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Background: Postural instability is one of the most restricting motor symptoms for patients with Parkinson’s disease (PD). While medication therapy only shows minor effects, it is still unclear whether medication in conjunction with deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves postural stability. Hence, the aim of this study was to investigate whether PD patients treated with medication in conjunction with STN-DBS have superior postural control compared to patients treated with medication alone. Methods: Three study groups were tested: PD patients on medication (PD-MED), PD patients on medication and on STN-DBS (PD-MED–DBS), and healthy elderly subjects (HS) as a reference. Postural performance, including anticipatory postural adjustments (APA) prior to perturbation onset and compensatory postural responses (CPR) following multidirectional horizontal perturbations, was analyzed using force plate and electromyography data. Results: Regardless of the treatment condition, both patient groups showed inadequate APA and CPR with early and pronounced antagonistic muscle co-contractions compared to healthy elderly subjects. Comparing the treatment conditions, study group PD-MED–DBS only showed minor advantages over group PD-MED. In particular, group PD-MED–DBS showed faster postural reflexes and tended to have more physiological co-contraction ratios. Conclusion: medication in conjunction with STN-DBS may have positive effects on the timing and amplitude of postural control.

Introduction: The OPTIPARK study confirmed the effectiveness and safety of opicapone as adjunct therapy to levodopa in patients with Parkinson’s disease (PD) and motor fluctuations under real-world conditions. The aim of this sub-analysis was to evaluate opicapone in the German patient cohort of OPTIPARK in order to provide country-specific data. Methods: OPTIPARK was an open-label, single-arm study conducted in routine clinical practice across Germany and the UK. Patients with PD and motor fluctuations received once-daily opicapone 50 mg for 3 months in addition to levodopa. The primary endpoint was Clinicians’ Global Impression of Change (CGI-C). Secondary assessments included Patients’ Global Impressions of Change (PGI-C), Unified Parkinson’s Disease Rating Scale (UPDRS) I–IV, Parkinson’s Disease Questionnaire (PDQ-8), and Non-Motor Symptoms Scale (NMSS). This sub-analysis reports outcomes from the German patients only. Results: Overall, 363 (97.6%) of the 372 patients included in the German cohort received ≥1 dose of opicapone and 291 (80.2%) completed the study. Improvements on CGI-C and PGI-C were reported by 70.8% and 76.3% of patients, respectively. UPDRS scores improved for activities of daily living during OFF time by −3.3 ± 4.5 points and motor scores during ON time by −5.3 ± 7.9 points. PDQ-8 and NMSS scores also demonstrated improvements. Treatment emergent adverse events considered at least possibly related to opicapone occurred in 37.7% of patients, with most being of mild or moderate intensity. Conclusion: Opicapone added to levodopa in patients with PD and motor fluctuations was effective and generally well tolerated in routine clinical practice across Germany.

Background Botulinum neurotoxin (BoNT) is an effective treatment for chronic sialorrhea; however, reliable and robust evidence supporting long-term efficacy and safety is lacking. This study investigated the efficacy and safety of repeated incobotulinumtoxinA injections for chronic sialorrhea over 64 weeks. Methods Adults with sialorrhea were randomized (2:2:1) to incobotulinumtoxinA 75 U, incobotulinumtoxinA 100 U (n = 74 each), or placebo (n = 36) in the double-blind, placebo-controlled main period (NCT02091739). Eligible subjects entered the extension period and received dose-blinded incobotulinumtoxinA 75 or 100 U in three further 16±2-week injection cycles. Efficacy and safety assessments in subjects who received incobotulinumtoxinA throughout the study included unstimulated salivary flow rate (uSFR), subjects' Global Impression of Change Scale (GICS), Drooling Severity and Frequency Scale (DSFS), modified Radboud Oral Motor Inventory for Parkinson's Disease (mROMP) drooling, speech, and swallowing symptom scores, and incidence of adverse events (AEs). Results In total, 173/184 subjects (94%) completed the main period and entered the extension period; 141 subjects received incobotulinumtoxinA 75 U (n = 69) or 100 U (n = 72) in both periods. Mean uSFR decreased consistently with repeated incobotulinumtoxinA 75 and 100 U treatment and by −0.16 and −0.17, respectively, at the end-of-study visit. Subjects’ GICS, DSFS, and mROMP drooling scores also improved at all assessments. mROMP speech and swallowing scores remained stable. The most common treatment-related AEs during the extension period were dry mouth (4.4% and 11.1%) and dysphagia (1.5% and 4.2%). Conclusions Data support long-term efficacy and safety of repeated incobotulinumtoxinA treatment for sialorrhea, with no additional safety concerns reported over 64 weeks.

