Validation of a non-motor fluctuations questionnaire in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.

The anterior insula bidirectionally modulates cost-benefit decision-making on a rodent gambling task.

Deficits in cost-benefit decision-making, as assessed in the Iowa Gambling Task (IGT), are commonly observed in neuropsychiatric disorders such as addiction. There is considerable variation in the maximization of rewards on such tasks, both in the general population and in rodent models, suggesting individual differences in decision-making may represent a key endophenotype for vulnerability to neuropsychiatric disorders. Increasing evidence suggests that the insular cortex, which is involved in interoception and emotional processes in humans, may be a key neural locus in the control of decision-making processes. However, the extent to which the insula contributes to individual differences in cost-benefit decision-making remains unknown. Using male Sprague Dawley rats, we first assessed individual differences in the performance over the course of a single session on a rodent analogue of the IGT (rGT). Rats were matched for their ability to maximize reward and received bilateral excitotoxic or sham lesions of the anterior insula cortex (AIC). Animals were subsequently challenged on a second rGT session with altered contingencies. Finally, animals were also assessed for instrumental conditioning and reversal learning. AIC lesions produced bidirectional alterations on rGT performance; rats that had performed optimally prior to surgery subsequently showed impairments, and animals that had performed poorly showed improvements in comparison with sham-operated controls. These bidirectional effects were not attributable to alterations in behavioural flexibility or in motivation. These data suggest that the recruitment of the AIC during decision-making may be state-dependent and help guide response selection towards subjectively favourable options.

Neurostimulation for Parkinson's disease with early motor complications.

BACKGROUND: Subthalamic stimulation reduces motor disability and improves quality of life in patients with advanced Parkinson's disease who have severe levodopa-induced motor complications. We hypothesized that neurostimulation would be beneficial at an earlier stage of Parkinson's disease. METHODS: In this 2-year trial, we randomly assigned 251 patients with Parkinson's disease and early motor complications (mean age, 52 years; mean duration of disease, 7.5 years) to undergo neurostimulation plus medical therapy or medical therapy alone. The primary end point was quality of life, as assessed with the use of the Parkinson's Disease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100 and higher scores indicating worse function). Major secondary outcomes included parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (as assessed with the use of the Unified Parkinson's Disease Rating Scale, parts III, II, and IV, respectively), and time with good mobility and no dyskinesia. RESULTS: For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P=0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P<0.001), activities of daily living (P<0.001), levodopa-induced motor complications (P<0.001), and time with good mobility and no dyskinesia (P=0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group. CONCLUSIONS: Subthalamic stimulation was superior to medical therapy in patients with Parkinson's disease and early motor complications. (Funded by the German Ministry of Research and others; EARLYSTIM ClinicalTrials.gov number, NCT00354133.).

[Geriatric particularities of Parkinson's disease: Clinical and therapeutic aspects]. / Particularités gériatriques de la maladie de Parkinson: aspects cliniques et thérapeutiques.

Parkinson's disease (PD) is a frequent and complex progressive neurological disorder that increases in incidence with age. Although historically PD has been characterized by the presence of progressive dopaminergic neuronal loss of the substantia nigra, the disease process also involves neurotransmitters other that dopamine and regions of the nervous system outside the basal ganglia. Its clinical presentation in elderly subjects differs from that in younger subjects, with more rapid progression, less frequent tremor, more pronounced axial signs, more frequent non-motor signs linked to concomitant degeneration of non-dopaminergic systems, and more frequent associated lesions. Despite the high prevalence of PD in elderly subjects, few therapeutic trials have been conducted in geriatric patients. Nevertheless, to improve functional disability while ensuring drug tolerance, the principles of optimized and multidisciplinary clinical management have to be known. The aim of this review is to provide an update on clinical and therapeutic features of PD specifically observed in elderly subjects.

Alzheimer's disease and impairment of the Self.

UNLABELLED: Impairment of the Self has been described in frontal-temporal dementia but little research has been carried out in patients with Alzheimer's disease (AD). OBJECTIVE: The aim of this study was to explore changes in the self in patients with AD. METHOD: Forty-seven patients with mild to moderate AD were examined using a semi-structured scale designed to assess the self-concept along three dimensions, namely, the Material Self, the Social Self and the Spiritual Self. RESULTS: The majority of patients (43 out of 47) presented impairment of at least one dimension of the Self. When only one dimension was affected, it was always the Social Self. The severity of impairment of the Self was correlated to the impairment of the semantic autobiographical memory and apathy. CONCLUSION: The Self is impaired in AD and the Social Self dimension appears to be more vulnerable in AD than other dimensions.

