Can Motor Recovery in Stroke Patients Be Predicted by Early Transcranial Magnetic Stimulation?
Background and Purpose We used transcranial magnetic stimulation of the motor cortex to evaluate the functional state of corticospinal pathways innervating the first dorsal interosseous muscle of the hand in 26 patients suffering from a first-ever ischemic stroke in the middle cerebral artery territory.
Methods All patients had complete hand palsy and were tested within the first 24 hours from stroke onset. Patients were also tested clinically with the MRC, Rankin, and National Institutes of Health (NIH) stroke scales at day 1 and with MRC and NIH scales and the Barthel Index at day 14. Electrophysiological testing was repeated at day 14. Patients were divided into three subgroups according to the amplitude of the maximal response (motor evoked potential [MEP]) evoked at day 1.
Results After 2 weeks, all 6 patients with initial MEPs >5% maximum motor response (Mmax) showed some first dorsal interosseous muscle motor function recovery, whereas 19 of 20 patients with initially absent or small (<5% Mmax) MEPs were left with complete hand palsy. There were strong positive correlations between MEP amplitude at day 1 and MRC and Barthel Index scores at day 14. However, measurement of central motor conduction time proved to be of little prognostic value.
Conclusions We conclude that early-performed transcranial magnetic stimulation is a valuable prognostic tool for motor recovery from stroke and that relatively preserved MEP amplitude shortly after stroke is a better prognostic factor than normal central motor conduction time.
Motor function recovery after stroke is largely variable. In the first days, it is difficult to predict from clinical and even x-ray findings. In the management of stroke patients, it could be important to obtain an early indication that a significant motor recovery will occur. This would be an advantage for planning rehabilitation and for patient motivation.
The prognostic value of TMS in stroke has been recently discussed.1 TMS is a safe, painless, and noninvasive method to stimulate motor cortex in humans and investigate the function of descending motor pathways.2 3 Several recent studies have indicated that TMS can be useful to predict motor outcome after stroke,4 5 6 but the conclusions of these studies are sometimes contradictory and remain disputed.7 8 9 Some discrepancies could stem from the inclusion, in all previous series, of patients with different degrees of motor deficit at first assessment and with lesions located in various arterial territories. Moreover, in many of these studies, attention was mostly focused on alterations of CMCT. Methodologically, it would be more accurate to study patients with comparable motor deficits (eg, complete hand palsy) and, because of the nature of the disease considered, to pay more attention to MEP amplitude changes. This parameter might reflect more accurately than CMCT the number of corticospinal projections damaged by the ischemic lesion. The aim of the present study was to assess the value of early-performed TMS in predicting hand motor recovery in a homogeneous group of patients after a first-ever ischemic stroke in the MCA territory. All patients showed complete hand palsy at onset. We compared the prognostic values of CMCT and MEP amplitude abnormalities for motor recovery, and correlations between electrophysiological abnormalities and individual scores on standard clinical scales were calculated.
Subjects and Methods
The study was approved by the local ethics committee, and informed consent was obtained from all stroke patients or from close relatives.
Twenty-six stroke patients (mean age, 67.7 years [range, 39 to 87 years]; 17 men and 9 women) were studied. All were hospitalized in the first hours after onset of the neurological deficit. They were treated according to current recommendations for ischemic stroke management10 and received appropriate neurorehabilitation during hospitalization. Most of them were discharged from the neurological unit after 2 weeks. The patients were included in the protocol if they fulfilled the following criteria: (1) first-ever ischemic stroke in the MCA territory, (2) complete hand palsy at onset, (3) age between 18 and 90 years, (4) clinical classification of stroke subsequently confirmed by CT or MR scans that showed an MCA territory infarct of thrombotic or embolic origin, and (5) electrophysiological assessment within 24 hours from onset of symptoms (defined as day 1). Patients were excluded if CT or MR scan demonstrated primary cerebral hemorrhage or if they were comatose, in terminal phase, or unable to understand simple orders. In addition, patients showing a significant motor recovery within 24 hours of stroke onset were excluded.
