Multiple system atrophy

Dysmetria is a classical sign which designates the overshoot, also called hypermetria, and the undershoot, or hypometria, when the patient attempts to reach rapidly an aimed target. Dysmetria is typically observed in patients presenting a cerebellar dysfunction. Dysmetria of distal movements is associated with an imbalance between the timing and/or the intensity of agonist and antagonist EMG activities. So far, 1. there is only one description in human of a shift from hypermetria to hypometria for fast goal-directed single-joint movements during an aberrant recovery following a cerebellar infarction, and 2. such a shift has not been described for proximal movements. We report a patient presenting a multiple system atrophy (MSA). Initially, he exhibited a marked cerebellar syndrome. Fast wrist flexions and fast upper limb reaches in the sagittal plane were hypermetric. The distal hypermetria was associated with a delayed onset latency of the antagonist EMG activity and reduced intensities of both the agonist and the antagonist EMG activities. The proximal hypermetria was associated with a defect in the phasic spatial tuning of the EMG activities. He developed progressively severe extra-pyramidal signs. Distal hypermetria turned into hypometria, as a result of a decrease in the intensity of the agonist muscle. Proximal hypermetria turned into hypometria, as a result of the loss of directional preference of the EMG activities in proximal muscles. MSA is the second human model of a shift from hypermetria to hypometria. [Neurol Res 2002; 24: 249-258]

Keywords: Movement; dysmetria; phasic spatial tuning, EMG; direction; MSA

INTRODUCTION

Gordon Holmes defined dysmetria, a cardinal sign of cerebellar disease, as a movement not proportioned to the aim1-3. Dysmetria is particularly prominent in fast movements when the patient attempts to reach a target, and is divided into hypermetria (or overshoot) and hypometria (undershoot)4-9.

Fast single-joint movements are under the control of a triphasic pattern of EMG activity5,10,11. The acceleratory pulse is provided by the agonist muscle and the deceleratory pulse is generated by the antagonist muscle. The most critical EMG deficit associated with cerebellar hypermetria is a delayed onset latency of the antagonist EMG activity. In addition, a delay in the initiation of movement, an increased duration and a reduced intensity of both the agonist and antagonist EMG activities may be observed9,12. Concerning cerebellar hypometria, three mechanisms have been identified:

1. A deficit in the rate of rise in the intensity of the agonist EMG activity.

2. A reduction in the intensity of the agonist muscle associated with a prolongation of the duration of the antagonist EMG activity.

3. A prolongation of the duration of the EMG activity in the antagonist muscle6,8.

Hypokinetic symptoms are also major features of extra-pyramidal disorders13. Indeed, patients with Parkinson's disease move slowly and perform small movements. They make hypometric movements, especially under nonvisual conditions. Several mechanisms have been suggested to explain Parkinsonian hypometria, in particular a mismatch between kinesthesia and visual perception of movement13.

We have reported previously the clinical and neuroand visual perception of patient presenting a stroke in the territory of the superior cerebellar artery and who presented a severe dysmetria7. The initial hypermetria associated with fast wrist flexions turned into a marked hypometria, as a result of an aberrant recovery. We report here the second description of a shift from hypermetria to hypometria, occurring in a patient exhibiting a multiple system astrophy (MSA). The underlying mechanism was distinct from the one described in the aberrant recovery which follows a stroke. We analysed the phasic spatial tuning of the EMG activities during reaches in a sagittal plane. Follow-up studies of the changes in phasic activation of proximal muscles for movements in the vertical plane have not been reported so far in patients with MSA.

CASE REPORT

This 63-year-old man complained of speech difficulties, gait unsteadiness leading to falls, impotence and constipation beginning progressively four years before. There was no history of neurological disorder in the family. He worked as a driver. General physical examination was normal. Standing position was associated with a blood pressure drop from 160/90 mmHg (heart rate 76 bpm) to 120/85 (heart rate 78 bpm). Neurological examination (session 1, see below) of this right-handed man showed a marked cerebellar syndrome including ocular dysmetria, cerebellar dysarthria, severe hypermetria of fast proximal and distal movements in upper limbs. Stewart-Holmes sign was positive bilaterally. Gait was ataxic and tandem gait was not possible. In addition, he exhibited very slight extrapyramidal signs: slight hypomimia and slight decreased arm swing during gait. There was no rigidity in limbs, no supranuclear gaze palsy and no alien limb syndrome. Strength and sensations were normal. Tendon reflexes were brisk. Brain CT-scan disclosed a marked pancerebellar atrophy with moderate brainstem atrophy (Figure 1). Blood studies were unremarkable. Brainstem auditory evoked potentials, motor evoked potentials and somatosensory evoked potentials in four limbs were normal. EEG was unremarkable.

