Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. METHODS: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. RESULTS: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). CONCLUSIONS: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

[Restless-legs syndrome]. / Le syndrome des jambes sans repos.

Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an irresistible urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations. It begins or worsens during periods of rest or inactivity, is partially or totally relieved by movements and is exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to 3% of the general population in Western countries. Supportive criteria include a family history, the presence of periodic-leg movements (PLM) when awake or asleep and a positive response to dopaminergic treatment. The RLS phenotypes include an early onset form, usually idiopathic with a familial history and a late onset form, usually secondary to peripheral neuropathy. Recently, an atypical RLS phenotype without PLM and l-DOPA resistant has been characterized. RLS can occur in childhood and should be distinguished from attention deficit/hyperactivity disorder, growing pains and sleep complaints in childhood. RLS should be included in the diagnosis of all patients consulting for sleep complaints or discomfort in the lower limbs. It should be differentiated from akathisia, that is, an urge to move the whole body without uncomfortable sensations. Polysomnographic studies and the suggested immobilization test can detect PLM. Furthermore, an l-DOPA challenge has recently been validated to support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor quality of life, depressive and anxious symptoms and may be a risk factor for cardiovascular disease. In most cases, RLS is idiopathic. It may also be secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral neuropathy and drugs, such as antipsychotics and antidepressants. The small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with many neurological and sleep disorders including Parkinson's disease, but does not predispose to these diseases. The pathophysiology of RLS includes an altered brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain control systems and a genetic susceptibility with nine loci and three polymorphisms in genes serving developmental functions. RLS treatment begins with the elimination of triggering factors and iron supplementation when deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA or codeine; the first-line treatment for moderate to severe RLS is dopaminergic agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid (oxycodone, tramadol) drugs can be used.

Clinical predictive factors of subthalamic stimulation in Parkinson's disease.

High-frequency stimulation of the subthalamic nucleus (STN) constitutes one of the most effective treatments for advanced forms of Parkinson's disease. The cost and potential risks of this procedure encourage the determination of clinical characteristics of patients that will have the best postoperative outcome. Forty-one Parkinson's disease patients underwent surgery for bilateral STN stimulation. The selection criteria were severe parkinsonian motor disability, clear response of symptoms to levodopa, occurrence of disabling levodopa-related motor complications and the absence of dementia and significant abnormalities on brain MRI. Clinical evaluation was performed 1 month before and 6 months after surgery. The improvement in the activities of daily living subscale of the Unified Parkinson's Disease Rating Scale, Part II (UPDRS II) and parkinsonian motor disability (UPDRS III) was greater when the preoperative scores for activities of daily living and parkinsonian motor disability, in particular axial symptoms, such as gait disorders and postural instability assessed at the time of maximal clinical improvement (on drug), were lower. Age and disease duration were not predictive, but parkinsonian motor disability tended to be more improved in patients with younger age and shorter disease duration. The severity of levodopa-related motor complications was not a predictive factor. The outcome of STN stimulation was excellent in levodopa-responsive forms of Parkinson's disease, i.e. in patients with selective brain dopaminergic lesions, and moderate in patients with axial motor symptoms and cognitive impairment known to be less responsive or unresponsive to levodopa treatment, i.e. when brain non-dopaminergic lesions develop in addition to the degeneration of the nigrostriatal dopaminergic system. The results are consistent with the classical inclusion criteria for STN stimulation, but imply that the decision to operate on the oldest patients and/or patients with gait and postural disorders, who are poorly responsive to levodopa, should be weighed carefully.

Concurrent excitatory and inhibitory effects of high frequency stimulation: an oculomotor study.

OBJECTIVE: To describe a reversible neurological condition resembling a crossed midbrain syndrome resulting from high frequency stimulation (HFS) in the midbrain. METHODS: Postoperative evaluation of quadripolar electrodes implanted in the area of the subthalamic nucleus of 25 patients with Parkinson's disease (PD) successfully treated by HFS. RESULTS: Four of the 25 patients experienced reversible acute diplopia, with dystonic posture and tremor in the contralateral upper limb when the white matter between the red nucleus and the substantia nigra was stimulated. The motor signs resembled those caused by lesions of the red nucleus. The ipsilateral resting eye position was "in and down" (three patients) or "in" (one patient). Enophthalmos was seen. Abduction was impaired and vertical eye movements were limited, but adduction was spared. The movements of the controlateral eye were normal. The ocular signs could be best explained by sustained hyperactivity of the extrinsic oculomotor nerve. Simultaneous tonic contraction of the superior rectus, the inferior rectus, and inferior oblique may cause the enophthalmos and partial limitation of upward and downward eye movements. Antagonist tonic contraction of the ipsilateral medial rectus severely impairs abduction. CONCLUSION: This crossed midbrain syndrome, possibly resulting from simultaneous activation of oculomotor nerve and lesion-like inhibition of the red nucleus suggests that high frequency stimulation has opposite effects on grey and white matter.

Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson's disease.

Our objective was to elaborate a functional map of the globus pallidus by correlating the intrapallidal localization of quadripolar electrodes implanted in parkinsonian patients with the clinical effect of the stimulation of each contact. Five patients with L-DOPA-responsive Parkinson's disease presenting severe motor fluctuations and L-DOPA-induced dyskinesias were treated by continuous bilateral high-frequency stimulation of the globus pallidus. The effects of stimulation on parkinsonian disability were tested through each of the four stimulating contacts of each electrode. The anatomical localization of each of the stimulating contacts was determined by confronting the pre- and post-operative magnetic resonance imaging with the anatomical atlas of Schaltenbrand and Wharen.(34) The registration procedure comprised digitization of the atlas, the use of deformation tools to fit atlas sections with magnetic resonance imaging sections, and three-dimensional reconstruction of both the atlas and the magnetic resonance imaging sections. Analysis of the 32 stimulating contacts tested did not reveal a somatotopic organization in the pallidal region investigated but demonstrated that high-frequency stimulation had contrasting effects depending on whether it was applied to the external or the internal pallidum. Akinesia was improved by stimulation of the external pallidum but worsened by stimulation of the internal pallidum. In contrast, parkinsonian rigidity was improved by stimulation of either part of the pallidum. The areas in the internal pallidum where stimulation worsened akinesia were those in which stimulation reduced or suppressed L-DOPA-induced dyskinesias. Conversely, stimulation applied to the external pallidum induced dyskinesias. The fact that rigidity was improved by stimulation of the internal and external pallidum suggests that the neuronal bases of parkinsonian rigidity are different from those of akinesia and dyskinesias. The effect on akinesia and dyskinesias is in agreement with the current model of basal ganglia circuitry(10) if high-frequency stimulation activates rather than inhibits pallidal neurons, a possibility which is very likely since there are marked anatomical, biochemical and electrophysiological differences between the globus pallidus and the subthalamic nucleus. This study demonstrates that high-frequency stimulation of the globus pallidus in parkinsonian patients has contrasting effects depending on whether it is applied to the external or the internal part of this nucleus. The effect on akinesia and dyskinesias suggests that stimulation activates pallidal neurons, a result which challenges the generally accepted concept that high-frequency stimulation inactivates neurons in the region stimulated.

Irregular jerky tremor, myoclonus, and thalamus: a study using low-frequency stimulation.

High-frequency thalamic stimulation alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The origin of thalamic myoclonus is unexplained and the effects of low-frequency thalamic stimulation on movement control are still unknown. We studied the effects of stimulation at a low frequency of 15 Hz in five drug-free patients (3 PD, 2 ET) 6 months after thalamic implantation of quadripolar electrodes (unilateral in four patients, bilateral in one patient). Clinical, electrophysiological, and videotaped assessment, using a monopolar 15 Hz frequency (3 V, 90 micros) stimulation current applied simultaneously through two adjacent contacts of the electrode, was performed. We observed myoclonus and irregular jerky tremor in the upper limb contralateral to the site of stimulation. The jerks lasted less than 200 ms, were irregular and not synchronous with stimulation, were superimposed on rest or postural tremor, and increased in response to tactile, proprioceptive, or vibratory stimuli. The fact that this complex movement disorder can be induced by low-frequency stimulation in the ventral intermediate nucleus (Vim) of the thalamus suggests that it results, at least partly, from dysfunction of the Vim and possibly adjacent nuclei of the thalamus.

Levodopa-induced dyskinesias in Parkinson's disease: is sensitization reversible?

Levodopa-induced dyskinesias (LIDs) in patients with Parkinson's disease are considered to result from the severity of dopaminergic denervation in the striatum, which is an irrevocable phenomenon, and sensitization induced by long-term intermittent administration of levodopa. Taking advantage of the 64% reduction of levodopa treatment allowed in 12 Parkinson's disease patients by continuous high-frequency stimulation of the subthalamic nucleus, we evaluated the severity of parkinsonian motor disability and LIDs during two levodopa challenges performed before the surgical implantation of the stimulation electrodes and after 8.8 months of continuous bilateral subthalamic nucleus stimulation that was interrupted 2 hours before the levodopa test. Motor disability during the "off" and "on" drug periods was unchanged. The severity of LIDs during the "on" period and dystonia during the "off" period decreased by 54% and 62%, respectively. The reduced severity of LIDs in the absence of subthalamic nucleus stimulation demonstrates that the sensitization phenomenon resulting from long-term intermittent levodopa administration is partially reversible.