Patients were examined clinically, and MEPs in response to TMS were recorded within 24 hours after symptom onset (day 1) and again at day 14. Unfortunately, a later evaluation was not possible because many patients, once discharged from the hospital, failed to return as outpatients or were transferred to neurorehabilitation units located outside the hospital.
Patients lay supine in a quiet room. TMS was performed using a Magstim 200 magnetic stimulator with a circular coil of 9 cm in mean diameter. Cortical stimuli were administered with the coil maintained in the tangential plane above the vertex. Stimulation intensity was 70% of maximal stimulator output or 100% if no response was obtained at 70%. The latter intensity was chosen because in normal subjects it is sufficient to evoke MEPs of maximal amplitude in hand muscles. A counterclockwise current in the coil was used to stimulate the left hemisphere and clockwise to stimulate the right. The affected side was always stimulated first. Cervical motor roots were stimulated with the lower edge of the coil overlooking the spinous process of the C7 vertebra with a 100% maximum stimulation intensity. Counterclockwise current was used to stimulate the right cervical roots and clockwise for the left. MEPs were recorded with surface electrodes positioned over the FDI muscle and amplified using a Nicolet Viking IV with two different gains (20 μV and 1 mV/div; band pass, 30 Hz to 3 kHz) for accurate latency and amplitude discrimination. Subjects were studied while producing a slight isometric contraction of the target muscle or of the contralateral homologous muscle if no ipsilateral voluntary contraction could be achieved.11 A 100-millisecond poststimulus period was analyzed. Four consecutive responses were averaged, and their peak-to-peak amplitudes were measured. Latencies were measured between the stimulus artifact and the onset of the first negative departure from baseline, excluding random electromyographic activity if responses were collected during voluntary contraction. An MEP was considered absent if no response could be obtained after four stimulations at 100% intensity. Four responses to cervical stimulation were recorded from the FDI muscle at rest. The MEP latency after cervical stimulation was taken as peripheral latency. TMCT was defined as the shortest time interval between cortical stimulation and muscle response. CMCT was calculated by subtracting peripheral latency from TMCT. Mmax to electrical stimulation of the ulnar nerve was also measured, and the amplitude of MEPs to cortical stimulation was expressed as the MEP/Mmax ratio. MEP amplitude and CMCT were also measured on the subject's healthy side at day 1. CMCT and amplitude of MEPs were compared with normative data previously obtained in the laboratory12 ; CMCT was considered prolonged if longer than 8.2 milliseconds (mean +2.5 SD of mean) under voluntary contraction or longer than 10.3 milliseconds at rest; amplitude was considered reduced if <20% Mmax (mean −2.5 SD of mean) under voluntary contraction and <10% Mmax at rest.
Hand muscle strength was assessed using a rating scale derived from the MRC scale (0, no movement; 1, movement only if gravity is removed; 2, weakness against gravity; 3, weakness against slight resistance; 4, weakness against stronger resistance; and 5, normal strength). Evaluations were performed at days 1 and 14. Every patient was also assessed with the Rankin Disability Scale13 at day 1, the NIH Stroke Scale14 at days 1 and 14, and the Barthel Index15 at day 14.
Group differences were tested statistically with the Mann-Whitney rank-sum test, and correlations between electrophysiological and clinical variables were calculated using Spearman's rank-order correlation test.
An illustrative example (patient 6) is given in Fig 1⇓. A cortical-subcortical infarct in the right MCA territory can be seen on the CT scan. Although the patient had a complete left hand palsy, TMS was able to evoke an MEP in the left FDI muscle. Responses were smaller than contralateral ones but within the normal range for CMCT and amplitude.
After contralateral cortex stimulation, MEPs on the healthy side had normal latencies and amplitudes in all but 2 patients. The first was an 87-year-old subject whose MEP amplitude was 16.6% Mmax and CMCT was 9.05 milliseconds; the second showed MEPs of normal amplitude, but the CMCT was 8.3 milliseconds. MEPs after cervical stimulation were elicited in all cases, with normal latencies and amplitudes on both sides. Electrophysiological and clinical data on the affected side of all patients are shown in the Table⇓. Some findings are detailed below.