[Reduplication of an event after right caudate nucleus haemorrhage]. / Paramnésie De Réduplication D'évènement Après Hémorragie Du Noyau Caudé Droit.

BACKGROUND: Environmental reduplication which is characterized by reduplication of places has been reported in right hemispheric lesions, particularly but not only in the right frontal region. However, spatial delirium may follow right sub-cortical lesions. METHODS: We describe a 53 years-old man who had a reduplicative paramnesia for event alone after an intracerebral haematoma of the right caudate nucleus. RESULTS: MRI Scan showed also an extension of the right caudate nucleus haemorrhage into the ventricular system. Regional cerebral blood flow studied with 99Tcm-HMPAO showed a decrease of perfusion in the right dorso-lateral frontal cortex. To our knowledge, we reported the first case of reduplicative paramnesia of event associated with a right caudate nucleus injury. Similar right frontal deactivation was observed in two cases of reduplicative paramnesia for place, one of them after an infarction of the retro-lenticular portion of the right internal capsulae, the other after a right thalamo-capsular haemorrhage. CONCLUSION: We suggest that reduplicative paramnesia for event, like the previous cases reported of reduplicative paramnesia for place, may be linked to a subcortical lesion of the frontal lobe inducing a right functional frontal deactivation.

A randomized controlled double-blind study of rotigotine on neuropsychiatric symptoms in de novo PD.

Management of apathy, depression and anxiety in Parkinson's disease (PD) represents a challenge. Dopamine agonists have been suggested to be effective. This multicenter, randomized (1:1), double-blind study assessed the 6-month effect of rotigotine versus placebo on apathy, depression and anxiety in de novo PD. The primary outcome was the change of apathy, measured with the LARS. The secondary outcomes were the change in depression and anxiety, measured with BDI-2 and STAI-trait and state. Forty-eight drug-naive PD patients were included. The primary outcome was not reached, with a surprisingly high placebo effect on apathy (60%). There was no significant difference in the change of depression at 6 months between rotigotine and placebo. Trait-anxiety was significantly improved by rotigotine compared to placebo (p = 0.04). Compared to placebo, low dose rotigotine significantly improved trait anxiety, but not apathy and depression. The major placebo effect on apathy points towards the importance of a multidisciplinary and tight follow-up in the management of neuropsychiatric symptoms.

Programming parameters of subthalamic deep brain stimulators in Parkinson's disease from a controlled trial.

BACKGROUND: Programming algorithms have never been tested for outcome. The EARLYSTIM study showed superior outcomes of deep brain stimulation of the subthalamic nucleus (STN-DBS) over best medical treatment in early Parkinson's disease (PD). Patients were programmed according to common guidelines but customized for each patient. METHODS: Stimulation parameters were systematically documented at 1, 5, 12, and 24 month in the cohort of 114 patients who had bilateral STN-DBS at 24 month. We investigated the influence of atypical programming, changes of stimulated electrode contacts and stimulation energy delivered. Outcomes were the Unified Parkinson's Disease Rating Scale (UPDRS) motor and ADL-subscores, health-related quality of life (PDQ-39) summary index and mobility- and ADL-subscores. RESULTS: At 1/5/12/24 months follow up, mean amplitude (1.8/2.5/2.6/2.8 V), impedance (1107/1286/1229/1189 Ω) and TEED (33.7/69.0/84.4/93.0 V2*µs*Hz/Ω) mainly increased in the first 5 months, while mean pulse width (60.0/62.5/65.1/65.8 µs), frequency (130/137.7/139.1/142.7 Hz) remained relatively stable. Typical programming (single monopolar electrode contact) was used in 80.7% of electrodes. Double monopolar (11/114) and bipolar (2/114) stimulation was only rarely required. There was no significant difference in clinical outcomes between the patient groups requiring contact changes (n = 32/28.1%) nor between typical (n = 83/72.8%) versus non-typical programming. Energy used for STN-DBS was higher for the dominant side of PD. CONCLUSION: In the first 5 months an increase in amplitude is required to compensate for various factors. Monopolar stimulation is sufficient in 80% of patients at 24 months. Homogeneous stimulation strategies can account for the favorable outcomes reported in the Earlystim study.

Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.

BACKGROUND: Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21. METHODS: We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. RESULTS: Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders. CONCLUSION: This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

Parkinson's disease with camptocormia.

