Publications by authors named "Ben Illigens"

61 Publications

Cerebrovascular Risk Profiles in a Saudi Arabian Cohort of Young Stroke Patients.

Front Neurol 2021 12;12:736818. Epub 2021 Nov 12.

Department of Neurology, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany.

The constantly increasing incidence of stroke in younger individuals substantiates an urgent need for research to elucidate underlying risk factors and etiologies. Heretofore, the vast majority of studies on stroke in the young have been carried out in European and North American regions. We aimed to characterize cerebrovascular risk profiles in a Saudi Arabic cohort of consecutive young stroke patients. We retrospectively analyzed data from consecutive ischemic stroke patients aged 15 to 49 years who underwent detailed cardiocerebrovascular evaluation at a tertiary stroke care center in Makkah, Saudi Arabia. Distributions of risk factors and stroke etiologies were assessed in the entire cohort and in two strata of very young (15-40 years) and young to middle-aged patients (41-49) to account for variability in suggested age cutoffs. In the entire cohort [ = 63, ages 44 (34-47) median, interquartile range], dyslipidemia (71.4%) and small vessel occlusion (31.7%) displayed highest prevalence followed by diabetes (52.4%) and cardioembolism (19%). In very young patients, cardioembolism was the most prevalent etiology (27.3%). Risk profiles were similar between both age strata except for a higher prevalence of diabetes among the older cohort (31.8 vs. 63.4%, = 0.01). Logistic regression identified diabetes as strongest predictor for association to the older strata (odds ratio = 4.2, 95% confidence interval = 1.2-14.1, = 0.02). Cerebrovascular risk profiles and stroke etiologies in our cohort of young stroke patients differ from those of previous cohorts, suggesting the need for tailored prevention strategies that take into account local epidemiological data on cerebrovascular health.
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http://dx.doi.org/10.3389/fneur.2021.736818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632802PMC
November 2021

Mapping of predictors of the disengagement of the descending inhibitory pain modulation system in fibromyalgia: an exploratory study.

Br J Pain 2021 May 30;15(2):221-233. Epub 2020 May 30.

Graduate Program in Medical Science, School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.

Background: The main symptoms of fibromyalgia comprise diffuse pain, disability, depressive symptoms, catastrophizing, sleep disruption and fatigue, associated with dysfunction of the descending pain-modulating system (DPMS).

Objectives: We aimed to identify patterns of main symptoms of fibromyalgia and neuroplasticity biomarkers (i.e. brain-derived neurotrophic factor (BDNF) and S100B protein) in non-responders to the conditioned pain modulation task (CPM-task) induced by immersion of hand in cold water (0-1°C). Furthermore, we evaluated if these patterns predict responsiveness to CPM-task.

Methods: This cross-sectional study included 117 women with fibromyalgia (( = 60) non-responders and ( = 57) responders), with age ranging from 30 to 65 years old. We analysed changes in numerical pain scale (NPS-10) during the CPM-task using a standardized protocol.

Results: A hierarchical multivariate logistic regression analysis was used to construct a propensity score-adjusted index to identify non-responders compared to responders to CPM-task. The following variables were retained in the models: analgesic use four or more times per week, heat pain threshold (HPT), poor sleep quality, pain catastrophizing, serum levels of BDNF, number of psychiatric diagnoses and the impact of symptoms of fibromyalgia on quality of life. Receiver operator characteristics (ROC) analysis showed non-responders can be discriminated from responders by a composite index of more frequent symptoms of fibromyalgia and neuroplasticity markers (area under the curve (AUC) = 0.83, sensitivity = 100% and specificity = 98%).

Conclusion: Patterns of fibromyalgia symptoms and neuroplasticity markers may be helpful to predict responsiveness to the CPM-task which might help personalize treatment and thereby contribute to the care of patients with fibromyalgia.
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http://dx.doi.org/10.1177/2049463720920760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138619PMC
May 2021

Percutaneous edge-to-edge repair of severe mitral regurgitation using the MitraClip XTR versus NTR system.

Clin Cardiol 2021 May 24;44(5):708-714. Epub 2021 Mar 24.

Medizinische Klinik und Poliklinik I, University Hospital Munich Campus Grosshadern, Marchioninistraße, München, Deutschland, Germany.

Background: Transcatheter mitral valve repair (TMVR) has shown to improve symptoms and functional capacity in patients with severe mitral valve regurgitation (MR). Novel device developments provide the technology to treat patients with complex anatomies and large coaptation gaps. Nevertheless, the question of superiority of one device remains unanswered. We aimed to compare the MitraClip XTR and MitraClip NTR system in a real world setting.

Hypothesis: TMVR with the MitraClip XTR system is equally effective, but associated with a higher risk of leaflet injury.

Methods: We retrospectively analyzed peri-procedural and mid-term clinical and echocardiographic outcomes of 113 patients treated for severe MR between March 2018 and August 2019 at the University Hospital of Munich.

Results: Postprocedural MR reduction to ≤2+ was comparable in both groups (XTR: 96.1% vs. NTR: 97.6%, p = .38). There was a significant difference in a composite safety endpoint of periprocedural Major adverse cardiac and cerebrovascular events (MACCE) including leaflet injury between groups (XTR 14.6% vs. NTR 1.7%, 95% CI [2.7, 24.6], p = .012). After a median follow-up of 8.5 (4.4, 14.0) months, durable reduction of MR was confirmed (XTR: in 91.9% vs. NTR: 96.8%, p = .31) and clinical and symptomatic improvement was comparable in both groups accordingly.

