Propofol-Induced Dyskinesias in Parkinson’s Disease

Spontaneous involuntary movements have been reported with the use of propofol, a parenteral anesthetic, in patients who had no prior history of movement disorders [1-4]. These movements were described as dystonic, choreoathetoid, or myoclonic. In patients with Parkinson's disease, propofol may temporarily suppress tremor [5]. We describe two patients with Parkinson's disease who underwent a stereotactic pallidotomy while off levodopa medication. In both patients, temporary sedation with propofol induced dyskinesias, which occurred in the same distribution and were phenomenologically similar to the levodopa-induced dyskinesias that these patients experienced. Possible antiparkinsonian and dyskinesia-inducing mechanisms of propofol are discussed. Case Reports Patient 1 A right-handed 65-yr-old woman had a 24-yr history of Parkinson's disease which was first noted when her handwriting became illegible. She later developed right upper extremity bradykinesia, bilateral rigidity, and hypophonia. At age 52 yr, she was treated with levodopa which resulted in marked improvement of her parkinsonian symptoms. Within months after the treatment was started, however, she developed severe dyskinesias consisting of facial grimacing and twisting body movements. The medication was discontinued 2 yr later when she complained of severe nausea. Her parkinsonian symptoms, particularly bradykinesia, progressed gradually, and at age 60 yr, levodopa treatment was restarted. Her parkinsonian symptoms again improved, but the benefit was once again limited by levodopa-induced dyskinesias which became apparent after several months. Over the next several years she experienced increased gait difficulties with freezing, on-off fluctuations, and unpredictable responses to levodopa treatment. Because of her unsatisfactory response to medical therapy she was then considered to be a good candidate for pallidotomy. At the time of surgery she was being treated with a total dose of 75 mg of carbidopa and 300 mg of levodopa daily. Her preoperative general physical examination was unremarkable. Her neurological examination revealed hypomimia and hypokinetic dysarthria. In the off state, there was bilateral bradykinesia and mild rigidity. She suffered from severe levodopa-induced dyskinesias which started 20-30 min after taking levodopa, and which were present about 50% of her on-time. These dyskinesias consisted of grimacing facial movements and choreic and dystonic involuntary movements of her arms and legs, more obvious on the right side. Magnetic resonance imaging of the head was normal except for mild nonspecific leukoaraiosis. All medications had been terminated for 14 h when she was admitted to the hospital for the pallidotomy. While her head was shaved and prepared, sedation with intravenous propofol was begun. Small boluses of propofol (30 mg) were given at 1- to 2-min intervals to achieve and maintain sedation while the stereotactic frame was attached to her head. About 5 min after sedation was begun, she began to display choreic and dystonic dyskinesias, predominantly affecting her right extremities, which were severe enough to make it difficult to attach the head frame. These involuntary movements were very similar to her levodopa-induced dyskinesias. They gradually subsided within minutes after the sedation was stopped. The patient had an excellent improvement after a left pallidotomy with complete abolition of her right-sided dyskinesias. Patient 2 A right-handed 59-yr-old man noted clumsiness of his right hand at age 35 yr. This was followed by right-sided tremor at rest 1 yr later. At that time, he was diagnosed as having Parkinson's disease and treated with levodopa, which provided considerable relief of his symptoms. Subsequently, however, he developed bilateral bradykinesia and involuntary painful flexion of his toes. His disease progressed insidiously. At age 40 yr, he noted involuntary levodopa-induced dyskinesias. These dyskinesias gradually became disabling and consisted of facial grimacing, swinging movements of his head and upper trunk, as well as of twisting choreic and dystonic movements of his arms and legs. In subsequent years, the duration of the effect of levodopa decreased, and he began to have on-off fluctuations. His dyskinesias became more severe. He was considered an excellent candidate for a pallidotomy. At the time of surgery, he was 59 yr old. He took carbidopa/levodopa 10/100 mg orally five times daily. His general appearance and physical examination were unremarkable. He required total care and was wheelchair-bound during the "off" state. He had hypomimia, hypophonia, and severe hypokinesia. There was right-sided tremor at rest and bilateral bradykinesia and rigidity, more pronounced on the right side. Furthermore, he suffered from gait ignition failure, freezing, and postural instability. He was "on" only 50% of his awake time, and whenever he noted benefit from levodopa he experienced dyskinesias; he did not have "on" periods without dyskinesias. Magnetic resonance imaging of the head demonstrated mild cortical atrophy. When he was admitted to the hospital for the pallidotomy he had not had any antiparkinsonian medication for more than 14 h and he was barely able to move. His head was shaved and prepared and an infusion of propofol was started at 75 micro gram centered dot kg-1 centered dot min-1. Before fixation of the stereotactic frame to his head, a bolus of 30 mg of propofol was given. Shortly thereafter his right-sided tremor decreased and he had severe dyskinesias consisting of facial grimacing, swinging head, and upper trunk movements and twisting movements of his extremities. In an attempt to sedate him further, he had another bolus of 30 mg of propofol which, however, worsened his dyskinesias markedly and impeded fixation of the frame. Again the distribution and appearance of those dyskinesias were similar to his levodopa-induced dyskinesias. These movements subsided after 2 mg of midazolam were injected intravenously. He had a remarkable improvement after the pallidotomy with complete relief of his right-sided dyskinesias and improvement of his parkinsonian symptoms. Discussion Functional stereotactic operations for movement disorders are performed under local anesthesia because cooperation of the patient during neurophysiologic recording, electric stimulation, and lesion-making are crucial to the results of the procedure and the avoidance of side effects [6]. It is desirable to operate on Parkinson's disease patients while they are off levodopa medication, since the effect of the procedure on the parkinsonian symptoms is more readily assessable. Furthermore, levodopa-induced dyskinesias can be disturbing during certain steps of the procedure. The stereotactic frame is fixed rigidly to the patient's head with screws, which is sometimes unpleasant for the patient. Mild or moderate sedation may be desirable in certain patients during fixation of the frame. A variety of drugs can induce spontaneous movements during induction of anesthesia [7,8]. The description of the frequency and intensity of these movements varies and seems to be related to a variety of factors. It is unclear how often dyskinetic movements appear during induction with propofol. Many instances of mild dystonic reactions after administration of propofol may go unreported [9], and some have even questioned whether their occurrence is adverse [10]. Minor spontaneous movements were seen significantly more often after induction of anesthesia with propofol than with thiopental/halothane in a randomized trial of pediatric patients [1]. Such movements were observed in 75% of children receiving propofol as compared to 20% receiving thiopental. They were classified as dystonic and choreiform by videotape analysis. These spontaneous movements after induction of anesthesia with propofol seem to be rare in adults [11]. The influence of the dosage and speed of injection on their incidence is not entirely clear [12]. There have been case reports of more severe transient involuntary movements after injections of propofol. Violent choreoathetoid movements requiring physical restraint were reported in a 47-year-old woman [2] and recently also in a seven-year-old boy [4]. Involuntary movements described as "myoclonic" and "myotonic" were observed in a 37-year-old woman who required intubation [13]. Borgeat et al. [12] have shown that such spontaneous movements induced by propofol are not related to cortical epileptic activity and a subcortical origin has been suggested. In our two patients, propofol induced dyskinesias, which were very similar to these patients' levodopa-induced dyskinesias, in both and temporarily suppressed parkinsonian tremor in one. We have observed propofol-induced dyskinesias, as described in this report, in two of six Parkinson's disease patients who underwent a pallidotomy. Similar events did not occur in 20 subsequent patients when midazolam instead of propofol was used. There is only one previous report of propofol in patients suffering from movement disorders [5]. In that report, temporary abolition of tremor after injection of propofol was described in two patients with parkinsonian rest tremor who were to undergo a thalamotomy. In both patients the stereotactic procedure was abandoned and repeated later. These observations suggest that propofol might have an antiparkinsonian effect. The excitatory and inhibitory mechanisms of anesthetics are not fully understood [14]. There is little information available on the effects of propofol on dopaminergic receptors. There was no clear evidence for relevant interactions in binding studies of D2-receptors in Chinese hamster ovary cells [15]. However, propofol is known to interact with other neurotransmitters involved in signal transmission of the two segregated striatopallidal pathways which are controlled by striatal dopamine receptors. Propofol, like other anesthetics, potentiates GABAergic transmission. Furthermore, propofol appears to interact with excitatory amino acid transmission. It inhibits the glutamate-dependent calcium entry in rat synaptosomes and the adenosine triphosphate-dependent uptake of glutamate [16]. It may also have a slight inhibitory effect on the release of glutamate [16]. There has been little investigation of the action of anesthetics on the subtypes of excitatory amino acid receptors [14]. However, it has been shown, that propofol suppresses N-methyl-D-aspartic acid receptor channels in clinically relevant concentrations [17]. Facilitatory effects of propofol on GABAergic transmission and inhibitory effects on glutamate transmission could be responsible for the antiparkinsonian effect of propofol, as well as for the induction of involuntary movements. This might particularly be so for propofol-induced dyskinesias seen in Parkinson's disease patients. Current concepts of basal ganglia circuitry postulate that degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease results in functional changes of the two parallel segregated striatopallidal pathways [18]. These changes involve increased glutamate-mediated subthalamopallidal transmission, as well as decreased activity of inhibitory GABAergic striatopallidal transmission. It has also been suggested that the appearance of levodopa-induced dyskinesias might be related to alterations in the effects of dopamine on striatal output resulting in an imbalance with a relative underactivity of the subthalamopallidal projections [19]. Furthermore, it is known that hemichorea-hemiballism is often associated with lesions of the subthalamic nucleus which also reduce activity of the subthalamopallidal pathways [20]. With respect to its interactions with GABAergic and glutamatergic transmission, it is conceivable that propofol induces a temporary imbalance on the regulation of pallidal activity resulting in dyskinetic movements, particularly in predisposed patients, such as those with Parkinson's disease. Since propofol may elicit abnormal movements and may also improve parkinsonian tremor, it might not be ideally suited for patients with movement disorders undergoing functional stereotactic neurosurgery.