Lázaro Álvarez

Dorsal subthalamotomy for Parkinson's disease

We report our experience of unilateral subthalamotomy in patients with Parkinsons disease (PD). Eleven patients were included in a pilot, open‐labeled study to assess the effect of unilateral lesion of the subthalamic nucleus (STN) with a minimum of 12 months of follow‐up. The guidelines of CAPIT (Core Assessment Program for Intracerebral Transplantation) were followed for recruitment into the study and follow‐up assessment. Levodopa equivalents daily intake (mean 967 mg) were unchanged during the first 12 months in all but one patient who stopped medication. The sensorimotor region of the STN was defined by semimicrorecording and stimulation and a thermolytic lesion was placed accordingly. There was a significant reduction in both UPDRS parts II and III in the “off” state at 1‐, 6‐, and 12‐month follow‐up. This effect was maintained in four patients up to 24 months. The dyskinesia score did not change postoperatively. Lesion‐induced dyskinesias were not a management problem except in one patient who developed a large infarction several days postsurgery. This initial study indicates that a lesion of the STN is not generally associated with hemiballismus in PD. Subthalamotomy may induce considerable motor benefit and could become another surgical option under specific circumstances. Mov. Disord. 16:72–78, 2001.

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.

What can man do without basal ganglia motor output? The effect of combined unilateral subthalamotomy and pallidotomy in a patient with Parkinson's disease.

We have studied motor performance in a man with Parkinsons disease (PD) in whom thermolytic lesions of the left subthalamic and left globus pallidus nuclei interrupted the basal ganglia (BG)-thalamo-cortical motor circuit in the left hemisphere. This allowed us to study remaining motor capabilities in the absence of aberrant BG activity typical of PD. Movements of the left arm were slow and parkinsonian whereas movement speed and simple reaction times (RT) of the right (operated) arm were within the normal range with no obvious deficits in a range of daily life activities. Two main abnormalities were found with the right hand. (a) Implicit sequence learning in a probabilistic serial reaction time task was absent. (b) In a go/no-go task when the percent of no-go trials increased, the RT superiority with the right hand was lost. These deficits are best explained by a failure of the cortex, deprived of BG input, to facilitate responses in a probabilistic context. Our findings confirm the idea that it is better to stop BG activity than allowing faulty activity to disrupt the motor system but dispute earlier claims that interrupting BG output in PD goes without an apparent deficit. From a practical viewpoint, our observations indicate that the risk of persistent dyskinesias need not be viewed as a contraindication to subthalamotomy in PD patients since they can be eliminated if necessary by a subsequent pallidotomy without producing deficits that impair activities of daily life.

Anatomic and neurophysiological methods for the targeting and lesioning of the subthalamic nucleus: Cuban experience and review.

OBJECTIVETo develop a method to place a lesion precisely in the subthalamic nucleus (STN) and evaluate its effectiveness. METHODSA retrospective study of targeting data collected during stereotactic planning to lesion the STN in 31 patients with Parkinson’s disease and of results in more than 50 procedures was performed. The targeting method was based on computed tomographic imaging together with semimicroelectrode recording digital processing and electrical stimulation. Two statistical methods were used to correlate initial with final target coordinates and assess the efficacy of the targeting procedure. RESULTSThe anatomic target based on computed tomographic imaging data showed electrical activity in the subthalamus in the first pass in 82% of the procedures. In the remaining 18%, the STN was an average of 1.93 mm away from the nearest trajectory that recorded the STN (range, 1.41–2.24 mm). The average number of trajectories per procedure was 7.2; the location of the first trajectory relative to the center of the nucleus determined by electrical and physiological means (P < 0.01, analysis of variance, Student’s t test) was as follows: in the lateral direction, 1.25 ± 1.15 mm; in the anteroposterior direction, 1.53 ± 1.31 mm; and in the vertical direction, 0.67 ± 0.51 mm. The average number of tracts necessary to lesion the STN was two. CONCLUSIONThe combination of computed tomographic imaging, semimicroelectrode recording, and microstimulation provides an effective method to identify the STN lesion in parkinsonian patients. The method used for anatomic localization and electrophysiological mapping of the subthalamus was found to be effective in reaching the sensorimotor region of the nucleus. We carried out an accurate determination of the subthalamus location and its volume in the lesioning.

Semantic and phonemic verbal fluency in Parkinson's disease: Influence of clinical and demographic variables.

