Onset of Postural Instability in Parkinson's Disease Depends on Age rather than Disease Duration.

Background: Postural instability and falls are considered a major factor of impaired quality of life in patients with advanced Parkinson's disease (PD). The knowledge of the time at which postural instability occurs will help to provide the evidence required to introduce fall-prevention strategies at the right time in PD. Objective: To investigate whether postural instability of patients with different age at disease onset is associated with age or with disease duration of PD. Methods: Patients diagnosed with sporadic PD between 1991 and 2017 and postural instability (according to the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III, item 3.12 postural instability) were included, with strict inclusion criteria including regular follow-ups, agreement on data use, and exclusion of comorbidities affecting the free stand. Results: Applying these strict inclusion criteria, we included 106 patients. Those younger than 50 years at PD onset took significantly longer to develop postural instability (n = 23 patients, median: 18.4 years) compared with patients with later onset of PD (50-70 years, n = 66, median: 14.2 years, p < 0.001; and >70 years, n = 17, median: 5.7 years, p < 0.001, Kruskal-Wallis test followed by Dunn's multiple comparisons test). There was no association between total MDS-UPDRS III (as a measure of motor symptom severity) at onset of postural instability. Conclusions: In PD, postural instability is primarily associated with the age of the patient and not with disease duration.

Differentiation of Parkinson's disease tremor and essential tremor based on a novel hand posture.

Background: Tremor is one of the most common movement disorders but the correct diagnosis of tremor disorders, especially the differentiation between Parkinson's disease tremor (PT) and essential tremor (ET) remains a challenge for clinicians. Method: We examined a novel hand position to distinguish PT from ET. We prospectively collected accelerometric tremor data in 14 ET patients and 14 PT patients with arms and hands fully stretched against arms stretched and hands relaxed, i. e. hanging down. The total acceleration from the three pairwise-perpendicular accelerometric axes during the 1-minute blocks of the two hand positions were computed and high-passed filtered at 2 Hz. The power spectral density during each hand position was calculated and summed up over the frequency domain. Results: Our results showed a significantly higher occurrence of tremor in the hands hanging down position in PT patients compared to ET patients (p = 0.0262). Moreover, in PT patients the tremor intensity significantly increased when transitioning from the stretched hand position to the hanging-down position (83 % of cohort) and vice versa in ET patients (75 % of cohort). Conclusion: In conclusion, the new hand posture can differentiate between PT and ET with high accuracy (sensitivity 83 %, specificity 75 % for PT) and may be a helpful tool in the clinical assessment of tremor.

Worsened Parkinson's Disease Progression: Impact of the COVID-19 Pandemic.

Whilst some studies investigated the impact of viral infection or reduced access to medication during the COVID-19 pandemic in patients with Parkinson's disease (PD), data on the effects of pandemic restrictions are still scarce. We retrospectively analyzed motor symptoms of longitudinally followed PD patients (n = 264) and compared motor disease progression before and during the COVID-19 pandemic. Additionally, we performed a trend analysis of the yearly evolution of motor symptoms in 755 patients from 2016 until 2021. We observed a worsening of motor symptoms and a significantly increased motor disease progression during pandemic-related restrictions as compared to before the COVID-19 outbreak.

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Partners' view after subthalamic deep brain stimulation: Better relationships despite patients being less active.

INTRODUCTION: After deep brain stimulation (DBS) of the subthalamic nucleus (STN), Parkinson patients report difficulties in the relationship with their partners. The partners' experience after DBS appears to be variable and complex. Purpose of this pilot study was to investigate the partners' perspective on the relationship following STN-DBS. SUBJECTS AND METHODS: We conducted a postoperative questionnaire assessment in 56 partners of Parkinson patients with STN-DBS, using questionnaires addressing partnership satisfaction, dyadic coping, and role allocation in duties and activities of daily living. RESULTS: Regarding overall relationship satisfaction after surgery, 40% of partners were happier with their relationship than before DBS, and 14% were less satisfied. Partners reported that patients involved themselves distinctly less in duties and activities of daily living, leaving partners to take over. A need for more professional support for the relationship following surgery was noted by 27% of the partners. CONCLUSION: Although quality of relationship and dyadic coping improved or remained unchanged according to the majority of partners, patients became less prone to take over common duties and activities despite being in a better and more stable motor state. Potential conflicts and problems in role allocation in relationships following DBS need to be addressed in patients care.

Distinct Vestibular Evoked Myogenic Potentials in Patients With Parkinson Disease and Progressive Supranuclear Palsy.

