Recommandations pour l’utilisation de la toxine botulinique de type A (Botox®) dans l’hyperactivité vésicale réfractaire idiopathique

RésuméObjectifsDéfinir des recommandations pour l’utilisation pratique de la toxine botulinique de type A (BoNTA) dans l’hyperactivité vésicale réfractaire idiopathique (HAVRI).MéthodeÉlaboration de recommandations de bonne pratique par consensus formalisé, validées par un groupe de 13 experts puis par un groupe de lecture indépendant.RésultatsEn cas d’infection urinaire celle-ci doit être traitée et l’injection reportée. Avant l’injection, il est recommandé de s’assurer de la faisabilité et de l’acceptabilité de l’auto-sondage. L’injection peut être réalisée après une anesthésie locale urétro-vésicale (lidocaïne), éventuellement complétée par l’inhalation de protoxyde d’azote et parfois sous anesthésie générale. L’injection sera réalisée au bloc opératoire ou en salle d’endoscopie. La vessie ne doit pas être trop remplie (risque de perforation). Le traitement doit être appliqué en 10 à 20 injections de 0,5 à 1mL réparties de manière homogène dans la vessie en restant à distance des méats urétéraux. Il n’est pas recommandé de laisser en place une sonde vésicale sauf en cas d’hématurie importante. Le patient doit être surveillé jusqu’à la reprise mictionnelle. Une note d’information sur les effets indésirables éventuels doit lui être remise à sa sortie. Une consultation doit être prévue 3 mois après la première injection (calendrier mictionnel, débitmétrie, résidu post-mictionnel et examen cytobactériologique des urines). Un résidu >200mL et/ou symptomatique doit faire discuter des auto-sondages. Une nouvelle injection pourra être envisagée lorsque le bénéfice clinique de la précédente s’estompe (entre 6 et 9 mois).ConclusionsLe respect de ces recommandations devrait permettre une utilisation optimale de la BoNTA.Niveau de preuve3.SummaryObjectivesProvide guidelines for practical usage of botulinum toxin type A (BoNTA) for refractory idiopathic Overactive Bladder management.Patients and methodsGuidelines using formalized consensus guidelines method. These guidelines have been validated by a group of 13 experts quoting proposals, subsequently reviewed by an independent group of experts.ResultsIn the case of patients with urinary tract infection, it must be treated and injection postponed. Before proposing an injection, it is recommended to ensure the feasibility and acceptability of self-catheterisation by patient. The injection can be performed after local anesthesia of the bladder and urethra (lidocaine), supplemented where necessary by nitrous oxide inhalation and sometimes under general anesthesia. Injection is performed in the operating room or endoscopy suite. The bladder should not be too filled (increased risk of perforation). Treatment should be applied in 10 to 20 injections of 0.5 to 1mL homogeneously distributed in the bladder at a distance from the urethral orifices. It is not recommended to leave a urinary catheter in place except in cases of severe hematuria. The patient should be monitored until resumption of micturition. After the first injection, an appointment must be scheduled within 3 months (micturition diary, uroflowmetry, measurement of residual urine and urine culture). Performance of self-catheterisation should be questioned in the case of a symptomatic post-void residual and/or a residue>200mL. A new injection may be considered when the clinical benefit of the previous injection diminishes (between 6 and 9 months). A period of three months must elapse between each injection.ConclusionsImplementation of these guidelines may promote best practice usage of BoNTA with optimal risk/benefit ratio

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease

Engineered antibodies: new possibilities for brain PET?

International audienceAlmost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands

The RhoGEF Trio Functions in Sculpting Class Specific Dendrite Morphogenesis in Drosophila Sensory Neurons

As the primary sites of synaptic or sensory input in the nervous system, dendrites play an essential role in processing neuronal and sensory information. Moreover, the specification of class specific dendrite arborization is critically important in establishing neural connectivity and the formation of functional networks. Cytoskeletal modulation provides a key mechanism for establishing, as well as reorganizing, dendritic morphology among distinct neuronal subtypes. While previous studies have established differential roles for the small GTPases Rac and Rho in mediating dendrite morphogenesis, little is known regarding the direct regulators of these genes in mediating distinct dendritic architectures.Here we demonstrate that the RhoGEF Trio is required for the specification of class specific dendritic morphology in dendritic arborization (da) sensory neurons of the Drosophila peripheral nervous system (PNS). Trio is expressed in all da neuron subclasses and loss-of-function analyses indicate that Trio functions cell-autonomously in promoting dendritic branching, field coverage, and refining dendritic outgrowth in various da neuron subtypes. Moreover, overexpression studies demonstrate that Trio acts to promote higher order dendritic branching, including the formation of dendritic filopodia, through Trio GEF1-dependent interactions with Rac1, whereas Trio GEF-2-dependent interactions with Rho1 serve to restrict dendritic extension and higher order branching in da neurons. Finally, we show that de novo dendritic branching, induced by the homeodomain transcription factor Cut, requires Trio activity suggesting these molecules may act in a pathway to mediate dendrite morphogenesis.Collectively, our analyses implicate Trio as an important regulator of class specific da neuron dendrite morphogenesis via interactions with Rac1 and Rho1 and indicate that Trio is required as downstream effector in Cut-mediated regulation of dendrite branching and filopodia formation

Dysfunction of the Default Mode Network in Parkinson Disease: A Functional Magnetic Resonance Imaging Study

International audienceObjective-To examine the integrity of the default mode network in patients with Parkinson disease (PD). Previous functional neuroimaging experiments have studied executive deficits in patients with PD with regard to task-related brain activation. However, recent studies suggest that executive performance also relies on the integrity of the default mode network (ie, medial prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal and medial temporal cortices), characterized by a deactivation of these cortical areas during the performance of executive tasks. Design-We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed. Setting-Tertiary outpatient clinic. Participants-Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls. Main Outcome Measure-Cortical deactivations. Results-Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD

Perceptual factors contribute to akinesia in Parkinson’s disease

International audienceParkinson's disease (PD) patients have longer reaction time (RT) than age-matched control subjects. During the last decades, conXicting results have been reported regarding the source of this deWcit. Here, we addressed the possibility that experimental inconsistencies originated in the composite nature of RT responses. To investigate this idea, we examined the eVect of PD on diVerent processes that compose RT responses. Three variables were manipulated: the signal quality, the stimulus-response compatibility and the foreperiod duration. These variables have been shown to aVect, respectively, the ability to extract the relevant features of the stimulus (perceptual stage), the intentional selection of the motor response (cognitive stage) and the implementation of the muscle command (motor stage). Sixteen PD patients were tested on and oV-medication and compared with an age and gender-matched control group. Results indicated that degrading the legibility of the response stimulus aVected the latency of simple key-press movements more dramatically in the oV-medication PD group than in the control population. The stimulus-response compatibility and the foreperiod duration had similar eVects in the two groups. Interestingly, the response slowing associated with the degradation of the stimulus was the same whether the patients were on or oV dopaminergic medication. This suggests that the high-level perceptual deWcits observed in the present study do not have a dopaminergic origin

Motor urgency is mediated by the contralateral cerebellum in Parkinson's disease

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