Papers by Pierre Krystkowiak
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In Parkinson's disease, the neurodegenerative process of the nigrostriatal dopaminergic p... more In Parkinson's disease, the neurodegenerative process of the nigrostriatal dopaminergic pathways induces an increase in activity of the subthalamic nucleus and the medial globus pallidus, which cause inhibition of thalamo-cortical outputs explaining parkinsonism. HIGH-FREQUENCY DEEP BRAIN STIMULATION: The adverse effects induced by lesions of subcortical structures (thalamotomy, pallidotomy) have increased interest in chronic electrical stimulation proposed as a new therapy in Parkinson's disease. This technique is reversible and can be modulated with less adverse effects. Two targets may be proposed in case of severe motor fluctuations: the medial globus pallidus and the subthalamic nucleus. Pallidial stimulation improves dramatically levodopa-induced dyskinesia and, with a variable degree, the parkinsonian triad. Subthalamic stimulation rapidly reverses akinesia, rigidity and tremor and also dyskinesias which progressively tend to diminish after decreasing L-dopa dosage. LONG-TERM EFFICACY: A follow-up period of a few years has confirmed that the beneficial effect is maintained. However, stimulation dose not prevent the development of certain symptoms (postural impairment, cognitive decline). Chronic electrical stimulation of medial globus pallidus and subthalamic nucleus may be proposed for parkinsonian patients with severe motor fluctuations associated with abnormal involuntary movements which are not controlled by different medical therapies. Parkinsonian symptoms must still be levodopa responsive and cause severe clinical disability severely limiting daily living activities. Cognitive impairment and other severe pathologies are contraindications.
Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversi... more Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversible neurosurgical procedure that has been used for the treatment of dystonia, but assessment of its efficacy has been limited to open studies. We performed a prospective, controlled, multicenter study assessing the efficacy and safety of bilateral pallidal stimulation in 22 patients with primary generalized dystonia. The severity of dystonia was evaluated before surgery and 3, 6, and 12 months postoperatively during neurostimulation, with the use of the movement and disability subscores of the Burke-Fahn-Marsden Dystonia Scale (range, 0 to 120 and 0 to 30, respectively, with higher scores indicating greater impairment). Movement scores were assessed by a review of videotaped sessions performed by an observer who was unaware of treatment status. At three months, patients underwent a double-blind evaluation in the presence and absence of neurostimulation. We also assessed the patients' quality of life, cognition, and mood at baseline and 12 months. The dystonia movement score improved from a mean (+/-SD) of 46.3+/-21.3 before surgery to 21.0+/-14.1 at 12 months (P<0.001). The disability score improved from 11.6+/-5.5 before surgery to 6.5+/-4.9 at 12 months (P<0.001). General health and physical functioning were significantly improved at month 12; there were no significant changes in measures of mood and cognition. At the three-month evaluation, dystonia movement scores were significantly better with neurostimulation than without neurostimulation (24.6+/-17.7 vs. 34.6+/-12.3, P<0.001). There were five adverse events (in three patients); all resolved without permanent sequelae. These findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.
Dystonia is a syndrome characterized by prolonged muscle contractions that cause sustained twisti... more Dystonia is a syndrome characterized by prolonged muscle contractions that cause sustained twisting movements and abnormal posturing of body parts. Patients with the severe and generalized forms can benefit from bilateral high-frequency pallidal stimulation. To investigate the functional map of the globus pallidus (GP) in patients with primary generalized dystonia. Prospective multicenter, double-blind, video-controlled study in patients treated at a university hospital. University secondary care centers. Twenty-two patients with primary generalized dystonia. Acute internal and external pallidal deep-brain stimulation or pallidal deep-brain stimulation. The clinical effects of acute bilateral high-frequency ventral vs acute dorsal pallidal stimulation were assessed with the Movement subscale of the Burke-Fahn-Marsden Dystonia Rating Scale. Intrapallidal localization of the contacts of the quadripolar electrodes was performed using a 3-dimensional atlas-magnetic resonance imaging coregistration method by investigators blinded to the clinical outcome. Bilateral acute ventral stimulation of the GP significantly improved the Burke-Fahn-Marsden Dystonia Rating Scale score by 42% and resulted in stimulation of contacts located in the internal GP or medullary lamina in 18 of 21 patients. Bilateral acute dorsal pallidal stimulation, primarily localized within the external GP, had variable effects across patients, with half demonstrating slight or no improvement or even aggravation of dystonia compared with baseline. Ventral pallidal stimulation, primarily of the internal GP or medullary lamina or both, is the optimal method for the treatment of dystonia. The varying effects across patients of bilateral acute dorsal pallidal stimulation, primarily of the external GP, suggest that unknown factors associated with dystonia could have a role in and contribute to the effects of the electrical stimulation.