BACKGROUND: Camptocormia is defined as an abnormal flexion of the trunk that appears when standing or walking and disappears in the supine position. The origin of the disorder is unknown, but it is usually attributed either to a primary or a secondary paravertebral muscle myopathy or a motor neurone disorder. Camptocormia is also observed in a minority of patients with parkinsonism. OBJECTIVE: To characterise the clinical and electrophysiological features of camptocormia and parkinsonian symptoms in patients with Parkinson's disease and camptocormia compared with patients with Parkinson's disease without camptocormia. METHODS: Patients with parkinsonism and camptocormia (excluding patients with multiple system atrophy) prospectively underwent a multidisciplinary clinical (neurological, neuropsychological, psychological, rheumatological) and neurophysiological (electromyogram, ocular movement recording) examination and were compared with age-matched patients with Parkinson's disease without camptocormia. RESULTS: The camptocormia developed after 8.5 (SD 5.3) years of parkinsonism, responded poorly to levodopa treatment (20%) and displayed features consistent with axial dystonia. Patients with camptocormia were characterised by prominent levodopa-unresponsive axial symptoms (ie, axial rigidity, gait disorder and postural instability), along with a tendency for greater error in the antisaccade paradigm. CONCLUSION: We suggest that (1) the salient features of parkinsonism observed in patients with camptocormia are likely to represent a specific form of Parkinson's disease and camptocormia is an axial dystonia and (2) both camptocormia and parkinsonism in these patients might result from additional, non-dopaminergic neuronal dysfunction in the basal ganglia.

Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so?

Despite the overall excellent outcome of neurosurgery in patients with Parkinson's disease, there is often a contrast between the improvement in motor disability and the difficulties of patients to reintegrate a normal life. In this study, the personal, familial and professional difficulties experienced by patients two years after bilateral high frequency stimulation of the subthalamic nucleus were carefully analyzed. To avoid such socio-familial maladjustment, we strongly suggest taking into consideration the patients' psychological and social context before the operation and during the post-operative follow-up.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up.

Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

[Relapse of acute promyelocytic leukemia in the central nervous system revealed by isolated dementia]. / Récidive neuroméningée d'une leucémie aiguë promyélocytaire révélée par un syndrome démentiel isolé.

INTRODUCTION: Approximately 1.5% of dementia is due to curable aetiology. We report an isolated dementia syndrome due to a meningeal relapse of acute promyelocytic leukaemia with favourable outcome after appropriate treatment. CASE REPORT: A 72-year-old woman, in remission of an acute promyelocytic leukaemia, presented a loss of autonomy for several months due to corticosubcortical dementia. Lumbar puncture showed blast cells indicating meningeal relapse of leukaemia. Intrathecal chemotherapy and arsenic trioxide obtained biological and molecular remission as well as restoration of normal cognitive functions. CONCLUSION: In patients with hematologic past history such as acute promyelocytic leukaemia, an isolated cognitive impairment should alert physicians to search for an isolated neuromeningeal relapse.

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.

Neuropsychological changes between "off" and "on" STN or GPi stimulation in Parkinson's disease.

BACKGROUND: In a previous study on a consecutive series of 62 patients with PD, the authors showed that bilateral subthalamic or pallidal continuous high-frequency deep brain stimulation (DBS) affects neither memory nor executive functions 3 to 6 months after surgery. OBJECTIVE: To investigate the specific effects of DBS by comparing the performance of patients with the stimulator turned "on" and "off." METHODS: The performance of 56 patients on clinical tests of executive function was compared after 3 and 12 months of DBS of the subthalamic nucleus (STN; n = 48) or the internal globus pallidus (GPi; n = 8) with the stimulator "on" or "off." Global intellectual efficiency, verbal learning, and mood were also evaluated with the stimulator "on." The performance of another group of 20 patients was compared after 6 months of DBS of the STN (n = 15) or the GPi (n = 5) with the stimulator "on" or "off" on more experimental tests recently shown to be more sensitive to l-dopa therapy. RESULTS: When the stimulator was "on," STN patients showed a mild but significant improvement in psychomotor speed and working memory. In comparison with the presurgical state, STN patients had no cognitive deficit at 12 months, except for lexical fluency. There was no differential effect of STN or GPi stimulation. CONCLUSIONS: 1) The specific effect of DBS seems to mimic the action of l-dopa treatment in the cognitive as in the motor domain; 2) the surgery associated with DBS does not appear to affect the cognitive performance of patients with PD 12 months later, except for a mild deficit in lexical fluency.

Improvement of sleep architecture in PD with subthalamic nucleus stimulation.