Changes of cognitive function in PD have been extensively documented and defined as a ‘frontal’ type executive dysfunction. One of the main components of this executive dysfunction is the impairment of verbal fluency. The aim of the present study was to assess semantic and phonemic fluency in a large sample of PD patients and to investigate the effect of clinical and sociodemographic variables on verbal fluency in this patient group. Three hundred patients with idiopathic Parkinsons disease who were consecutive referrals to our clinic and 50 age and education matched healthy controls completed the phonemic and semantic verbal fluency tasks. Both phonemic and semantic verbal fluency were significantly impaired in PD patients relative to matched controls. Stage of illness, presence of depression, education and age influenced verbal fluency measures. Regression analyses established that global measures of cognitive ability (MMSE) and executive function (FAB) and side of onset of motor symptoms predicted 36–37% of variance of phonemic or semantic verbal fluency measures. Thus, future studies aimed at assessing cognitive functioning in PD patients treated by deep brain stimulation (DBS) should adequately take into account several factors (stage of illness, depression, executive functioning) which may potentially influence performance on verbal fluency tasks.

Cognitive and neuropsychiatric effects of subthalamotomy for Parkinson’s disease

Since the advent of deep brain stimulation (DBS) for the treatment of Parkinsons disease (PD), subsequent cognitive and neuropsychiatric effects of this procedure have become well-chronicled. Yet, thermolitic lesion of the subthalamic nucleus (STN) is still a valid option when DBS cannot be applied, and little has been published regarding its impact on cognition and mood. We examined the cognitive and neuropsychiatric functions of 10 consecutive patients with advanced PD undergoing simultaneous bilateral subthalamotomies. With 24 months of follow-up, the patients, three of whom were on anticholinergics prior to surgery, showed no deterioration in cognitive assessments including verbal fluency. Hypoactive behaviors (depression and apathy) showed lasting improvement, while hyperactive behaviors (euphoria and disinhibition) transiently increased after surgery. Improvement in hypoactive behaviors correlated with improvement in hypokinetic movements, and enhanced hyperactive behaviors followed the course of post-operative hyperkinetic movements. Such correlations may support the role of the STN in modulating limbic connections between the basal ganglia and frontal cortex. The results of this proof-of-concept pilot study suggest the need for larger, long-term, randomized controlled studies to assess motor, neuropsychiatric, behavioral and radiologic correlations after subthalamotomies.

Levodopa‐induced dyskinesias in Parkinson's disease

Publisher Summary Hyperkinetic or dyskinetic disorders are characterized by excessive motor activity that interferes with normal motor control mechanism. Levodopa-induced dyskinesias (LID) are mainly associated with several molecular, biochemical, and physiological changes in the basal ganglia (BG). This chapter focuses on LID. The origin of LID in PD is mainly related to the impact on striatal physiology of nigrostriatal dopaminergic depletion and discontinuous levodopa replacement therapy. These combine to induce abnormal expression of dopamine-receptor signaling and neuropeptides, leading to deranged corticostriatal plasticity. LID generally occur in patients with motor fluctuations and can be classified into three main groups: (1) peak-dose choreic or dystonic movements, (2) diphasic dyskinesias, and (3) off -period dystonia. Avoiding pulsatile dopaminergic stimulation results in reduction in the incidence and severity of LID in the general PD population. Treatment of severe LID requires continuous dopaminergic stimulation by means of infusions. DBS of the GPi or the STN is also highly efficacious in the treatment of LID. In patients with very severe and complex LID, GPi-DBS can be a safer indication, even when pallidal surgery is not associated with a significant reduction in daily levodopa intake.

Personal-Computer-Based System for Three-Dimensional Anatomic-Physiological Correlations during Stereotactic and Functional Neurosurgery

This paper describes the automatic three-dimensional (3D) graphic possibilities that are supplied by the Neurosurgical Deep Recording System (NDRS) to facilitate anatomic-physiological targeting during stereotactic and functional neurosurgery using depth recording. This software has been developed to substitute the complex electronic equipment ordinarily used for deep brain electrical recording, display and processing by a personal computer. It may also help to improve on-line graphic analysis, automatic management of the recorded information and flexibility to implement different forms of signal analysis. It can automatically show a 2D or 3D representation of the electrode track, with the electrophysiological findings superimposed as well as the corresponding sagittal, coronal and axial views of a brain atlas using automatic scaling. The NDRS has already successfully been applied during more than 300 neurosurgeries in Spain and Cuba, enabling improved targeting accuracy and safety.

A New Family Affected by the Syndrome of Hyperornithinaemia, Hyperammonaemia and Homocitrullinuria

We have reported three cases of hyperornithinaemia associated with hyperammonaemia and homocitrullinuria (HHH). They deal with two brothers and a sister from a family where the parents and four other children are healthy on clinical and biochemical examination. The biochemical findings in our patients indicate the existence of a defect in the transport of ornithine into the mitochondria. Cultured skin fibroblasts from two of these patients incorporated six times less [14C]ornithine into protein as compared to control cells. The most characteristic sign of the clinical picture is the progressive spastic paraparesis found in one of the cases. Ornithine supplementation and restricted protein intake may be useful in the treatment of this syndrome since after three years of treatment the clinical response was favourable and the patients showed no adverse clinical effects.