Background: Early brainstem neurodegeneration is common in Parkinson's disease (PD) and progressive supranuclear palsy (PSP). While previous work showed abnormalities in vestibular evoked myogenic potentials (VEMPs) in patients with either disorder as compared to healthy humans, it remains unclear whether ocular and cervical VEMPs differ between PD and PSP patients. Methods: We prospectively included 12 PD and 11 PSP patients, performed ocular and cervical VEMPs, and calculated specific VEMP scores (0 = normal, 12 = most pathological) based on latencies, amplitude, and absent responses. In addition, we assessed disease duration, presence of imbalance, motor asymmetry, and motor disability using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III). Moreover, we ascertained various sleep parameters by video-polysomnography. Results: PSP and PD patients had similar oVEMP scores (6 [3-6] vs. 3 [1.3-6], p = 0.06), but PSP patients had higher cVEMP scores (3 [0-6] vs. 0 [0-2.8], p = 0.03) and total VEMP scores (9 [5-12] vs. 4 [2-7.5], p = 0.01). Moreover, total VEMP scores >10 were only observed in PSP patients (45%, p = 0.01). MDS-UPDRS III correlated with cVEMP scores (rho = 0.77, p = 0.01) in PSP, but not in PD. In PD, but not in PSP, polysomnographic markers of disturbed sleep, including decreased rapid eye movement sleep, showed significant correlations with VEMP scores. Conclusions: Our findings suggest that central vestibular pathways are more severely damaged in PSP than in PD, as indicated by higher cervical and total VEMP scores in PSP than PD in a between-groups analysis. Meaningful correlations between VEMPs and motor and non-motor symptoms further encourage its use in neurodegenerative Parkinsonian syndromes.

Functionally separated networks for self-paced and externally-cued motor execution in Parkinson's disease: Evidence from deep brain recordings in humans.

Spatially segregated cortico-basal ganglia networks have been proposed for the control of goal-directed and habitual behavior. In Parkinson's disease, selective loss of dopaminergic neurons regulating sensorimotor (habitual) behavior might therefore predominantly cause deficits in habitual motor control, whereas control of goal-directed movement is relatively preserved. Following this hypothesis, we examined the electrophysiology of cortico-basal ganglia networks in Parkinson patients emulating habitual and goal-directed motor control during self-paced and externally-cued finger tapping, respectively, while simultaneously recording local field potentials in the subthalamic nucleus (STN) and surface EEG. Only externally-cued movements induced a pro-kinetic event-related beta-desynchronization, whereas beta-oscillations were continuously suppressed during self-paced movements. Connectivity analysis revealed higher synchronicity (phase-locking value) between the STN and central electrodes during self-paced and higher STN to frontal phase-locking during externally-cued movements. Our data provide direct electrophysiological support for the existence of functionally segregated cortico-basal ganglia networks controlling motor behavior in Parkinson patients, and corroborate the assumption of Parkinson patients being shifted from habitual towards goal-directed behavior.

Movement disorders in genetically confirmed mitochondrial disease and the putative role of the cerebellum.

BACKGROUND: Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE: The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS: In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS: Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION: This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.

Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial.

Importance: Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce. Objective: To determine whether nocturnal administration of sodium oxybate, a first-line treatment in narcolepsy, is effective and safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in patients with PD. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled, crossover phase 2a study carried out between January 9, 2015, and February 24, 2017. In a single-center study in the sleep laboratory at the University Hospital Zurich, Zurich, Switzerland, 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] score >10) were screened in the sleep laboratory. Five patients were excluded owing to the polysomnographic diagnosis of sleep apnea and 1 patient withdrew consent. Thus, 12 patients were randomized to a treatment sequence (sodium oxybate followed by placebo or placebo followed by sodium oxybate, ratio 1:1) and, after dropout of 1 patient owing to an unrelated adverse event during the washout period, 11 patients completed the study. Two patients developed obstructive sleep apnea during sodium oxybate treatment (1 was the dropout) and were excluded from the per-protocol analysis (n = 10) but included in the intention-to-treat analysis (n = 12). Interventions: Nocturnal sodium oxybate and placebo taken at bedtime and 2.5 to 4.0 hours later with an individually titrated dose between 3.0 and 9.0 g per night for 6 weeks with a 2- to 4-week washout period interposed. Main Outcomes and Measures: Primary outcome measure was change of objective EDS as electrophysiologically measured by mean sleep latency in the Multiple Sleep Latency Test. Secondary outcome measures included change of subjective EDS (ESS), sleep quality (Parkinson Disease Sleep Scale-2), and objective variables of nighttime sleep (polysomnography). Results: Among 12 patients in the intention-to-treat population (10 men, 2 women; mean [SD] age, 62 [11.1] years; disease duration, 8.4 [4.6] years), sodium oxybate substantially improved EDS as measured objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; P = .002) and subjectively (ESS score, -4.2 points ; 95% CI, -5.3 to -3.0 points; P = .001). Thereby, 8 (67%) patients exhibited an electrophysiologically defined positive treatment response. Moreover, sodium oxybate significantly enhanced subjective sleep quality and objectively measured slow-wave sleep duration (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; P < .001). Differences were more pronounced in the per-protocol analysis. Sodium oxybate was generally well tolerated under dose adjustments (no treatment-related dropouts), but it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient, as detected by polysomnography, all of whom did not benefit from sodium oxybate treatment. Conclusions and Relevance: This study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD. Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation. Trial Registration: clinicaltrials.gov Identifier: NCT02111122.