Conclusion: While efficacy was comparable in both treatment groups, patients treated with the MitraClip XTR systems showed more events of acute leaflet tear and single leaflet device attachment (SLDA). A detailed echocardiographic assessment should be done to identify risk candidates for acute leaflet injury.
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http://dx.doi.org/10.1002/clc.23599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119798PMC
May 2021

Association of RASSF1A, DCR2, and CASP8 Methylation with Survival in Neuroblastoma: A Pooled Analysis Using Reconstructed Individual Patient Data.

Biomed Res Int 2020 15;2020:7390473. Epub 2020 Dec 15.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Neuroblastoma (NB) is a heterogeneous tumor affecting children. It shows a wide spectrum of clinical outcomes; therefore, development of risk stratification is critical to provide optimum treatment. Since epigenetic alterations such as DNA methylation have emerged as an important feature of both development and progression in NB, in this study, we aimed to quantify the effect of methylation of three distinct genes (RASSF1A, DCR2, and CASP8) on overall survival in NB patients. We performed a systematic review using PubMed, Embase, and Cochrane libraries. Individual patient data was retrieved from extracted Kaplan-Meier curves. Data from studies was then merged, and analysis was done on the full data set. Seven studies met the inclusion criteria. Methylation of the three genes had worse overall survival than the unmethylated arms. Five-year survival for the methylated arm of RASSF1A, DCR2, and CASP8 was 63.19% (95% CI 56.55-70.60), 57.78% (95% CI 47.63-70.08), and 56.39% (95% CI 49.53-64.19), respectively, while for the unmethylated arm, it was 93.10% (95% CI 87.40-99.1), 84.84% (95% CI 80.04-89.92), and 83.68% (95% CI 80.28-87.22), respectively. In conclusion, our results indicate that in NB patients, RASSF1A, DCR2, and CASP8 methylation is associated with poor prognosis. Large prospective studies will be necessary to confirm definitive correlation between methylation of these genes and survival taking into account all other known risk factors. (PROSPERO registration number CRD42017082264).
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http://dx.doi.org/10.1155/2020/7390473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755470PMC
June 2021

Risk of Adverse Clinical Outcomes in Hyponatremic Adult Patients Hospitalized for Acute Medical Conditions: A Population-Based Cohort Study.

J Clin Endocrinol Metab 2020 11;105(11)

Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland.

Context: Hyponatremia has been associated with excess long-term morbidity and mortality. However, effects during hospitalization are poorly studied.

Objective: The objective of this work is to examine the association of hyponatremia with the risk of in-hospital mortality, 30-day readmission, and other short-term adverse events among medical inpatients.

Design And Setting: A population-based cohort study was conducted using a Swiss claims database of medical inpatients from January 2012 to December 2017.

Patients: Hyponatremic patients were 1:1 propensity-score matched with normonatremic medical inpatients.

Main Outcome Measure: The primary outcome was a composite of all-cause in-hospital mortality and 30-day hospital readmission. Secondary outcomes were intensive care unit (ICU) admission, intubation rate, length-of-hospital stay (LOS), and patient disposition after discharge.

Results: After matching, 94 352 patients were included in the cohort. Among 47 176 patients with hyponatremia, 8383 (17.8%) reached the primary outcome compared with 7994 (17.0%) in the matched control group (odds ratio [OR] 1.06 [95% CI, 1.02-1.10], P = .001). Hyponatremic patients were more likely to be admitted to the ICU (OR 1.43 [95% CI, 1.37-1.50], P < .001), faced a 56% increase in prolonged LOS (95% CI, 1.52-1.60, P < .001), and were admitted more often to a postacute care facility (OR 1.38 [95% CI 1.34-1.42, P < .001). Of note, patients with the syndrome of inappropriate antidiuresis (SIAD) had lower in-hospital mortality (OR 0.67 [95% CI, 0.56-0.80], P < .001) as compared with matched normonatremic controls.

Conclusion: In this study, hyponatremia was associated with increased risk of short-term adverse events, primarily driven by higher readmission rates, which was consistent among all outcomes except for decreased in-hospital mortality in SIAD patients.
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http://dx.doi.org/10.1210/clinem/dgaa547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500475PMC
November 2020

Excess Mortality Among Hospitalized Patients With Hypopituitarism-A Population-Based, Matched-Cohort Study.

J Clin Endocrinol Metab 2020 11;105(11)

Division of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland.

Context: Patients with hypopituitarism face excess mortality in the long-term outpatient setting. However, associations of pituitary dysfunction with outcomes in acutely hospitalized patients are lacking.

Objective: The objective of this work is to assess clinical outcomes of hospitalized patients with hypopituitarism with or without diabetes insipidus (DI).

Design, Setting, And Patients: In this population-based, matched-cohort study from 2012 to 2017, hospitalized adult patients with a history of hypopituitarism were 1:1 propensity score-matched with a general medical inpatient cohort.

Main Outcome Measures: The primary outcome was in-hospital mortality. Secondary outcomes included all-cause readmission rates within 30 days and 1 year, intensive care unit (ICU) admission rates, and length of hospital stay.

Results: After matching, 6764 cases were included in the study. In total, 3382 patients had hypopituitarism and of those 807 (24%) suffered from DI. All-cause in-hospital mortality occurred in 198 (5.9%) of patients with hypopituitarism and in 164 (4.9%) of matched controls (odds ratio [OR] 1.32, [95% CI, 1.06-1.65], P = .013). Increased mortality was primarily observed in patients with DI (OR 3.69 [95% CI, 2.44-5.58], P < .001). Patients with hypopituitarism had higher ICU admissions (OR 1.50 [95% CI, 1.30-1.74], P < .001), and faced a 2.4-day prolonged length of hospitalization (95% CI, 1.94-2.95, P < .001) compared to matched controls. Risk of 30-day (OR 1.31 [95% CI, 1.13-1.51], P < .001) and 1-year readmission (OR 1.29 [95% CI, 1.17-1.42], P < .001) was higher among patients with hypopituitarism as compared with medical controls.

Conclusions: Patients with hypopituitarism are highly vulnerable once hospitalized for acute medical conditions with increased risk of mortality and adverse clinical outcomes. This was most pronounced among those with DI.
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http://dx.doi.org/10.1210/clinem/dgaa517DOI Listing
November 2020

Evidence for cephalic phase insulin release in humans: A systematic review and meta-analysis.

Appetite 2020 12 21;155:104792. Epub 2020 Jul 21.

Clinic of Endocrinology, Diabetes and Metabolism University Hospital Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland.

The initial release of insulin in response to food stimuli acting on receptors in the head and oropharynx is called the cephalic phase of insulin secretion. Insulin has been shown to act centrally to regulate food intake and glucose metabolism and the cephalic phase of insulin secretion may contribute to these functions. Though well documented in laboratory animals, the existence of cephalic phase insulin release in humans has recently come into question. We therefore performed a systematic review and meta-analysis of studies of cephalic phase insulin release in humans. Efficacy outcomes included any change in circulating insulin levels in healthy human volunteers post any food stimulus as compared to baseline or control in a time period of no longer than 10 min. Primary outcome: The overall pooled effect size estimate for cephalic phase insulin release was 0.47 [0.36, 0.58] p-value <0.0001. Secondary outcomes: A random effects meta-analysis with an added moderator for type of stimulus presentation (one, two, four or five sensory qualities) and type of stimulus offered (liquid, solid formulation) also significantly influenced results p = 0.0116 and p = 0.0024 respectively, while sex had no significant effect. Sensitivity Analysis: More restrictive analyses only including studies that used non-ingestive stimuli (p = 0.0001), or studies that reported insulin values within 5 min post stimulus presentation (p < 0.0001) still showed significant positive overall effect size estimates. In summary, our analysis shows that there is evidence for the presence of cephalic phase insulin secretion in humans. Secondary analyses suggest that the type and presentation of stimulus may significantly influence cephalic phase insulin secretion, while sex had no significant effect on cephalic phase insulin secretion.
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http://dx.doi.org/10.1016/j.appet.2020.104792DOI Listing
December 2020

Machine-learning based exploration of determinants of gray matter volume in the KORA-MRI study.

Sci Rep 2020 05 20;10(1):8363. Epub 2020 May 20.

Department of Radiology, University Hospital, LMU Munich, Munich, Germany.

To identify the most important factors that impact brain volume, while accounting for potential collinearity, we used a data-driven machine-learning approach. Gray Matter Volume (GMV) was derived from magnetic resonance imaging (3T, FLAIR) and adjusted for intracranial volume (ICV). 93 potential determinants of GMV from the categories sociodemographics, anthropometric measurements, cardio-metabolic variables, lifestyle factors, medication, sleep, and nutrition were obtained from 293 participants from a population-based cohort from Southern Germany. Elastic net regression was used to identify the most important determinants of ICV-adjusted GMV. The four variables age (selected in each of the 1000 splits), glomerular filtration rate (794 splits), diabetes (323 splits) and diabetes duration (122 splits) were identified to be most relevant predictors of GMV adjusted for intracranial volume. The elastic net model showed better performance compared to a constant linear regression (mean squared error = 1.10 vs. 1.59, p < 0.001). These findings are relevant for preventive and therapeutic considerations and for neuroimaging studies, as they suggest to take information on metabolic status and renal function into account as potential confounders.
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http://dx.doi.org/10.1038/s41598-020-65040-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239887PMC
May 2020

Biologics and small molecules in patients with scalp psoriasis: a systematic review.

J Dermatolog Treat 2020 Jun 19:1-10. Epub 2020 Jun 19.

Department of Dermatology and Allergology, Ludwig-Maximilian University Munich, Munich, Germany.

Scalp psoriasis is common in psoriasis patients, difficult to treat and manifests a significant burden on quality of life. Efficacy assessment of biologics and small molecules in scalp psoriasis with reported safety and quality of life.: Biological therapies and small molecules licensed for treatment of plaque psoriasis are assessed. Fourteen studies reporting results from RCTs are included. Efficacy assessment is measured through improvement of Psoriasis Scalp Severity Index (PSSI), Scalp Physician Global Assessment (ScPGA) and/or Scalp-Specific Investigator's Global Assessment (ss-IGA). Among biologics measured by PSSI, brodalumab, secukinumab and in a subgroup ixekizumab showed high efficacy in moderate to severe scalp psoriasis. Both brodalumab and ixekizumab demonstrated rapid response within 2 weeks. Guselkumab was superior to adalimumab and ixekizumab was superior to etanercept. Apremilast showed long-term efficacy. Only few studies reported quality of life in treatment of scalp involvement which showed improvement. All treatments demonstrated acceptable safety profile. Effective treatment of scalp psoriasis is essential for improving the quality of life of psoriasis patients. Both Biologics and small molecules proved efficacy. This review may help choosing the appropriate treatment in cases where scalp psoriasis is the main complaint. A unified measurement tool for scalp psoriasis severity is needed to facilitate comparisons.
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http://dx.doi.org/10.1080/09546634.2020.1770167DOI Listing
June 2020

Symptom Recognition Is Impaired in Patients With Orthostatic Hypotension.

Hypertension 2020 05 30;75(5):1325-1332. Epub 2020 Mar 30.

From the Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (R.F., B.M.W.I., I.B., C.H.G.).

Failure to recognize symptoms of orthostatic hypotension (OH) may result in falls, syncope, and injuries. The relationship between orthostatic changes in blood pressure and symptom occurrence and severity is not known. The goal of the present study was to define the relationship between the occurrence and severity of the symptoms of orthostatic hypotension (OH) and (1) the upright systolic blood pressure (SBP) and (2) the fall in SBP after tilting in patients with OH. We prospectively studied 89 patients with OH. Reported BP values include the lowest BP in the first 3 minutes of tilt and the change in blood pressure during tilt. Subjects were queried about symptoms of orthostatic intolerance while supine and during the first 3 minutes of tilt testing using Question 1 of the Orthostatic Hypotension Questionnaire. Mean tilted SBP was 101.6±26.1 mm Hg and mean SBP fall 47.9±18.1 mm Hg. Mean symptom scores when upright were: light-headedness (2.3/10±2.7), dizziness (1.6/10±2.5), and impending blackout (0.8/10±1.9). The majority of patients were asymptomatic or mildly symptomatic and no discrete cutoff for symptoms was observed. The magnitude of the SBP fall (=-0.07, =NS) and the lowest upright SBP (=0.08, =NS) did not correlate with any reported symptom. These results suggest a poor relationship between the magnitude of the orthostatic BP fall, the upright orthostatic BP, and symptoms. Many patients are asymptomatic despite substantial SBP falls and low orthostatic blood pressures. These findings have implications for clinical care of patients with OH and clinical trials to treat patients with OH.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13619DOI Listing
May 2020

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers.

Neurol Sci 2020 Jul 3;41(7):1685-1696. Epub 2020 Mar 3.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson's disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.
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http://dx.doi.org/10.1007/s10072-020-04293-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359149PMC
July 2020

Architecture of the Cutaneous Autonomic Nervous System.

Front Neurol 2019 10;10:970. Epub 2019 Sep 10.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

The human skin is a highly specialized organ for receiving sensory information but also to preserve the body's homeostasis. These functions are mediated by cutaneous small nerve fibers which display a complex anatomical architecture and are commonly classified into cutaneous A-beta, A-delta and C-fibers based on their diameter, myelinization, and velocity of conduction of action potentials. Knowledge on structure and function of these nerve fibers is relevant as they are selectively targeted by various autonomic neuropathies such as diabetic neuropathy or Parkinson's disease. Functional integrity of autonomic skin nerve fibers can be assessed by quantitative analysis of cutaneous responses to local pharmacological induction of axon reflex responses which result in dilation of cutaneous vessels, sweating, or piloerection depending on the agent used to stimulate this neurogenic response. Sensory fibers can be assessed using quantitative sensory test. Complementing these functional assessments, immunohistochemical staining of superficial skin biopsies allow analysis of structural integrity of cutaneous nerve fibers, a technique which has gained attention due to its capacity of detecting pathogenic depositions of alpha-synuclein in patients with Parkinson's disease. Here, we reviewed the current literature on the anatomy and functional pathways of the cutaneous autonomic nervous system as well as diagnostic techniques to assess its functional and structural integrity.
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http://dx.doi.org/10.3389/fneur.2019.00970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746903PMC
September 2019

Autonomic Dysfunction in Preeclampsia: A Systematic Review.

Front Neurol 2019 6;10:816. Epub 2019 Aug 6.

Division of Healthcare Sciences, Center for Clinical Research and Management Education, Dresden International University, Dresden, Germany.

Preeclampsia (PE) is a major obstetric complication that leads to severe maternal and fetal morbidity. Early detection of preeclampsia can reduce the severity of complications and improve clinical outcomes. It is believed that the autonomic nervous system (ANS) is involved in the pathogenesis of PE. We aimed to review the current literature on the prevalence and nature of ANS dysfunction in women with PE and the possible prognostic value of ANS testing in the early detection of PE. Literature search was performed using Medline (1966-2018), EMBase (1947-2018), Google Scholar (1970-2018), BIOSIS (1926-2018), Web of science (1900-2018); CINAHL (1937-2018); Cochrane Library, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Methodology Register (1999-2018). Additionally, the reference lists of articles included were screened. A total of 26 studies were included in the present review presenting data of 1,854 pregnant women. Among these women, 453 were diagnosed with PE, 93.6% (424/453) of which displayed autonomic dysfunction. ANS function was assessed by cardiovascular reflex tests ( = 9), heart rate variability ( = 11), cardiac baroreflex gain ( = 5), muscle sympathetic nerve activity (MSNA) ( = 3), and biomarkers of sympathetic activity ( = 4). Overall, 21 studies (80.8%) reported at least one of the following abnormalities in ANS function in women diagnosed with PE compared to healthy pregnant control women: reduced parasympathetic activity ( = 16/21, 76%), increased sympathetic activity ( = 12/20, 60%), or reduced baroreflex gain ( = 4/5, 80%). Some of these studies indicated that pressor and orthostatic stress test may be useful in early pregnancy to help estimate the risk of developing PE. However, autonomic function tests seem not to be able to differentiate between mild and severe PE. Current evidence suggests that autonomic dysfunction is highly prevalent in pre-eclamptic women. Among autonomic functions, cardiovascular reflexes appear to be predominantly affected, seen as reduced cardiac parasympathetic activity and elevated cardiac sympathetic activity. The diagnostic value of autonomic testing in the prediction and monitoring of autonomic failure in pre-eclamptic women remains to be determined.
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http://dx.doi.org/10.3389/fneur.2019.00816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691156PMC
August 2019

Sex-specific efficacy and safety of cryoballoon versus radiofrequency ablation for atrial fibrillation: A systematic review and meta-analysis.

J Cardiovasc Electrophysiol 2019 10 24;30(10):1819-1829. Epub 2019 Jul 24.

Cardiology Department, University Hospital Basel, Basel, Switzerland.

Background: Atrial fibrillation (AF) is a growing healthcare burden, for which pulmonary vein isolation (PVI) using cryoballoon (CB) or radiofrequency (RF) represent attractive therapies. Women are at higher risk of recurrence after AF ablation and present a specific complications profile. Therefore, a systematic catheter-specific assessment of pulmonary vein isolation is urgently needed in women.

Objective: Systematically assessing the sex-specific efficacy/safety of CB vs RF ablation.

Methods: We performed a structured database search of the scientific literature for randomized controlled trials (RCTs) and observational prospective studies (OPS) comparing CB and RF ablation efficacy at 1 year. We investigated the reporting of sex-specific analyses and assessed the comparative sex-specific efficacy, safety and procedural characteristics of CB vs RF using random-effect meta-regression accounting for the proportion of enrolled women.

Results: Twenty-three studies were included (18 OPS and 5 RCTs) for a total of 13 509 patients. Sex-specific outcomes by ablation device were reported in two and sex-specific regression in four studies, none of which took the ablation device into account. Meta-regression accounting for the proportion of enrolled women showed no significant difference in outcomes between RF or CB.

Conclusion: The sex-specific reporting in trials comparing CB to RF is extremely low. A quantitative meta-regression using the percentage of enrolled women as sex-specific indicator did not show any difference between CB and RF but acknowledging the low percentage of enrolled women and the lack of sex-specific data, further research including patient-level data is urgently needed to draw more definitive conclusions.
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http://dx.doi.org/10.1111/jce.14071DOI Listing
October 2019

Autonomic testing, methods and techniques.

Handb Clin Neurol 2019 ;160:419-433

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States. Electronic address:

The evaluation of autonomic function requires indirect assessment of neurophysiologic function using specialized equipment that is often available only at tertiary care centers, with few specialists available. However, the evaluation of autonomic function is rooted in basic physiology, and the results can be interpreted by careful consideration of the context of the problem. Many automated devices have become widely available to test autonomic function, but they tend to gather inadequate data leading to frequent misdiagnosis and clinical confusion. We review the details necessary for the neurophysiologist to properly perform, and interpret, autonomic function testing.
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http://dx.doi.org/10.1016/B978-0-444-64032-1.00028-XDOI Listing
December 2019

Alpha-Synuclein in Skin Nerve Fibers as a Biomarker for Alpha-Synucleinopathies.

J Clin Neurol 2019 Apr;15(2):135-142

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The common pathological features of synucleinopathies are abnormal aggregates of the synaptic protein alpha-synuclein (αSN) in the cytoplasm of neurons or glia. These abnormal aggregates appear several years before the onset of clinical manifestations, and so the early detection of αSN in body fluids or peripheral tissues (e.g., cerebrospinal fluid, colonic mucosa, salivary glands, and skin) is considered a potential tool for identifying synucleinopathies. Performing a skin biopsy is a practical option because it is a relatively noninvasive, safe, and reliable method to measure αSN deposition in the peripheral nervous system. Moreover, there is growing research interest in the use of cutaneous synuclein deposition as a biomarker for synucleinopathies. The aim of this study was to interpret the current data on cutaneous αSN deposition and present the current perspectives and future prospects.
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http://dx.doi.org/10.3988/jcn.2019.15.2.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444158PMC
April 2019

Carcinoid Heart Disease and Decreased Overall Survival among Patients with Neuroendocrine Tumors: A Retrospective Multicenter Latin American Cohort Study.

J Clin Med 2019 Mar 23;8(3). Epub 2019 Mar 23.

Department of Clinical Oncology, AC Camargo Cancer Center, Sao Paulo 01509-900, Brazil.

The background to this study was that factors associated with carcinoid heart disease (CHD) and its impacts on overall survival (OS) are scantly investigated in patients (pts) with neuroendocrine tumors (NETs). In terms of materials and methods, a retrospective multicenter cohort study was conducted of factors associated with CHD in advanced NET pts with carcinoid syndrome (CS) and/or elevated urinary 5-hidroxyindole acetic acid (u5HIAA). CHD was defined as at least moderate right valve alterations. The results were the following: Among the 139 subjects included, the majority had a midgut NET (54.2%), 81.3% had CS, and 93% received somatostatin analogues. In a median follow-up of 39 months, 48 (34.5%) pts developed CHD, with a higher frequency in pts treated in public (77.2%) versus private settings (22.9%). In a multivariate logistic regression, unknown primary or colorectal NETs (Odds Ratio (OR) 4.35; = 0.002), at least 50% liver involvement (OR 3.45; = 0.005), and being treated in public settings (OR 4.76; = 0.001) were associated with CHD. In a Cox multivariate regression, bone metastases (Hazard Ratio {HR} 2.8; = 0.031), CHD (HR 2.63; = 0.038), and a resection of the primary tumor (HR 0.33; = 0.026) influenced the risk of death. The conclusions were the following: The incidence of CHD was higher in pts with a high hepatic tumor burden and in those treated in a public system. Delayed diagnosis and limited access to effective therapies negatively affected the lives of NET patients.
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http://dx.doi.org/10.3390/jcm8030405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463128PMC
March 2019

Feature selection and prediction of treatment failure in tuberculosis.

PLoS One 2018 20;13(11):e0207491. Epub 2018 Nov 20.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America.

Background: Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control.

Objective: To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure.

Methods: On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone.

Results: The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30-51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance.

Conclusion: Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207491PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245785PMC
April 2019

Assessment of sudomotor function.

Clin Auton Res 2019 02 8;29(1):41-53. Epub 2018 May 8.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Purpose: To review the currently available literature on clinical autonomic tests of sudomotor function.

Methods: We searched PubMED/MEDLINE for articles on technical principles and clinical applications of sudomotor tests with a focus on their drawbacks and perspectives in order to provide a narrative review.

Results: The quantitative sudomotor axon reflex sweat test (QSART) is the most widely used test of sudomotor function. The technique captures pathology with low intra- and inter-subject variability but is limited by technical demands. The thermoregulatory sweat test comprises topographic sweat pattern analysis of the ventral skin surface and allows differentiating preganglionic from postganglionic sudomotor damage when combined with a small fiber test such as QSART. The sympathetic skin response also belongs to the more established techniques and is used in lie detection systems due to its high sensitivity for sudomotor responses to emotional stimuli. However, its clinical utility is limited by high variability of measurements, both within and between subjects. Newer and, therefore, less widely established techniques include silicone impressions, quantitative direct and indirect axon reflex testing, sensitive sweat test, and measurement of electrochemical skin conductance. The spoon test does not allow a quantitative assessment of the sweat response but can be used as bedside-screening tool of sudomotor dysfunction.

Conclusion: While new autonomic sudomotor function testings have been developed and studied over the past decades, the most were well-studied and established techniques QSART and TST remain the gold standard of sudomotor assessment. Combining these techniques allows for sophisticated analysis of neurally mediated sudomotor impairment. However, newer techniques display potential to complement gold standard techniques to further improve their precision and diagnostic value.
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http://dx.doi.org/10.1007/s10286-018-0530-2DOI Listing
February 2019

Should Skin Biopsies Be Performed in Patients Suspected of Having Parkinson's Disease?

Parkinsons Dis 2017 30;2017:6064974. Epub 2017 Oct 30.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.

In patients with Parkinson's disease (PD), the molecularly misfolded form of -synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of -synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural -synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural -synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by -synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson's disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.
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http://dx.doi.org/10.1155/2017/6064974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682910PMC
October 2017

Effect of short-term heart rate variability biofeedback on long-term abstinence in alcohol dependent patients - a one-year follow-up.

BMC Psychiatry 2017 09 6;17(1):325. Epub 2017 Sep 6.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany.

Background: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence.

Methods: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses.

Results: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback.

Conclusion: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRV-biofeedback for alcohol dependence in addition to rehabilitation.

Trial Registration: The original randomized controlled trial was registered in the German Clinical Trials Register ( DRKS00004618 ). This one-year follow-up survey has not been registered.
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http://dx.doi.org/10.1186/s12888-017-1480-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585893PMC
September 2017

Laser Doppler Assessment of Vasomotor Axon Reflex Responsiveness to Evaluate Neurovascular Function.

Front Neurol 2017 14;8:370. Epub 2017 Aug 14.

Department of Neurology, Carl Gustav Carus University Hospital, Technische Universität Dresden, Dresden, Germany.

The vasomotor axon reflex can be evoked in peripheral epidermal nociceptive C-fibers to induce local vasodilation. This neurogenic flare response is a measure of C-fiber functional integrity and therefore shows impairment in patients with small fiber neuropathy. Laser Doppler flowmetry (LDF) and laser Doppler imaging (LDI) are both techniques to analyze vasomotor small fiber function by quantifying the integrity of the vasomotor-mediated axon reflex. While LDF assesses the flare response following acetylcholine iontophoresis with temporal resolution at a single defined skin point, LDI records flare responses with spatial and temporal resolution, generating a two-dimensional map of superficial blood flow. LDF is characterized by a high intra- and interindividual measurement variability, which is smaller in LDI due to its spatial resolution. Nevertheless, LDI still lacks standardized methods for image analysis. Consequently, use of the technique currently remains on an experimental level. Here, we sought to review the current literature on laser Doppler assessment of vasomotor function and discuss potential future applications of established techniques as well as those that are still experimental.
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http://dx.doi.org/10.3389/fneur.2017.00370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557735PMC
August 2017

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease (CAPTURE PD): Protocol for a Multicenter Study.

Front Neurol 2017 26;8:212. Epub 2017 May 26.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.

Background: In Parkinson's disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function quantitative direct and indirect test of sudomotor function.

Methods/design: A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1-2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation.

Discussion: We anticipate that progression of autonomic nerve dysfunction assessed pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD.

Clinical Trail Registration: TRN NCT03043768.
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http://dx.doi.org/10.3389/fneur.2017.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445122PMC
May 2017

Towards standardization of F-FET PET imaging: do we need a consistent method of background activity assessment?

EJNMMI Res 2017 Dec 30;7(1):48. Epub 2017 May 30.

Department of Nuclear Medicine, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Background: PET with O-(2-F-fluoroethyl)-L-tyrosine (F-FET) has reached increasing clinical significance for patients with brain neoplasms. For quantification of standard PET-derived parameters such as the tumor-to-background ratio, the background activity is assessed using a region of interest (ROI) or volume of interest (VOI) in unaffected brain tissue. However, there is no standardized approach regarding the assessment of the background reference. Therefore, we evaluated the intra- and inter-reader variability of commonly applied approaches for clinical F-FET PET reading. The background activity of 20 F-FET PET scans was independently evaluated by 6 readers using a (i) simple 2D-ROI, (ii) spherical VOI with 3.0 cm diameter, and (iii) VOI consisting of crescent-shaped ROIs; each in the contralateral, non-affected hemisphere including white and gray matter in line with the European Association of Nuclear Medicine (EANM) and German guidelines. To assess intra-reader variability, each scan was evaluated 10 times by each reader. The coefficient of variation (CoV) was assessed for determination of intra- and inter-reader variability. In a second step, the best method was refined by instructions for a guided background activity assessment and validated by 10 further scans.

Results: Compared to the other approaches, the crescent-shaped VOIs revealed most stable results with the lowest intra-reader variabilities (median CoV 1.52%, spherical VOI 4.20%, 2D-ROI 3.69%; p < 0.001) and inter-reader variabilities (median CoV 2.14%, spherical VOI 4.02%, 2D-ROI 3.83%; p = 0.001). Using the guided background assessment, both intra-reader variabilities (median CoV 1.10%) and inter-reader variabilities (median CoV 1.19%) could be reduced even more.

Conclusions: The commonly applied methods for background activity assessment show different variability which might hamper F-FET PET quantification and comparability in multicenter settings. The proposed background activity assessment using a (guided) crescent-shaped VOI allows minimization of both intra- and inter-reader variability and might facilitate comprehensive methodological standardization of amino acid PET which is of interest in the light of the anticipated EANM technical guidelines.
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http://dx.doi.org/10.1186/s13550-017-0295-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5449315PMC
December 2017

Vascular Endothelial Growth Factor Prevents Endothelial-to-Mesenchymal Transition in Hypertrophy.

Ann Thorac Surg 2017 Sep 5;104(3):932-939. Epub 2017 May 5.

Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: In hypertrophy, progressive loss of function caused by impaired diastolic compliance correlates with advancing cardiac fibrosis. Endothelial cells contribute to this process through endothelial-to-mesenchymal transition (EndMT) resulting from inductive signals such as transforming growth factor (TGF-β). Vascular endothelial growth factor (VEGF) has proven effective in preserving systolic function and delaying the onset of failure. In this study, we hypothesize that VEGF inhibits EndMT and prevents cardiac fibrosis, thereby preserving diastolic function.

Methods: The descending aorta was banded in newborn rabbits. At 4 and 6 weeks, hypertrophied animals were treated with intrapericardial VEGF protein and compared with controls (n = 7 per group). Weekly transthoracic echocardiography measured peak systolic stress. At 7 weeks, diastolic stiffness was determined through pressure-volume curves, fibrosis by Masson trichrome stain and hydroxyproline assay, EndMT by immunohistochemistry, and activation of TGF-β and SMAD2/3 by quantitative real-time polymerase chain reaction.

Results: Peak systolic stress was preserved during the entire observation period, and diastolic compliance was maintained in treated animals (hypertrophied: 20 ± 1 vs treated: 11 ± 3 and controls: 12 ± 2; p < 0.05). Collagen was significantly higher in the hypertrophied group by Masson trichrome (hypertrophied: 3.1 ± 0.9 vs treated: 1.8 ± 0.6) and by hydroxyproline assay (hypertrophied: 2.8 ± 0.6 vs treated: 1.4 ± 0.4; p < 0.05). Fluorescent immunostaining showed active EndMT in the hypertrophied group but significantly less in treated hearts, which was directly associated with a significant increase in TGF-β/SMAD-2 messenger RNA expression.

Conclusions: EndMT contributes to cardiac fibrosis in hypertrophied hearts. VEGF treatment inhibits EndMT and prevents the deposition of collagen that leads to myocardial stiffness through TGF-β/SMAD-dependent activation. This presents a therapeutic opportunity to prevent diastolic failure and preserve cardiac function in pressure-loaded hearts.
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http://dx.doi.org/10.1016/j.athoracsur.2017.01.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572504PMC
September 2017

Neuropsychiatric symptoms in untreated Parkinson's disease.

Neuropsychiatr Dis Treat 2017 16;13:815-826. Epub 2017 Mar 16.

Department of Neurology, Semmelweis University, Budapest, Hungary.

Neuropsychiatric and cognitive symptoms are common in Parkinson's disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.
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http://dx.doi.org/10.2147/NDT.S130997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360401PMC
March 2017

Alpha-synuclein in cutaneous small nerve fibers.

Neuropsychiatr Dis Treat 2016 25;12:2731-2735. Epub 2016 Oct 25.

Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Despite progression in the development of pharmacological therapy, treatment of alpha synucleinopathies, such as Parkinson's disease (PD) and some atypical parkinsonism syndromes, is still challenging. To date, our knowledge of the mechanisms whereby the pathological form of alpha-synuclein causes structural and functional damage to the nervous system is limited and, consequently, there is a lack of specific diagnostic tools to evaluate pathology in these patients and differentiate PD from other neurodegenerative proteinopathies. Recent studies indicated that alpha-synuclein deposition in cutaneous small nerve fibers assessed by skin biopsies might be a valid disease marker of PD and facilitate early differentiation of PD from atypical parkinsonism syndromes. This observation is relevant since early diagnosis may enable timely treatment and improve quality of life. However, challenges include the necessity of standardizing immunohistochemical analysis techniques and the identification of potential distinct patterns of intraneural alpha-synuclein deposition among synucleinopathies. In this perspective, we explore the scientific and clinical opportunities arising from alpha-synuclein assessment using skin biopsies. These include elucidation of the peripheral nervous system pathology of PD and other synucleinopathies, identification of novel targets to study response to neuroprotective treatment, and improvement of clinical management. Furthermore, we discuss future challenges in exploring the diagnostic value of skin biopsy assessment for alpha-synuclein deposition and implementing the technique in clinical practice.
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http://dx.doi.org/10.2147/NDT.S117423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087811PMC
October 2016

Pilomotor function is impaired in patients with Parkinson's disease: A study of the adrenergic axon-reflex response and autonomic functions.

Parkinsonism Relat Disord 2016 10 11;31:129-134. Epub 2016 Aug 11.

Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Introduction: Autonomic nervous system disturbances including sweating abnormalities and cardiovascular symptoms are frequent in Parkinson's disease (PD) and often precede motor involvement. Cholinergic vasomotor and sudomotor skin nerves are impaired in patients with PD even at early disease stages. We hypothesized that adrenergic pilomotor nerve function is similarly impaired in early PD and might constitute a novel diagnostic target.

Methods: We conducted a study in 12 PD patients (Hoehn&Yahr 1-2) and 12 healthy control subjects. Pilomotor function was evaluated after iontophoresis of phenylephrine on the dorsal forearm to elicit axon-reflex mediated pilomotor erection (goose bumps). Silicone impressions were obtained, scanned and quantified for pilomotor muscle impressions by number, area and axon-reflex spread. Vasomotor function was evaluated using laser Doppler flowmetry and sudomotor function via sympathetic skin response. Cardiac autonomic function was assessed via heart rate variability. Severity of autonomic symptoms was evaluated using the Scales for Outcomes in Parkinson's disease-Autonomic questionnaire.

Results: Pilomotor response was reduced in PD patients compared to control subjects (impression number: 12.2 ± 8.2 vs. 16.5 ± 5.9, p < 0.05; impression area: 10.8 ± 2.2 mm vs. 24.8 ± 3.1 mm, p < 0.01; axon-reflex spread: 89.0 ± 10.6 mm vs. 185.9 ± 10.8 mm, p < 0.01) and correlated negatively with severity of autonomic symptoms (p < 0.01). Similarly, sudomotor (p < 0.01) and vasomotor (p < 0.05) but not cardiac autonomic (p = n.s.) function were reduced in PD patients versus control subjects.

Conclusion: Pilomotor function is impaired in early stages of PD. Pilomotor axon-reflex assessment might be useful in the investigation of disease related pathology and supplement other clinical markers of autonomic neuropathy in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2016.08.001DOI Listing
October 2016

Randomized controlled trials - a matter of design.

Neuropsychiatr Dis Treat 2016 10;12:1341-9. Epub 2016 Jun 10.

Center for Clinical Research and Management Education, Division of Health Care Sciences, Dresden International University, Dresden, Saxony, Germany; Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Saxony, Germany; Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, Oxfordshire, UK.

Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.
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http://dx.doi.org/10.2147/NDT.S101938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910682PMC
June 2016
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