Athetosis

Extradural motor cortex stimulation was introduced in 1989 for control of central pain. In recent years this has been found useful in several patients with movement disorders. This paper attempts to bring together all the relevant literature, discuss mechanisms and lay out guidelines for future research and clinical applications. [Neurol Res 2003; 25: 118-122]

Keywords: Motor cortex stimulation; motor disorders

INTRODUCTION

At the end of the 1980s, Tsubokawa introduced extradural motor cortex stimulation (MCS) for the relief of central pain1. Its use has been extended to peripheral neuropathic pain conditions, and very recently to patients with movement disorders. This paper attempts to summarize current evidence on this latter topic.

POST-STROKE MOVEMENT DISORDERS

Movement disorders are one of the most disabling sequelae of stroke. Katayama et al.2,3 reported eight patients with post-stroke involuntary movements out of 48 submitted to MCS (42 for the purpose of controlling central pain). These demonstrated hemichorea-athetosis associated with thalamic infarct or hemorrhage in three, distal resting and/or action tremor associated with multiple lacunar, striatal or thalamic infarcts in two, and proximal postural tremor associated with infarct or hemorrhage within the midbrain or thalamic regions in three. In two of the three patients with hemichoreoathetosis, the involuntary movements were appreciably attenuated by the MCS. However, in one patient, central pain was not satisfactorily relieved. In the remaining two patients, VIM stimulation afforded better control of the involuntary movements. In both of the two patients who demonstrated distal resting and/or action tremor, the tremor was completely abolished by MCS, along with central pain. In another paper, these authors reported on MCS (50-125 Hz) greatly relieving hemichorea and resting tremor in two post-stroke pain patients (pain was relieved in one). SI and SMA stimulation was ineffective. A patient with Wallenberg's syndrome and tremor following striatal injury had both pain and tremor relieved by MCS (75 Hz), whereas thalamo-capsular stimulation increased the pain. Another patient with the same syndrome had dysarthria and paresis improved by MCS.

Postural tremor and frozen gait seemed resistant to stimulation. When the MCS attenuated the involuntary movements, such an effect began to be observed immediately after the start of stimulation, and reappeared after termination of the stimulation. The effects on involuntary movements occurred at an intensity below the threshold for muscle contraction and a frequency of more than 15 Hz. However, frequencies tested never exceeded 50 Hz, which, in their experience is sufficient for pain control, and the inhibition of tremor was partial in this frequency range. Thus, post-stroke motor disorders seem to respond to higher frequencies (50-125 Hz) than pain (25-75 Hz) at intensities below the threshold for muscle contraction. In contrast to the distal resting or action tremor, proximal postural tremor was not well controlled by MCS: only one of the three patients demonstrated partial although unsatisfactory attenuation of her involuntary movements.

Subjective improvement of motor performance was reported by eight patients out of 42 central post-stroke pain patients during MCS4, all with mild or moderate motor weakness (no improvement was experienced in patients who demonstrated severe motor weakness and/ or no muscle contraction in response to MCS at a higher intensity). The improvement of motor performance occurred at an intensity below the threshold for muscle contraction and within the frequency range employed for pain control although independently of analgesia. Since there was no objective muscle strength increase, the effect was likely due to attenuation of rigidity. In one patient the effect was excellent, despite no pain relief.

N'guyen et al.5 reported a case of severe upper limb action tremor and facial pain following removal of an acoustic Schwannoma. MCS completely relieved both pain and tremor for at least 32 months. No lesion was disclosed on MRI.

During intra-operative stimulation (bipolar stimulation, 60 msec, 50 Hz, 1.5 mA), no muscle twitches or paresthesias were induced. There was an immediate decrease of facial pain and within 20 sec a cessation of tremor. Monopolar stimulation of all electrodes was ineffective on both tremor and pain, while bipolar (1 +/ 0-) was effective on both. The reverse setting (11 -/0 +) was effective on tremor only with pain reappearing within 30 sec even with the stimulator on (impedance: 1886 Ohm, 1.8 V, 60 msec, 50 Hz, 3 h on, 3 h off, then 12 on and 12 off). The dystonic flexion posture of wrist was not influenced by MCS. At 2 V and 120 msec, both pain and tremor reappeared, at 30 Hz and 2 V, only tremor reappeared, while pain reappeared and tremor was abolished at 70 Hz. On blind control, a placebo effect was excluded. Thirty seconds after switching off the stimulator, tremor reappeared, unlike pain which had a 12-h post-effect (except for it returning at night if arm was moved). Thus, tremor increased by decreasing frequency and voltage. During follow-up, changes of parameters were related to changes in impedance.

