Early Globus Pallidus Internus Stimulation in Pediatric Patients With Generalized Primary Dystonia: Long-Term Efficacy and Safety

Primary generalized dystonia presents mainly at a young age and commonly is severely disabling. The authors report the long-term follow-up (mean, 73 months; range, 50-101 months) of 5 pediatric patients (mean age at surgery 13 years; range, 8-16 years) undergoing globus pallidus internus deep brain stimulation. Mean improvement in the Burke-Fahn-Marsden movement score was 67.4% (range, 47.0%-87.5%), 75.4% (range, 61.5%-91.7%), and 83.5% (range, 72.0%-93.3%) at 3 months, 12 months, and long-term follow-up (>36 months), respectively. Hardware problems (electrode dislocation/breakage of extension cable, and imminent perforation of extension cable) were observed in 2 patients (operative revision without sequelae). Except for mild dysarthria in 2 patients, no other therapy-related morbidity was observed. The authors found globus pallidus internus stimulation to offer a very effective and safe therapy in pediatric patients with primary dystonia. Early neurosurgical intervention seems to be crucial to prevent irreversible impairment of motor function

Place of death in patients with dementia and the association with comorbidities: a retrospective population-based observational study in Germany

Background: Due to increasing life expectancy, more and more older people are suffering from dementia and comorbidities. To date, little information is available on place of death for dementia patients in Germany. In addition, the association of place of death and comorbidities is unknown. Methods: A population-based cross-sectional survey was conducted in Westphalia-Lippe (Germany), based on the analysis of death certificates from 2011. Individuals with dementia >= 65 years were identified using the documented cause of death. In this context, all mentioned causes of death were included. In addition, ten selected comorbidities were also analyzed. The results were presented descriptively. Using multivariate logistic regression, place of death was analyzed for any association with comorbidities. Results: A total of 10,364 death certificates were analyzed. Dementia was recorded in 1646 cases (15.9%;mean age 86.3 +/- 6.9 years;67.3% women). On average, 1.5 +/- 1.0 selected comorbidities were present. Places of death were distributed as follows: home (19.9%), hospital (28.7%), palliative care unit (0.4%), nursing home (49.5%), hospice (0.9%), no details (0.7%). The death certificates documented cardiac failure in 43.6% of cases, pneumonia in 25.2%, and malignant tumour in 13.4%. An increased likelihood of dying in hospital compared to home or nursing home, respectively, was found for the following comorbidities (OR [95%-CI]): pneumonia (2.96 [2.01-4.35], p = 0.001);(2.38 [1.75-3.25], p = 0.001);renal failure (1.93 [1.26-2.97], p = 0.003);(1.65 [1.18-2.32], p = 0.003);and sepsis (13.73 [4.88-38.63], p = 0.001);(7.34 [4.21-12.78], p = 0.001). Conclusion: The most common place of death in patients with dementia is the retirement or nursing home, followed by hospital and home. Specific comorbidities, such as pneumonia or sepsis, correlated with an increased probability of dying in hospital

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD

Contrôle des crises d'épilepsie par les ganglions de la bases: approches cliniques et expérimentales