Ten months later (session 2), neurological examination showed an increase of hypomima, sialorrhea and a marked decrease in arm swing during gait. The following cerebellar signs were still present but less obvious: cerebellar dysarthria, dysmetria during finger-to-nose test, ataxia of gait. He presented dysphagia, a marked postural hypotension and incontinence. Motor evoked potentials were normal in upper limbs. Brain CT showed a marked cerebellar atrophy and a moderate brainstem atrophy.

Twenty-five months later (session 3), bradykinesia and hypokinesia were severe, especially at the level of proximal joints. Saccades were hypometric. He exhibited hypophonia, marked sialorrhea, shuffling gait and absence of arm swing. He was unable to walk without aid. Cerebellar signs were difficult to appreciate. He showed a significant orthostasis, which was exacerbated after prolonged recumbency and mealtime. There was no response of extra-pyramidal signs to levodopa or apomorphine. Brain MRI confirmed the cerebellar and brainstem atrophy.

While the patient perceived an inability to perform a fast movement with accuracy at session 1, the perception of a discrepancy between motor intention and performed movements decreased clearly during the follow-up from session 1 to session 3.

METHODS

In our patient, recordings of distal and proximal movements on the right side were made during the three successive sessions.

Recording of fast wrist movements

The methods have been described elsewhere14-16 Briefly, the patient and each subject of a control group (n = 15 subjects; mean age 76, with a range from 68 to 89 years; nine women) were asked to make fast goaldirected movements with the fingers extended. In response to a 'go' signal, a horizontal wrist flexion had to be made towards an aimed target located at 15 degrees from the start position (see Figure 1 of reference 14). Computerized motion analysis was made with a Selspot II system (Selcom, Sweden). One infra-red lightemitting diode was attached to the forefinger. Two cameras recorded the positioning of the LED, at a sampling rate of 300 Hz and with a resolution of 0.25 mm. The activity of the flexor carpi radial is (agonist muscle) and of the extensor carpi radialis (antagonist muscle) was recorded with surface electrodes. EMG signals were amplified, filtered (x2000, 30-8000 Hz) and full-wave rectified. For each session, 12 observations were made and were averaged after aligning them when the finger crossed a light beam received by a photoelectric cell located at 4 degrees from the start position. The rectified envelope of the agonist EMG activity was integrated over the interval from the onset to the first zero-crossing of the acceleration curve (acceleration phase of movement). The antagonist EMG activity was integrated over the deceleration phase of the movement, from the onset to the second zerocrossing of the acceleration. Each of these two integrated EMG activities (expressed in microvolts sec-1) was calibrated using an isometric contraction against a load of 200 g which was intended to stretch the muscle (see reference 15 for the details of the method). We computed the ratios of the integrated EMG activity by the calibration activity (also expressed in microvolts sec-1). These ratios were expressed in arbitrary units. For each muscle, the reliability of this method was checked by computing these rations in six control subjects during three successive days, with a variation from day to day not exceeding 3%.