Changes in personality are one of the main concerns Parkinson's disease (PD) patients raise when facing the decision to undergo neurosurgery for deep brain stimulation (DBS) of the subthalamic nucleus (STN). While clinical instruments for monitoring functional changes following DBS surgery are well-established in the daily therapeutic routine, personality issues are far less systematically encompassed. Moreover, while sex disparities in the outcomes of STN-DBS therapy have been reported, little is known about the different effects that DBS treatment may have on mood and personality traits in female and male patients. To this aim, the effect of STN-DBS on personality traits was assessed in 46 PD patients (12 women and 34 men) by means of the Freiburg Personality Inventory. The Becks Depression Inventory (BDI-I) and the Parkinson's Disease Questionnaire were used to evaluate patients' level of depression and quality of life (QoL). Patients completed the questionnaires a few days before, within the first year, and 2 years after surgery. The 12 personality traits defined by the FPI-R questionnaire did not change significantly after STN-DBS surgery (p = 0.198). Women declared higher depression scores through all study stages (p = 0.009), but also showed a stronger QoL amelioration after surgery than male patients (p = 0.022). The BDI-I scores of female patients clearly correlated with their levodopa equivalent daily dose (LEDD; r = 0.621, p = 0.008). Remarkably, in both male and female patients, higher pre-operative LEDDs were related to worse post-operative QoL scores (p = 0.034). These results mitigate the concerns about systematic personality changes due to STN-DBS treatment in PD patients and encourage an early DBS approach, before severe levodopa-induced sequelae may irreparably compromise the patients' QoL. In the future, more focus should lie on sex-related effects, since female patients seem to profit more than male patients from STN-DBS, in terms of reduced depressive symptoms associated with a reduction of the LEDD and amelioration of QoL. These aspects may help to redress the sex imbalance in PD patients treated with DBS, given that women are still strongly under-represented.

ZusammenfassungSchmerzen beim idiopathischen Parkinsonsyndrom (IPS) treten bei 40 %–95 % der Patienten auf und beeinträchtigen die Lebensqualität, sind jedoch oftmals unterdiagnostiziert und werden nur unsystematisch therapiert.Schmerzätiologie und Schmerzcharakter können sehr vielfältig sein und obwohl die Optimierung der Parkinson-Medikation die Basis der Schmerzbehandlung ist, sind in den meisten Fällen zusätzliche Therapien zur suffizienten Behandlung der Schmerzen notwendig.In dieser Arbeit werden Epidemiologie und Pathophysiologie des Schmerzes beim IPS dargestellt sowie Schmerzcharakteristika beschrieben. Es wird aufgezeigt, welche Methoden der Schmerzbehandlung beim IPS genutzt werden und wie Patienten die Effektivität der Therapien beurteilen. Auf Basis der begrenzten Datenlage und eines Expertenkonsens wurden praxisrelevante Vorschläge zu Diagnostik und Therapie bei Schmerz und IPS gegeben.Diese Arbeit soll dazu beitragen, Neurologen für das Thema Schmerz beim IPS zu sensibilisieren. Aufgrund der Komplexität und Besonderheiten der neurodegenerativen Erkrankung sollten Neurologen an der interdisziplinären Schmerztherapie beim IPS beteiligt sein und ihren Patienten differenziertere Therapieoptionen bereitstellen als bisher.

Parkinson's disease (PD) is a neurodegenerative multisystem disorder characterized by progressive motor symptoms such as bradykinesia, tremor and muscle rigidity. Over the course of the disease, numerous non-motor symptoms, sometimes preceding the onset of motor symptoms, significantly impair patients' quality of life. The significance of non-motor symptoms may outweigh the burden through progressive motor incapacity, especially in later stages of the disease. The advanced stage of the disease is characterized by motor complications such as fluctuations and dyskinesias induced by the long-term application of levodopa therapy. In recent years, it became evident that various non-motor symptoms such as psychiatric symptoms, fatigue and pain also show fluctuations after chronic levodopa therapy (named non-motor fluctuations or NMFs). Although NMFs have moved into the focus of interest, current national guidelines on the treatment of PD may refer to non-motor symptoms and their management, but do not mention NMF, and do not contain recommendations on their management. The present article summarizes major issues related to NMF including clinical phenomenology and pathophysiology, and outlines a number of open issues and topics for future research.