Electrophysiological Data at Day 1
MEPs in response to cortical stimulation were present in the affected FDI muscle in 11 of 26 patients. In 5 patients, MEPs showed normal amplitudes and latencies. In 3, MEPs had prolonged latency and reduced amplitude, and another 3 patients showed MEPs with reduced amplitude and normal latency. No response could be elicited in the affected FDI muscle of the 15 remaining patients. According to the presence and the amplitude of MEPs, the patients were classified into three subgroups.
Group 1 included patients with MEP amplitudes >5% Mmax (n=6). This value was chosen because it represents 50% of the lower limit of normal amplitudes in the absence of voluntary contraction of the target muscle. Group 2 included 5 patients with present MEP but with amplitudes <5% Mmax. Group 3 included the 15 patients in whom MEPs were absent.
Clinical Data at Day 1
Hand muscle strength index was 0 in all three groups. Mean Rankin scores (Fig 2⇓) were 4.2±0.4 in group 1, 4.4±0.6 in group 2, and 4.8±0.4 in group 3 (each group including subjects with scores of 4 and 5). However, mean Rankin score was significantly higher in group 3 than in group 1 (P<.05, Mann-Whitney); no significant differences were found between groups 1 and 2 or between groups 2 and 3. Mean NIH scores were 9.4±3.9 for group 1, 11.7±3.7 for group 2, and 15.5±5.4 for group 3, with large interindividual variations (see Table). Again, the mean NIH score at day 1 was significantly higher in group 3 than in group 1 (P=.01, Mann-Whitney); no differences were observed between groups 2 and 3 or groups 1 and 2.
Electrophysiological Data at Day 14
One subject (patient 3) refused further electrophysiological assessment. MEPs to cortical stimulation were present on the affected side of 10 of 25 patients tested; they disappeared in 1 (patient 9) who had a very small response at day 1 (0.2% Mmax with CMCT of 10.3 milliseconds). Amplitude of MEPs increased in 7 subjects, 6 of whom were able to perform a voluntary contraction of the FDI muscle at day 14, but diminished in 3 subjects. CMCT time was reduced in 7 subjects and was longer in 2. One patient (patient 22) showed a small MEP at day 14, whereas no response had been evoked at day 1.
Clinical Data at Day 14
The hand muscle strength index remained 0 in all patients but 1 (patient 11) of groups 2 and 3. On the other hand, it showed an improvement (scores from 2 to 4) in group 1. Mean NIH scores were 4.8±3.2 in group 1, 9.8±4.7 in group 2, and 13.9±5.8 in group 3. Here again, individual values showed large variability within the three groups, and mean score was significantly lower in group 1 than in group 3 (P=.005, Mann-Whitney); no significant differences were observed between groups 1 and 2 or groups 2 and 3. Mean Barthel Index score at day 14 was 84.2±16.9 in group 1, 38±23.9 in group 2, and 18.3±22.5 in group 3 (Fig 2⇑). No significant differences were observed between groups 2 and 3, but group 1 scored significantly better than both groups 2 (P=.05) and 3 (P=.001, Mann-Whitney).
No significant correlations could be found between muscle strength at day 14 and CMCT values at day 1 or between muscle strength at day 14 and NIH or Rankin scores at day 1. On the other hand, there were strong positive correlations between muscle strength scores at day 14 and MEP amplitude at day 1 (P<.001, r=.876, Spearman), and between Barthel Index scores at day 14 and MEP amplitude at day 1 (P<.001, r=.745, Spearman). Not surprisingly, there was also a significant negative correlation between the NIH score at day 1 and Barthel Index score at day 14 (P<.001, r=−.746, Spearman).
Despite the conclusions of several recent publications,4 5 6 the value of cortical magnetic stimulation to predict motor recovery from stroke is still controversial. As stated in the introduction, most previous studies were conducted on heterogeneous groups of patients (distinct types of strokes, various degrees of motor deficit), and the first magnetic stimulation was performed at various delays after stroke onset: 12 to 72 hours,5 1 to 5 days,4 within the first week,6 9 during the second week,8 or during the first month.7 The clinical rating scales used were sometimes different, patients were assessed clinically at various delays after stroke, and studies had different primary end points. Not surprisingly, the conclusions were not always convergent. In our study, particular attention was paid to the following points. (1) All 26 patients included were similar in many aspects (ischemic stroke due to MCA infarct and complete hand palsy at day 1). (2) Electrophysiological testing was always performed within 24 hours from stroke onset (ie, before any motor recovery had time to occur), and measurements were repeated at day 14. (3) The clinical rating scales used are widely accepted.
