Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease.

We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved.

Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.

[Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment]. / Maladie de Parkinson: de la physiopathologie des troubles psychiques à la maîtrise du traitement dopaminergique.

INTRODUCTION: Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. STATE OF THE ART: Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. PERSPECTIVES: Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and nonmotor fluctuations, a better understanding of their underlying mechanisms and the development of new evaluation tools for these nonmotor symptoms. CONCLUSIONS: The neurologist who strives to gain mastery of dopaminergic treatment needs to fine tune the dosage of levodopa and dopamine agonists on an individual basis, depending on the presence of motor and nonmotor signs respectively.

[Assessment of hyper- and hypodopaminergic behaviors in Parkinson's disease]. / Evaluation des troubles comportementaux hyper- et hypodopaminergiques dans la maladie de Parkinson.

The common perception that Parkinson's disease patients tend to be depressed, anxious, apathetic and harm-avoiding has currently been challenged by the recognition that they can also exhibit a hedonistic, novelty-seeking personality. Thus, Parkinson's disease patients may indulge in their passions in an irresponsible and disinhibited manner, and engage in repetitive, compulsive behaviors that may be harmful and destructive to their social or professional lives. The dopamine dysregulation syndrome includes hypersexuality, pathological gambling, and compulsive shopping; it is associated with addiction to dopaminergic medication. However, not all behavioral changes are necessarily accompanied by a dopaminergic addiction. After antiparkinson treatment is initiated, patients enter a 'honeymoon period' during which changes in mood and behavior reflect a return to the patients' premorbid personality. The increased motivation and higher level of activity in professional as well as leisure activities are considered positive changes by both the patients and their relatives. With prolonged and increased dopaminergic treatment, these positive behavioral changes can become excessive and evolve into nocturnal hyperactivity and stereotyped, repetitive and time consuming behaviors which ultimately disorganize the patient's everyday routine and herald behavioral addictions. These drug-induced behavioral changes are under-appreciated by neurologists and under-reported by the patients who neither complain about the behaviors nor understand the relationship between motivated behavior and dopaminergic medication. For these reasons, we propose a new scale for the assessment of behavior and mood to quantify and track changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This scale is based on the concept of hypo- and hyperdopaminergic mood and behavior. The scale consists of 18 items addressing non-motor symptoms, grouped in four parts: general psychological evaluation, apathy, non-motor fluctuations and hyperdopaminergic behaviors. The rating in five points (0-4 from absent to severe) is carried out during a semi-structured interview. Open-ended questions introduce each item, allowing patients to express themselves as freely as possible. Close-ended questions permit the rating of severity and intensity. This new instrument can be used by psychologists, psychiatrists or neurologists familiar with Parkinson's disease. Designed to detect changes in mood and behavior of Parkinson's disease patients resulting either from the disease or its treatment, this tool can be used in conjunction with the neurocognitive evaluation, to help tailor the treatment of motor and non-motor symptoms to each individual's needs.

Neuropsychological changes between "off" and "on" STN or GPi stimulation in Parkinson's disease.

BACKGROUND: In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery. OBJECTIVE: To investigate the specific effects of DBS by comparing the performance of patients with the stimulator turned "on" and "off." METHODS: The performance of 56 patients on clinical tests of executive function was compared after 3 and 12 months of DBS of the subthalamic nucleus (STN; n = 48) or the internal globus pallidus (GPi; n = 8) with the stimulator "on" or "off." Global intellectual efficiency, verbal learning, and mood were also evaluated with the stimulator "on." The performance of another group of 20 patients was compared after 6 months of DBS of the STN (n = 15) or the GPi (n = 5) with the stimulator "on" or "off" on more experimental tests recently shown to be more sensitive to l-dopa therapy. RESULTS: When the stimulator was "on," STN patients showed a mild but significant improvement in psychomotor speed and working memory. In comparison with the presurgical state, STN patients had no cognitive deficit at 12 months, except for lexical fluency. There was no differential effect of STN or GPi stimulation. CONCLUSIONS: 1) The specific effect of DBS seems to mimic the action of l-dopa treatment in the cognitive as in the motor domain; 2) the surgery associated with DBS does not appear to affect the cognitive performance of patients with PD 12 months later, except for a mild deficit in lexical fluency.

