The role of magnetic stimulation as a quantifier of motor disability in patients with multiple sclerosis

Journal of the Neuroh,gical S¢'ien¢e.s, 106 ( 1991 ) 31 34

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, 1991 Elsevier Science Publishers B.V. All rights reserved 0~122-510X/t)l/$113.5(~ JNS 03636

The role of magnetic stimulation as a quantifier of motor disability in patients with multiple sclerosis R.H. Kandler, J.A. Jarratt, G.A.B. Davies-Jones, E.J.W. Gumpert, G.S. Venables, H.J. Sagar and A. Zeman Departments of Clinical Neurophysiology and Neurotoh'3', Royal ttallarnshilv Hospital, (;h~ssop Road, Sh~fficld S I0 ZII," ~l,'. K. I (Received 5 March. 19911 (Revised. received 30 May. 19911 (Accepted 28 June. 19911

Key words: M a g n e t i c s t i m u l a t i o n ; M o t o r e v o k e d p o t e n t i a l : C e n t r a l m o t o r c o n d u c t i o n : M u l t i p l e sclerosis

Summary Magnetic stimulation was used to measure motor conduction time (MCT) between head and neck in a prospective longitudinal study of patients with multiple sclerosis (MS) and normal subjects. M(_q" measurements showed a high degree of reproducibility in normal subjects and patients with stable MS. In patients with definite MS, there was significant positive correlation between MCT and motor disability. In patients treated with steroids for relapse of MS, there was significant shortening of MCT following treatment in those who clinically improved, but not in thosc who were clinically unchanged. In a smaller group of patients followed for 3 months, MCT changes tended to mirror the clinical pattern. Magnetic stimulation should prove a useful tool for the quantification of motor disability, and monitoring the response to new treatments in MS.

Introduction Objective measurements to assess new treatments for multiple sclerosis (MS) are required (Matthews 1984). Although clinical scales for grading disability exist, quantification of spasticity remains a well recognised problem. Sensory evoked responses and magnetic resonance imaging (MRI), are useful in the diagnosis of MS, but have not shown correlation with activity of the disease (Matthews and Small 1979; Kesselring et al. 1989). Magnetic stimulation has been used since 1985 to measure conduction times in central motor pathways (Barker et al. 19851. Early work showed prolongation of central motor conduction times in MS patients and the evidence suggested that the results were quantitative for motor dysfunction (Barker et al. 1987; Ingrain ct al. 1988; Kandler et al. 1989). This study has two objectives. First, to confirm the correlation between disability and motor conduction times in a larger number of patients. Second, to examine the possibility that

Correspondence to: Dr. R.H. Kandler, Departments of Clinical Neurophysiology and Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield SI0 2JF, U.K.

magnetic stimulation may be used to monitor clinical responses to treatment.

Materials and methods The study was approved by the Local Ethical Committee and all patients and normal subjects gave prior informed consent. We consider that at present a history of epilepsy, neurosurgery to the head or the possession of a cardiac pacemaker are absolute contraindications to examination with magnetic stimulation (Barker et al. 1988). Details of the examination technique have been reported elsewhere (Barker et al. 1987; Jarratt et al. 19901. Briefly, surface recording electrodes were placed over abductor digiti minimi (ADM). The stimulating coil (Novametrix, type Magstim 200)was placed in the neck as close as possible to the exit foramina of the peripheral nerves, and the stimulus strength increased to give a maximal response. The latency to the compound muscle action potential was measured using a conventional E M G recording system (Nicolet Viking). Positioning the centre of the coil in the region of the vertex usually proved to be the most effective site for cortical stimulation. Approximately 90% power output

32 was used in all cases. The motor evoked potentials (MEP) varied in form. amplitude and latency from stimulus to stimulus. However, a series of stimuli were given to ensure a consistent minimum latency. Usually 6 or more wcrc required. The difference between the latency measurements obtained at the two stimulus sites represents the conduction time in pathways from head to neck, which lie mainly within the central nervous system. We describe the wduc obtained as the motor conduction time (M('T). All recordings were performed with the target muscle relaxed. Potentials were excluded from analysis it" motor unit activity could bc heard or seen in the background recording at the time the stimulus was given to the head. Voluntary contraction of the target rnusclc during cortical stimulation results in shorter latency and larger amplitude responses (Merton et al. 1982).

Of the original 27 patients. 14 wcrc examined on a third occasion at 6 weeks. The same 14 and two others from the original group, attended for examination at 12 weeks aftcr the completion of treatment. There sccmcd to be more possiblity of observer bias with the clinical than with the elcctrophysiological assessment because it was quite clear lhat. providing a sufficient number of rcsponscs was recorded, the minireal latency value could bc obtained frequently at the same examination. Therefore, on each occasion. Kurtzkc grades for pyramidal function wcrc assessed initially and then magnetic stimulation was performed. However, Kurtzkc grades were estimated by an indcpcndent obscrver on 10 occasions and good correlation between the grades was found (r, - [I.S0: P < 1).()5).

