A comparative blind study between skin biopsy and seed amplification assay to disclose pathological α-synuclein in RBD.

To compare the diagnostic accuracy of the immunofluorescence (IF) technique and aSyn-seed amplification assay (aSyn-SAA) of skin and cerebrospinal fluid (CSF) in disclosing pathological α-syn in idiopathic idiopathic REM sleep behavior disorder (iRBD) as early phase of a synucleinopathy. We prospectively recruited 41 patients with iRBD and 40 matched clinical controls including RBD associated with type 1 Narcolepsy (RBD-NT1, 21 patients), iatrogenic causes (2 pt) or OSAS (6 pt) and 11 patients with peripheral neuropathies. IF from samples taken by skin biopsy and aSyn-SAA from skin and CSF samples were analysed blinded to the clinical diagnosis. IF showed a good diagnostic accuracy (89%) that was lower in the case of skin and CSF-based aSyn-SAA (70% and 69%, respectively) because of a lower sensitivity and specificity. However, IF showed a significant agreement with CSF aSyn-SAA. In conclusion, our data may favor the use of skin biopsy and aSyn-SAA as diagnostic tools for a synucleinopathy in iRBD.

Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study.

OBJECTIVE/METHODS: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. RESULTS: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. CONCLUSIONS: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Objective rest-activity cycle analysis by actigraphy identifies isolated rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviours during REM sleep. Several studies showed that iRBD is a prodromal stage of synucleinopathies. Therefore, identifying iRBD in the general population is of utmost importance. In this study, we explore whether the assessment of rest-activity rhythm features can distinguish patients with iRBD from patients with disorders characterized by other pathological motor activity during sleep and healthy controls. METHODS: Nineteen patients with video-polysomnographic diagnosis of iRBD, 39 patients with other disorders with motor activity during sleep [19 with restless leg syndrome (RLS) and 20 with untreated sleep apnea syndrome (SAS)] and 16 healthy controls underwent 2-week actigraphy and video-polysomnography, and completed REM sleep behavior disorder screening questionnaires. Non-parametric analyses were applied to assess the rest-activity rhythm features. RESULTS: Patients with iRBD showed lower sleep efficiency, increased estimated wake after sleep onset and increased frequency of prolonged activity bouts compared to those with RLS and controls, while no difference emerged compared with SAS patients. Moreover, patients with iRBD presented increased occurrence of estimated nap in comparison to those with RLS, those with SAS and controls. The I < O, a 24-h measure that expresses the relationship between nocturnal and diurnal motor activity intensity, distinguished patients with iRBD from those with RLS, those with SAS and controls, with an area under the curve greater than that of REM sleep behavior disorder screening questionnaires. An I < O of 98.32 shows the best balance between sensitivity (63.2%) and specificity (89.1%). DISCUSSION: The I < O index distinguished iRBD patients from those with other pathological motor activity during sleep and controls, confirming its use as an objective measure suitable to screen large at-risk populations.

Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility.

BACKGROUND AND PURPOSE: Visualization of phosphorylated α-synuclein at serine 129 (p-syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to establish the intra- and inter-laboratory reproducibility of measurement of intraneural p-syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna). METHODS: In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA-P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p-syn and the pan-axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re-evaluated to understand the reasons for the discrepancy. RESULTS: The intra-laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter-laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals. CONCLUSIONS: Analysis of p-syn showed excellent inter- and intra-laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique.

Cerebral Mitochondrial Microangiopathy Leads to Leukoencephalopathy in Mitochondrial Neurogastrointestinal Encephalopathy.

BACKGROUND AND PURPOSE: Mitochondrial neurogastrointestinal encephalopathy is a rare disorder due to recessive mutations in the thymidine phosphorylase gene, encoding thymidine phosphorylase protein required for mitochondrial DNA replication. Clinical manifestations include gastrointestinal dysmotility and diffuse asymptomatic leukoencephalopathy. This study aimed to elucidate the mechanisms underlying brain leukoencephalopathy in patients with mitochondrial neurogastrointestinal encephalopathy by correlating multimodal neuroradiologic features to postmortem pathology. MATERIALS AND METHODS: Seven patients underwent brain MR imaging, including single-voxel proton MR spectroscopy and diffusion imaging. Absolute concentrations of metabolites calculated by acquiring unsuppressed water spectra at multiple TEs, along with diffusion metrics based on the tensor model, were compared with those of healthy controls using unpaired t tests in multiple white matters regions. Brain postmortem histologic, immunohistochemical, and molecular analyses were performed in 1 patient. RESULTS: All patients showed bilateral and nearly symmetric cerebral white matter hyperintensities on T2-weighted images, extending to the cerebellar white matter and brain stem in 4. White matter, N-acetylaspartate, creatine, and choline concentrations were significantly reduced compared with those in controls, with a prominent increase in the radial water diffusivity component. At postmortem examination, severe fibrosis of brain vessel smooth muscle was evident, along with mitochondrial DNA replication depletion in brain and vascular smooth-muscle and endothelial cells, without neuronal loss, myelin damage, or gliosis. Prominent periependymal cytochrome C oxidase deficiency was also observed. CONCLUSIONS: Vascular functional and histologic alterations account for leukoencephalopathy in mitochondrial neurogastrointestinal encephalopathy. Thymidine toxicity and mitochondrial DNA replication depletion may induce microangiopathy and blood-brain-barrier dysfunction, leading to increased water content in the white matter. Periependymal cytochrome C oxidase deficiency could explain prominent periventricular impairment.