High-frequency stimulation of the subthalamic nucleus (STN) was used to investigate the relationship of sleep disorders with motor handicap in PD. In 10 insomniac patients with PD, stimulation reduced nighttime akinesia by 60% and completely suppressed axial and early morning dystonia, but did not alleviate periodic leg movements (n = 3) or REM sleep behavior disorders (n = 5). Total sleep time increased by 47%; wakefulness after sleep onset decreased by 51 minutes. Insomnia in patients with PD may predominantly result from nighttime motor disability.

Failure of long-term pallidal stimulation corrected by subthalamic stimulation in PD.

Bilateral high-frequency continuous stimulation of the internal globus pallidus or subthalamic nucleus constitutes a new therapeutic approach for the treatment of patients with severe PD. The authors report two patients in whom stimulation of the globus pallidus failed to give long-term relief and was successfully replaced by bilateral subthalamic stimulation. The results emphasize the reversibility of deep brain stimulation therapy and suggest that the subthalamic target is preferable to the pallidal target.

Aggressive behavior induced by intraoperative stimulation in the triangle of Sano.

The authors report a patient with advanced PD, successfully treated by bilateral stimulation of the subthalamic nucleus, who developed acute transient aggressive behavior during intraoperative electrical test stimulation. The electrode responsible for this abnormal behavior was located within the lateral part of the posteromedial hypothalamic region (triangle of Sano). The authors suggest that affect can be dramatically modulated by the selective manipulation of deep brain structures.

Parkinson's disease and sleepiness: an integral part of PD.

OBJECTIVE: To investigate the potential causes of excessive daytime sleepiness in patients with PD-poor sleep quality, abnormal sleep-wakefulness control, and treatment with dopaminergic agents. METHODS: The authors performed night-time polysomnography and daytime multiple sleep latency tests in 54 consecutive levodopa-treated patients with PD referred for sleepiness, 27 of whom were also receiving dopaminergic agonists. RESULTS: Sleep latency was 6.3 +/- 0.6 minutes (normal >8 minutes), and the Epworth Sleepiness score was 14.3 +/- 4.1 (normal <10). A narcolepsy-like phenotype (> or = 2 sleep-onset REM periods) was found in 39% of the patients, who were sleepier (4.6 +/- 0.9 minutes) than the other 61% of patients (7.4 +/- 0.7 minutes). Periodic leg movement syndromes were rare (15%, range 16 to 43/h), but obstructive sleep apnea-hypopnea syndromes were frequent (20% of patients had an apnea-hypopnea index >15/h; range 15.1 to 50.0). Severity of sleepiness was weakly correlated with Epworth Sleepiness score (r = -0.34) and daily dose of levodopa (r = 0.30) but not with dopamine-agonist treatment, age, disease duration, parkinsonian motor disability, total sleep time, periodic leg movement, apnea-hypopnea, or arousal indices. CONCLUSIONS: In patients with PD preselected for sleepiness, severity of sleepiness was not dependent on nocturnal sleep abnormalities, motor and cognitive impairment, or antiparkinsonian treatment. The results suggest that sleepiness-sudden onset of sleep-does not result from pharmacotherapy but is related to the pathology of PD.

Motivation, reward, and Parkinson's disease: influence of dopatherapy.

"Orbitofrontal" and "cingulate" striatofrontal loops and the mesolimbic dopaminergic system that modulates their function have been implicated in motivation and sensitivity to reinforcement in animals. Parkinson's disease (PD) provides a model to assess their implications in humans. The aims of the study were to investigate motivation and sensitivity to reinforcement in non-demented and -depressed PD patients and to evaluate the influence of dopaminergic therapy by comparing patients in "on" (with L-Dopa) and "off" (without L-Dopa) states. Twenty-three PD patients were compared, in both the "on" and "off" states, to 28 controls, using: (1) an Apathy Scale; (2) Stimulus-Reward Learning, Reversal, and Extinction tasks; and (3) a Gambling task. PD patients were found: (1) mildly apathetic; (2) impaired on Stimulus-Reward Learning and Reversal, but not on Extinction; and (3) able to progress in the Gambling task during the first, but not the second assessment. There was no significant correlation between these various deficits. L-Dopa treatment clearly improved motivation, but had more limited and contrasting effects on other variables, decreasing the number of omission errors in Reversal, but increasing the number of perseveration errors in Extinction. These results suggest: (1) an implication of striatofrontal loops in human motivation and explicit and implicit sensitivity to reinforcement; (2) a positive influence of L-Dopa treatment on the subjective evaluation of motivation, but contrasting effects on reward sensitivity.