To evaluate Parkinson's disease (PD)-associated pain as perceived by the patients (subjective characterization), and how this may change following initiation of rotigotine transdermal patch.SP1058 was a non-interventional study conducted in routine clinical practice in Germany and Austria in patients experiencing PD-associated pain (per the physician's assessment). Data were collected at baseline (ie, before rotigotine initiation) and at a routine visit after ≥25 days (-3 days allowed) of treatment on a maintenance dose of rotigotine (end of study [EoS]). Pain perception was assessed using the 12-item Pain Description List of the validated German Pain Questionnaire (each item ranked 0 = 'not true' to 3 = 'very true'). Primary effectiveness variable: change from baseline to EoS in the sum score of the 4 'affective dimension' items of the Pain Description List. Secondary effectiveness variables: change from baseline to EoS in Unified Parkinson's Disease Rating Scale (UPDRS) II, III, and II+III scores, and Parkinson's Disease Questionnaire (PDQ-8) total score (PD-related quality-of-life). Other variables included scores of the eight 'sensory dimension' items of the Pain Description List.Of 93 enrolled patients (mean [SD] age: 71.1 [9.0] years; male: 48 [52%]), 77 (83%) completed the study, and 70 comprised the full analysis set. The mean (SD) change from baseline in the sum score of the four 'affective dimension' items was -1.3 (2.8) indicating a numerical improvement (baseline: 3.9 [3.4]). In the 'sensory dimension', pain was mostly perceived as 'pulling' at baseline (49/70 [70%]); 'largely true'/'very true'). Numerical improvements were observed in all UPDRS scores (mean [SD] change in UPDRS II+III: -5.3 [10.5]; baseline: 36.0 [15.9]), and in PDQ-8 total score (-2.0 [4.8]; baseline: 10.7 [5.9]). Adverse drug reactions were consistent with dopaminergic stimulation and transdermal administration.The perception of the 'affective dimension' of PD-associated pain numerically improved in patients treated with rotigotine. ClinicalTrials.gov identifier: NCT01606670; https://clinicaltrials.gov/ct2/show/NCT01606670?term=NCT01606670rank=1.

10.1016/j.toxicon.2018.11.209

Objective: SIAXI (NCT02091739), a pivotal double-blind, randomised, placebo-controlled study with an extension period (EP), assessed the efficacy and safety of incobotulinumtoxinA 75 or 100 U in patients with sialorrhea due to Parkinson's disease (PD), atypical parkinsonism, stroke or traumatic brain injury. This subgroup analysis assessed the impact of injection guidance technique. Background: Literature suggests that ultrasound (US) guidance of botulinum neurotoxin injections, especially into the submandibular glands, may be needed to improve efficacy and safety. Methods: Patients were randomized (2:2:1) to incobotulinumtoxinA 75 or 100 U, or placebo, distributed in bilateral parotid and submandibular glands in a single injection cycle (IC) in the main period (MP). All eligible patients completing the MP received three further incobotulinumtoxinA ICs (75 or 100 U; each 16+/-2 weeks) in the EP. Injections were consistently guided by US or anatomical landmarks (AL) at investigators' discretion. Outcomes included unstimulated salivary flow rate (uSFR) and patients' Global Impression of Change Scale (GICS). The incidence of adverse events (AEs) was reported. Results: 184 patients were randomised and received either incobotulinumtoxinA 75 U (n=74) or 100 U (n=74), or placebo (n=36) in the MP; 173 completed the MP and entered the EP. In the MP, injections were guided by US in 56.5% of patients and by AL in 43.5%. Among patients treated with incobotulinumtoxinA in all 4 ICs, with US and AL guidance mean uSFR decreased with 75 U and 100 U from study baseline to 4 weeks post-injection, (mean [SD] change from study baseline to end of study: US, -0.15 [0.20] and -0.17 [0.25]; AL, -0.19 [0.22] and -0.17 [0.20]). Patients' GICS also showed improvement at 4 weeks post-injection with both US and AL guidance. The incidence of AEs over all ICs with incobotulinumtoxinA treatment was similar with US and AL guidance (67.0% and 61.0%). The most frequent treatment-related AEs were dry mouth (10.7% and 6.5%) and dysphagia (3.9% and 2.6%). No new safety concerns with respect to guidance technique were reported. Conclusions: In contrast to current literature, repeated incobotulinumtoxinA injections under either US or AL guidance are similarly effective and well tolerated for sialorrhea in patients with PD or other neurological disorders.

Schmerzen beim idiopathischen Parkinsonsyndrom (IPS) treten bei 40 %–95 % der Patienten auf und beeinträchtigen die Lebensqualität, sind jedoch oftmals unterdiagnostiziert und werden nur unsystematisch therapiert.Schmerzätiologie und Schmerzcharakter können sehr vielfältig sein und obwohl die Optimierung der Parkinson-Medikation die Basis der Schmerzbehandlung ist, sind in den meisten Fällen zusätzliche Therapien zur suffizienten Behandlung der Schmerzen notwendig.In dieser Arbeit werden Epidemiologie und Pathophysiologie des Schmerzes beim IPS dargestellt sowie Schmerzcharakteristika beschrieben. Es wird aufgezeigt, welche Methoden der Schmerzbehandlung beim IPS genutzt werden und wie Patienten die Effektivität der Therapien beurteilen. Auf Basis der begrenzten Datenlage und eines Expertenkonsens wurden praxisrelevante Vorschläge zu Diagnostik und Therapie bei Schmerz und IPS gegeben.Diese Arbeit soll dazu beitragen, Neurologen für das Thema Schmerz beim IPS zu sensibilisieren. Aufgrund der Komplexität und Besonderheiten der neurodegenerativen Erkrankung sollten Neurologen an der interdisziplinären Schmerztherapie beim IPS beteiligt sein und ihren Patienten differenziertere Therapieoptionen bereitstellen als bisher.

