M. C. Rodriguez-Oroz

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.

Deficits in inhibitory control and conflict resolution on cognitive and motor tasks in Parkinson’s disease

Recent imaging studies in healthy controls with a conditional stop signal reaction time (RT) task have implicated the subthalamic nucleus (STN) in response inhibition and the pre-supplementary motor area (pre-SMA) in conflict resolution. Parkinson’s disease (PD) is characterized by striatal dopamine deficiency and overactivity of the STN and underactivation of the pre-SMA during movement. We used the conditional stop signal RT task to investigate whether PD produced similar or dissociable effects on response initiation, response inhibition and response initiation under conflict. In addition, we also examined inhibition of prepotent responses on three cognitive tasks: the Stroop, random number generation and Hayling sentence completion. PD patients were impaired on the conditional stop signal reaction time task, with response initiation both in situations with or without conflict and response inhibition all being significantly delayed, and had significantly greater difficulty in suppressing prepotent or habitual responses on the Stroop, Hayling and random number generation tasks relative to controls. These results demonstrate the existence of a generalized inhibitory deficit in PD, which suggest that PD is a disorder of inhibition as well as activation and that in situations of conflict, executive control over responses is compromised.

Therapeutic efficacy of unilateral subthalamotomy in Parkinson’s disease: results in 89 patients followed for up to 36 months

Background: Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson’s disease (PD). Patients and methods: 89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months. Results: The Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the “off” and “on” states throughout the follow-up, except for the “on” state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort. Conclusion: Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesion. Further work is needed to ascertain what factors led to severe, persistent chorea-ballism in a subset of patients. Subthalamotomy may be considered an option in circumstances when deep brain stimulation is not viable.

Bilateral stimulation of the subthalamic nucleus has differential effects on reactive and proactive inhibition and conflict-induced slowing in Parkinson’s disease

It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson’s disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.

High frequency stimulation of the subthalamic nucleus and levodopa induced dyskinesias in Parkinson's disease

Reduction in the neuronal activity of the subthalamic nucleus leading to diminished excitation of the globus pallidum internum is associated with chorea-ballism in monkeys.1 Levodopa induced dyskinesias are currently thought to share a similar pathophysiology2 but recent findings also suggest that abnormal patterns of neuronal firing in the globus pallidum internum may be as relevant.3 Data from both parkinsonian monkeys and patients with Parkinsons disease submitted to lesion4 5 or functional blockade of the subthalamic nucleus6 are in keeping with such a general principle, but the threshold to induce dyskinesias in the parkinsonian state is higher than in intact animals.7 The case recently described by Figueiras-Mendez et al  8 is extremely interesting as it suggests that functional inhibition of the subthalamic nucleus by high frequency stimulation blockades levodopa induced dyskinesias. This is clearly at odds with the current pathophsyiological model of the basal ganglia.9 Thus, the finding of Figueiras-Mendez et al  8 rises the intriguing possibility that dyskinesias depend or are mediated by neuronal firing in a given region of the subthalamic nucleus, which was blocked by high frequency stimulation. Measurement of afferent synaptic activity by the technique of 2-deoxylucose (2-DG) uptake showed an increment in the subthalamic nucleus (compatible with increased inhibition from the globus pallidum externum), particularly in the ventromedial tip of the nucleus.9 This contrasts with the findings in monkeys with chorea induced by pharmacological blockade of the globus pallidum externum, in which 2-DG uptake was maximal in the dorsolateral portion of the subthalamic nucleus, where the sensorimotor region lies. A recent anatomical study10 also showed that the cortical-subthalamic … Dr F Jimenez-Jimenez, C/Corregidor, Jose de Pasamonte 24 3°D, E 28030 Madrid, Spain

Revisión crítica de la estimulación subtalámica en la enfermedad de Parkinson

Resumen Los autores realizan una revision critica de la estimulacion del nucleo subtalamico (NST) en la enfermedad de Parkinson (EP) a largo plazo (3–5 anos). La estimulacion del NST produce una mejoria significativa de la parte motora de la escala UPDRS (Unified Parkinson Disease Rating Scale) sin medicacion a los 3–5 anos de la cirugia. Los resultados muestran que los beneficios obtenidos tanto en el temblor, la rigidez, la bradicinesia y las disquinesias, asi como la reduccion de la medicacion estan mantenidos significativamente a largo plazo. Otros signos de la enfermedad como la marcha y la estabilidad postural no se mantienen al comparar los beneficios al ano de la cirugia. Un porcentaje alto de pacientes intervenidos muestra un deterioro cognitivo durante el seguimiento que puede estar relacionado con la propia evolucion de la enfermedad. La conclusion es que la estimulacion bilateral del NST continua siendo efectiva a largo plazo pero deberia considerarse la cirugia en un momento mas precoz de la evolucion de la enfermedad.

Trastornos del sueño en la enfermedad de Parkinson y otros trastornos del movimiento

Neurodegenerative processes with movement disorders is predominant features show a high incidence of sleep alterations at some point in their evolution. The degeneration of structures responsible for maintaining the sleep-wakefulness cycles and the architecture of sleep could be at their root. Other factors like the drugs employed in the treatment of motor problems, the limitations to movement, etc., aggravate the problem. Although, at present, there is no medical therapy able to restore the defects derived from the degeneration of the key structures of sleep, an individual analysis of the coadyuvant factors in each patient could help to improve these problems. In this article we describe the main sleep disorders in Parkinson’s disease and other degenerative diseases such as multi-system atrophies or progressive supranuclear paralysis.

Deep Brain Stimulation and Parkinson’s Disease

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) portrays a great antiparkinsonian benefit. However, the STN has become the preferred target mainly because, in contrast to GPi, dopaminergic drugs could be reduced. The success of DBS pivots on three major facts: (1) the selection of the adequate patient; (2) the accuracy in targeting the nucleus; and (3) the selection of the best programmation alongside the proper adjustment of medication. In this article, we review these topics and discuss the long-term benefits and adverse events associated with this treatment.

Terapia celular "neuro-restauradora" en la enfermedad de Parkinson: un debate pendiente

At present there is great enthusiasm over the perspectives deriving from so-called cell therapy in Parkinsons disease. This enthusiasm has spread beyond the ambit of the medical community, reaching the general public, and has been fuelled by a considerable ethical and political debate, sidestepping the need for a really scientific analysis of the real qualities and limitations of treatment with stem-cells in neurodegenerative diseases. Parkinsons disease is frequently observed from a simplistic perspective, as a mere neurodegeneration of the nigrostriatal dopaminergic pathway. This viewpoint encompasses different designs that tend to replace the lack of dopamine in the striatum through the use of different types of cell therapy. In this respect, it is important to indicate, on the one hand, the multisystemic and generalised nature of the disease and, on the other, the progressive character of the neurodegenerative process of Parkinsons disease. With this approach, to claim that the mere replacement of striatal dopamine through replacement cell therapy can correct the generalised and progressive character of the disease is a fanciful aspiration, which can only contribute to generating unfounded expectations in the general public. This article attempts to set out from a purely scientific point of view the doubts over the expectations created by these new therapeutic designs.