DBS in Dystonia and Other Hyperkinetic Movement Disorders.

OPINION STATEMENT: The diagnosis and appropriate treatment of hyperkinetic movement disorders require a work up of potentially reversible metabolic, infectious and structural disorders as well as side effects of current medication. In pharmacoresistant movement disorders with a disabling impact on quality of life, deep brain stimulation (DBS) should be considered. At different targets, DBS has become an established therapy for Parkinson's disease (GPi-STN), tremor (VIM) and primary dystonia (GPi) with reasonable perioperative risks and side effects, established guidelines and some clinical and radiological predictive factors. In contrast, for other hyperkinetic movement disorders, including secondary dystonia, Gilles de la Tourette, chorea and ballism, only few data are available. Definite targets are not well defined, and reported results are of less magnitude than those of the recognized indications. In this expanding therapeutical field without worked out recommendations, an individual approach is needed with DBS indication assessment only after rigorous multidisciplinary scrutiny, restricted to expert centres.

[Therapeutic advances in neurology]. / Neurologie.

This article summarizes the main therapeutic advances of 2010 in the field of neurology. It focuses on aspects that are likely to change the care of patients in clinical practice. Among these, we discuss the new oral treatments that have proved to be effective in multiple sclerosis, the results of two large studies comparing endarterectomy and stenting in carotid stenosis, novel therapeutic approaches for the treatment of non-motor symptoms in Parkinson's disease as well as the results of several pharmacological studies in the field of epilepsy.

Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.

BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score

[Neuropsychiatry of epilepsy, stroke, Parkinson's disease and multiple sclerosis]. / Neuropsychiatrie de l'épilepsie, des accidents vasculaires cérébraux, de la maladie de Parkinson et de la sclérose en plaques.

The assessement of behavior is common part of the neurological examination. This article reviews the behavioral and mood manifestations in four classical syndroms: Epilepsy, stroke, Parkinson's disease and multiple sclerosis.

[Impulse control disorders and Parkinson's disease]. / Troubles du contrôte des impulsions et maladie de Parkinson.

A variety of behavioral disorders occurring abruptly in patients with Parkinson's disease (PD) has been recently published and attracted considerable attention in the press. Taking the form of pathological gambling, compulsive shopping, addiction to Internet and to other recreational activities, hypersexuality or bulimia, impulse control disorders (ICD) related to PD are probably more frequent than previously appreciated and may have consequences as spectacular as disastrous for the involved patients. ICD are currently viewed as particular adverse reactions to antiparkinsonian medications, notably to dopamine agonists, and, accordingly, tend to improve or disappear when PD therapy is appropriately adjusted.

[Hysteria: an historical entity, a psychiatric condition or a neurological disease?]. / L'hystérie: une entité historique, un trouble psychiatrique ou une maladie neurologique?

It has been suggested that hysteria had waned and was an old-fashioned, stigmatizing and false concept, reflecting the incapacity of the medical community to establish a diagnosis in certain situations. Nowadays, however, those disturbances, now referred to as conversion or dissociative disorders, still remain a frequent and incapacitating condition that every clinician faces. These past decades, several studies have tried to better describe their clinical presentation and their neurobiological mechanisms, with the help of the development of new neuroimaging techniques. If the neurobiological correlates are now better understood, efficient treatments are still lacking and only a multidisciplinary (general practitioners, neurologists and psychiatrists) and individually-tailored therapy might be beneficial to the patients.

Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.

AIM: To describe a large family with autosomal dominant parkinsonism. BACKGROUND: Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. MATERIAL AND METHODS: Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. RESULTS: Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. CONCLUSION: Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.

Sub-acute delayed failure of subthalamic DBS in Parkinson's disease: the role of micro-lesion effect.

