Dyskinesias induced by subthalamotomy in Parkinson's disease are unresponsive to amantadine.

BACKGROUND: Dyskinesias are a transient but severe complication of subthalamotomy in some patients. PATIENTS AND METHODS: Three patients with Parkinson's disease undergoing bilateral micro-recording guided surgery of the subthalamic nucleus (STN) are described; deep brain stimulation (DBS) was used in one case, and subthalamotomy in the other two. Prior to surgery, levodopa induced dyskinesia had improved (< or = 50%) under treatment with amantadine (400 mg/day, po) in all three patients. The patient treated with DBS developed severe dyskinesia a few days after discharge and began self medication with amantadine but showed no improvement. This suggested a possible lack of response to amantadine for treatment of dyskinesias induced by surgery of the STN. RESULTS: Both patients treated with bilateral subthalamotomy developed unilateral choreoballistic movements immediately after surgery, despite not taking levodopa (L-dopa). Patients were scored using the dyskinesia scale and started treatment with 400 mg amantadine (po) for 4 days within the first postoperative week with no effect on dyskinesia score or its phenomenology. Amantadine was therefore discontinued. One month after surgery both patients were free of involuntary movements with an improvement of about 60% in the "off" state UPDRS motor score. Six month follow up showed maintained antiparkinsonian benefit, without need for levodopa treatment and complete absence of dyskinesia. CONCLUSION: The present findings suggest that: (i) amantadine probably exerts its anti-dyskinetic effect by acting on the "indirect" pathway; (ii) the pathophysiological mechanisms of subthalamotomy induced dyskinesias may differ from those involved in L-dopa induced dyskinesias; (iii) dyskinesias induced by STN surgery resolve spontaneously as compensatory mechanisms develop.

Efficacy of deep brain stimulation of the subthalamic nucleus in Parkinson's disease 4 years after surgery: double blind and open label evaluation.

OBJECTIVE: To evaluate the long term (4 years) efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's disease. METHODS: We performed a double blind crossover evaluation of the efficacy of DBS of the STN in the "off" medication condition in 10 patients with Parkinson's disease. Assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor) and two timed tests (arm tapping and walking). Open evaluation of the effect of stimulation in the off and on drug states preoperatively and at 1 and 4 years postoperatively was also conducted. The latter assessment included the UPDRS parts II (activities of daily living) and III (dyskinesia scale and global assessment) as judged by the patient and examiner. The mean amount of levodopa daily dose at base line, 1 year, and 4 years after surgery was compared. RESULTS: A significant (p<0.04) effect of stimulation was observed in the overall group regarding both the UPDRS motor and the timed tests. Open evaluation also showed a significant benefit of STN DBS with respect to preoperative assessment in both the motor and activities of daily living scales, dyskinesia scale, and in global assessment. Levodopa daily dose was reduced by 48% and 50% at 1 and 4 years, respectively. There was no difference between the 1 and 4 years evaluations in any of the parameters evaluated. Complications due to stimulation were minor. CONCLUSIONS: DBS of the STN provides a significant and persistent anti-parkinsonian effect in advanced Parkinson's disease 4 years after surgery.

Neuronal activity in the substantia nigra in the anaesthetized rat has fractal characteristics. Evidence for firing-code patterns in the basal ganglia.

Current models of the basal ganglia assume a firing-rate code for information processing. We have applied five complementary computing methods to assess firing patterns in 188 cells of the substantia nigra in the anaesthetized rat. Fractal firing activity was found in 100% of nigral cells projecting to the superior colliculus, in 51% of cells projecting to the thalamus and in 33% of cells projecting to the pedunculopontine nucleus, but was practically absent in dopaminergic nigrostriatal neurons (3%). The finding of fractal firing patterns may lead to a better understanding of the normal operational mode and pathological manifestations of the basal ganglia.

Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.

BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.

The subthalamic nucleus, hemiballismus and Parkinson's disease: reappraisal of a neurosurgical dogma.

The subthalamic nucleus (STN) currently is considered to play a key role in the pathophysiological origin of the parkinsonian state and is therefore the main target for surgical treatment of Parkinson's disease. The authors review the incidence of hemichorea/ballism (HCB) as a complication of thalamotomy, pallidotomy or campotomy procedures before the introduction of levodopa therapy, including the few reported cases accompanied by a neuropathological study. The literature shows that only a small number of parkinsonian patients with HCB had a lesion of the STN. Preliminary data in Parkinson's disease patients submitted to a subthalamotomy with current functional stereotaxy also indicate that HCB is a very rare complication. To explain this observation, we suggest that the parkinsonian state is characterized by an increased threshold for the induction of dyskinesia following STN lesioning. This arises as a consequence of reduced activity in the 'direct' GABA projection to the globus pallidus medialis (GPm) which accompanies dopamine depletion. Lesioning of the STN reduces excitation of the GPm, and theoretically this should induce dyskinesias. However, an STN lesion also, simultaneously, further reduces the hypoactivity in the globus pallidus lateralis (GPl) that is a feature of Parkinson's disease, and hence may compensate for GPm hypoactivity, thus self-stabilizing basal ganglia output activity and reducing the risk of HCB. We conclude that lesioning of the STN in Parkinson's disease is a feasible approach in some circumstances.

Targeting the basal ganglia for deep brain stimulation in Parkinson's disease.

The revitalization of surgery for Parkinson's disease (PD) has fueled discussion about the best methodology to define the target. Placement of electrodes for deep brain stimulation (DBS) requires the usual stereotactic technique but the argument is mainly centered on whether or not microrecording neuronal activity is necessary. We compared the accuracy of calculating the coordinates X (medio-lateral) and Y (rostro-caudal) considered by the classic stereotactic method, i.e., definition of the AC-PC intercomissural line by MRI and a digitized version of the Schaltenbrand's atlas, with final electrode placement according with microrecording and microstimulation in 21 patients. For both the globus pallidum internum (GPi) (n = 21) and the subthalamic nucleus (STN) (n = 36) there was, respectively, a 43% and 45% mismatching of more than 3 mm between the theoretic coordinates and the final site of electrode location. This applies to both the X and Y planes. Accuracy was not improved in patients (n = 11) in whom the bilateral procedure was undertaken in a single day. We conclude that proper electrode positioning of the STN and GPi requires fine electrophysiologic assessment.

Deep brain stimulation of the globus pallidus pars interna in advanced Parkinson's disease.

Pallidotomy is now widely performed for the treatment of advanced Parkinson's disease (PD). Preliminary reports of the effect of globus pallidus pars interna deep brain stimulation (GPi DBS) have also been promising. We have analyzed a cohort of 22 consecutive patients enrolled in a multicenter study. Surgery was bilateral in 17 and unilateral in five patients. At 6-month follow-up, the bilaterally GPi-implanted patients demonstrated a marked improvement when examined after drug withdrawal ("off") and under optimal medication ("on") using the Unified Parkinson's Disease Rating Scale (UPDRS). The benefit induced by the stimulation in the "off" medication condition in the total motor score was 31% and in the activities of daily living (ADL) scores was 39%. During the "on" medication period, the reduction in the total "on" dyskinesias score was 66% and in the ADL score was 32%. A similar pattern of improvement was seen in the group of patients with unilateral GPi stimulation, although a second cohort of 12 patients not included in the multicenter study showed greater improvements in "on" motor functioning. Although the effect of DBS is predominantly reversible, electrode insertion alone resulted in measurable clinical effects in the absence of stimulation. Thus, at 6-month follow-up, the benefit observed without stimulation was up to 44% in the "on" dyskinesias score and 29% in timed tapping scores undertaken in the "off" medication state. Complications among 34 patients from all centers included perioperative infection (n=3), hardware fracture (n=2), and premature battery failure (n=3). These results show a positive antiparkinsonian effect of pallidal DBS. No specific complications were observed with bilateral procedures.

Bilateral deep brain stimulation of the subthalamic nucleus in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is rapidly becoming the preferred surgical choice for the treatment of advanced Parkinson's disease (PD). We report initial results in 15 patients after 12 months and in nine patients evaluated between 30 and 36 months postoperatively. Our experience confirms the robust antiparkinsonian effect of DBS of the STN in advanced PD. The severity of "off" episodes, as assessed by the Unified Parkinson Disease Rating Scale (UPDRS), was drastically reduced by 74% at 12 months, and dyskinesia scores (Dyskinesia Rating Scale) decreased. The levodopa daily dose was reduced by 55% at 12 months. A double-blind assessment to determine the effect of stimulation performed in nine patients at 3 months in the "off" medication condition was very significant (p<0.05). Nine patients have been followed for 3 years with maintained efficacy in the UPDRS "off" score and the dyskinesia score. The experience of other groups using a similar technique is reviewed. The overall assessment indicates a high antiparkinsonian effect of DBS of the STN even in advanced patients. The existence of a learning curve for this procedure should be taken into account when initial results are evaluated.

The role of deep brain stimulation as a surgical treatment for Parkinson's disease.

Patients with advanced Parkinson's disease (PD) frequently suffer disabling motor complications that cannot be satisfactorily controlled with medical therapy. Deep brain stimulation (DBS) has recently been introduced by Benabid and his colleagues in Grenoble, France, as a new surgical procedure for the treatment of PD patients. DBS simulates the effects of a lesion without the need to make a destructive brain lesion. In this procedure, an electrode is implanted in the brain target and connected to a subcutaneous pacemaker. DBS of the ventro-intermediate (Vim) nucleus of the thalamus has been shown to ameliorate tremor in patients with tremor-dominant PD. DBS of the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) have been shown to improve all of the cardinal features of PD and to markedly reduce dyskinesia and motor fluctuations. Adverse events are associated with the surgical procedure, the device, and stimulation, but the procedure is usually well tolerated. On the basis of these findings, the FDA has recently approved unilateral DBS of the Vim for treatment of tremor in PD and is currently considering approval of DBS for STN and GPi. This article reviews existing information with respect to DBS.

[Pathophysiological bases, clinical results and indications for surgical treatment in Parkinson disease]. / Bases fisiopatológicas, resultados clínicos e indicaciones del tratamiento quirúrgico de la enfermedad de Parkinson.

We review the present status of surgery for Parkinson's disease. Surgical options for Parkinson's disease are rapidly spanding. The main objectives of surgical techniques are to restore the dopaminergic deficit in the striatum (transplantation) and to normalize the neuronal activity of the subthalamic-pallidal circuit (pallidotomy and deep brain stimulation). Whereas cell transplantation is still considered an experimental procedure, ablative procedures and deep brain stimulation are widely used. Both types of surgical procedures are supported by strong scientific data. However, much work remains to be done in order to understand several aspects not clearly elucidated at present. The results and current indications for pallidotomy and deep brain stimulation are analyzed.

Pallidotomy in Parkinson's disease increases supplementary motor area and prefrontal activation during performance of volitional movements an H2(15)O PET study.

Supplementary motor area and right dorsal prefrontal cortex activation in Parkinson's disease is selectively impaired during volitional limb movements. Since posteroventral pallidotomy improves motor performance in Parkinson's disease patients 'off' medication (i.e. off medication for 9-12 h), we hypothesized that it would also concomitantly increase supplementary motor area and dorsal prefrontal cortex activation. Six Parkinson's disease patients with a median total motor Unified Parkinson's Disease Rating Scale (UPDRS) of 52.5 (range 34-66) 'off' medication underwent unilateral right posteroventral pallidotomy. The patients had H2(15)O PET when 'off' medication before and 3-4 months after surgery. Each PET study comprised four to six measurements of regional cerebral blood flow either at rest or while performing regularly paced joystick movements in freely selected directions (forward, backward, left or right) using the left hand. Pre- and postoperative scans were performed in an identical manner and the associated levels of activation were compared using statistical parametric mapping. After pallidotomy, the median total motor UPDRS score 'off' medication decreased by 34.7% (P = 0.03) and mean response times of joystick movements following the pacing tones improved by 13.8% (P = 0.08). Relative increases in activation of the supplementary motor area and right dorsal prefrontal cortex were observed during joystick movements (P < 0.001). Decreased activation was seen in the region of the right pallidum (P = 0.001). We conclude that pallidotomy reduces pallidal inhibition of thalamocortical circuits and reverses, at least partially, the impairment of supplementary motor area and dorsal prefrontal cortex activation associated with Parkinson's disease.