Bilateral subthalamic nucleus stimulation improves health-related quality of life in PD.

In order to assess the impact of bilateral subthalamic nucleus (STN) stimulation in PD on quality of life, the PD Quality of Life questionnaire was assessed in 60 consecutive patients with PD before surgery and 12 months after surgery. All aspects of quality of life, including motor (+48%), systemic (+34%), emotional (+29%), and social (+63%) dimensions, significantly improved with long-term STN stimulation.

[Deep brain stimulation]. / La stimulation cérébrale profonde dans la maladie de Parkinson.

The present renewal of the surgical treatment of Parkinson's disease, almost abandoned for twenty Years, arises from two main reasons. The first is the better understanding of the functional organization of the basal ganglia. It was demonstrated in animal models of Parkinson's disease that the loss of dopaminergic neurons within the substantia nigra, at the origin of the striatal dopaminergic defect, induces an overactivity of the excitatory glutamatergic subthalamo-internal pallidum pathway. The decrease in this hyperactivity might lead to an improvement in the pakinsonian symptoms. The second reason is the improvement in stereotactic neurosurgery in relation with the progress in neuroimaging techniques and with intraoperative electrophysiological microrecordings and stimulations, which help determine the location of the deep brain targets. In the 1970s chronic deep brain stimulation in humans was applied to the sensory nucleus of the thalamus for the treatment of intractable pain. In 1987, Benabid and colleagues suggested high frequency stimulation of the ventral intermediate nucleus of the thalamus in order to treat drug-resistant tremors and to avoid the adverse effects of thalamotomies. How deep brain stimulation works is not well known but it has been hypothetized that it could change the neuronal activities and thus avoid disease-related abnormal neuronal discharges. Potential candidates for deep brain stimulation are selected according to exclusion and inclusion criteria. Surgery can be applied to patients in good general and mental health, neither depressive nor demented and who are severely disabled despite all available drug therapies but still responsive to levodopa. The first session of surgery consists in the location of the target by ventriculography and/or brain MRI. The electrodes are implanted during the second session. The last session consists in the implantation of the neurostimulator. The ventral intermediate nucleus of the thalamus was the first target in which chronic deep brain stimulation electrodes were implanted in order to alleviate tremor. This technique can be applied bilaterally without the adverse effects of bilateral thalamotomies. Like pallidotomy, internal globus pallidum stimulation has a dramatic beneficial effect on levodopa-induced dyskinesia but its effects on the parkinsonian triad are less constant and opposite motor effects are sometimes observed in relation with the stimulated contact. The inconstant results, perhaps related to the complexity of the structure led to the development of subthalamic nucleus stimulation. The alleviation of motor fluctuations and the improvement in all motor symptoms allows a significant decrease in levodopa daily dose and in levodopa-induced dyskinesia. Presently, deep brain stimulation is a fashionable neurosurgical technique to treat Parkinson's disease. Subthalamic nucleus stimulation seems to be the most suitable target to control the parkinsonian triad and the motor fluctuations. Because of the possible adverse effects it must be reserved for disabled parkinsonian patients. No large randomized study comparing different targets and different neurosurgical techniques has been performed yet. Such studies, including cost benefit studies would be useful to assess the respective value of these different techniques.

[Value of liver needle-biopsy in Djibouti (1.1110 specimens) (author's transl)]. / Considérations sur la valeur de la ponction-biopsie du foie à Djibouti. A propos de 1.110 examens.

Liver diseases, specially hepatomegalies and hepatosplenomegalies are very frequent in Republic of Dijibouti. Needle-biopsy of the liver is a good approach of this pathology as demonstrated by controlling 1.110 specimens within a period of 9 years, leading to very different diagnosis.