It has been suggested that in patients with Parkinson’s disease (PD) metabolism of the MAO-B inhibitor selegiline to methamphetamine may contribute and/or exacerbate sleep problems, possibly leading to deficits of cognition. This open-label exploratory study included 30 PD patients currently being treated with selegiline (7.5 mg/day) and complaining of sleep disturbances. The aim of the study was to determine whether switching from selegiline to another MAO-B inhibitor without amphetamine-like metabolites, namely rasagiline, would improve sleep behaviour and cognitive function in PD patients. Pathologic aberrations as determined by comparison of the frequency pattern of patients to a database consisting of healthy subjects revealed an approximation of electric brain activity to normality. For verification of efficacy, a combination of questionnaires, quantitative source density EEG recording with CATEEMo and performance of two psychometric tasks (d2-test of attention and reading) during the EEG recording were done on the last day of selegiline treatment (7.5 mg/day) as well as 2 and 4 months later, during which the patients were treated with rasagiline (1 mg/day). In addition, performance of the mental tasks revealed a statistically significant (p < 0.05) increase of theta power (4.75 - 6.75 Hz) indicative of improved cognitive abilities at the end of the treatment period. At the same time evaluation of the psychometric test results indicated a statistical improvement with respect to the score of the d2-test (increase from 6.54 to 7.37; p < 0.05). Serum levels of methamphetamine were measured before and after intake of selegiline or rasagiline. They were correlated to alpha2 power, which is under dopaminergic control, within the temporal lobe. From these results it is concluded that the switch from selegiline to rasagiline not only improved sleep behaviour as reported separately but also had a positive effect on electric brain activity and on cognition in these patients.

Background and Objectives: Individually manufactured microTargeting™ platforms (MT) provide a novel generation of stereotactic systems based on preoperatively implanted bone markers and screws. The feasibility and reliability of these frames were evaluated for bilateral deep brain stimulation (DBS) in patients with idiopathic Parkinson's disease (IPD). Surgical and clinical results were compared to conventional Zamorano Dujovny frames (ZD) in this prospective study. Materials and Methods: Twenty-six IPD patients undergoing surgery for DBS were divided into 2 groups. In group I, electrode implantation was accomplished using conventional ZD. Group II underwent electrode implantation using MT. Microrecording and macrostimulation were performed and surgery time was measured. The clinical outcome was determined using the Unified Parkinson's Disease Rating Scale Part III (UPDRS III) and L-dopa-equivalent doses for a 12-month follow-up postoperatively. Results: Clinical evaluation confirmed comparable outcomes for both targeting procedures and electrode positioning. Surgical time was lower in group II than in group I. Significant improvements were determined for both groups in UPDRS III and L-dopa-equivalent dose. Conclusions: Both systems allow for reliable and safe neurosurgical procedures, yielding comparable clinical results. MT improved handling and automatic adjustment of frame coordinates. Surgery time was reduced markedly compared to conventional frames.

Background and objective The extent to which deep brain stimulation (DBS) can improve quality of life may be perceived as a permanent trade-off between neurological improvements and complications of therapy, comorbidities, and disease progression. Patients and methods We retrospectively investigated 123 consecutive and non-preselected patients. Indications for DBS surgery were Parkinson's disease (82), dystonia (18), tremor of different etiology (21), Huntington's disease (1) and Gilles de la Tourette syndrome (1). AEs were defined as any untoward clinical occurrence, sign or patient complaint or unintended disease if related or unrelated to the surgical procedures, implanted devices or ongoing DBS therapy. Results Over a mean/median follow-up period of 4.7 years (578 patient-years) 433 AEs were recorded in 106 of 123 patients (86.2%). There was no mortality or persistent morbidity from the surgical procedure. All serious adverse events (SAEs) that occurred within 4 weeks of surgery were reversible. Neurological AEs (193 in 85 patients) and psychiatric AEs (78 in 48 patients) were documented most frequently. AEs in 4 patients (suicide under GPI stimulation, weight gain >20 kg, impairment of gait and speech, cognitive decline >2 years following surgery) were severe or worse, at least possibly related to DBS and non reversible. In PD 23.1% of the STN-stimulated patients experienced non-reversible (or unknown reversibility) AEs that were at least possibly related to DBS in the form of impaired speech or gait, depression, weight gain, cognitive disturbances or urinary incontinence (severity was mild or moderate in 15 of 18 patients). Age and Hoehn&Yahr stage of STN-simulated PD patients, but not preoperative motor impairment or response to levodopa, showed a weak correlation (r = 0.24 and 0.22, respectively) with the number of AEs. Conclusions DBS-related AEs that were severe or worse and non-reversible were only observed in PD (4 of 82 patients; 4.9%), but not in other diseases. PD patients exhibited a significant risk for non-severe AEs most of which also represented preexisting and progressive axial and non-motor symptoms of PD. Mild gait and/or speech disturbances were rather frequent complaints under VIM stimulation. GPI stimulation for dystonia could be applied with negligible DBS-related side effects.