Surgical treatment of Parkinson's disease.

At present, there are three major surgical approaches to Parkinson's disease (PD): (1) Ablative surgery (i.e. pallidotomy, thalamotomy); (2) deep brain stimulation (DBS) of the thalamus, internal globus pallidus (GPi) and subthalamic nucleus (STN); and (3) grafting fetal mesencephalic cells into the striatum. As a result of increasing understanding of the pathophysiology of the basal ganglia and the demonstration of surgical alleviation of experimental parkinsonism, surgery has regained a paramount importance in the management of PD. The aim of pallidotomy and DBS is to reduce the excessive inhibitory output from the GPi and substantia nigra reticulata (SNr). Pallidotomy and DBS of the STN or GPi aim to reverse the pathophysiological consequences of dopamine deficiency in PD, and should be considered entirely symptomatic treatments. The ideal candidates for pallidotomy are young patients in good general health in whom dyskinesias are the main reasons for disability. Patients with severe bilateral problems uncontrollable with present pharmacological tools are candidates for DBS. As yet, there are no formal data to help decide how to choose between GPi and STN stimulation. In our practice, patients are allocated to GPi stimulation when 'on' dyskinesias are extremely severe. In most other instances, we prefer to perform STN stimulation. At present there is almost no reason to decide for the thalamic stimulation since tremor is equally arrested by STN stimulation, which in addition improves all other features of PD. Equally the only indication for thalamotomy would be a patient with long-standing tremor as the main clinical manifestation, which can not be controlled with drugs. The proportion of patients in whom the thalamus will be the preferable target for either DBS or thalamotomy is small (less than 5%). Grafting aims to repair the nigrostriatal pathway and restore dopaminergic function in the striatum. In the future implants containing not only dopaminergic cells but also growth factors and a variety of other substances could become a method to not only functionally compensate the biochemical abnormalities of PD but also to arrest its progression. This technique is limited to a few centres around the world owing to the technical, logistical and ethical problems of obtaining and handling embryonic cells. At present, grafting of dopaminergic cells is perhaps best suited for patients with young-onset PD (less than 45 years old) who are at high risk of developing complications within a short time of beginning pharmacological treatment and in whom the idea of making lesions or implanting electrodes into the brain for decades seems less appealing. Consideration of surgery in any given patient should be weighed against the risks (about 1% mortality and 2-6% of severe morbidity-hemiplegia, cognitive deficit, speech problems, etc.) associated with these techniques. The development of better imaging methods and the growing expertise of multidisciplinary teams will undoubtedly make surgery for PD safer and more effective in the future.

[Stereotactic surgery in Parkinson's disease]. / Cirugía estereotáctica en la enfermedad de Parkinson.

Stereotactic surgery for Parkinson's disease (PD) has regained interest due to the recently described hyperactivity of the subthalamic-pallidal pathway. Many patients suffering from complications associated with the chronic use of levodopa may benefit from surgical treatments. There are different surgical targets and techniques (ablative and deep brain stimulation). The choice of one particular target and technique relies on the clinical symptoms of the patient. The risk/benefit ratio of surgery is related to the careful selection of patients and the technical accuracy. Intraoperative microrecording is considered the best method to avoid side effects and partial results. A series of patient's selection and follow-up assessment criteria are proposed.

Subthalamotomy in parkinsonian monkeys. Behavioural and biochemical analysis.