Recording of fast reaching movements in the sagittal plane

The methodology was similar to that described by Flanders et al.17. Targets were located in 12 directions in a sagittal plane, at a distance of 25 cm from the central starting position (Target 1, 0 degrees; target 2, 30 degrees; target 3, 60 degrees; target 4, 90 degrees; target 5, 120 degrees; target 6, 150 degrees; target 7, 180 degrees, target 8, 210 degrees; target 9, 240 degrees; target 10, 270 degrees; target 11, 300 degrees; target 12, 330 degrees). The patient and each subject of control group (n = 7 subjects, mean age 65, range from 39 to 77; two women) maintained initially the right upper arm vertically and the forearm horizontally (elbow angle 90 degrees). The right upper limb was parallel to the midsagittal plane of the body. Subjects were asked to move as fast as possible from the central starting position to the target position after a 'go' signal. Three practice trials were followed by sets of 12 fast reaching movements for each direction of movement. A LED was affixed at the level of the index. We recorded the activity of the following muscles: brachioradialis (BR, elbow flexor), biceps (Bi, elbow and shoulder flexor), medial head of triceps (MT, elbow extensor), long head of triceps (LoT, elbow and shoulder extensor), anterior deltoid (AD, shoulder flexor and adductor), posterior deltoid (PD, shoulder extensor and adductor), latissimus dorsi (LaD, shoulder extensor and medial rotator) . We collected 3 sec of data for each trial. EMG activities were amplified x2000; 30-1000 Hz) and rectified EMG were averaged after aligning them to the movement onset. To isolate the phasic aspects of the EMG activity, a subtraction procedure was applied 17-18. The rectified and averaged EMG activity related to slow movements (12 for each direction) was digitally compressed into the time frame of the fast EMG trace. Subsequently, the fast EMG trace and the slow EMG trace were subtracted. The result is called the phasic trace. For each target, the peak of EMG activity of the phasic trace was identified for each of the seven muscles. Polar plots of peak EMG activities for each muscle were obtained to analyse the spatial tuning. For each muscle, peak EMG intensities were expressed in % of the largest peak EMG in the sagittal plane (for each muscle, the maximal peak EMG among the 12 peaks of EMG activity in the sagittal plane is called M peak EMG). The reliability of this method was checked by analysing the spatial tuning in four control subjects during three successive days. For each muscle and for each direction of movement, the variation of the peak EMG intensities from day to day did not exceed 5%. In all cases, the M peak EMG for each muscle was always found in the same direction of the movement (invariability of the privileged direction of the M peak EMG). Similar results were obtained using the most intense (the largest) 100-msec epoch17.

RESULTS

Distal single-joint movements

Movement was considered hypermetric when it exceeded 18.6 degrees, corresponding to the mean value+2.5 SDs of the control values (mean +/- SD= 15.8 +/- 1.1 degrees). Movement was hypometric when the amplitude was lower than 13.1 degrees (mean-2.5 SDs of control values). At session 1, movement was hypermetric (Figure 2). . The mean movement amplitude was 21.7 +/- 2.1 degrees. The hypermetria was associated with three EMG deficits: a decreased intensity of the agonist EMG activity, a delayed onset latency of the antagonist EMG activity and a decreased intensity of the antagonist EMG activity. Indeed, the calibrated agonist EMG activity was 49.9 a.u. (control group: 73.2 +/- 8.0 a.u.), the onset latency of the antagonist EMG activity was 102 msec (control group: 46 +/- 10 msec) and the calibrated antagonist EMG activity was 46.4 a.u. (control group: 79.4 +/- 10.7 a.u.). At session 2, mean movement amplitude was 16.4 +/- 1.9 degrees. The onset latency of the antagonist EMG activity had returned to a normal value (60 msec). However, both the intensities of the agonist and the antagonist EMG activities were depressed, respectively at 41.2 a.u. and 49.7 a.u. At session 3, movements were hypometric. The mean movement amplitude was 10.4 +/- 1.6 degrees. The intensity of the agonist EMG activity was 24.8 a.u., whereas the intensity of the antagonist EMG activity was reduced at 40.7 a.u. Thus, the ratio of the intensity of the agonist EMG activity divided by the intensity of the antagonist EMG activity was 1.08 at session 1, 0.83 at session 2 and 0.61 at session 3.