Bilateral subthalamic stimulation for Parkinson's disease by using three-dimensional stereotactic magnetic resonance imaging and electrophysiological guidance.

OBJECT: Several methods are used for stereotactically guided implantation of electrodes into the subthalamic nucleus (STN) for continuous high-frequency stimulation in the treatment of Parkinson's disease (PD). The authors present a stereotactic magnetic resonance (MR) method relying on three-dimensional (3D) T1-weighted images for surgical planning and multiplanar T2-weighted images for direct visualization of the STN, coupled with electrophysiological recording and stimulation guidance. METHODS: Twelve patients with advanced PD were enrolled in this study of bilateral STN implantation. Both STNs were visible as 3D ovoid biconvex hypointense structures located in the upper mesencephalon. The coordinates of the centers of the STNs were determined with reference to the patient's anterior commissure-posterior commissure line by using a new landmark, the anterior border of the red nucleus. Electrophysiological monitoring through five parallel tracks was performed simultaneously to define the functional target accurately. Microelectrode recording identified high-frequency, spontaneous, movement-related activity and tremor-related cells within the STNs. Acute STN macrostimulation improved contralateral rigidity and akinesia, suppressed tremor when present, and could induce dyskinesias. The central track, which was directed at the predetermined target by using MR imaging, was selected for implantation of 19 of 24 electrodes. No surgical complications were noted. CONCLUSIONS: At evaluation 6 months after surgery, continuous STN stimulation was shown to have improved parkinsonian motor disability by 64% and 78% in the "off' and "on" medication states, respectively. Antiparkinsonian drug treatment was reduced by 70% in 10 patients and withdrawn in two patients. The severity of levodopa-induced dyskinesias was reduced by 83% and motor fluctuations by 88%. Continuous high-frequency stimulation of the STN applied through electrodes implanted with the aid of 3D MR imaging and electrophysiological guidance is a safe and effective therapy for patients suffering from severe, advanced levodopa-responsive PD.

Subthalamic stimulation in Parkinson disease: a multidisciplinary approach.

BACKGROUND: High-frequency stimulation of the subthalamic nucleus constitutes a therapeutic advance for severely disabled patients with Parkinson disease. OBJECTIVE: To evaluate the efficacy and safety of continuous bilateral high-frequency stimulation of the subthalamic nucleus in patients with Parkinson disease. DESIGN: A prospective study of patients with Parkinson disease treated at a university hospital. PATIENTS AND METHODS: Electrodes were implanted bilaterally in the subthalamic nucleus of 23 consecutive patients with Parkinson disease who responded well to levodopa but had severe motor complications. There were 16 men and 7 women (mean +/- SEM age, 53 +/- 2 years) who had a mean +/- SEM disease duration of 14.7 +/- 1.0 years. Targets were determined by 3-dimensional magnetic resonance imaging, combined with intraoperative electrophysiologic recordings and stimulation. RESULTS: Six months after surgery, motor disability, levodopa-induced motor fluctuations, dyskinesias, and the daily dose of levodopa equivalent decreased significantly by 67%, 78%, 77%, and 61%, respectively, compared with the preoperative state. No significant morbidity was observed, except transient depression in 4 patients. CONCLUSIONS: The beneficial effects of subthalamic stimulation depend on (1) the criteria used for patient selection, (2) the precision with which the subthalamic nucleus is targeted (dependent on the 3-dimensional magnetic resonance imaging and the intraoperative electrophysiologic and clinical assessments), and (3) the long-term postoperative adjustment of stimulation variables.

Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral subthalamic stimulation.

OBJECTIVE: To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's disease (PD). METHODS: The efficacy of STN stimulation on total motor disability score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson's disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to levodopa. Patients were clinically assessed in the "off" and "on" drug condition during a levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the "activities of daily living" (ADL)-that is, speech, swallowing, turning in bed, falling, walking, and freezing-was obtained from each patient's questionnaire (UPDRS, part II). RESULTS: Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when levodopa and STN stimulation were combined. CONCLUSION: These findings suggest that bilateral STN stimulation improves most axial features of Parkinson's disease and that a synergistic effect can be obtained when stimulation is used in conjunction with levodopa treatment.

Effect of low and high frequency thalamic stimulation on sleep in patients with Parkinson's disease and essential tremor.