As about one third of epileptic patients are resistant to antiepileptic drugs, and only 30% of them are candidates for resective surgery, it exists a great demand for the development of alternative surgical therapies. It has been shown in animal studies, that the basal ganglia and especially the substantia nigra (SN) are involved in the control of epilepsy. Clinical evidence, using either electrophysiological or imaging approaches, also supports the involvement of the basal ganglia in some epileptic syndromes. The influence of seizure spread into the basal ganglia in patients with focal epilepsies was investigated on the rate of secondary generalization. We showed that activation of the basal ganglia was associated with an inhibitory effect on seizure propagation, when seizures spread into the frontal lobe. The elucidation of inhibitory mechanisms in epilepsy may open a new approach for therapeutic strategies such as electrical deep brain stimulation. First open case series, investigating deep brain stimulation of the basal ganglia to suppress epileptic seizures, showed encouraging results in some patients. However, more preclinical studies are mandatory to investigate the optimal stimulation parameters. The aim of our experimental approach was to determine the optimal stimulation parameters to control spontaneous seizures in a genetic model of absence epilepsy in the rat. In this model, the optimal parameters of single substantia nigra pars reticulata (SNr) stimulation were determined as bilateral, bipolar, monophasic, 60 Hz frequency and 60 µs pulse width. When these parameters were used for repeated stimulations, no long-term suppression and even increase of the number of seizures was observed. A delay of at least 60 sec was necessary between stimulations to be fully effective. Although single high-frequency stimulation of the SNr can be used to suppress ongoing seizures, repeated stimulation are ineffective and could even aggravate seizures, thus supporting the need of closed-loop stimulation procedures to chronically suppress seizures in therapeutical applications. Such an adaptative device would be effective only when detectable changes heralds the seizure onset. In a genetic model of absence epilepsy such changes in the EEG-coherence between the left and right SNr could be identified. Such changes might be used as an hallmark for adaptative procedures like triggered single stimulation to avoid the occurrence of the presumed seizures. To date it remains unknown, if such changes in coherence between left and right SNr, are specific to the model of GAERS and if such changes occur also in other animal models or humans with different epileptic syndromes. Accumulating evidences support that epilepsy is not a pathology restricted to the cortex as a seizure generator, but that subcortical structures are also involved, which might open new therapeutic options for patients who are pharmacoresistant and no candidates for a resective surgical treatment.Près de 30% des patients qui souffrent d´une épilepsie sont résistants aux traitements pharmacologiques et seuls 30% de ces patients peuvent bénéficier d'une alternative thérapeutique par résection chirurgicale. La recherche de cibles et stratégies thérapeutiques innovantes constitue un enjeu majeur pour la prise en charge de ces patients. De nombreuses études expérimentales chez l'animal indiquent que les ganglions de la base, et en particulier la substance noire, exercent un contrôle sur la survenue des crises d'épilepsie. Des arguments cliniques, obtenus par électrophysiologie ou imagerie médicale, sont également en faveur de la mise en jeu des ganglions de la base dans certains syndromes épileptiques. Chez des patients souffrant d'épilepsie focale, l'influence de la propagation des crises au travers des ganglions de la base a été examinée en rapport avec le taux de généralisation secondaire. Chez ces patients l'activation des ganglions de la base semble associée à une influence inhibitrice sur la propagation des crises lorsque celles-ci envahissent le lobe frontal. L'exploration de ces mécanismes inhibiteurs des crises est susceptible d'ouvrir de nouvelles perspectives thérapeutiques comme celle portant sur la stimulation intracérébrale profonde. Les premières études de cas explorant les effets de la stimulation intracérébrale des ganglions de la base chez quelques patients ont permis d'obtenir des résultats encourageants chez certains d'entre eux. Cependant de nombreuses études précliniques devraient permettre de préciser les paramètres de stimulation à appliquer. Une approche expérimentale chez l'animal nous a permis de déterminer les paramètres optimaux à appliquer pour controler la survenue de crises spontanées dans un modèle d'épilepsie-absence chez le rat. Dans ce modèle les paramètres optimaux à appliquer à la substance noire réticulée consistent en des stimulations bilatérales, bipolaires, monophasiques, de 60 Hz en fréquence et de 60 µs en largeur d'impulsion. Appliqués de façon répétée, ces paramètres ne permettent cependant pas de supprimer durablement la survenue des crises et ont même tendance à augmenter le nombre de crises enregistrées. Un délais d'au moins 60 seconde entre l'application de deux stimulations consécutives est à respecter pour interrompre les crises. Dans nos conditions, bien qu'une stimulation haute-fréquence de la substance noire réticulée appliquée de façon aigue puisse interrompre une crise en cours, des stimulations répétées semblent inefficaces. Ceci est en faveur du développement en cours, dans de nombreux laboratoire à travers le monde, de procédures de stimulation des crises asservie à leur détection afin de les supprimer de façon chronique dans le cadre d'applications thérapeutiques. De tels systèmes, dits « adaptatifs », seront particulièrement pertinents s'ils sont couplés à des modifications détectables, signalant l'arrivée d'une crise. Dans le modèle d'épilepsie-absence chez le rat, de telles modifications ont été identifiées au niveau de la cohérence entre signaux électroencéphalographiques issus des deux substances substances noires réticulées. Ces modifications pourraient etre utilisées comme signature spécifique de l'imminence d'une crise dans le couplage de la stimulation à la détection des crises. Toutefois, rien ne permet de dire si ces modifications sont spécifiques du modèle etudié ou encore si de telles modifications existent dans certains syndromes épileptiques en clinique. De nombreux arguments existent pour dire que l'épilepsie n'est pas une pathologie restreinte au seul cortex en tant que circuit générateur de crises, mais implique également des structures sous-corticales susceptibles d'exercer un contrôle à distance sur les circuits générateurs de crises. Cette conception de l'épilepsie permet d'envisager le développement de nouvelles stratégies thérapeutiques pour les patients pharmaco-résistants et qui ne peuvent pas bénéficier d'une intervention chirurgicale