Sebastian R. Schreglmann

Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome

INTRODUCTION Dopaminergic drugs are the mainstay of treatment for restless legs syndrome (RLS). We analyzed the frequency and clinical characteristics of impulse control disorders (ICD) in patients with RLS on transdermal rotigotine treatment. METHODS Retrospective case series at a university movement disorder clinic (n = 28, 17 women). Symptoms of ICD were assessed via detailed history taking and scoring with the Zurich Screening Questionnaire for ICD (ZICD) prior to and after initiation of treatment. RESULTS None of the patients had a history of ICD prior to treatment. Baseline mean scores for patients who did (8.0 ± 2.5) and did not (6.2 ± 2.7) develop ICD under treatment did not differ. Six male patients (21%) developed various symptoms of ICD (mean ZICD scores 20.7 ± 10.2) on rotigotine treatment (mean dose: 3.8 mg/d), including binge eating, hypersexuality, compulsive shopping, pathological gambling, and punding, equaling a prevalence rate of 21%. Also in the non-ICD group, ZICD scores increased (7.5 ± 2.8). CONCLUSION This is the first report of ICD in patients treated with transdermal rotigotine for RLS. In contrast to literature, even low doses of rotigotine (mean 3.8 mg/d) can cause ICD. Therefore every prescribing physician should be aware that ICD may emerge in both RLS and PD patients on any dopaminergic treatment, and should actively ask for such symptoms. The ZICD questionnaire not only replicated the findings of detailed history taking but also showed an increased tendency towards impulsive behaviour in subjects that did not develop ICD.

Unilateral cerebellothalamic tract ablation in essential tremor by MRI-guided focused ultrasound

Objective: To report results of a prospective trial of unilateral transcranial MRI-guided focused ultrasound (MRIgFUS) ablation of the cerebellothalamic tract in essential tremor (ET). Methods: This was a prospective, uncontrolled, single-center interventional study. Patients with ET fulfilling criteria for interventional therapy received unilateral ablation of the cerebellothalamic tract (CTT) by MRIgFUS. Motor symptoms, manual dexterity, cognition, and quality of life were assessed before intervention and at 48 hours and 1, 3, and 6 months after intervention. Rating of standardized video recordings was blinded for evaluation time points. Primary outcome was the change in unilateral hand tremor score of the treated hand. Results: Six patients received MRIgFUS ablation of the CTT contralateral to the treated hand. Repeated-measures comparison determined a statistically significant 83% reduction (before vs 6 months after intervention mean ± SD; absolute reduction; 95% confidence interval) in the unilateral treated hand subscore (14.3 ± 4.9 vs 2.5 ± 2.6; 11.8; 8.4–15.2; p < 0.001), while quality of life improved by 52% (50.5 ± 19.4 vs 24.8 ± 11.4; 25.7; 3.5–47.28; p = 0.046). Measures for manual dexterity, attention and coordination, and overall cognition were unchanged. Transient side effects (n = 3) were ipsilateral hand clumsiness and mild gait instability for up to 3 months. Conclusions: Unilateral MRIgFUS lesioning of the CTT was highly efficacious in reducing contralateral hand tremor in ET without affecting fine motor function and dexterity over 6 months of follow-up. Adverse effects were mild and transient. Classification of evidence: This study provides Class IV evidence that for patients with ET, transcranial MRIgFUS ablation of the cerebellothalamic tract improves tremor.

Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain – A multimodal MRI study

Background Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders. Methods In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH (N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16). Results In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula. Conclusions Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

Pyridostigmine bromide versus fludrocortisone in the treatment of orthostatic hypotension in Parkinson's disease - a randomized controlled trial

Evidence for effective treatment options for orthostatic hypotension (OH) in Parkinsons disease (PD) is scarce. Elevation of cholinergic tone with pyridostigmine bromide has been reported as a way to improve blood pressure (bp) regulation in neurogenic hypotension without causing supine hypertension.