Continuous high frequency stimulation of the ventral intermediate nucleus of the thalamus (Vim), delivered through surgically implanted quadripolar electrodes, alleviates tremor in Parkinson's disease (PD) and essential tremor (ET). The Vim is adjacent to the thalamic reticular nuclei, where sleep spindles originate according to animal models. In order to determine whether Vim stimulation affects sleep spindles, six patients (4 PD, 2 ET), aged 60-69 years, were recorded on a control night and a stimulation night (130 Hz, 2-3 V; right stimulation in five patients and bilateral stimulation in one patient). Stimulation did not modify sleep quality or architecture. Sleep spindles were present and symmetrical in five out of six patients under stimulation. However, in one patient with a sustained 'thalamotomy-like effect' that abolished tremor, spindles were asymmetrical even without stimulation. In each patient, spindle density was similar on both nights (mean+/- SEM: 2.25+/-0. 61 spindles per min of stage 2 sleep vs. 1.84+/-0.31). In an attempt to promote sleep two different patterns of stimulation were applied in the region of ventrooralis posterior and reticularis nuclei in five patients in the awake state. Continuous low frequency stimulation (5 Hz, 0.1 V), and repeated trains of 15 Hz for 1 s every 15 s mimicking the pattern of physiological spindles, each failed to induce sleep or cortical synchronization. We conclude that Vim stimulation, unlike thalamotomy, selectively reduces tremor without altering sleep or sleep spindles. Our results also suggest that low frequency stimulation applied in the region of the reticular nuclei does not induce sleep.

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.

Pallidal stimulation for Parkinson's disease. Two targets?

There has been renewed interest in functional surgery as treatment for Parkinson's disease (PD). Although pallidotomy and chronic pallidal stimulation are highly effective in suppressing levodopa-induced dyskinesia (LID), both methods also seem to be effective in reducing parkinsonian disability. However, the simultaneous improvement of LID and motor signs is hard to explain with the classic model of basal ganglia circuitry. Taking advantage of the fact that deep brain stimulation is reversible and that implanted electrodes contain four discrete stimulation sites, we investigated the effect of stimulation on different sites of the globus pallidus (GP) in five PD patients. Stimulation in the dorsal GP (upper contact) significantly improved gait, akinesia, and rigidity and could induce dyskinesia when patients were in the "off" state. In contrast, stimulation in the posteroventral GP (lower contact) significantly worsened gait and akinesia, although the reduction in rigidity remained. For patients in the "on" state, stimulation in the posteroventral GP dramatically reduced LID but, as in the "off" state, worsened gait and akinesia, thus canceling out the antiparkinsonian effect of levodopa. Our results indicate that stimulation had a striking different effect on parkinsonism and dyskinesia when applied at two different loci of the GP and that stimulation applied in the posteroventral GP produced opposite effects on rigidity and on akinesia. We conclude that parkinsonian signs and LID are a reflection of at least two different anatomofunctional systems within the GP and that this functional organization of the GP needs to be considered when determining the optimal target for surgical treatment of PD.

Influence of neck muscles on mouth pressure response to cervical magnetic stimulation.

Measurement of mouth pressure (Pm) in response to electrical phrenic nerve stimulation (Es) provides a simple noninvasive means to assess diaphragm function. An even simpler measure would be to use the Pm twitch response (Pm,t) to cervical magnetic stimulation (CMS) rather than to Es. Because CMS coactivates the diaphragm and inspiratory neck muscles (INM), CMS-Pm,t accurately reflects diaphragm function only if the corresponding INM contraction does not produce inspiratory pressures by itself. In patients with recent-onset bilateral diaphragm paralysis, it has been demonstrated that CMS-Pm,t was indeed zero; however, INM hypertrophy could change this situation and lead CMS-Pm,t to overestimate the performance of the diaphragm. To address this issue, we studied nine patients with amyotrophic lateral sclerosis (ALS) who had evidence of diaphragmatic paralysis and compensatory hypertrophy and hyperactivity of inspiratory neck muscles. The response to CMS was described in terms of diaphragm electromyogram (EMG), Pm, and abdominal (AB) and rib cage (RC) motion. No EMG response to CMS could be observed in most cases, and CMS was always associated with AB paradox. Nevertheless, a negative Pm,t swing was recorded with an amplitude of -2.6 +/- 1.0 cm H2O (mean +/- SD). We conclude that inspiratory neck muscle hypertrophy can significantly influence the Pm response to CMS. This should be taken into account when using the CMS-Pm combination in patients with possible chronic diaphragm dysfunction.