Franzini et al.6 reported on a patient with central poststroke pain and focal dystonia (thalamic hand). MCS led to immediate cessation of dystonia, which relapsed immediately upon stopping the stimulator (0.4 V, 130 Hz). Results were stable at two years (including pain relief).

PARKINSONISM

We submitted three patients with advanced Parkinson's disease to MCS. Due to advanced age (above 70), MR evidence of atrophy, ventricular enlargement or ischemic white matter disease, plus neuropsychiatric deficits, these were poor candidates for STN DBS. All benefited bilaterally from low-frequency unilateral MCS, with improvement of all three cardinal signs of PD. Our first two patients have been reported elsewhere 7,8 . Here we report a third patient plus another with parkinsonism.

Case 1

This woman, born in 1928, gradually developed tremor to the right hand in 1980. Four years later, L-- Dopa was instituted along with anticholinergics with excellent response. Thereafter, she complained of tremor to the right leg and focal dystonias to the right foot. Six years after starting Dopa, she developed LongTerm Dopa Syndrome, with worsening wearing-off episodes and focal dystonias to the feet. Increase of Dopa to 1000 mg brought about generalized choreic dyskinesias. Dose reduction and fractioning plus addition of pergolide (3 mg die) controlled the dyskinesias. The picture worsened due to the onset of unpredictable motor fluctuations (on/off phenomena) and diphasic dyskinesias. Over the two years prior to surgery, she went through a severe worsening of postural instability with frequent falls to the ground, so that in the end she was basically bed-ridden. On admission she was on 425 mg of L-Dopa and 2 mg of lisuride. She had mild bradykinesia, diffuse choreiform dyskinesias (worse in the upper limbs), severely impaired postural reflexes with gait possible only if fully supported (choreiform gait), no rigidity to the four limbs, hypophonic dysarthria, medium jerk resting tremor to right arm (++) and leg (+), cognitively within range for her age but with some psychiatric symptoms. UPDRS section scores were: I, 3; II, 29; III, 34; IV, 9. CT showed severe atrophy, mild ventricular enlargement and ischemic encephalopathy This patient could not tolerate f-MR conditions. Identification of the motor cortex was thus achieved with backreconstructed helical CT images and by comparison with an external marker positioned along classic projection lines. Under general anesthesia, a Resume paddle was positioned over the right motor cortex overlying the arm area. Intra-operative stimulation (5 Hz, 450 microsecs, fast ramping to 10 V) triggered left arm contraction followed by a jacksonian fit. An Itrel III IPG (Medtronic Inc., Minneapolis, MN, USA) was positioned subclavearly and the system hooked up to the paddle (Figure 1). After a post-operative test period, best parameters were 0+/3-, 2 V, 330 microsecs, 20 Hz. ECD SPECT showed dishomogeneous uptake of the tracer, with extensive left parietotemporal, right parietal and bilateral focal frontal hypoperfusion. IBZM SPECT with DOPA reduced to 275 mg showed normal uptake with values in the low-normal range. At one month follow-up, the patient could speak more clearly; gait was much improved and she could walk with some external support. There was no tremor or rigidity.

Case 2

At age 61 this priest developed bradykinesia and fatigability in 1990. In 1992, his gait was impaired by initiation difficulties, festination and freezing. He had severe hypophonic speech, numb hands (especially the left), rigidity of the four limbs (he had difficulty in playing the organ). CT scan and MRI showed diffuse brain atrophy, ventricular enlargement, plus hypodense areas in the corona radiata and periventricular areas, particularly in temporo-occipital regions. At further follow-up, he had severe freezing, impaired righting reflexes, unsteady gait with frequent falls, frozen, almost unintelligible voice, dysphagia for liquids, urinary incontinence. L-Dopa (about 300 mg) and selegiline at effective dosages were ineffective.

In January 1999, a double subthalamic stimulator was implanted elsewhere. For two days he could walk again but this effect was short-lasting (monopolar stimulation, 1 V, 60 microsec, 130 Hz). He was scored Hoehn-Yahr 4. At this time, an apomorphine challenge test was ineffective. A L-Dopa challenge test (250 mg) 2.5 h after switching off the stimulator improved his UPDRS score by 18% to the arms only (71/108 to 58.5/108). The diagnosis was multisystem atrophy with parkinsonian symptoms. After obtaining written informed consent, in June 2000 and February 2001, two motor cortex (MI) extradural paddles (Resume, Medtronic) were implanted (Figure 2). Identification of the motor strip was carried out with CT localization and an external marker along classic stereometric lines. After a test period, best parameters were as follows: 25-40 Hz, 90-180 microsec, 2-2.5 V, bipolar ( 3+/0 or vice-versa), continuous mode. Voltages higher than 2.5 V worsened his status, particularly rigidity; tremor could also be induced. Cyclical mode was also deleterious.