[Marburg, Lassa and Ebola viral hemorrhagic fevers (author's transl)]. / Les fièvres hémorragiques virales de Marburg, Lassa et Ebola.

For each of these three fevers recently described, the authors report the history of their identification. The features of the three viruses, and the clinical aspects of the diseases they induce, are also indicated. The laboratory diagnosis is described. Practical indications are given for the transportation of the specimens to the only three high security laboratories in the world. The laboratory diagnosis is described. Some cautions are indicated handling and treating patients. It must be envisaged also to organize a four degrees quarantive cautions; compulsory for necropsies, burials, and occasionally for long distant transportations of patients are indicated.

Preservation of cognitive function in dystonia treated by pallidal stimulation.

OBJECTIVE: To assess the effects of bilateral pallidal deep brain stimulation (DBS) on mood and cognitive performance in patients with dystonia before surgery (at baseline, while patients received their usual treatment) and 12 months postoperatively (while patients received neurostimulation and their medications) in a multicenter prospective study. METHODS: Twenty-two patients with primary generalized dystonia were evaluated with tests focused on executive functions. The authors considered the patients' severe disability and selected the following tests: Raven Progressive Matrices 38, Similarities and Arithmetic subtests of the Wechsler Adult Intelligence Scale-R, Grober and Buschke, Wisconsin Card Sorting Test (WCST), verbal fluency, Trail Making Test, and the Beck Depression Inventory. Median age at surgery was 30 years (range = 14 to 54 years), median duration of disease was 18.5 years (range = 4 to 37 years). RESULTS: Before surgery, no patients showed cognitive decline or depression. The surgical procedure appeared to be benign cognitively. One year after surgery, free recall improved. There was a significant reduction in the number of errors in the WCST. No behavioral or mood changes were found. CONCLUSIONS: Bilateral pallidal stimulation has a good benefit-to-risk ratio as it did not negatively affect cognitive performance and mood in primary dystonia, while a significant motor improvement was obtained. Moreover, a significant mild improvement in executive functions was observed, which may have been related either to the surgical treatment or to the marked decrease in anticholinergic drugs.

Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson's disease.

BACKGROUND: High frequency stimulation of the subthalamic nucleus (STN) is an alternative but expensive neurosurgical treatment for parkinsonian patients with levodopa induced motor complications. OBJECTIVE: To assess the safety, clinical effects, quality of life, and economic cost of STN stimulation. METHODS: We conducted a prospective multicentre study in 95 consecutive Parkinson's disease (PD) patients receiving bilateral STN stimulation and assessed its effects over 12 months. A double blind randomised motor evaluation was carried out at 3 month follow up, and quality of life, self care ability, and predictive factors of outcome following surgery were assessed. The cost of PD was estimated over 6 months before and after surgery. RESULTS: The Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved by 57% (p<0.0001) and activities of daily living improved by 48% (p<0.0001) at 12 month follow up. Double blind motor scoring improved by 51% at 3 month follow up (p<0.0001). The total PD Quality of Life Questionnaire (PDQL-37) score improved by 28% (p<0.001). The better the preoperative motor score after a levodopa challenge, the better the outcome after STN stimulation. Five patients developed an intracerebral haematoma during electrode implantation with permanent after effects in two. The 6 month costs of PD decreased from 10,087 euros before surgery to 1673 euros after surgery (p<0.0001) mainly because of the decrease in medication. These savings allowed a return on the procedure investment, estimated at 36,904 euros over 2.2 years. CONCLUSIONS: STN stimulation has good outcomes with relatively low risk and little cost burden in PD patients with levodopa induced motor complications.

Subthalamic nucleus stimulation in tremor dominant parkinsonian patients with previous thalamic surgery.