Spectral electroencephalography profile of rapid eye movement sleep at sleep onset in narcolepsy type 1.

BACKGROUND AND PURPOSE: The sleep-onset rapid eye movement (REM) period (SOREMP), the hallmark of narcolepsy, may be a specific state and not the simple anticipation of REM sleep. METHODS: We analyzed the electroencephalographic spectral content in untreated patients with narcolepsy type 1 (NT1) during the sleep-onset period (SOP) and during nocturnal REM sleep in two consecutive nocturnal recordings from 31 patients with NT1 (mean age 34 ± 15 years, 18 males) and a single nocturnal recording from 36 controls (mean age 38 ± 13 years, 21 males). The SOP was defined as the first 10 min starting at the beginning of the first epoch of any sleep stage, and further divided into two consecutive 5-min periods (SOP-1 and SOP-2); 1 min of artifact-free quiet wakefulness after lights-off was identified as well as 5 min of REM sleep in the middle of the night and another 5 min during the last REM sleep period. Electroencephalographic spectral analysis was performed using the C3/A2 channel. RESULTS: The SOP-1 and, more strikingly, SOP-2 had significantly less delta and sigma activity in patients with NT1 in the SOREMP condition versus both controls and patients with NT1 without SOREMP. SOP-2 also showed less theta and alpha activity. Conversely, sigma and beta activity were more represented during SOREMP compared with the nocturnal REM period in patients with NT1. CONCLUSIONS: The analysis of the SOP supports the concept that SOREMP is a different state compared with both nocturnal REM sleep and non-REM sleep onset.

World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG).

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5-10 s long or bilateral LM 0.5-15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval <10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM > 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

Age-related differences in sleep-dependent consolidation of motor skills in patients with narcolepsy type 1.

OBJECTIVE: The influence of post-training sleep on the consolidation process of procedural (ie, visual and motor) knowledge has shown to be less effective in patients with chronic sleep disorders compared with healthy subjects. To ascertain whether the influence of the altered architecture of sleep in patients with narcolepsy type 1 (ie, with cataplexy: NT1) also varies with age, we compared the performance values of 16 children (aged from nine to 14 years) and 16 adults (aged from 24 to 51 years) on finger tapping task (FTT) after daytime and nighttime periods of sleep in the 24 hours following training. METHODS: All patients, who were drug-free and underwent continuous polysomnographic recordings, could take one or more naps after the training session (at 10 a.m.) until one hour before the first retrieval session (at 6 p.m.) and had an undisturbed period of nighttime sleep from about 10 p.m. to two hours before the second retrieval session (again at 10 a.m.). RESULTS: The pattern of sleep-dependent consolidation was significantly different in the two groups of patients: while performance accuracy was higher in adults compared with children at each session, performance speed improved after daytime sleep in children and after nighttime sleep in adults. The improvement in performance speed, although not related with any sleep parameters in both groups, was positively correlated with the daytime and nighttime total sleep time (TST) in children with greater consolidation gain. CONCLUSION: The interaction between time of day and age in the time course of consolidation of new motor skills discloses a different role of daytime sleep (active in children, simply protective from interferences in adults) in NT1 patients and suggests a flexible use of napping in the educational context.

Neuropathic pain following spinal cord injury: what we know about mechanisms, assessment and management.

BACKGROUND: In biology, it is easy to understand how a damaged functional system may generate wrong signals, but why this should happen when the system is disconnected is less clear. For this reason, among other pain syndromes, neuropathic pain (NP) following spinal cord injury (SCI) leaves most questions unanswered. AIMS AND METHODS: Our purpose is to review current knowledge on NP after SCI, focusing on the mechanisms, assessment and management of the syndrome. RESULTS: The mechanisms responsible for NP following SCI are poorly understood: NP is classically considered a "central pain syndrome" but recent evidence from experimental models reveals a possible "peripheral sensitization". Assessment of NP following SCI is well-established: in addition to clinical evaluation and self-reported scales, many neurophysiological, radiological and microscopic investigations may be performed. The management of NP following SCI is very difficult: evidence of effective drugs is lacking and alternative new treatment approaches yield different outcomes. CONCLUSIONS: Recently clinical and instrumental tools have increased our knowledge on NP, suggesting that the discovery of new treatment agents will depend on an explanation of what changes after SCI: future research must point in this direction.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Sleep-dependent consolidation of motor skills in patients with narcolepsy-cataplexy.

BACKGROUND AND OBJECTIVES: This study investigated whether the altered organization of post-training sleep in patients with narcolepsy-cataplexy (NC) is associated with a lower off-line improvement in the consolidation of motor skills compared with normal subjects. STUDY DESIGN: Fourteen drug-naive NC patients, fulfilling the international clinical and polysomnographic diagnostic criteria, and 14 individually-matched controls underwent training at a sequential finger tapping task (FTT) and were re-tested on the next morning (after a night with polysomnographic recording) and after another six nights (spent at home). SETTING: Training and retrieval sessions were performed in a controlled laboratory setting. RESULTS: FTT performance was worse in NC patients than controls at training and at both retrieval sessions and showed a fairly different time course (slower than in controls) of consolidation. Several sleep indices (lower values of stage-2 NREM sleep and SWS) were compatible with a lower effectiveness of sleep for consolidation of motor skills in NC patients, although no statistically significant relationship was found between such indices and improvement rate. CONCLUSION: The consolidation process of motor skills results less effective in NC patients since training and slower than in normal subjects over the week following training. The wider variations in performance scores and sleep parameters of post.-training night in NC patients relative to controls suggest that a) the lower initial consolidation may be due to a less effective encoding consequent to altered prior sleep, and b) the consolidation process over the 24 h following training is negatively influenced not only by the altered characteristics of post-training sleep, but also by the daytime sleepiness following training.

Combined brain voxel-based morphometry and diffusion tensor imaging study in idiopathic restless legs syndrome patients.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the presence of abnormalities in the brain of patients with restless legs syndrome (RLS) using voxel-based morphometry and diffusion tensor imaging (DTI). METHODS: Twenty patients and twenty controls were studied. Voxel-based morphometry analysis was performed using statistical parametric mapping (SPM8) and FSL-VBM software tools. For voxel-wise analysis of DTI, tract-based spatial statistics (TBSS) and SPM8 were used. RESULTS: Applying an appropriate threshold of probability, no significant results were found either in comparison or in correlation analyses. CONCLUSIONS: Our data argue against clear structural or microstructural abnormalities in the brain of patients with idiopathic RLS, suggesting a prevalent role of functional or metabolic impairment.

Family recurrence and oligo-anuria predict uremic restless legs syndrome.

OBJECTIVES: To determine clinical and laboratory predictors of restless legs syndrome (RLS) in patients with end-stage kidney disease (ESKD) undergoing long-term hemodialysis (HD). MATERIALS AND METHODS: One hundred and sixty-two consecutive patients were assessed. History of sleep disturbances, neurological examination, clinical, and laboratory data were collected. Patients with and without RLS were compared, and a logistic regression model described the relations between independent predictors and RLS. RESULTS: Fifty-one patients (32%) currently had RLS (RLS+). RLS+ vs RLS- patients were more frequently women (49% vs 29%, P = 0.012), had first-degree relative with RLS (22% vs 6%, P = 0.004), insomnia (59% vs 36%, P = 0.007), peripheral neuropathy (41% vs 21%, P = 0.006), and low residual diuresis (92% vs 68% with below 500 ml/24 h, P = 0.001). Low (OR = 8.71, CI = 2.27-33.41; P = 0.002) and absent (OR = 4.96, CI = 1.52-16.20; P = 0.008) residual diuresis, peripheral neuropathy (OR = 4.00, CI = 1.44-11.14; P = 0.008), and first-degree relative with RLS (OR = 3.82, CI = 1.21-12.13; P = 0.023) significantly predicted RLS in ESKD patients undergoing HD. CONCLUSION: Positive family history for RLS together with reduced/absent residual renal function and peripheral neuropathy predicts the risk for RLS in ESKD patients undergoing HD. Longitudinal studies are warranted to correlate RLS occurrence with genetic and environmental factors.

[Guidelines for the fitness to drive assessment in people with obstructive sleep apnoea syndrome (OSAS) and narcolepsy]. / Linee guida per l'accertamento dell'idoneità alla guid in soggetti affetti da Sindrome delle apnee ostruttive del sonno (OSAS) e Narcolessia.

Given the prevalence of sleep disorders and sleep deprivation in modern societies, and the correlation between sleepiness and work and driving accidents, the excessive daytime sleepiness is an important issue. Although many studies showed that patients with untreated Obstructive sleep apnoea syndrome (OSAS) and narcolepsy have an higher risk for driving accidents, neither the European Community regulation nor the Italian law of the driving licence mention restrictions for these disorders. In 2010 the scientific association COMLAS (Association of legal medicine professionals of the Italian National Health Service) published the Guidelines for the examination by the Local Medical Commissions. The author presented the guidelines to assess the fitness to drive of people with OSAS or narcolepsy. The proposed criteria, set up in collaboration with the Commission "Sleepiness, Safety and Transportation" of the Italian Association of Sleep Medicine (AIMS), can be considered among the most advanced internationally.

Spectral analysis of heart rate variability reveals an enhanced sympathetic activity in narcolepsy with cataplexy.

OBJECTIVE: To test the autonomic control of cardiovascular reflexes and heart rate variability (HRV) at rest and during orthostatic stress in narcolepsy with cataplexy (NC). METHODS: Ten NC patients with a hypocretin deficit and 18 control subjects underwent head-up tilt test (HUTT), Valsalva manoeuvre, deep breathing and cold face under controlled laboratory conditions. Heart rate variability (HRV) was analysed during supine rest and HUTT considering the normalized unit of LF and HF power (LFnu; HFnu), using autoregressive (AR) and fast Fourier transform (FFT) algorithms. RESULTS: Cardiovascular changes during HUTT, Valsalva manoeuvre, deep breathing, isometric handgrip and cold face were normal and comparable in the two groups. AR and FFT analysis showed an increased LF/HF ratio in NC patients during supine rest. As expected, LFnu increased and HFnu decreased in the control group during HUTT, but did not change in narcoleptics being comparable to values in the supine condition. CONCLUSIONS: NC patients showed an increased sympathetic drive on heart rate (HR) in the supine condition that did not further increase during HUTT. SIGNIFICANCE: These results suggest the proper functioning of cardiovascular reflexes in NC but support an impairment of HR modulation at rest in favour of an enhanced sympathetic activity.

Increased prevalence of nocturnal smoking in restless legs syndrome (RLS).

OBJECTIVE: We investigated the prevalence of nocturnal smoking (NS) in patients with RLS. METHODS: One hundred RLS patients living in Emilia-Romagna (Northern Italy) and 100 matched controls, randomly selected from the general population, underwent interviews for the presence of nocturnal smoking and for obsessive-compulsive traits, depression, excessive daytime sleepiness (EDS) and subjective sleep quality. RESULTS: NS was more prevalent in RLS patients than controls (lifetime prevalence: 12% vs. 2%, P=0.012). Patients with NS had more frequently Sleep-Related Eating Disorders (SRED) than patients without NS (83.3% vs. 26.1%, P=0.0002). Pathological and borderline Maudsley Obsessive-Compulsive Inventory (MOCI) values as well as pathological values at the Beck Depression Inventory (BDI) increased from controls to RLS patients without NS to RLS patients with NS (P=0.005 and P=0.01, respectively). CONCLUSIONS: We demonstrate an increased prevalence of NS in patients with RLS, in many cases associated with increased SRED. NS may be associated with psychopathological traits in RLS and may be relevant in the management of RLS patients.

Agrypnia Excitata: a microneurographic study of muscle sympathetic nerve activity.

OBJECTIVE: Agrypnia Excitata (AE) is characterized by autonomic over-activity and cardiovascular fluctuations but direct evidence of sympathoexcitation is lacking. AE is a common feature of acquired (i.e. Morvan's syndrome--MS) and genetic (i.e. fatal familial insomnia--FFI) conditions where a dysfunction of the thalamo-limbic system has been suggested. The aim of this study is to report the first microneurographic recordings of sympathetic activity in acquired and genetic AE to investigate the pattern of sympathetic activation. METHODS: We describe two patients presenting acquired AE (MS) as demonstrated by elevated serum antibody levels to voltage-gated potassium channels and one patient with genetically confirmed FFI. Patients and fifteen sex and age-matched healthy controls underwent microneurography from peroneal nerve to assess muscle sympathetic nerve activity (MSNA) and heart rate (HR). RESULTS: Mean level of resting awake MSNA and HR was significantly increased in patients compared to controls. Patients presented a similar pattern of MSNA with a normal cardiac rhythmicity and a very high burst incidence expressed in approximately each cardiac beat. CONCLUSIONS: Acquired and genetic AE presented a resting awake sympathetic over-activity. SIGNIFICANCE: AE patients may develop high blood pressure and/or cardiovascular instability potentially increasing the morbidity/mortality of the underlying disorders.