Optimizing MSLT Specificity in Narcolepsy With Cataplexy.

Study Objectives: Multiple sleep onset rapid eye movement (R) periods (SOREMPs) and a mean sleep latency of ≤8 minutes on the multiple sleep latency test (MSLT) are diagnostic criteria of narcolepsy (NC), but also occur in other conditions with increased sleep pressure, including insufficient sleep syndrome (ISS), sleep-disordered breathing (SDB), or Parkinson's disease (PD). These false positives are common, may create diagnostic uncertainty, and highlight the need for complementary MSLT measures with high specificity for NC. Methods: Detailed analysis of MSLT findings in 56 NC, 83 PD, 89 SDB, and 23 ISS patients, using receiver operating characteristic curves. Results: A positive MSLT (mean sleep latency ≤ 8.0 minutes and ≥2 SOREMPs) was found in 53 NC (95%), 1 PD (1%), 8 SDB (9%), and 12 ISS patients (52%). MSLT-based differentiation between NC and non-NC patients was best when applying a mean R latency of ≤5 minutes (sensitivity/specificity/positive predictive value [PPV]: 49%/95%/96%) or a mean percentage of sleep stage R ≥ 40% (sensitivity/specificity/PPV: 60%/100%/100%) as cutoffs. When analyzing all 252 naps with SOREMPs in isolation, the combination of both R latency of ≤5 minutes and R percentage of ≥50% yielded a sensitivity/specificity/PPV of 50%/99%/99%. In addition, a sleep stage sequence with R occurring prior to N2 was more common in NC than in non-NC (71% vs. 32%, p < .001), and in combination with R percentage of ≥50% yielded a sensitivity/specificity/PPV of 53%/96%/97%. Conclusions: A better characterization of R sleep by latency, duration, and sleep stage sequence facilitates detection of false positives and, hence, contributes to a higher MSLT specificity in NC.

The Impact of Subthalamic Deep Brain Stimulation on Sleep-Wake Behavior: A Prospective Electrophysiological Study in 50 Parkinson Patients.

Study Objectives: This prospective observational study was designed to systematically examine the effect of subthalamic deep brain stimulation (DBS) on subjective and objective sleep-wake parameters in Parkinson patients. Methods: In 50 consecutive Parkinson patients undergoing subthalamic DBS, we assessed motor symptoms, medication, the position of DBS electrodes within the subthalamic nucleus (STN), subjective sleep-wake parameters, 2-week actigraphy, video-polysomnography studies, and sleep electroencepahalogram frequency and dynamics analyses before and 6 months after surgery. Results: Subthalamic DBS improved not only motor symptoms and reduced daily intake of dopaminergic agents but also enhanced subjective sleep quality and reduced sleepiness (Epworth Sleepiness Scale: -2.1 ± 3.8, p < .001). Actigraphy recordings revealed longer bedtimes (+1:06 ± 0:51 hours, p < .001) without shifting of circadian timing. Upon polysomnography, we observed an increase in sleep efficiency (+5.2 ± 17.6%, p = .005) and deep sleep (+11.2 ± 32.2 min, p = .017) and increased accumulation of slow-wave activity over the night (+41.0 ± 80.0%, p = .005). Rapid eye movement sleep features were refractory to subthalamic DBS, and the dynamics of sleep as assessed by state space analyses did not normalize. Increased sleep efficiency was associated with active electrode contact localization more distant from the ventral margin of the left subthalamic nucleus. Conclusion: Subthalamic DBS deepens and consolidates nocturnal sleep and improves daytime wakefulness in Parkinson patients, but several outcomes suggest that it does not normalize sleep. It remains elusive whether modulated activity in the STN directly contributes to changes in sleep-wake behavior, but dorsal positioning of electrodes within the STN is linked to improved sleep-wake outcomes.

Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression.

Patients with Parkinson's disease most often have asymmetric motor features at onset, and specific motor signs (ie, tremor versus bradykinesia and rigidity) frequently characterize the first few years of disease evolution. Some previous clinical evidence has suggested that body side and a predominance of motor manifestations at disease onset are linked to long-term evolution and disease progression. We prospectively analyzed 206 patients with Parkinson's disease according to the most affected side and predominant motor signs at onset. Patients were divided into left-side rigid-akinetic (n = 71), right-side rigid-akinetic (n = 59), left-side tremor (n = 41), and right-side tremor (n = 35) subgroups. These subgroups were compared in terms of motor and cognitive functions, mean motor deterioration per year (calculated as the motor score divided by disease duration), total equivalent doses of dopaminergic drugs, and the presence of hallucinations and rapid eye movement sleep behavior disorder. Disease duration was similar in all groups. Motor fluctuations were more likely to occur in rigid-akinetic patients. In a multiple model analysis adjusted for potential confounders, faster disease progression was associated with right-side (P = 0.045) and rigid-akinetic onset (P = 0.001). With respect to nonmotor symptoms, the rigid-akinetic type was associated with increased risk of cognitive decline (P = 0.004) compared with the tremor type. A trend was noticed toward an increased risk of developing visual hallucinations in rigid-akinetic patients and toward an increased frequency of rapid eye movement sleep behavior disorder in those who had left-sided onset of symptoms. Our findings corroborate that body side and type of motor signs at the time of diagnosis affect the evolution of motor severity and may also have an impact on some nonmotor manifestations.

[The treatment of Parkinson's disease]. / Die Therapie der Parkinson-Erkrankung.

Parkinson's disease belongs to the most prevalent neurodegenerative disorders and manifests both with motor and non-motor symptoms. Symptomatic treatment of this disorder became more multifaceted over the past years: besides classical dopaminergic drugs and physiotherapy, novel invasive escalation treatment strategies became gold standard in many countries. On the other hand, non-motor symptoms significantly impacts quality of life in many patients which necessitates initiation of adequate therapy.

La maladie de Parkinson est une maladie neurologique chronique neurodégénérative fréquente qui se présente avec des troubles moteurs et non-moteurs progressifs. Récemment, le traitement de cette maladie est devenu plus varié. En plus de l'usage des médicaments dopaminergiques et de la physiothérapie, beaucoup des centres offrent des nouveaux traitements invasifs. En outre, les troubles non-moteurs détériorent da qualité de vie de beaucoup des patients et nécessitent l'initiation d'un traitement adéquat.

Progressive dopamine and hypocretin deficiencies in Parkinson's disease: is there an impact on sleep and wakefulness?

Sleep-wake disturbances are frequent in patients with Parkinson's disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep-wake disturbances in Parkinson's disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson's disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson's disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin-deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson's disease. Poorer sleep quality is linked to dopamine deficiency and other disease-related factors. Despite hypocretin cell loss in Parkinson's disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Heart rate variability in patients with idiopathic Parkinson's disease with and without obstructive sleep apnea syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with repeated apnea-induced sympathetic surges leading to specific alterations of the power spectrum of heart rate variability (HRV). Sympathetic dysfunction evolves early in idiopathic Parkinson's disease (PD), but the consequences on cardiac autonomic response to OSAS have not been studied so far in PD patients. METHODS: Sixty-two patients with PD (35 without OSAS (PD-wo), 27 with OSAS (PD-OSAS)) and 62 age-matched control subjects (25 without OSAS (Co-wo), 37 with OSAS (Co-OSAS)) were included. HRV variables - including mean R-R interval, standard deviation of all normal-to-normal R-R intervals (SDNN), both low frequency (LF) and high frequency (HF) power bands, and the LF/HF ratio - were computed automatically from full-night polysomnography and calculated separately for each sleep stage. RESULTS: HRV variables were similar in PD-wo and PD-OSAS. In contrast, Co-OSAS showed significantly higher LF power in NREM1 and NREM2 sleep and higher LF/HF ratio in NREM1, NREM2 and slow wave sleep than Co-wo. Similarly, correlations between HRV variables and parameters of OSAS severity were found only in controls but not in PD patients. CONCLUSION: Our results suggest that the sympathetic response to OSAS is blunted in PD, giving further clinical evidence of the sympathetic denervation commonly observed in this neurodegenerative disorder.