Before the introduction of high frequency stimulation of the subthalamic nucleus (STN), many disabled tremor dominant parkinsonian patients underwent lesioning or chronic electrical stimulation of the thalamus. We studied the effects of STN stimulation in patients with previous ventral intermediate nucleus (VIM) surgery whose motor state worsened. Fifteen parkinsonian patients were included in this study: nine with unilateral and two with bilateral VIM stimulation, three with unilateral thalamotomy, and one with both unilateral thalamotomy and contralateral VIM stimulation. The clinical evaluation consisted of a formal motor assessment using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological tests encompassing a 50 point frontal scale, the Mattis Dementia Rating Scale, and the Beck Depression Inventory. The first surgical procedure was performed a mean (SD) of 8 (5) years after the onset of disease. STN implantation was carried out 10 (4) years later, and duration of follow up after beginning STN stimulation was 24 (20) months. The UPDRS motor score, tremor score, difficulties in performance of activities of daily living, and levodopa equivalent daily dose significantly decreased after STN stimulation. Neither axial symptoms nor neuropsychological status significantly worsened after the implantation of the STN electrodes. The parkinsonian motor state is greatly improved by bilateral STN stimulation even in patients with previous thalamic surgery, and STN stimulation is more effective than VIM stimulation in tremor dominant parkinsonian patients.

Relationship between levodopa-independent symptoms and central atrophy evaluated by magnetic resonance imaging in Parkinson's disease.

Thirty patients with Parkinson's disease were studied for the purpose of investigation relations between motor symptoms and cerebral atrophy evaluated by magnetic resonance imaging (MRI). Axial symptoms (gait disorder, postural instability and difficulty in arising from a chair), assessed at the time of maximum clinical improvement, were significantly correlated with frontal atrophy, while no correlation was found between the basal parkinsonian disability score and cerebral atrophy. It is suggested that frontal atrophy observed by MRI is linked with axial motor symptoms resulting from non-dopaminergic lesions. The origin of this atrophy is unknown.

Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease.

BACKGROUND: In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an "off" period, when the medication is not working and the motor symptoms of parkinsonism are present, and an "on" period, when the medication is causing improved mobility, often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. METHODS: We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clinical evaluations included the Unified Parkinson's Disease Rating Scale, a dyskinesia scale, and timed tests conducted before and after surgery, when patients were off and on medications. RESULTS: After one year of electrical stimulation of the subthalamic nucleus, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III, respectively) off medication improved by 60 percent (P<0.001). The subscores improved for limb akinesia, rigidity, tremor, and gait. In the testing done on medication, the scores on part III improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was reduced by half. The cognitive-performance scores remained unchanged, but one patient had paralysis and aphasia after an intracerebral hematoma during the implantation procedure. CONCLUSIONS: Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The severity of symptoms off medication decreases, and the dose of levodopa can be reduced with consequent reduction in dyskinesias.

Mirthful laughter induced by subthalamic nucleus stimulation.

High-frequency stimulation of the subthalamic nucleus (STN) improves the motor signs of Parkinson's disease (PD). The three main components (motor, associative, and limbic) of the cortical-basal ganglia-cortical circuits pass through the STN. It is not known whether STN stimulation can influence the limbic loop. We present two PD patients in whom acute stimulation of an electrode located in the STN using high stimulation parameters (50% higher than therapeutic) induced funny associations, leading to infectious laughter and hilarity, whereas the therapeutic parameters induced a hypomanic behavior and marked improvement of akinesia. Our report suggests that the STN, with its sensorimotor, cognitive, and limbic parts is not only involved in motor, but also in psychomotor regulation.

Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease.