After the first implant the patient could walk for ten days with a walker, which he could not do before implantation. There was a modest improvement in his bradykinesia. Stimulation improved feeding (he could swallow semisolid food) and sialorrhea and allowed him, at times, to type on the computer keyboard, which he could not do before implantation. The UPDRS motor score was only modestly improved in the hand-tapping test. Also, he could write his name, which he was not able to do before surgery. A diary of daily activities and mood kept by assisting personnel signalled increased alertness and cognitive (ability to respond to external stimuli) improvement. L-Dopa (at dosages as above) was now synergistic with the stimulator. Unfortunately, nine months into his second implantation, all motor, but not vegetative, benefits were lost.

Dario et al.9 reported on a central post-stroke pain patient whose associated parkinsonian tremor was not relieved by parameters which were analgesic, nor was the UPDRS score improved (2-2.5 V, 50-75 Hz, 120-- 210 msec, continuous mode). Clearly the frequency was too high as we have found that benefit is seen at low frequency (20-40 Hz). Moreover, stroke had likely altered the motor loop upon which MCS acted.

DYSTONIA

We have experience with one patient. In 1984, this 37-- year-old woman started to complain of muscular contractions of the right sternocleidomastoid muscle with head torsion. She slowly worsened and by 1987 the head was almost constantly rotated, involving the right trapezius and splenius. Several intensely painful spasmodic crises occurred during the day, with pain involving the right hemiface and neck, posterior aspect of right upper limb and first three fingers of the hand, where tingling was also felt. On 5-21-1987, the left thalamic Voi was stereotactically coagulated with two thermal lesions (70, 50 and 30 sec) with total post-- operative disappearance of her ST. Symptoms soon recurred. In 1988, section of right XI cranial nerve, right anterior C1-3 and posterior C2-3 rhizotomies successfully relieved ST. Again, there was a relapse and by 1990, her painful dystonic crises involved the right side of her body without pyramidal involvement. Between 1991 and 1993, several tenotomies of both right limbs were performed. During the course of her disease, several drugs were tried, including myorelaxants, anticholinergics, benzodiazepines, neuroleptics, local marcaine infiltrations, phenol blocks of posterior rami at Cl 3, intrathecal baclofen infusion (up to 1800 micrograms a day!), botulinum toxin, all with temporary or no benefit or unacceptable side effects. Contrast-enhanced MRI of the brain was normal, bar the mark of the previous left thalamotomy. A cerebral angiography was also normal.

On admission in 2001 at age 53, she had painful dystonic paroxysms involving her right hemibody every 4 h and lasting about 30 min. During these attacks she would cry and complain of the pain. In between, she could walk normally with a moderate leftward head torsion; no pain outside the crises was acknowledged. Neurologically, there was touch and thermal hypesthesia of the right neck and limbs. No allodynia could be evoked. A video-EEG did not show epileptiform activity during the paroxysms. Her pain was not controlled by NSAIDs nor by prophylactic tramadol and lamotrigine. Psychological investigation disclosed depression, frustration and neuroticism. Basal HMPAO SPECT was normal, while ictal SPECT showed left thalamic hypoperfusion. In view of the painful component, after obtaining written informed consent, a Resume paddle (Mod. 3587A, Medtronic, Minneapolis, MN, USA) was epidurally applied under local anesthesia over the motor cortex (MI) overlying the left thigh, chest and arm area. During the trial period, stimulation at low frequency (10 Hz), long impulse duration (450 microseconds) and low voltage (1 V) relieved the pain and dystonia almost completely, while the neck symptoms were not affected or slightly worsened. Increasing rate to 60 Hz and even more at 130 Hz at short impulse duration (60 microseconds) worsened both pain and dystonia and increased the duration of her crises up to 40 min. In addition, previously never reported rebound crises lasting 5-10min were triggered. Duration of paroxysms and free interval were not affected. A second plate was then positioned over the neck-head area. Stimulation at effective parameters as above worsened the pain and dystonia; the picture was even worse at 700 microseconds. At this time the patient refused further trial stimulations and both paddles were removed. During the test period, placebo stimulation was always ineffective.