Our study also has some limitations. The number of patients studied was limited, caused largely by very strict inclusion criteria (see above). The 14-day interval between initial testing and final evaluation may appear short. However, it has been reported that the major part of motor recovery after stroke occurs within the first 30 days, regardless of the initial stroke severity.16 The 14-day delay was chosen for practical reasons (length of hospitalization), and a longer interval would have led to many patients dropping out of the study or failing to return for a final evaluation. Motor recovery at day 14 may be considered as a compromise that is likely a reliable indicator of final outcome. One original feature of this study is that more attention was paid to amplitude of MEPs recorded at day 1 than to CMCT. In previous studies, the former parameter was seldom taken into account. This could be explained by the large interindividual variability of MEP amplitudes of patients. Marked differences between both sides in normal subjects have also been reported.17 18 For this reason, we chose 5% Mmax as the lower MEP amplitude limit for group 1 (ie, 50% of the lower limit of normal values at rest). In the present series, there was no significant correlation between CMCT values at day 1 and motor recovery at day 14, whereas a strong correlation was observed between initial MEP amplitude and motor recovery, as well as with activities of daily living (Barthel Index). As examples, patients 7 and 8 showed normal or near-normal CMCTs at day 1 without significant recovery at day 14, whereas prolonged CMCT was sometimes linked with good outcome, as illustrated by patient 1. In this study, MEP amplitude was chosen to initially define three subgroups of patients. This choice is justified in Fig 2⇑, which shows that at day 1 all patients presented with similar Rankin scores and could not be discriminated clinically for prediction of recovery. Nevertheless, clinical evaluation at day 14 showed that patients of group 1 (initial MEP amplitude >5% Mmax) behaved differently from those included in groups 2 and 3. Their motor recovery (muscle strength scale) and ability to perform activities of daily living (Barthel Index) were significantly better than in the other two groups (Fig 2⇑). No significant difference of functional outcome could be outlined at day 14 between groups 2 and 3.
In the present series, it was possible to elicit an MEP in about one third of the subjects despite complete hand palsy. These results may appear surprising because in some previous studies4 5 9 complete palsy was usually associated with absence of responses. Nevertheless, others have made similar observations.12 17 19 20 21 They have also observed stroke patients in whom no voluntary motor activity could be achieved but in whom MEPs could be evoked using TMS12 17 19 or electrical20 21 stimulation. For example, Dominkus et al21 performed cortical electrical stimulation 0 to 3 days after stroke. They observed the presence of MEPs, sometimes normal, on the affected side in 4 of 11 patients with complete palsy. Because our patients were studied very early after stroke, the persistence of MEPs in some of them cannot be ascribed to ongoing recovery. This probably indicates that some corticospinal neurons, although unable to respond normally on voluntary command, remain anatomically intact and can still be excited by highly synchronized external stimuli. An alternative explanation would be that persistent responses reflect the activity of uncrossed ipsilateral corticospinal pathways. Studies conducted in our department (E.B., G.R., G.P., A.M. de N., P.J.D., unpublished data, 1996) showed that when using focal “figure of eight” stimulating coils, it was never possible to elicit a motor response in affected muscles of stroke patients when selectively stimulating the ipsilateral motor cortex.
The present study indicates that early preservation of MEPs >5% of Mmax on the affected side of a stroke patient with complete hand palsy represents a significant prognostic factor for motor recovery. Conversely, failure to evoke MEP or MEPs <5% of Mmax is associated with a poor motor prognosis, at least after 2 weeks. The amplitude of MEPs at day 1 also seemed to be more useful than the clinical scales used in this study. As shown in Fig 2⇑, Rankin scores in this series were not helpful in predicting hand motor recovery, as scores at day 1 were similar in patients who later recovered and those who did not. NIH scores were lower for patients with good recovery. If group mean values are considered, some prognostic value may be derived from this scale. However, because of large interpatient variability, the NIH score is not useful for individual cases, as exemplified by patient 4 and inversely by patient 22.