BACKGROUND: Long term effects of subthalamic nucleus (STN) stimulation on cognition, mood, and behaviour are unknown. OBJECTIVE: This study evaluated the cognitive, mood, and behavioural effects of bilateral subthalamic nucleus deep brain stimulation (STN DBS) in patients with Parkinson's disease (PD) followed up for three years. METHODS: A consecutive series of 77 PD patients was assessed before, one, and three years after surgery. Mean (SD) age at surgery was 55 (8). Seven patients died or were lost for follow up. Neuropsychological assessment included a global cognitive scale, memory, and frontal tests. Depression was evaluated using the Beck depression inventory. Assessment of thought disorders and apathy was based on the unified Parkinson's disease rating scale. Reports of the behavioural changes are mainly based on interviews done by the same neuropsychologist at each follow up. RESULTS: Only two cognitive variables worsened (category fluency, total score of fluency). Age was a predictor of decline in executive functions. Depression improved whereas apathy and thought disorders worsened. Major behavioural changes were two transient aggressive impulsive episodes, one suicide, four suicide attempts, one permanent apathy, one transient severe depression, four psychoses (one permanent), and five hypomania (one permanent). CONCLUSIONS: Comparing baseline, one year, and three year postoperative assessments, STN stimulation did not lead to global cognitive deterioration. Apathy scores mildly increased. Depression scores mildly improved. Behavioural changes were comparatively rare and mostly transient. Single case reports show the major synergistic effects of both medication and stimulation on mood and behaviour, illustrating the importance of a correct postoperative management.

Bilateral subthalamic or pallidal stimulation for Parkinson's disease affects neither memory nor executive functions: a consecutive series of 62 patients.

There is a renewal of interest in surgical approaches including lesions and deep brain stimulation directed at motor subcorticofrontal loops. Bilateral lesioning presents a far greater risk of adverse effects, especially cognitive impairment. Furthermore, the main advantages of the stimulation procedure over lesioning are adaptability and reversibility of effects. The aim of this study was to assess the influence of bilateral stimulation of the subthalamic nucleus or internal globus pallidus on memory and executive functions in Parkinson's disease. Sixty-two patients were assessed before and after 3 to 6 months of chronic bilateral stimulation of the subthalamic nucleus (n = 49) or internal globus pallidus (n = 13). The neuropsychological tests used were the Mattis Dementia Rating Scale, the Grober and Buschke Verbal Learning Test, the Wisconsin Card Sorting Test, category and literal fluency, graphic and motor series, the Stroop Test, and the Trail Making Test. Mood was evaluated by the Beck Depression Inventory. Only 4 of 25 cognitive variables were affected by deep brain stimulation. Under stimulation, performance improved for Parts A and B of the Trail Making Test, but there was a deterioration in literal and total lexical fluency. There was also a mild but significant improvement in mood. It may therefore be concluded that stimulation of the subthalamic nucleus or internal globus pallidus does not change the overall cognitive performance in Parkinson's disease and does not greatly affect the functioning of subcorticofrontal loops involved in cognition in humans. This relative absence of cognitive impairment in bilateral deep brain stimulation is likely because of the accurate positioning of the electrodes, allowing the effects of stimulation to be confined to sensorimotor circuits.

The impact of deep brain stimulation on executive function in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) improves Parkinson's disease and increases frontal blood flow. We assessed the effects of bilateral DBS on executive function in Parkinson's disease patients, seven with electrodes implanted in the STN and six in the GPi. Patients were assessed off medication with stimulators off, on and off again. The groups showed differential change with stimulation on the Reitan Trail-Making test (TMT B) (STN more improved) and on some measures of random number generation and Wisconsin Card Sorting (STN improved, GPi worse with stimulation). Across the groups, stimulation speeded up responding (Stroop control trial, TMT A) and improved performance on paced serial addition and missing digit tests. Conversely, conditional associative learning became more errorful with stimulation across the two groups. In general, change in performance with stimulation was significant for the STN but not the GPi group. These results support two opposite predictions. In support of current models of Parkinson's disease, 'releasing the brake' on frontal function with DBS improved aspects of executive function. Conversely, disruption of basal ganglia outflow during DBS impaired performance on tests requiring changing behaviour in novel contexts as predicted by Marsden and Obeso in 1994.