Nineteen Macaca fascicularis monkeys were divided into four different groups: Group A (n = 3), control; Group B (n = 3), monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Group C (n = 8), animals treated with MPTP in which the subthalamic nucleus (STN) was unilaterally lesioned by kainic acid injection; in Group D (n = 5), the STN was lesioned prior to MPTP administration. Subthalamotomy resulted in a bilateral improvement of tremor, spontaneous activity, bradykinesia (evaluated by a manual motor test) and freezing in Group C. All these monkeys developed hemichorea contralateral to the lesion. The improvement was maintained and the hemichorea continued until death. The monkeys in group D showed severe hemiballism which persisted throughout MPTP administration and developed parkinsonian signs mainly on the side ipsilateral to the lesion. Analysis of the in situ hybridization of the mRNA coding for glutamic acid decarboxylase (GAD) of MPTP monkeys showed a significant increase in the mean density of silver grains over every labelled neuron in the globus pallidum lateralis (56.8% over control) as well as the globus pallidus medialis (GPM) (45.7% over control) and the substantia nigra reticulata (SNR) (35.8% over control). No significant change was observed in the thalamic nucleus reticularis. Subthalamotomy (Groups C and D) produced a significant reduction in mRNA GAD expression on the side of the lesion in the GPM and the SNR (34% and 42.3%, respectively) with respect to the ipsilateral (non-lesioned) side and also when compared with parkinsonian monkeys. These results confirm and expand, at the cellular level, the paramount role of STN hyperactivity in the pathophysiology of parkinsonism. The therapeutic consequences of these findings for surgical treatment of Parkinson's disease are discussed.

Performance of repetitive wrist movements in Parkinson's disease.

The timing of repetitive alternating 80 degrees flexion-extension movements of the right wrist was studied in 42 patients with Parkinson's disease, tested while not receiving dompaminergic medication and 20 age- and sex-matched controls. Five rates of movement (0.5 Hz, 1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz) were examined. The interval between two successive flexion movements, as measured from the electromyography (EMG) records was taken as the unit of analysis or inter-response interval (IRI). At 0.5 Hz, 1 Hz and 1.5 Hz there were no differences between groups in mean IRIs. At higher rates of movement (2 Hz and 2.5 Hz), however, the controls were significantly more accurate in timing of repetitive movements than the patients. At all five frequencies, the patients with moderate or severe Parkinson's disease were less accurate in timing of repetitive movements than those with mild disease, although the differences were not significant. In nine patients tested in the 'on' and 'off' medication states, administration of 250 mg of levodopa/carbidopa resulted in significantly more accurate timing of repetitive movements. Wing and Kristofferson's (1973b) two-process model of repetitive movements was applied to the IRI data. At various rates of movement, the primary prediction of the model that lag 1 autocorrelations should be in the 0 to -0.5 range was violated in 40-70% of the patient and controls. For those subjects who had lag 1 autocorrelations in the expected range, IRI variability was to break down into a timekeeper and a motor delay variance. At all frequencies, the patients had significantly higher variance for IRI, timekeeper and motor delay than the controls. Although not significant, more severe Parkinson's disease was associated with greater IRI, timekeeper and motor delay variance, while administration of levodopa resulted in reduction of the three types of variance. The validity of the Wing and Kristofferson model for the analysis of this type of movement is discussed.

Toxic myoclonus.

Several toxins produce encephalopathies in which myoclonus can be a prominent feature. These include intoxications with bismuth, methyl bromide, cooking oil containing anilines, and tetraethyl lead. The clinical features in many cases resemble the action myoclonus syndrome of posthypoxic encephalopathy.

The anatomical basis of symptomatic hemidystonia.

Twenty-eight patients with focal (arm or leg) or hemidystonia due to tumour, arteriovenous malformation, infarction, haemorrhage or hemiatrophy are described. All had typical dystonic movements and/or postures, identical to those seen in idiopathic (primary) torsion dystonia. The site(s) of the lesion responsible, as defined by CT (computerized tomography) scan or pathological examination, was in the contralateral caudate nucleus, lentiform nucleus (particularly the putamen) or thalamus, or in a combination of these structures. Review of 13 other patients in the literature with hemidystonia and lesions defined by CT scan, and of 7 other patients with pathologically discrete lesions associated with hemidystonia, also indicated involvement of these structures. Dystonia may be due to abnormal input from thalamus to premotor cortex, due to lesions either of the thalamus itself, or of the striatum projecting by way of the globus pallidus to the thalamus.