In conclusion, TMS in the first hours after a stroke seems to be a safe and useful tool in predicting hand motor recovery in subjects with complete palsy due to ischemic stroke. An MEP amplitude >5% Mmax appears to have a higher prognostic value than CMCT and to be a more reliable indicator of motor recovery than the standard clinical scales.
Selected Abbreviations and Acronyms
|CMCT||=||central motor conduction time|
|FDI||=||first dorsal interosseous|
|MCA||=||middle cerebral artery|
|MEP||=||motor evoked potential|
|Mmax||=||maximum motor response|
|MRC||=||Medical Research Council|
|NIH||=||National Institutes of Health|
|TMCT||=||total motor conduction time|
|TMS||=||transcranial magnetic stimulation|
- Received May 30, 1996.
- Revision received August 2, 1996.
- Accepted August 14, 1996.
- Copyright © 1996 by American Heart Association
Muellbacher W, Mamoli B. Prognostic value of transcranial magnetic stimulation in acute stroke. Stroke. 1995;26:1962-1963. Letter.
Barker AT, Freeston IL, Jalinous R, Jarratt JA. Magnetic and electric stimulation of the brain: safety aspects. In: Rossini PM, Marsden CD, eds. Neurology and Neurobiology: Vol 41, Noninvasive Stimulation of Brain and Spinal Cord. New York, NY: Alan R Liss Inc; 1988:131-144.
Chu N, Wu T. Motor response patterns and prognostic value of transcranial magnetic stimulation in stroke patients. In: Lissens M, ed. Clinical Applications of Magnetic Transcranial Stimulation. Leuven, Belgium: Peeters Press; 1992:127-145.
Heald A, Bates D, Cartlidge NEF, French JM, Miller S. Longitudinal study of central motor conduction time following stroke. Brain. 1993;116:1371-1385.
van Rijckevorsel-Harmant K, Boon V. Central magnetic stimulation, somatosensory potentials and clinical evaluation during a rehabilitation treatment in hemiplegic patients. Electroencephalogr Clin Neurophysiol. 1993;87:102. Abstract.
Zgur T, Prevec TS, Golfar N. Correlation of motor evoked potentials to motor deficit during the recovery of ischemic stroke. Electroencephalogr Clin Neurophysiol. 1993;87:102. Abstract.
Arac N, Sagduyu A, Binai S, Ertekin C. Prognostic value of transcranial magnetic stimulation in acute stroke. Stroke. 1994;25:2183-2186.
Marshall RS, Mohr JP. Current management of ischaemic stroke. J Neurol Neurosurg Psychiatry. 1993;56:6-16.
Maertens de Noordhout A. Stimulation percutanée du cortex moteur chez l'homme: données physiologiques et utilisation clinique. Liège Mardaga; 1991:232. Thesis.
Special report from the National Institute of Neurological Disorders and Stroke: classification of cerebrovascular disease III. Stroke. 1990;21:637-676.
Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol. 1989;56:660-662.
Wade DT, Collin C. The Barthel ADL index: a standard measure of physical disability. Int Disabil Studies. 1988;19:604-607.
Duncan PW, Goldstein LB, Matchar D, Divine GW, Feussner J. Measurement of motor recovery after stroke. Stroke. 1992;23:1084-1089.
Eisen A. Cortical and peripheral nerve magnetic stimulation. Methods Clin Neurophysiol. 1992;3:65-84.
Muellbacher W, Mathis J, Hess CW. Electrophysiological assessment of central and peripheral motor routes to the lingual muscles. J Neurol Neurosurg Psychiatry. 1994;57:309-315.
Dominkus M, Grisold W, Jellinek V. Transcranial electrical motor evoked potentials as a prognostic indicator for motor recovery in stroke. J Neurol Neurosurg Psychiatry. 1990;53:745-748.