Introduction: Intractable sialorrhea results from various causes, including Parkinson's disease (PD). The pivotal, double-blind, randomized, Phase 3 SIAXI study (NCT02091739) assessed the efficacy and safety of incobotulinumtoxinA (botulinum neurotoxin type A [BoNT-A] free from complexing proteins) 75 U and 100 U for the treatment of sialorrhea. Methods: Adults included in the main phase (MP) had chronic, troublesome sialorrhea due to PD, atypical Parkinsonism, stroke, or traumatic brain injury (TBI) and were randomized (2:2:1) to a single injection cycle (16±2 weeks) of incobotulinumtoxinA 75 U or 100 U, or placebo (PBO) distributed in bilateral parotid and submandibular glands (dose ratio of 3:2). Co-primary endpoints were change in unstimulated salivary flow rate (uSFR) and subjects' Global Impression of Change Scale (GICS) at Week 4. Safety was also assessed. Results: One hundred eighty-four subjects were randomized to either incobotulinumtoxinA 75 U (n=74), 100 U (n=74), or PBO (n=36) in the MP. Primary drooling etiologies were: PD (70.7%), atypical Parkinsonism (8.7%), stroke (17.9%), and TBI (2.7%). Injection was guided by anatomic landmarks in 39.2%, 44.6%, and 50.0%, and ultrasonography in 60.8%, 55.4%, and 50.0% of subjects in the incobotulinumtoxinA 75 U, 100 U, and PBO groups, respectively. At week 4, incobotulinumtoxinA 100 U significantly improved uSFR, and subjects' GICS scores were significantly higher vs PBO (both, P

Background and objective To determine rates of adverse events (AEs) related to deep brain stimulation (DBS) surgery or implanted devices from a large series from a single institution. Sound comparisons with the literature require the definition of unambiguous categories, since there is no consensus on the reporting of such AEs. Patients and methods 123 consecutive patients (median age 63 yrs; female 45.5%) treated with DBS in the subthalamic nucleus (78 patients), ventrolateral thalamus (24), internal pallidum (20), and centre median-parafascicular nucleus (1) were analyzed retrospectively. Both mean and median follow-up time was 4.7 years (578 patient-years). AEs were assessed according to three unambiguous categories: (i) hemorrhages including other intracranial complications because these might lead to neurological deficits or death, (ii) infections and similar AEs necessitating the explantation of hardware components as this results in the interruption of DBS therapy, and (iii) lead revisions for various reasons since this involves an additional intracranial procedure. For a systematic review of the literature AE rates were calculated based on primary data presented in 103 publications. Heterogeneity between studies was assessed with the I2 statistic and analyzed further by a random effects meta-regression. Publication bias was analyzed with funnel plots. Results Surgery- or hardware-related AEs (23) affected 18 of 123 patients (14.6%) and resolved without permanent sequelae in all instances. In 2 patients (1.6%), small hemorrhages in the striatum were associated with transient neurological deficits. In 4 patients (3.3%; 0.7% per patient-year) impulse generators were removed due to infection. In 2 patients electrodes were revised (1.6%; 0.3% per patient-year). There was no lead migration or surgical revision because of lead misplacement. Age was not statistically significant different (p>0.05) between patients affected by AEs or not. AE rates did not decline over time and similar incidences were found among all patients (423) implanted with DBS systems at our institution until December 2016. A systematic literature review revealed that exact AE rates could not be determined from many studies, which could not be attributed to study designs. Average rates for intracranial complications were 3.8% among studies (per-study analysis) and 3.4% for pooled analysis of patients from different studies (per-patient analysis). Annual hardware removal rates were 3.6 and 2.4% for per-study and per-patient analysis, respectively, and lead revision rates were 4.1 and 2.6%, respectively. There was significant heterogeneity between studies (I2 ranged between 77% and 91% for the three categories; p< 0.0001). For hardware removal heterogeneity (I2 = 87.4%) was reduced by taking study size (p< 0.0001) and publication year (p< 0.01) into account, although a significant degree of heterogeneity remained (I2 = 80.0%; p< 0.0001). Based on comparisons with health care-related databases there appears to be publication bias with lower rates for hardware-related AEs in published patient cohorts. Conclusions The proposed categories are suited for an unequivocal assessment of AEs even in a retrospective manner and useful for benchmarking. AE rates in the present cohorts from our institution compare favorable with the literature.