I'atients atut normal subjects

Con'elation between electrophysioh~gical abnormality and clinical disability

Magnetic stimulation, using bilateral recordings, was performed on all normal subjects and patients. The MS patients were a sub-group of the patients described in a separate paper and the group of normal subjects was the same (Kandlcr et al. 1991).

There was highly significant correlation between MCI" results performed on 2 occasions in both the normal subjects (r = 0.57: P = (I.01) and clinically stable MS patients (r = 0.95; P < 0.0001 ). The coefficient of variation was 0.09 and 0.09 fi~r normal subjects, and {).26 and 0.29 for the patients. M('T measurements were therefore reproducible. If the technique was to prove useful in longitudinal monitoring of patients" disability, it was important first to establish a correlation between clcctrophysiological and clinical findings in patients in stable states. There was significant correlation between MCT (the more abnormal of the two sides tested) and the degree of pyramidal disability as assessed by the Kurtzkc scale ( r = 0.59; P < (L0001) as shown in Fig. 1. This confirms the original observation (Barker 1987) which

Normal subjects Normal ranges wcrc established from a group of 30 normal subjects (mean age 38 years; range 22-74). 9 normal subjects had the mcasurements repeated on a second occasion (mean 5 months: range 1 week-10 months).

MS patients One hundred patients (mean age 38 years; range 19-75) with clinically definite or laboratory-supported dcfinitc MS according to the criteria of Poser et al. (1983) wcrc examined using the Kurtzkc scale for pyramidal dysfunction (Kurtzke 1965), and with magnetic stimulation. Eleven patients with stable MS were re-examined with magnetic stimulation on a second occasion (mean 6 weeks: range 1-6 months).

Results

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MS patients in relapse Magnetic stimulation was performed on 27 patients, treated with steroids, betore commencement of treatmcnt and at the end of the course. Nineteen received a 2-week course of ACTH and 8 were treated with 5 days of methyl prednisolone intravenously. Nineteen were in acute relapse and 8 were in the progressive phase of MS; 23 had clinically definite MS, 1 clinically probable; 3 had progressive MS. All patients exhibited pyramidal signs.

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compared the degree of MCT abnormality in a smaller group of MS patients who were mobile to those who were chairbound. Monitoring of clinical response to treatment The 27 patients who were tested before and after steroid treatment were grouped into those who had clinically improved by one or more Kurtzke grades and those who were clinically unchanged at the end of the course of treatment. Fourteen patients improved and 13 did not. MCTs were abnormal prior to treatment in 35 of the 54 arms - bilaterally in 8 patients and unilaterally in 19. Only the results from the limbs with an initially abnormal MCT were analysed. Those who improved clinically showed a corresponding reduction in mean MCT - 17.6 ms to 15.8 ms ( P < 0.001; paired t-test). Those who did not improve clinically showed no significant change in MCT - 17.3 to 17.0 ms. The results from individual patients are shown in Fig. 2. The clinical pattern of the 16 patients who were followed for 3 months fell into 4 groups: 7 patients improved by the time of discharge and then remained stable: 4 patients showed no clinical improvement at any stage; 2 patients (who were not examined at 6 weeks) made a late recovery at 12 weeks; 3 patients improved initially but then relapsed at 12 weeks. In those who clinically improved and remained stable, MCTs shortened initially and then remained static. In those who did not change clinically during the period of observation, MCTs varied very little. Those who improved late showed a corresponding reduction in MCT at 12 weeks. In those who improved and relapsed later, MCTs initially decreased and then increased at 12 weeks. These trends are displayed in Fig. 3.

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The numbers in the individual groups are to() small for statistical analysis. However, there was significant correlation (r, = 0.26; P < 0.05) between Kurtzke grade and MCT for the group of patients as a whole on the different occasions the tests were performed. In addition, there was significant correlation (r, = 0.46: P < 0.005) between the change at the follow-up testings in Kurtzke grade and the change in MCI" from the initial assessments for the whole group.

Discussion

Motor conduction time measurements show conszstency at repeated examination not only in normal subjects but also in MS patients in a stable clinical state. This is a prerequisite for the technique to be useful as a tool for quantifying and monitoring disease activity. The suggestion that repeat testing in patients correlated better than in normal subjects raises the interesting possibility that the pathology might reduce the numbers of functioning pathways and therefore the spectrum of motor conduction times which can be measured. We have confirmed the original observation that MCF measurements correlate positively with motor disability (Barker ct al. 1987). This probably explains the poor yield of silent lesions produced by MEP measurements in MS (Kandler et al. 1989). Correlation between changes in MCT and clinical outcome were good for individual patients, although there were some exceptions. However, for the grouped data there was a statistically significant relationship between improvement in group mean MCT before and after treatment in patients who improved, whereas the group mean MCT remained unchanged in patients who were clinically unchanged. Whether or not steroids are beneficial and if so, their mechanism of action, is

34

outside the scope of this paper. Improvements in central motor conduction following physiotherapy in MS have also been described (Kandler and Childs 1990), and it is more likely that alterations in MCT reflect clinical changes rather than a primary effect of steroids. Matthews and Small (1979) showed that although clinical deterioration may be accompanied by increasing SSEP and VEP abnormality, remission did not result in improvement of the abnormalities. The persistence of abnormalities in the VEP and SSEP following clinical remission allows them to be effcctivc diagnostic tests but precludcs them from being useful in the rnonitoring of patient disease. Kcsselring el al. (1989), using MRI scanning, have shown in MS patients treated with methyl prednisolone the devclopmcnt of new scan lesions which were clinically silent, and the reduction in size of other lesions where no clinical improvement was evident.

Evoked potentials anti MRI scanning arc both extremely useful diagnostic tests. Their sensitivity in demonstrating subclinical abnormality makes them valuable in assessing diseasc activity, but disqualifies them l'rom monitoring thc degree of clinical disability. Magnetic stimulation is a painless and easy technique which provides quantitative information about motor dysfunction. Results mirror clinical change and remain constant during periods of stability. In view of the well rccogniscd difficulties in quantifying pyramidal dysfunction clinically, magnetic stimulation should prove vahtable in MS as an objective monitor of treatments.

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Barker. A.T.. I.l.. Freeston. R..l,dmt~us and J A . Jarratt (19N8) Magnetic and electrical MJmulation o[ the brain: salcty aspects. In: Rossini. P.M. and Mar,,den. ('.D. (l!ds.L Non-invasivc Stimulation ot the Brain and Spinal ('ord: 1.undanlentals and ('lmical Applications. AI;ln R. I.iss. Nev, York. pp. 131 ..144. Ingrain. I).A.. ,,\.J. ] h o m p s t m and M. Nv,.ash (It?N~) ('entral motor conduction in multiple ,,clerosis: c\.aluation ol abnormalities re',ealcd I',.~ transcutaneous magnetic stimulation ol the brain. J. Neurol. N e u r o s u r g Psychiat.. 51:4,'47 4~.~4. Jarratt, .I.A., A.T. Barker, I.[.. f:reeston. R. Jalinous. R.It. Kandler and 1)..laskolski (lgt.~0'l Magnetic ,,lirnuhition of the human nem'ous system: clinical applicahons. In: ('hokruvert,, S. (Ed.). Magnetic Stimulation m Clinical Nctlrophysit~logy. Bntterworth~,. Stoneham, MA. pp. 185 2(13. Kandler, R.It.. J.A. Jarratt, t-.J.W. Oumpert. (i.A.B. Davies-Jones. (;.S. Venablcs and II.J. Sagar (1~,';';9) Ma;gnetic ~,tinlulation as a quantifier of nlotor disabilit!,. J. Neurol. N c u r o s u r g Psychiat., 52: 12115. Kandler. Rl, I. and .1. ('hilds ~ 19911) ('hanges m central motor condt,ction with physiotherapy in rnuhiplc ~,clcrosi~,: a c,,sc report. ('lin. Rehabil.. 4 : 5 7 - 6 2 . Kandler, R.II., J.A. Jarratt, I'~.J.W. (iurnpert, (i.A.13. Davies-Jones. (i.S. Venables and lt.J. Sagar (ITS91) "lhc rnlc of magnetic stimulatioul in the diagnosis ot multiple ~,clcrosi~,. J. Neurol Sci.. 1(16: 2~-31. Kesselring, L, I).ll,. Miller. I).G..McManus, (;. Johnson. N M . Milligan. N. Scolding. I).A.S. ('ompston and W.I. Mcl)onakt (1989) (.)uantitative magnetic resonance imaging ira muttiplc sclerosis: the ~:ffcct of high dose r'neth~,.I prednisohmc. J. Neurol. Neuro~,urg. Psychiat., 5: 14- 1"7. Kt,rtzke, J.l,:. (1t165) Further notes t~ll disability evah, ation in multipie sclerosis '.','ilia scale modifications. Neurok~g~. 15: 654-661. Matthev,'s. W.B. and 1).(;. Small (197t;) Serial recordings of visual ,llld sonl~ltOSellSOp,/ evoked potenti:lls ill rnultiple sclerosis. J. Ncurol. Sci., 4(): II 21. Matthews, W.B. ( 1 9 8 4 ) T h e treatment ol ml]ltiple sclerosis. In: Manhev, s. W.B. and (ilaser. (;.tt. (l.Xts.). Recent Advances in Clinical Neurology. Churchill I.ivingst~mc, Edinburgh. p. 182. Merton, P.A. 11.13. Morton. I)K. Itill and C.D. Marsden (19N2l, Scope of a technique for electrical stimulation ol human brain. spinal cord and muscle. Lancet. i~: 5t)7-.N)(L Poser. ( ' M . , l.).W. Paty. 1.. Scheinbcrg. ~ .1. McI)omdd, F A . Davis, G.('. t-bets. K.P. Johnson. W.A. Silqc~,. D.II. Silberbcrg and W.W. "l,'ourtellottc