Reaches in the sagittal plane

Figure 3 illustrates the amplitudes of reaches in a healthy subject and in our patient during the three recording sessions. In the healthy subject, movements were normometric for all the directions. By contrast, our patient performed hypermetric movements in all the directions at session 1. At session 2, movements were dysmetric, but to a lesser extent. At session 3, movements were markedly hypometric. This shift from overshoot to undershoot is also illustrated in Figure 4, which shows the hand paths in the vertical plane for one trial in each direction in a healthy subject and in the patient during the three sessions. Table 1 lists the amplitudes of the movements for the 12 directions in the control group and in our patient. At session 1, movements were hypermetric in all directions in the patient. At session 2, mean movement amplitudes were within the normal range in four directions and were hypometric in eight directions. At session 3, movements were hypometric in all directions. Table 2 lists the path ratios for the control group and in our patient. All the path ratios were larger than the normal range at session 1 and were below the normal range at session 3.

In the control group, the phasic EMG tuning was very analogous across subjects. Our data were similar to those reported previously (see Figure 11 of reference 17). For each muscle, the M peak EMG was always associated with the same privileged direction: +90 degrees for the BR, +120 degrees for the Bi, +270 degrees for the MT, + 180 degrees for the LoT, the PD, the LaD and 0 degrees for the AD (Figure 5). For each of the seven muscles, the EMG activity was always greater in some directions (directional preference). For instance, EMG activity was greater in directions 1 to 4 for the AD, while the level of activity was low in the other directions.

In our patient, there was a counter-clockwise displacement of the privileged direction of M peak EMG at session 1 for all the muscles. Indeed, the M peak EMG was found at + 120 degrees for the BR, + 150 degrees for the Bi, + 300 degrees for the MT, + 240 degrees for the LoT, + 30 degrees for the AD, + 210 degrees for the PD and the LaD. This counter-clockwise displacement persisted during all the recording sessions. At sessions 2 and 3, there was a 'spread' of the EMG activity in other directions. The activity of the BR and the Bi increased for targets 7, 8, 9, 10. The activity of the MT and the LoT extended in the direction of targets 4 to 7. The activity of the AD extended in the directions of targets 6 to 9. The activity of the PD extended towards targets 0 to 4. The activity of the LaD remained similar from session 1 to 3.

DISCUSSION

We report a patient presenting initially cerebellar signs and autonomic signs as the main clinical features of MSA. With the follow-up, the clinical picture was dominated by dysautonomic and extra-pyramidal signs. The diagnosis of MSA relies primarily on clinical data and diagnostic accuracy of MSA often requires a longterm follow-up19. The diagnosis of MSA in our patient was based upon the association of dysautonomia, cerebellar features and parkinsonism20. Initially, cerebellar signs were prominent, as described previously for the cerebellar form of MSA21.

It is known that cerebellar signs may be difficult to assess in patients presenting rigidity and bradykinesia19. We experienced similar difficulties, with cerebellar signs being difficult to appreciate at session 3 in our patient. Our data confirm that extra-pyramidal signs mask cerebellar hypermetria. Interestingly, the perception of the discrepancy between motor intention and performed movements decreased from session 1 to session 3. This is in agreement with the observation that patients with extra-pyramidal disorders do not feel the discrepancy between their motor intention and the movement13, by contrast with patients presenting a cerebellar disorder. We report for the first time a follow-up study of proximal and distal voluntary movements in MSA. For both wrist movements and reaching movements, the hypermetria turned into a hypometria in our patient. At the distal level, the hypermetria was due to the delayed onset latency of the antagonist EMG activity. The hypometria was due to an imbalance between the intensity of the agonist muscle and the intensity of the antagonist muscle. From session 1 to session 3, there was a marked reduction in the intensity of the agonist EMG activity, with a lower reduction in the intensity of the antagonist EMG activity. Consequently, the ratio of the intensity of the agonist EMG activity divided by the intensity of the antagonist EMG activity decreased noticeably. It is known that the size of the first agonist EMG burst in ballistic movements is decreased in Parkinson's disease 22. Therefore, the progression of the extra-pyramidal symptoms in our patient might explain to some extent the reduction in the intensity of the agonist EMG activity. The mechanism of the shift from hypermetria to hypometria described here differs from mechanism of the shift which occurs during the aberrant compensation following a cerebellar infarction7. In this latter case, the hypometria is due to a return to a normal value of the intensity of the antagonist EMG activity which was initially reduced, whereas the intensity of the agonist EMG activity shows a permanent decrease. We also observed a shift from overshoot to undershoot for upper limb reaches. We found that this shift was associated with a defect in the phasic tuning of the EMG activity. Muscles became more and more active for targets located outside their directions of main activity, or even for targets located in the opposite of the privileged direction of the maximal peak of EMG activity. This was observed for three muscles: the medial head of triceps, the anterior deltoid and the posterior deltoid. This spreading led to the loss of the directional preference for the EMG activities in the sagittal plane.