Depression is a common symptom in patients suffering from Parkinson's disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD-D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [(123)I]FP-CIT.A magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [(123)I]FP-CIT binding coefficient V(3)'' in the striatum, thalamus and midbrain/brainstem regions.PD+D patients had significantly lower V(3)'' compared with PD-D patients in the striatum (p0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V(3)'' than controls (p0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V(3)'' nor midbrain/brainstem V(3)'' differed from those in PD-D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318).Our data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder.

Mittels Positronen-Emissions-Tomografie (PET) bzw. Single-Photonen-Emissions-Computer-Tomografie (SPECT) und radioaktiven Markern konnen Veranderungen auf molekularer Ebene in vivo dargestellt werden. So lasst sich mittels Dopamin-Transporter-SPECT die Degeneration nigrostriataler dopaminerger Projektionen bei Patienten mit einer Parkinson-Krankheit (Morbus Parkinson, MP) sensitiv erfassen. Diese Verfahren haben jedoch nicht nur zum Verstandnis der Pathophysiologie des MP beigetragen, sondern bieten mittlerweile in Fallen schwieriger differenzialdiagnostischer Entscheidungen eine valide Hilfe in der klinischen Routine, so zum Beispiel in der Abgrenzung des MP vom essenziellen Tremor, von einem arzneimittelinduzierten Parkinson-Syndom (PS), in der Differenzialdiagnostik atypischer PS bzw. in der Unterscheidung einer Demenz vom Lewy-Korperchen-Typ und einer Alzheimer-Demenz. Der vorliegende Artikel gibt eine Ubersicht zur diagnostischen Wertigkeit der Dopamin-Transporter- und -D2-Rezeptor-SPECT in Klinik und Praxis unter Berucksichtigung weiterer bildgebender Verfahren. By means of positron emission tomography (PET) or, respectively, single photon emission computed tomography (SPECT) with labelled markers, changes at the molecular level can be demonstrated in vivo. For example, dopamine transporter SPECT can sensitively detect the degeneration of nigrostriatal dopaminergic projections in patients with Parkinson's disease (PD). However, these procedures have not only contributed to our understanding of the pathophysiology of PD but also now offer a valid aid in difficult differential diagnostic decisions in clinical routine. Some such examples are the delineation of PD from essential tremor, from a drug-induced Parkinsonian syndrome (PS), in the differential diagnosis of atypical PS or for distinguishing between dementia of the Lewy body type and one of Alzheimer's disease. The present article presents a review of the diagnostic utility of dopamine transporter and D2-receptor SPECT in clinical routine with consideration of other imaging procedures.

Although some reports on neurostimulation are positive, no effective treatment method for camptocormia in Parkinson's disease (PD) is known to date. We aim to identify prognostic factors for a beneficial DBS effect on camptocormia. In an observational cohort study, we investigated 25 idiopathic PD patients, who suffered additionally from camptocormia, and underwent bilateral neurostimulation of the subthalamic nucleus (STN) to improve classical PD symptoms. Using an established questionnaire, we examined deep brain stimulation (DBS) effects on camptocormia in addition to general neurostimulation effects. A beneficial neurostimulation effect on camptocormia was defined as an improvement in the bending angle of a least 50%. In 13 patients, the bending angle of camptocormia improved, in 12 patients it did not. A multifactorial analysis revealed a short duration between onset of camptocormia and start of neurostimulation to be the relevant factor for outcome. All patients with duration of camptocormia up to 1.5 years showed a beneficial effect; patients between 1.5 and ∼3 years showed mixed results, but none with a duration of more than 40 months improved except for 1 patient whose camptocormia was levodopa responsive. The bending angle was not a prognostic factor. Our data indicate that the main prognostic factor for a beneficial DBS effect on camptocormia is its short duration. As an explanation, we suggest that neurostimulation may improve camptocormia only as long as muscle pathology is limited. Our findings may help to elucidate the mode of action of neurostimulation. A prospective study is necessary. © 2015 International Parkinson and Movement Disorder Society

Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [(123)I]FP-CIT and dopamine D(2)/D(3) receptor SPECT with [(123)I]IBZM to evaluate whether there is a reduction of DAT and/or D(2)/D(3) receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37% of untreated patients were diagnosed as having Parkinson's disease. 17% of treated patients had additional loss of D(2)/D(3) receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38% clinically uncertain cases, SPECT was in concordance with 75% of initial clinical diagnoses. 25% were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS.