DISCUSSION

Woolsey et al.10 clearly showed how parkinsonian rigidity and tremor could be alleviated by direct MI stimulation. By slipping a 7-contact Delgado plate electrode through a frontal burr hole near the rolandic fissure between motor and sensory sites, Alberts11 could initiate or augment parkinsonian tremor by stimulating at 60 Hz (post-central cortical stimuli had the same effect at, above or below the sensory threshold). In monkeys pressure on or cooling MI stopped surgically-induced Parkinson-like tremor (references in reference 11).

Our report indicates modest, transitory effects of bilateral MCS, and no effect of STNS, for Dopa-- unresponsive parkinsonism. Krack et al.12 concluded that patients with levodopa-resistant parkinsonism associated with ischemia-anoxia, multisystern atrophy or progressive supranuclear palsy cannot expect a major benefit from STNS.

Dopa and apomorphine unresponsiveness are known poor predictors of STNS efficacy 12,13. The same might apply to MCS. However, our patient obtained modest, although transitory, benefit from MCS, which was better than per STNS. Modification of motor cortex metabolism contributes to the efficacy of several surgical procedures for Parkinson's disease.

Our patient with painful paroxysmal hemidystonia suggests that extradural MCS modulates cortical excitability seen in dystonia by a direct local effect. Pallidal stimulation for dystonia too modulates, among others, motor cortex activity15. The time course of motor cortical excitability changes are abnormal in patients with dystonia18 and in most models dysfunction at the basal ganglia level involving the direct and indirect pathways results in impaired inhibition at the cortical level, increased motor cortex excitability, with consequent loss of normal inhibitory reflexes at the brainstem and spinal level19. MCS influences the motor thalamic nuclei directly and these are the only thalamic nuclei directly connected to motor and premotor areas. In our patient, MCS may have normalized this circuit. Slight worsening of ST may have been due to overflow. Interestingly, cycling of attacks was not modified by MCS. It may be suggested that the paroxysmal generator is not influenced by the cortex, unlike the actual symptomatology.

Transcranial magnetic stimulation (TMS) studies suggest that cortical stimulation acts via an intracortical mechanism, descending inhibitory projections being unimportant 17. Low intensity TMS may selectively activate cortical inhibitory neurons that surround pyramidal cells18. A large coil activates all relevant surrounding interneurons. TMS is also able to inhibit the pyramidal cells without previously exciting them, while after-hyperpolarizations or recurrent inhibition of the pyramidal cells themselves can contribute little, since pyramidal cells have an extremely short refractory18. Thus, long trains of low frequency TMS reduce cortical excitability and this is also possible for MCS. However, another mechanism can be envisioned. Classical neurophysiology has focused on the encoding of information through changes in the firing rate of neurons. Yet, when networks of neurons interact the result is often rhythmic activity within defined frequency ranges that can engage in temporal synchronization and de-synchronization. It is now clear that disruption of oscillation and/or temporal synchronization may be a fundamental mechanism of neurological disease20.

We propose that MCS might actually act via oscillatory patterning. Evidence suggests that L-Dopa acts via enhancing 15-30 Hz and 35-60 Hz MEG-EMG coherence and that during therapeutic stimulation of the basal ganglia increases in 15-30 Hz muscle coherence correlate with improvements in bradykinesia (see references and discussion in reference 20). Given that 15-30 Hz oscillations are observed during physiologic postural maintenance, it may be surmised that MCS marshals this frequency to reset the abnormal pattern.

CONCLUSION

MCS holds great promise for the treatment of selected motor disorders, notably Parkinson's disease and several post-stroke disorders. Its advantages are a very low morbidity and apparently no mortality1 and, for PD, its bilateral effectiveness is also cost-effective. Moreover, practically all patients with PD may be submitted to such surgery unlike deep brain stimulation8. Future studies will address effect of stimulation of MI and also the supplementary motor area and better define targetable disorders.

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Sergio Canavero, Vincenzo Bonicalzi, Riccardo Paolotti, Giancarlo Castellano, Stefania Greco-Crasto, Laura Rizzo, Ottavio Davini and Raffaella Maina

Neuromodulation Unit, Department of Neurosciences, and Departments of Radiology and Nuclear Medicine, Molinette, Hospital, Turin, Italy

This paper is based in part on a lecture delivered by Sergio Canavero at the 3rd International Conference on Movement Disorders and Pain held in Oxford, UK, April 2002.

Correspondence and reprint requests to: Sergio Canavero, MD, Via Montemagno 46, 10132 Torino, Italy. [solara@infinito.it] Accepted for publication September 2002.

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