Spatial tuning is a critical phenomenon for the central nervous system, both for cortical and subcortical areas23. For reaching, the motor cortex has been studied the most extensively24,25. In human, the respective roles of the cerebellum and the basal ganglia in the spatial tuning of EMG activity at the level of proximal joints have not been identified so far. Both the cerebellum and the basal ganglia are implicated in the preparation and the execution of proximal movements in upper limbs26. There is evidence that the cerebellum controls the proximal joint rotations27,28. Cerebellar patients exhibit trajectory aberrations associated with a deficit in the rate of rotation of the shoulder and abnormal rate of torque development29. Fortier et al.30 have analysed in monkeys whole-arm reaching movements from a central starting position towards radially arranged targets in the horizontal plane. They recorded the activity of cerebellar neurons with proximal-arm receptive fields or discharge related to proximal movements. The authors found a significant percentage of cell populations with directional responses. The distribution of preferred directions of the population of cerebellar neurons covered all the movement directions. Using a vector representation, Fortier et al. observed that the overall activity of the cerebellar population during reaches generated a signal varying with the direction of the movement of the proximal arm. It has been shown also that movement direction is encoded by populations of neurones in motor cortex24. Individual neurones participate mainly in movements in a preferred direction, and to lesser degrees in a range of directions. In our patient, there was a violation of the invariability of the privileged direction of the maximal peak of EMG activity throughout session 1 to session 3. We suggest that the cerebellum computes the privileged direction which is associated with the maximal peak of EMG activity during pointing movements in the vertical plane. We hypothesize that motor cortex receives a signal from the cerebellum to select the direction which will be associated with the largest intensity of the activity in proximal muscles. In case of cerebellar dysfunction, this signal would be erroneous, leading to a mistake in the directional control of movement. The error of the positive feedback in the limb premotor network would result in an inappropriate spatiotemporal pattern of neuronal discharge31.

In healthy subjects, the inertial resistance to movement is least in the direction perpendicular to the forearm17. This is explained by the fact that only the mass of the forearm resists acceleration in this direction (target 4, +90 degrees and target 10, +270 degrees). For the horizontal direction (target 1, 0 degrees and target 7, + 180 degrees), the inertia is greatest. This is called the anisotropy in the inertial resistance to movement. This anisotropy implies that movements in various directions have different force requirements17. In our patient, both the counter-clockwise displacement of the maximal peak of EMG activity and the spreading of EMG activity might be explained by the loss of the neural adaptation to the anisotropy of inertial resistance. Whereas the first disturbance might be due to a cerebellar dysfunction, the second could result from the basal ganglia involvement.

We conclude that follow-up studies of voluntary movements in MSA appear to be the second human model of a shift from hypermetria to hypometria. Comparisons with patients exhibiting isolated cerebellar signs due to a stroke or with patients presenting Parkinson's disease will help to elucidate the rules underlying the neural control of spatial tuning in the vertical plane.

ACKNOWLEDGEMENTS

Supported by a grant from the Belgian National Research Foundation.

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M-U. Manto*^^^, J. Jacquy^, B. Legros^^; and P. Bosses(sec)

*Fonds National de la Recherche Scientifique, ULB, Bruxelles, ^Service de Neurologie, CHU-Charleroi, Charleroi ^^Service de Neurologie, Hopital Erasure, ULB, Bruxelles, (sec)University du Travail, HEC, Charleroi, Belgium

Correspondence and reprint requests to: Mario-Ubaldo Manto, MD, Fonds National de la Recherche Scientifique, Universite Libre de Bruxelles, Hopital Erasure - Neurologie, 808, Route de Lennik, 1070 Bruxelles, Belgium. [m.manto@belgium.com] Accepted for publication October 2001.

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