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5mg daily. Patients had been treated with levodopa for 10.7+/-4.8 years. Pergolide was increased to 8.2+/-4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733+/-468 mg and decreased to 348+/-186 mg after pergolide titration. The duration of OFF times decreased from 7.3+/-3.8 to 1.7+/-0.9 h per day (p < 0.001) measured by patients' diaries. Dyskinesias, present for 5.0+/-3.3 h per day at baseline, were reduced to 1.4+/-0.8 h per day (p < 0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5+/-7.0 to 2.8+/-2.2 h (p < 0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p < 0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.

Objective.To determine the influence of deep brain stimulation (DBS) on daily routine driving behavior in Parkinson’s disease (PD) patients.Methods.A cross-sectional questionnaire survey was done in 121 DBS-PD patients. The influences of patient characteristics and DBS on current driving and driving at time of surgery and the predictive value of the preoperative levodopa-test on postoperative driving were evaluated.Results.50% of 110 driving-license holders currently drove. 63.0% rated themselves as safe drivers, 39.4% reported improvement, and 10.9% noted deterioration in driving after DBS surgery. Inactive drivers had quit driving mainly due to disease burden (90.9%). Active drivers were younger, more often males, and less impaired according to H&Y and MMSE, had surgery more recently, and reported more often overall benefit from DBS. H&Y “on” and UPDRS III “off” scores at time of surgery were lower in pre- and postoperative active than in inactive drivers. Tremor and akinesia were less frequent reasons to quit driving after than before DBS surgery. Postoperatively, 22.7% (10/44) of patients restarted and 10.6% (7/66) of patients discontinued driving, independently of H&Y stage. The preoperative levodopa-test was not predictive for the postoperative driving outcome.Conclusion.50% of PD patients with DBS drive. DBS surgery changes daily routine driving behavior.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson’s disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

The objective of this study is to demonstrate that application of rasagiline instead of selegiline with concomitant determination of l-amphetamine and l-methamphetamine in plasma is safe and well tolerated and influences sleep, mood, and motor behavior in patients with Parkinson’s disease on a stable drug therapy. 30 patients, who took 7.5 mg selegiline daily for at least 3 months, were switched to 1 mg rasagiline. Then they were followed over an interval of 4 months. The remaining drug therapy remained stable. This changeover was safe and well tolerated. l-Amphetamine and l-methamphetamine only appeared during selegiline treatment. Motor behavior, motor complications, mood and sleep improved during rasagiline administration. Amphetamine-like derivatives of selegiline could contribute to sleep disturbances, which may be involved in worsening of mood. Motor behavior and motor complications probably became better due to the additional glutamate receptor antagonizing properties of rasagiline in this open label study.

Background Dopamine-D2 receptor imaging with single-photon emission computed tomography (SPECT) and [ 123 I]IBZM is of great interest for basic and applied neurosciences. However, the use of kinetic analyses for quantification of dynamic [ 123 I]IBZM SPECT and the validity of the commonly employed single-scan pseudo-equilibrium analysis (PsEA) have not been appropriately investigated. The present study addresses these shortcomings. Methods Ten movement disorder patients underwent dynamic SPECT (142 min) after single-bolus [ 123 I]IBZM injection. Kinetic analyses comprise: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2) and non-invasive graphical analysis (NIGA). Simplified single-scan analyses were performed at peak time of specific binding (peak-equilibrium analysis, PEA) and during pseudo-equilibrium (PsEA). Results SRTM and MRTM are compromised by the high noise level of dynamic SPECT. SRTM2 and MRTM2 yielded reliable binding potential estimates that agreed excellently (mean difference = − 0.1 ± 1.0%, R 2 > 0.99). Concordance between SRTM/MRTM and SRTM2/MRTM2 was high in cases in which SRTM/MRTM provided reliable results (SRTM2 or MRTM2 vs. SRTM: 3.7 ± 5.0%, R 2 = 0.88). NIGA was affected by a negative bias (− 9.1 ± 6.3%, R 2 = 0.75; MRTM2 as reference) or high variability (− 1.2 ± 7.4%, R 2 = 0.71) for analyses without and with inclusion of the k 2 ′-term, respectively. PsEA showed a positive bias and low correlation in comparison with SRTM2/MRTM2 (7.6 ± 10.8%, R 2 = 0.59), which was considerably improved for PEA (− 2.7 ± 7.6%, R 2 = 0.72). MRTM2 provided parametric images with minimal bias suited for voxel-wise statistical analyses. Conclusions MRTM2 and SRTM2 can be reliably applied to dynamic [ 123 I]IBZM SPECT. PEA is a suitable method for clinical routine, while our results discourage the use of PsEA (current clinical standard).