OBJECTIVE: To study delayed failure after subthalamic nucleus (STN) deep brain stimulation in Parkinson's disease (PD) patients. METHODS: Out of 56 consecutive bilaterally STN-implanted PD patients, we selected subjects who, after initial clinical improvement (1 month after surgery), lost benefit (delayed failure, DF). RESULTS: Five patients developed sub-acutely severe gait disorders (DF). In 4/5 DF patients, a micro-lesion effect, defined as improvement without stimulation, was observed; immediate post-operative MRI demonstrated electrode located above or behind to the STN. CONCLUSIONS: Patients presenting micro-lesion effect should be carefully monitored, as this phenomenon can mask electrodes misplacement and evolution in DF.

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis.

Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation.

OBJECTIVE: To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). METHOD: Assessments were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. RESULTS: Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years (p<0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved (p<0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery (p<0.01). CONCLUSIONS: STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression.

[Pathogenic mechanisms of neurodegenerative diseases: amyotrophic lateral sclerosis]. / Mécanismes pathogéniques des maladies neurodégénératives: l'exemple de la sclérose latérale amyotrophique.

Since its description by Charcot in 1869, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis (ALS) has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics have now identified two genes, SODI and ALS2 as primary causes of the disease and has implicated others as potential contributors. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response that it provokes, these model systems underscore the involvement of non-neuronal cells in disease progression and provide new therapeutic strategies.

[Neuronal death and growth factors: new therapeutic approaches in Parkinson's disease]. / Dégénérescence, régénérescence: un espoir thérapeu- tique pour la maladie de Parkinson.

Neurodegenerative disorders represent a major and growing cause of morbidity and mortality in our populations, and a therapeutic challenge for the years to come. This paper reviews the mechanisms implicated in neuronal death, focusing on the model of Parkinson's disease. Available data are critically presented, and oriented in a therapeutic perspective. Neuroprotective strategies are mentioned, along with stem cell transplantation, growth factor production and gene therapy.

[Pain in Parkinson's disease]. / Syndromes douloureux de la maladie de Parkinson.

INTRODUCTION: Pain may be a presenting symptom of Parkinson's disease or may occur during the motor fluctuation stages of the disease. The complexity and pathophysiology of pain in Parkinson's disease still remains poorly understood. OBJECTIVE: To characterize clinically the different painful presentations of Parkinson's disease, their relationship to the stage of the disease and their connections with motor fluctuations and treatment. METHODS: We reviewed painful syndromes in 388 consecutive parkinsonian patients of the Lausanne Movement Disorders Registry, based on an itemized questionnaire used prospectively to characterize the pain by its description, topography, date of appearance and possible relationship with motor fluctuations. Among these patients with clinically-diagnosed dopa-responsive Parkinson's disease, 269, i.e. 67 percent presented sensory or painful syndromes. Among them, 94 percent had muscular pain: stiffness (85 percent), cramps, pseudo-cramps, spasms (3 percent) or various myalgias (7 percent); 51 percent presented osteo-ligamentar "rheumatologic" pain, articular (23 percent), periarticular (3 percent) or spinal (31 percent), but less defined and localized neurogenic painful syndromes were less frequent (8 percent), such as paresthesia (6 percent), dysesthesia (<1 percent), burning sensation (2 percent), itching (<1 percent), ill defined discomfort (6 percent) or a feeling of heaviness (1 percent), with segmental (86 percent), axial (54 percent), radicular or pseudo-radicular (14 percent), acral distal (4 percent) or less frequently anorectal or visceral distribution. Restless legs or akathisia were occasional (10 percent). Headaches and facial pain were less frequent (1 percent), we did not encounter phantom pain. More than one quarter were present at the beginning of the disease, only (3 percent) of them resolved during the development of the disease. About one-third were clearly linked with motor fluctuations, the majority occurring in off phase (34 percent). We did not find any correlation with age, gender, duration or stage of disease, L dopa equivalent dose, depression, insomnia or autonomic dysfunction. CONCLUSION: Painful syndromes are found in two thirds of patients with Parkinson's disease, with mainly pain of muscular origin, followed by osteoarticular and neurogenic painful syndromes, a quarter of the patients experience pain in early phases of the disease and a third in relation with motor fluctuations.

[Current treatment of Parkinson's disease: problems and controversies]. / Traitement actuel de la maladie de Parkinson: difficultés et controverses.