PLOS ONE, 2015
There is an urgent need to assess and improve the consent process in clinical trials of innovativ... more There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders.
Revue d'Épidémiologie et de Santé Publique, 2011
Objectif.-Cette étude avait pour objectif de documenter les modalités de la prise en charge initi... more Objectif.-Cette étude avait pour objectif de documenter les modalités de la prise en charge initiale de l'hypothyroïdie. Méthode.-Il s'agit d'une étude prospective observationnelle de la prise en charge en médecine libérale de patients débutant un traitement par hormones thyroïdiennes pour hypothyroïdie ou ayant débuté ce traitement dans les six derniers mois, avec une phase de suivi jusqu'au premier dosage de contrôle de la TSH après l'initiation du traitement. Résultats.-Au total, 254 médecins généralistes et 82 endocrinologues ont respectivement inclus 835 et 420 patients entre le 30 octobre 2008 et le 5 février 2009. L'âge moyen des patients était 53 ans, (84,4 % de femmes). La plupart (76 %) des patients inclus par les endocrinologues étaient référés par un autre médecin, le plus souvent (78,4 %) par un généraliste. En revanche, les patients inclus par les généralistes étaient le plus souvent (94,5 %) des patients habituellement suivis par eux. La cause la plus fréquente de l'hypothyroïdie était une thyroïdite auto-immune (59 %). Les causes secondaires à un traitement suppressif (chirurgie, radiothérapie ou médicamenteux) représentent 21 % des cas. Une hypothyroïdie médicamenteuse a été notée dans 7 % des cas. Les signes cliniques les plus fréquents étaient : fatigue (89 %), prise de poids (53,4 %), signes digestifs (34,7 %), intolérance au froid (33,2 %). Le taux moyen de TSH avant prescription d'une hormonothérapie substitutive était de 23 mUI/L. Le délai entre la réalisation de la TSH et la mise sous traitement était inférieure à une semaine dans la moitié des cas et en moyenne de 17 jours. Les autres examens réalisés étaient : les anticorps antithyroglobuline (50 %), les anticorps anti-TPO (64 %), la T4-L (55 %), une échographie thyroïdienne (98 %) et une scintigraphie (18,8 %). Le Lévothyrox 1 était le médicament le plus fréquemment prescrit (à 98,3 % des patients). La posologie initiale était en moyenne de 57 mg/j et la moitié des patients ont eu une prescription inférieure à 50 mg/j. On constate d'importantes variations de cette posologie initiale puisque celle-ci variait entre 5 et 225 mg/j et que l'écart type de la moyenne est de 35,9. Les paliers d'augmentation en moyenne autour de 10 à 15 mg/j à chaque titration, la durée moyenne entre 2 titrations étant de 6 semaines. Les différences de prise en charge entre les généralistes et les endocrinologues étaient mineures. Une TSH de contrôle a été rapportée pour 94,4 % des patients. Celle-ci a été réalisée 2 à 3 mois après l'initiation du traitement. Le premier dosage de contrôle de la TSH montre une amélioration franche de l'hypothyroïdie, puisque le résultat passe de 23,2 mUI/L avant la mise sous traitement à 6,8 mUI/L après. Conclusion.-Il s'agit de la première étude réalisée en France sur les modalités de prise en charge initiale de l'hypothyroïdie. Les pratiques rapportées sont globalement conformes aux recommandations françaises et homogènes entre les généralistes et les endocrinologues. Objectifs.-Les rares essais cliniques disponibles ne permettent pas d'établir des recommandations pour traiter la maladie de Huntington (MH). Nous avons comparé l'utilisation et l'efficacité en conditions réelles des traitements neuroleptiques et apparentés chez les individus atteints de MH. Patients et méthode.-Il s'agit d'une étude observationnelle utilisant les données du réseau Huntington de langue française. Depuis 2002, parmi les 1082 patients évalués par les 13 sites participant au réseau, 965 avaient un diagnostic génétique de MH et au moins une visite avec une UHDRS (Unified Huntington's Disease Rating Scale), échelle uniforme de mesure de la MH permettant des évaluations motrices, fonctionnelles, cognitives et du comportement. Les données prises en compte sont l'échelle UHDRS, les traitements par neuroleptiques et apparentés, les antécédents et l'histoire de la maladie et l'analyse génétique des CAG. L'efficacité en conditions réelles des traitements neuroleptiques et apparentés a été comparée après ajustement pour le score de propension à traiter le malade.
Journal of neurology, neurosurgery, and psychiatry, 2004
Bilateral subthalamic nucleus (STN) stimulation is recognised as a treatment for parkinsonian pat... more Bilateral subthalamic nucleus (STN) stimulation is recognised as a treatment for parkinsonian patients with severe levodopa related motor complications. Although adverse effects are infrequent, some behavioural disturbances have been reported. To investigate the consequences of STN stimulation on emotional information processing in Parkinson's disease by assessing the performance of an emotional facial expression (EFE) decoding task in a group of patients before and after surgery. 12 non-demented patients with Parkinson's disease were studied. They were assessed one month before surgery and three months after. Their ability to decode EFEs was assessed using a standardised quantitative task. Overall cognitive function, executive function, visuospatial perception, depression, and anxiety were also measured. Twelve healthy controls were matched for age, sex, and duration of education. Before surgery, the patients showed no impairment in EFE decoding compared with the controls. ...
Revue de neuropsychologie, 2010
Adenosine, 2012
ABSTRACT Huntington’s disease is a devastating hereditary neurodegenerative disorder caused by CA... more ABSTRACT Huntington’s disease is a devastating hereditary neurodegenerative disorder caused by CAG mutation within the IT15 gene encoding Huntingtin protein. Even though mutant and normal Huntingtin are ubiquitously expressed, the degenerative processes primarily occur within the striatum and particularly hit the GABAergic enkephalin neuronal subpopulation of medium spiny neurons particularly enriched with adenosine A2ARs, suggesting that the latter might play a role in HD. In agreement, variants in the ADORA2A gene influence the age at onset in HD and A2AR dynamics is largely altered by mutated Huntingtin. Adenosine receptors are involved in a number of processes critical for neuronal function and homeostasis, such as modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions as well as the regulation of protein degradation mechanisms. In the present review, we critically reviewed the current knowledge involving adenosine receptors in HD and discussed whether they represent a suitable therapeutic target.
Revue Neurologique, 2005
En raison de sa fréquence et du handicap qu'elle entraîne, la maladie de Parkinson (MP) représent... more En raison de sa fréquence et du handicap qu'elle entraîne, la maladie de Parkinson (MP) représente un fardeau important pour les patients, leur entourage et la société en terme de mauvaise qualité de vie et d'augmentation des dépenses de santé publique. La stimulation bilatérale des noyaux subthalamiques (NST) est indiquée chez des patients dopa-sensibles souffrant presque exclusivement de complications motrices sévères de la dopathérapie. Ces patients sont souvent relativement jeunes, ont un bon état général, sans troubles cognitifs ni comportementaux. Cette nouvelle procédure neurochirurgicale chirurgicale soulève la question de son coût et de son impact financier. L'objectif du Groupe d'Étude SPARK était l'évaluation de la sécurité, des effets cliniques, de la qualité de vie et des dépenses de santé de la stimulation des NST dans la MP.
Revue Neurologique, 2008
La stimulation cérébrale profonde à haute fréquence (130 à 180 Hertz) des noyaux sub-thalamiques ... more La stimulation cérébrale profonde à haute fréquence (130 à 180 Hertz) des noyaux sub-thalamiques (NST) est très effi cace sur les symptômes segmentaires (akinésie, rigidité, tremblement) de la maladie de Parkinson. Malgré cela, certains patients présentent, en moyenne 5 ans après la chirurgie, une majoration des troubles de la marche (hypokinésie) et des troubles axiaux, notamment sous forme d'épisodes de freezing invalidants. 1 Voltage et fréquence sont les paramètres les plus fréquemment modifi és lors des réglages proposés après chirurgie du NST pour tenter d'optimiser le contrôle de ces symptômes, avec une tendance naturelle à augmenter l'amplitude de stimulation au fi l du temps, et parfois la fréquence, notamment en cas de tremblement.