The mechanisms by which deep brain stimulation (DBS) of the subthalamic nucleus (STN) leads to clinical benefit in Parkinson's disease (PD), especially with regard to dopaminergic transmission, remain unclear. Therefore, the objective of our study was to evaluate alterations of synaptic dopaminergic signaling following bilateral STN-DBS in advanced PD within a one-year follow-up. We used [(123)I]FP-CIT single-photon emission computed tomography (SPECT) to measure dopamine transporter (DAT) availability and [(123)I]IBZM SPECT to assess dopamine D(2) receptor (D2R) availability (stimulator ON condition).Patients (n=18) showed a tendency towards a better suppression of symptoms after STN-DBS (Unified Parkinson's Disease Rating Scale motor score with medication decreased from 24.1+/-16.1 to 15.4+/-7.45; p=0. 002) while medication was strongly reduced (61% reduction of levodopa equivalent units; p

Approximately 25% of patients with idiopathic Parkinson's disease (IPD) later develop dementia, with the typical characteristics as detailed in ICD-10 and DSM-IV. Differential diagnosis has to exclude dementia due to Lewy bodies, subcortical vascular encephalopathy and subcortical dementia due to progressive supranuclear paralysis or corticobasal degeneration. Several studies showed promising results for cholinesterase inhibitors such as donepezile, rivastigmine and galantamine. The demented Parkinsonian patients then present with improvement in cognitive function while motor skills do not deteriorate.

Depression occurs in approximately 45% of all patients with Parkinson's disease (PD), reduces quality of life independent of motor symptoms and seems to be underrated and undertreated. Characteristics of symptoms differ from major depression. Because of overlapping clinical symptoms, diagnosis is based on subjectively experienced anhedonia and feeling of emptiness. Available rating scales for major depression may not be adequate to correctly measure severity of depression in PD. Anxiety and depression may manifest as first symptoms of PD many years before motor symptoms. Serotonergic, noradrenergic and dopaminergic mechanisms play key roles in the etiology of depression in PD. Tricyclic and newer, selective antidepressants including serotonin and noradrenaline reuptake inhibitors (SSRI, SNRI) appear to be effective in treating depression in PD. Selective reuptake inhibitors seem to have a favorable side effect profile. Recent controlled studies show antidepressant effects of pramipexole in bipolar II depression. New dopamine agonists pramipexole and ropinirole appear to ameliorate depressive symptoms in PD in addition to effects on motor symptoms. There is a lack of appropriate rating scales and controlled studies regarding depression in PD.

ObjectiveThis pivotal phase III study, SIAXI, investigated the efficacy and safety of incobotulinumtoxinA for the treatment of chronic sialorrhea due to Parkinson disease (PD), atypical parkinsonism, stroke, or traumatic brain injury (TBI).MethodsAdult patients with PD (70.7%), atypical parkinsonism (8.7%), stroke (19.0%), or TBI (2.7%) were randomized (2:2:1) to double-blind treatment with placebo (n = 36), or total doses of incobotulinumtoxinA 75 U (n = 74) or 100 U (n = 74), in a single treatment cycle. The coprimary endpoints were change in unstimulated salivary flow rate from baseline to week 4, and patients' Global Impression of Change Scale score at week 4. Adverse events were recorded throughout.ResultsA total of 184 patients were randomized. Both incobotulinumtoxinA dose groups showed reductions in mean unstimulated salivary flow rate at week 4, with a significant difference vs placebo in the incobotulinumtoxinA 100 U group (p = 0.004). Patients' Global Impression of Change Scale scores also improved at week 4, with a significant difference vs placebo in the incobotulinumtoxinA 100 U group (p = 0.002). A lasting effect was observed at week 16 post injection. The most frequent treatment-related adverse events in the incobotulinumtoxinA 75 U and 100 U groups were dry mouth (5.4% and 2.7% of patients) and dysphagia (2.7% and 0.0% of patients).ConclusionsIncobotulinumtoxinA 100 U is an effective and well-tolerated treatment of chronic sialorrhea in adults.ClinicalTrials.gov identifierNCT02091739.Classification of evidenceThis study provides Class I evidence that incobotulinumtoxinA reduces salivary flow rates in patients with chronic sialorrhea due to PD, atypical parkinsonism, stroke, or TBI.

International audience; BackgroundExcessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide.ObjectiveThe aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS.MethodsThe method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score.ResultsBoth doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: −1.4 [−2.49; −0.31], P = 0.012) but did not change significantly with the 200/18 dosage.ConclusionsTHN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society