Treating patients with Parkinson's disease is not an easy task for the physician who is facing a disease well responsive to symptomatic therapy, yet escaping any curative approaches. In spite of the large therapeutic armamentarium available, many issues remained unsolved, as indications of a particular therapeutic agent are only loosely defined and evolving according to various parameters such as disease progression and severity, the profile of potentially serious adverse effects, the physician's level of expertise and patient's expectations. The growing experience acquired with subthalamic nucleus deep brain stimulation has shown that indications for such a surgery have to be cautiously examined. After initial therapeutic enthusiasm, we are now at a time of problems and controversies.

Suicide after successful deep brain stimulation for movement disorders.

The authors observed a high rate of suicide (6/140 patients, 4.3%) in a large cohort of patients with movement disorders treated with deep brain stimulation (DBS). Apparent risk factors included a previous history of severe depression and multiple successive DBS surgeries, whereas there was no relationship with the underlying condition, DBS target, electrical parameters, or modifications of treatment. Paradoxically, all patients experienced an excellent motor outcome following the procedure. The authors propose that patients at high risk for suicide should be excluded from DBS surgery.

Subthalamic nucleus deep brain stimulation in Parkinson disease patients over age 70 years.

The effects of subthalamic nucleus deep brain stimulation were studied in 52 consecutive patients (13 over age 70, 15 under age 60, 24 age 60 to 70). All groups had improvement of motor fluctuations and dyskinesia. Patients over age 70 had worsening of Unified Parkinson's Disease Rating Scale motor scores on medication, despite less medication reduction. Their activities of daily living and axial subscores worsened, particularly in those with preoperative gait difficulties.

L-dopa-induced dyskinesia improvement after STN-DBS depends upon medication reduction.

The authors studied the long-term evolution of levodopa-induced dyskinesia (LID) after levodopa challenge in two groups of six STN-deep brain stimulation-treated Parkinson disease (PD) patients, one requiring medication after surgery and the other not. A dramatic (96%) reduction of LID severity was obtained in the six postoperatively untreated patients compared to a moderate improvement (47%) in the treated group (p < 0.03). These data support dopaminergic stimulation and striatal desensitization as major determinants of LID in PD.

The effect of aging on postural stability: a cross sectional and longitudinal study.

AIMS OF THE STUDY: Only a good knowledge of the effects of age on postural stability allows differentiating between physiological aging and pathologies leading to its impairment. The aims of this study were to define the posturographic parameters which best reflected the effects of aging on postural stability and to determine the slope of postural stability impairment related to aging. PATIENTS AND METHODS: Postural stability of 50 normal volunteers aged 25-83 years (55.4) was studied with one Kistler force plate. Subjects were asked to stand for 30 s on two-legged stance, eyes open then closed. The center of pressure displacement (COPd) and velocities (COPv), in the antero-posterior (x) and the medio-lateral (z) axis, the sway axis, and the integral of COP displacement vs. time were computed. Eleven subjects were retested at 3 and 6 months to estimate the reliability of posturographic measurements. In addition, 28 subjects aged 25-83 years (60.2) were retested 2.2 years after their first posturographic assessment. RESULTS: COPxv best reflected postural stability impairment with aging. Closure of the eyes increased the variance of the results. This change was higher in subjects more than 60 years old: 0.019-0.157 cm2 s(-2) than in younger ones: 0.011-0.043 cm2 s(-2). Retesting at 3 and 6 months showed a reliability of 79%. According to the cross-sectional part of the study, the slope of postural stability impairment with aging was estimated at 0.0038 cm/s/year. These results were confirmed by the longitudinal part of the study, which showed that COPxv increased from 0.66-0.75 cm/s/year (P = 0.0001) (slope = 0.0041 cm/s/year). CONCLUSION: (1) Measurement of COPxv, on two-legged stance, is a simple and reliable way to assess postural stability. (2) Thanks to both a cross sectional and a longitudinal study, the rate of postural stability impairment due to aging was precisely estimated, which will be useful to help distinguishing between the part of postural stability impairment attributable to aging from the one due to neuro-degenerative diseases.