Revue Neurologique, 2012
ABSTRACT Rationnel Le très grand bénéfice des deux traitements pivots dans la Maladie de Parkinso... more ABSTRACT Rationnel Le très grand bénéfice des deux traitements pivots dans la Maladie de Parkinson (MP) que sont la L-dopa et la stimulation subthalamique sont mis en péril à long terme par l’apparition de troubles axiaux avec des freezing de la marche (FOG). Ceux-ci pourraient être en partie liés à une déplétion dopaminergique et noradrénergique dans les boucles striato-frontales. Le méthylphenidate (MPD) pourrait augmenter le niveau dopaminergique et noradrénergique synaptique striatal par inhibition des transporteurs pré synaptique. Objectif Nous avons étudié si le MPD améliorait les FOG et les capacités attentionnelles chez les patients non déments au stade avancé de la MP. Méthode Dans cette étude randomisée en double aveugle versus placebo (ClinicalTrials.gov : NCT00914095), les patients, de 13 centres en France, qui avaient des troubles axiaux sévères avec des FOG, en dépit d’un contrôle optimal des fluctuations motrices par dopathérapie et stimulation subthalamique, étaient éligibles pour l’inclusion. Les patients étaient assignés au groupe MPD (1 mg/kg/j) ou placebo pendant 3 mois. Le critère primaire était le nombre de pas au Stand Walk Sit Test (SWS) dans des conditions standardisées sans L-dopa entre la première et la dernière visite. Résultats Quatre vingt patients ont été screenés et 69 patients éligibles ont terminé l’étude. Par rapport au groupe placebo, on notait sous MPD une diminution significative du nombre de pas et du temps (au SWS), du nombre de freezing (au FOG trajectory) et du score de handicap moteur (UPDRS III) sans L-dopa associée à une diminution du nombre de freezing après test au L-dopa. L’attention et la somnolence étaient également améliorées sous MPD. Il n’y avait pas d’aggravation significative des dyskinésies, ni de l’humeur ou de comportement addictif. Une inhibition des transporteurs pré synaptiques de dopamine était observée sur le DaTSCAN™. Conclusions Le MPD améliore le freezing de la marche avec un impact positif sur la cognition et le comportement dans une population sélectionnée de patients parkinsoniens évolués sous stimulation subthalamique avec des doses modérées quotidiennes de L-dopa.
PLoS ONE, 2009
Background: Huntington's disease (HD) is a severe inherited neurodegenerative disorder characteri... more Background: Huntington's disease (HD) is a severe inherited neurodegenerative disorder characterized, in addition to neurological impairment, by weight loss suggesting endocrine disturbances. The aims of this study were to look for neuroendocrine disturbances in patients with Huntington's disease (HD) and to determine the relationship with weight loss seen in HD Methods and Finding: We compared plasma levels of hormones from the five pituitary axes in 219 patients with genetically documented HD and in 71 sex-and age-matched controls. Relationships between hormone levels and disease severity, including weight-loss severity, were evaluated. Growth hormone (GH) and standard deviation score of insulin-like growth factor 1 (SDS IGF-1) were significantly higher in patients than in controls (0.25 (0.01-5.89) vs. 0.15 (0.005-4.89) ng/ml, p = 0.013 and 0.1661.02 vs. 0.0660.91, p = 0.039; respectively). Cortisol was higher (p = 0.002) in patients (399.146160.5 nmol/L vs. 279.86130.1 nmol/L), whereas no differences were found for other hormone axes. In patients, elevations in GH and IGF-1 and decreases in thyroid-stimulating hormone, free triiodothyronine and testosterone (in men) were associated with severity of impairments (Independence scale, Functional score, Total Functional Capacity, Total Motor score, Behavioral score). Only GH was independently associated with body mass index (b = 20.26, p = 0.001).
New England Journal of Medicine, 2005
Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversi... more Severe forms of dystonia respond poorly to medical treatment. Deep-brain stimulation is a reversible neurosurgical procedure that has been used for the treatment of dystonia, but assessment of its efficacy has been limited to open studies. We performed a prospective, controlled, multicenter study assessing the efficacy and safety of bilateral pallidal stimulation in 22 patients with primary generalized dystonia. The severity of dystonia was evaluated before surgery and 3, 6, and 12 months postoperatively during neurostimulation, with the use of the movement and disability subscores of the Burke-Fahn-Marsden Dystonia Scale (range, 0 to 120 and 0 to 30, respectively, with higher scores indicating greater impairment). Movement scores were assessed by a review of videotaped sessions performed by an observer who was unaware of treatment status. At three months, patients underwent a double-blind evaluation in the presence and absence of neurostimulation. We also assessed the patients' quality of life, cognition, and mood at baseline and 12 months. The dystonia movement score improved from a mean (+/-SD) of 46.3+/-21.3 before surgery to 21.0+/-14.1 at 12 months (P<0.001). The disability score improved from 11.6+/-5.5 before surgery to 6.5+/-4.9 at 12 months (P<0.001). General health and physical functioning were significantly improved at month 12; there were no significant changes in measures of mood and cognition. At the three-month evaluation, dystonia movement scores were significantly better with neurostimulation than without neurostimulation (24.6+/-17.7 vs. 34.6+/-12.3, P<0.001). There were five adverse events (in three patients); all resolved without permanent sequelae. These findings support the efficacy and safety of the use of bilateral stimulation of the internal globus pallidus in selected patients with primary generalized dystonia.
Neurosurgery, 2007
To prospectively assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) at 1... more To prospectively assess the impact of subthalamic nucleus (STN) deep brain stimulation (DBS) at 12 months after surgery in a series of 100 consecutive patients treated in a single center. The primary objective was to describe the clinical outcome in terms of efficacy and tolerance in STN-DBS patients. A secondary objective was to discuss presurgery clinical characteristics a posteriori as a function of outcome. One hundred and three consecutive patients with severe Parkinson's disease received bilateral STN-DBS in our clinic between May 1998 and March 2003. Clinical assessment was performed before and 12 months after surgery and was based on the Unified Parkinson's Disease Rating Scale, Parts II, III, and IV A; the Schwab and England Scale; and cognitive evaluation. Patient-rated overall improvement was also evaluated. Twelve months after surgery, the Unified Parkinson's Disease Rating Scale Part III score decreased by 43%, the Unified Parkinson's Disease Rating Scale Part II score (activities of daily living) fell by 34%, and the severity of dyskinesia-related disability decreased by 61%. The main surgical complications after STN-DBS were as follows: infection (n = 7), intracerebral hematoma (n = 5), electrode fracture (n = 4), and incorrect lead placement (n = 8). We observed cognitive decline and depression in 7.7 and 18% of the patients, respectively. The mean patient-rated overall improvement score was 70.7%. The efficacy and safety of STN-DBS in our center's large cohort of Parkinsonian patients are generally similar to the results obtained by other groups, albeit at the lower limit of the range of reported values. In contrast to efficacy, the occurrence of adverse events cannot be predicted. Younger patients with Parkinson's disease (i.e., those younger than 60 yr) often show an excellent response to levodopa. However, in view of our data on overall patient satisfaction and the occurrence of adverse events, we suggest that older patients (but not those older than 70 yr) and less dopa-sensitive patients (but not those with a response <50%) should still be offered the option of STN-DBS.
Neuropsychology, 2013
Objective: Parkinson's disease (PD) is associated with behavioral disorders that can affect socia... more Objective: Parkinson's disease (PD) is associated with behavioral disorders that can affect social functioning but are poorly understood. Since emotional and cognitive social processes are known to be crucial in social relationships, impairment of these processes may account for the emergence of behavioral disorders. Method: We used a systematic battery of tests to assess emotional processes and social cognition in PD patients and relate our findings to conventional neuropsychological data (especially behavioral disorders). Twenty-three PD patients and 46 controls (matched for age and educational level) were included in the study and underwent neuropsychological testing, including an assessment of the behavioral and cognitive components of executive function. Emotional and cognitive social processes were assessed with the Interpersonal Reactivity Index caregiver-administered questionnaire (as a measure of empathy), a facial emotion recognition task and two theory of mind (ToM) tasks. Results: When compared with controls, PD patients showed low levels of empathy (p ϭ .006), impaired facial emotion recognition (which persisted after correction for perceptual abilities) (p ϭ .001), poor performance in a second-order ToM task (p ϭ .008) that assessed both cognitive (p ϭ .004) and affective (p ϭ .03) inferences and, lastly, frequent dysexecutive behavioral disorders (in over 40% of the patients). Overall, impaired emotional and cognitive social functioning was observed in 17% of patients and was related to certain cognitive dysexecutive disorders. In terms of behavioral dysexecutive disorders, social behavior disorders were related to impaired emotional and cognitive social functioning (p ϭ .04) but were independent of cognitive impairments. Conclusions: Emotional and cognitive social processes were found to be impaired in Parkinson's disease. This impairment may account for the emergence of social behavioral disorders.
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Papers by Pierre Krystkowiak