nervous system in man (Suzuki et al, 1969; McDonald, 19746), an apparent shortening of previously very prolonged reflex latencies may also occur secondary to development of an alternate reflex pathway bypassing the area of demyelination.
ELECTRICALLY ELICITED BUNK REFLEX IN MULTIPLE SCLEROSIS
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ACKNOWLEDGMENTS The author wishes to thank Dr. Maurice W. Van Allen for his advice, and Dr. Stephen S. Kennedy and Jean M. DeCoster for their assistance. This investigation was supported by a grant from the National Multiple Sclerosis Society. Part of this work was done when the author was associated with the Department of Internal Medicine (Neurology), College of Medicine, University of Manitoba, and was supported by a grant from the Multiple Sclerosis Society of Canada. Presented at the Fifth International Congress of Electromyography, Rochester, Minnesota, USA, September 21-24, 1975.
DESMEDT, G. E., and NOEL, P. (1973) Average cerebral evoked potentials in the evaluation of lesions of the sensory nerves and of the central somatosensory pathway. In: "New Developments in Electromyography and Clinical Neurophysiology." Edited by J. E. Desmedt. Basel: Kargcr, Vol. 2, p. 352. HALUDAY, A. M., and WAKEFIELD, G. S. (1963) Cerebral evoked potentials in patients with dissociated sensory loss. / . Neurol. Neurosurg. Psychiat., 26, 211-219. , MCDONALD, W. I., and MUSHIN, J. (1973) The visual evoked response in the diagnosis of multiple sclerosis. Br. med. J., 4, 661-664. KAHANA, E., LEraowiTZ, U., and ALTER, M. (1973) Brainstem and cranial nerve involvement in multiple sclerosis. Ada neurol. scand., 49, 269-279. KJMURA, J. (1970) Alteration of the orbicularis oculi reflex by pontine lesions: Study in multiple sclerosis. Archs Neurol., Chicago, 22, 156-161. (1973) The blink reflex as a test for brainstem and higher central nervous system function. In: "New Developments in Electromyography and Clinical Neurophysiology." Edited by J. E. Desmedt. Basel: Karger, Vol. 3, pp. 682-691. (1974) Effect of hemispheral lesions on the contralateral blink reflex: A clinical study. Neurology, Minneap., 24, 168-174. , and LYON, L. W. (1972) Orbicularis oculi reflex in the Wallenberg syndrome: Alteration of the late reflex by lesions of the spinal tract and nucleus of the trigeminal nerve. / . Neurol. Neurosurg. Psychiat., 35, 228-233. KUOELBERG, E. (1952) Facial reflexes. Brain, 75, 385-396. LUMSDEN, C. E. (1970) The neuropathology of multiple sclerosis. In: "Handbook of Clinical Neurology." Edited by P. J. Vinken and G. W. Bruyn. Amsterdam: North Holland, Vol. 9, pp. 217-309. LYON, L. W., and VAN ALLEN, M. W. (1972) Orbicularis oculi reflex: studies in internuclear ophthalmoplegia and pseudointernuclear ophthalmoplegia. Archs Ophthal., N.Y., 87, 148-154. , KIMURA, J., and MCCORMCK, W. F. (1972) Orbicularis oculi reflex in coma: Clinical, electrophysiological, and pathological correlations. / . Neurol. Neurosurg. Psychiat., 35, 582-588. MCALPINE, D. (1972) Course and prognosis. In: "Multiple Sclerosis: A Reappraisal." Edited by D. McAlpine, C. E. Lumsden and E. D. Acheson. Edinburgh and London: Livingstone, pp. 197-223. MCDONALD, W. I. (1974a) Pathophysiology in multiple sclerosis. Brain, 97, 179-196. (19746) Remyelination in relation to clinical lesions of the central nervous system. Br. med. Bull., 30, 186-189. , and SEARS, T. A. (1970) The effects of experimental demyelination on conduction in the central nervous system. Brain, 93, 583-598.
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REFERENCES
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(Received March 5, 1975)
Downloaded from http://brain.oxfordjournals.org/ at Princeton University on May 2, 2014
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