Functional lesional neurosurgery for tremor-a protocol for a systematic review and meta-analysis

Introduction The recent introduction of incision-less lesional neurosurgery using Gamma Knife and MRI-guided focused ultrasound has revived interest in lesional treatment options for tremor disorders. Preliminary literature researches reveal that the consistency of treatment effects after lesional neurosurgery for tremor has not formally been assessed yet. Similarly, the efficacy of different targets for lesional treatment and incidence of persistent side effects of lesional neurosurgical interventions has not been comprehensively assessed. This work therefore aims to describe a suitable process how to review the existing literature on efficacy and persistent side effects of lesional neurosurgical treatment for tremor due to Parkinson’s disease, essential tremor, multiple sclerosis and midbrain/rubral tremor. Methods and analysis We will search electronic databases (Medline, Cochrane) and reference lists of included articles for studies reporting lesional interventions for tremor in cohorts homogeneous for tremor aetiology and intervention (technique and target). We will include cohorts with a minimum number of five subjects and follow-up of 2 months. One investigator will perform the initial literature search and two investigators then independently decide which references to include for final efficacy and safety analysis. After settling of disagreement, data will be extracted from articles using a standardised template. We will perform a random-effect meta-analysis calculating standardised mean differences (Hedge’s g) for comparison in Forest plots and subgroup analysis after assessment of heterogeneity using I2 statistics. Ethics and dissemination This study will summarise the available evidence on the efficacy of lesional interventions for the most frequent tremor disorders, as well as for the incidence rate of persisting side effects after unilateral lesional treatment. This data will be useful to guide future work on incision-less lesional interventions for tremor. Systematic review registration This study has been registered with the PROSPERO database (no. CRD42016048049).

The Temporal Expression Pattern of Alpha-Synuclein Modulates Olfactory Neurogenesis in Transgenic Mice

Background Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS) under the murine Thy1 (mThy1) promoter, a model known to have a particularly high tg expression associated with impaired olfaction. Results Survival of newly generated neurons (NeuN-positive) in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF) promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex. Conclusions The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.

Functional lesional neurosurgery for tremor: back to the future?

For nearly a century, functional neurosurgery has been applied in the treatment of tremor. While deep brain stimulation has been in the focus of academic interest in recent years, the establishment of incisionless technology, such as MRI-guided high-intensity focused ultrasound, has again stirred interest in lesional approaches. In this article, we will discuss the historical development of surgical technique and targets, as well as the technological state-of-the-art of conventional and incisionless interventions for tremor due to Parkinson’s disease, essential and dystonic tremor and tremor related to multiple sclerosis (MS) and midbrain lesions. We will also summarise technique-inherent advantages of each technology and compare their lesion characteristics. From this, we identify gaps in the current literature and derive future directions for functional lesional neurosurgery, in particularly potential trial designs, alternative targets and the unsolved problem of bilateral lesional treatment. The results of a systematic review and meta-analysis of the consistency, efficacy and side effect rate of lesional treatments for tremor are presented separately alongside this article.

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

Dopamine-responsive pattern in tremor patients.

BACKGROUND Diagnosis and treatment of tremor are largely based on clinical assessment. Whereas in some patients tremor may respond to dopaminergic treatment, in general l-Dopa response to tremor varies considerably. The aim of this study was to predict l-Dopa response by accelerometry. METHODS We included 60 tremor patients and measured harmonic oscillations by accelerometry. In addition to neurological assessment, we performed l-Dopa challenge tests and the individual tremor response was compared to the amount of harmonic oscillations. RESULTS We found a strong correlation between harmonic oscillations and clinical l-Dopa response. Similarly, harmonic oscillations were significantly greater in patients with subjective tremor reduction upon l-Dopa administration. CONCLUSIONS We conclude that harmonic oscillations are a measure for l-Dopa response to tremor irrespective of the underlying disease. Because of the observational character of the study, any causal relation remains speculative. Nevertheless, we propose a novel, non-invasive approach to predict l-Dopa response in tremor patients.

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients.