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2.
Clin Auton Res ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193800

RESUMO

BACKGROUND: REM sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients presenting with idiopathic RBD (iRBD), and the predictive value of autonomic dysfunction for phenoconversion to a defined neurodegenerative disease. METHODS: We searched our electronic medical record for patients diagnosed with iRBD who also underwent standardized autonomic function testing within 6 months of iRBD diagnosis, and who had clinical follow-up of at least 3 years following iRBD diagnosis. The composite autonomic severity score (CASS) was derived and compared between phenoconverters and non-converters using chi-square and Wilcoxon rank-sum tests. RESULTS: We identified 18 patients who fulfilled inclusion and exclusion criteria. Average age at autonomic testing was 67 ± 6.6 years. Twelve (67%) patients phenoconverted during the follow-up period; six developed Parkinson's disease (PD), and the other six, dementia with Lewy bodies (DLB). Fifteen (83%) patients had at least mild autonomic dysfunction. There were no significant differences between overall converters and non-converters in total CASS or CASS subscores. However, iRBD patients who developed DLB had significantly higher total and cardiovagal CASS scores compared with those who developed PD (p < 0.05), and a trend for higher adrenergic CASS scores compared to those who developed PD and those who did not phenoconvert. DISCUSSION: Autonomic dysfunction was seen in 83% of iRBD patients, and more severe baseline cardiovagal autonomic dysfunction in iRBD was associated with phenoconversion to DLB but not PD. Prospective studies are needed to confirm the value of autonomic testing for predicting phenoconversion and disease phenotype in iRBD.

4.
Nature ; 578(7794): 273-277, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025029

RESUMO

Synucleinopathies are neurodegenerative diseases that are associated with the misfolding and aggregation of α-synuclein, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy1. Clinically, it is challenging to differentiate Parkinson's disease and multiple system atrophy, especially at the early stages of disease2. Aggregates of α-synuclein in distinct synucleinopathies have been proposed to represent different conformational strains of α-synuclein that can self-propagate and spread from cell to cell3-6. Protein misfolding cyclic amplification (PMCA) is a technique that has previously been used to detect α-synuclein aggregates in samples of cerebrospinal fluid with high sensitivity and specificity7,8. Here we show that the α-synuclein-PMCA assay can discriminate between samples of cerebrospinal fluid from patients diagnosed with Parkinson's disease and samples from patients with multiple system atrophy, with an overall sensitivity of 95.4%. We used a combination of biochemical, biophysical and biological methods to analyse the product of α-synuclein-PMCA, and found that the characteristics of the α-synuclein aggregates in the cerebrospinal fluid could be used to readily distinguish between Parkinson's disease and multiple system atrophy. We also found that the properties of aggregates that were amplified from the cerebrospinal fluid were similar to those of aggregates that were amplified from the brain. These findings suggest that α-synuclein aggregates that are associated with Parkinson's disease and multiple system atrophy correspond to different conformational strains of α-synuclein, which can be amplified and detected by α-synuclein-PMCA. Our results may help to improve our understanding of the mechanism of α-synuclein misfolding and the structures of the aggregates that are implicated in different synucleinopathies, and may also enable the development of a biochemical assay to discriminate between Parkinson's disease and multiple system atrophy.

5.
Auton Neurosci ; 223: 102550, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928708

RESUMO

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and above noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, POTS or other forms of dysautonomia. CONCLUSIONS: Certain conditions are prevalent in the same patient populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is insufficient proof of causality.

6.
Neurogastroenterol Motil ; 32(2): e13744, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31642143

RESUMO

BACKGROUND: The relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non-ulcer dyspepsia (NUD). METHODS: In 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study. KEY RESULTS: Baseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE. CONCLUSIONS & INFERENCES: Up to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM.

7.
Clin Auton Res ; 30(1): 13-18, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31475305

RESUMO

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

8.
Clin Auton Res ; 30(1): 69-77, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30604164

RESUMO

PURPOSE: To assess the ability of the Orthostatic Discriminant and Severity Scale (ODSS) to distinguish symptoms of orthostatic intolerance from non-orthostatic symptoms. METHODS: Clinical evaluations and questionnaire responses were collected in 73 healthy controls and 132 patients referred to the Autonomic Disorders Clinic from September 1, 2016, through April 30, 2018, for queries regarding autonomic dysfunction. A receiver operating characteristic (ROC) curve analysis was used to interpret sensitivity and specificity and to determine cutoff scores for symptom assessment. Inter-item reliability was assessed using Cronbach's alpha. To calculate positive and negative predictive powers, patient data were collected in a single-blinded fashion where the researcher collecting questionnaire data was blinded to the clinical evaluation and diagnosis. Predictive powers were calculated using a chi-squared cross-tabulation. RESULTS: The orthostatic and non-orthostatic symptoms scores produced ROC curves with an area under the curve of 0.89 and 0.79, respectively. The orthostatic scores yielded a positive and negative predictive power value of 73% and 81%, respectively. Combined, the ODSS identified patients with and without orthostatic symptoms with an overall accuracy of 76%. The reliability of the ODSS was significant, with a Cronbach's alpha of 0.88, and all dichotomous items were deemed worthy of retention following an inter-item reliability assessment. CONCLUSIONS: The ODSS demonstrated a strong ability to distinguish patients with and without orthostatic intolerance and demonstrated sensitivity and specificity equivalent to that of other standardized measures. Overall, the ODSS produces symptom scores that are both reliable and useful for both research and clinical practice.

10.
Auton Neurosci ; 222: 102589, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31706219

RESUMO

INTRODUCTION: Forearm QSWEAT recordings are occasionally absent in females, likely due to high skin resistance. METHODS: We identified consecutive subjects with no sudomotor abnormalities but absent/markedly reduced QSWEAT forearm volume, and repeated QSWEAT at the same site after gentle abrasion. RESULTS: QSWEAT volumes were absent for 4 subjects and markedly reduced for the other 4 (median 0.01, IQR 0-0.03). After gentle skin abrasion, repeat volumes were significantly higher for all subjects and became normal in 7 of 8 subjects. DISCUSSION: Skin abrasion restores QSWEAT volumes in previously absent/markedly reduced site suggesting that skin preparation using abrasion is more effective.

11.
Neurology ; 93(14): 630-639, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31570638

RESUMO

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a combination of autonomic failure, cerebellar ataxia, and parkinsonism. Laryngeal stridor is an additional feature for MSA diagnosis, showing a high diagnostic positive predictive value, and its early occurrence might contribute to shorten survival. A consensus definition of stridor in MSA is lacking, and disagreement persists about its diagnosis, prognosis, and treatment. An International Consensus Conference among experts with methodological support was convened in Bologna in 2017 to define stridor in MSA and to reach consensus statements for the diagnosis, prognosis, and treatment. Stridor was defined as a strained, high-pitched, harsh respiratory sound, mainly inspiratory, occurring only during sleep or during both sleep and wakefulness, and caused by laryngeal dysfunction leading to narrowing of the rima glottidis. According to the consensus, stridor may be recognized clinically by the physician if present at the time of examination, with the help of a witness, or by listening to an audio recording. Laryngoscopy is suggested to exclude mechanical lesions or functional vocal cord abnormalities related to different neurologic conditions. If the suspicion of stridor needs confirmation, drug-induced sleep endoscopy or video polysomnography may be useful. The impact of stridor on survival and quality of life remains uncertain. Continuous positive airway pressure and tracheostomy are both suggested as symptomatic treatment of stridor, but whether they improve survival is uncertain. Several research gaps emerged involving diagnosis, prognosis, and treatment. Unmet needs for research were identified.


Assuntos
Conferências de Consenso como Assunto , Atrofia de Múltiplos Sistemas/diagnóstico , Atrofia de Múltiplos Sistemas/fisiopatologia , Sons Respiratórios/fisiopatologia , Humanos , Atrofia de Múltiplos Sistemas/terapia , Prognóstico , Resultado do Tratamento
12.
Mayo Clin Proc ; 94(10): 2087-2098, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31515103

RESUMO

Pure autonomic failure (PAF) is a neurodegenerative disorder of the autonomic nervous system clinically characterized by orthostatic hypotension. The disorder has also been known as Bradbury-Eggleston syndrome, named for the authors of the 1925 seminal description. Patients typically present in midlife or later with orthostatic hypotension or syncope. Autonomic failure may also manifest as genitourinary, bowel, and thermoregulatory dysfunction. With widespread involvement, patients may present to a variety of different specialties and require multidisciplinary treatment approaches. Pathologically, PAF is characterized by predominantly peripheral deposition of α-synuclein. However, patients with PAF may progress into other synucleinopathies with central nervous system involvement.


Assuntos
Insuficiência Autonômica Pura/diagnóstico , Humanos , Prognóstico , Insuficiência Autonômica Pura/complicações , Insuficiência Autonômica Pura/terapia
13.
Neurology ; 93(14): e1339-e1347, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484717

RESUMO

OBJECTIVE: To evaluate the pattern and severity of autonomic dysfunction in autopsy-confirmed progressive supranuclear palsy (PSP) compared to α-synuclein pathology. METHODS: Autopsy-confirmed cases of 14 patients with PSP, 18 with multiple system atrophy (MSA), and 24 with Lewy body disease (LBD) with antemortem autonomic testing were reviewed retrospectively. All patients underwent comprehensive clinical evaluations by a movement disorder specialist, formal autonomic testing, and postmortem examinations at Mayo Clinic. RESULTS: The absence of orthostatic hypotension (OH) was the strongest autonomic parameter that distinguished PSP from α-synucleinopathies (0% vs 69%, p < 0.0001). Tests of adrenergic failure, which distinguish neurogenic OH, also differentiated PSP from other groups. These included the pressure recovery time (p = 0.0008), adrenergic impairment score (p = 0.001), and magnitude of change of systolic (p = 0.0002) and diastolic (p = 0.0001) blood pressures (BPs) during upright tilt. In addition, REM sleep behavior disorder was seen less frequently (p = 0.006) in PSP (33%) compared to MSA (87%) and LBD (90%). Antemortem clinical diagnostic accuracy for these phenotypically variable disorders was 57% for PSP and 83% for α-synucleinopathies. CONCLUSION: Our results suggest that the cardiovascular adrenergic system, which sustains BP during standing, is relatively unaffected, if not spared, in PSP. These findings increase our understanding of the clinical signature of PSP and have the potential to improve diagnostic accuracy in atypical parkinsonisms by distinguishing PSP from the α-synucleinopathies.


Assuntos
Hipotensão Ortostática/diagnóstico , Hipotensão Ortostática/fisiopatologia , Paralisia Supranuclear Progressiva/diagnóstico , Paralisia Supranuclear Progressiva/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
Neurol Ther ; 8(2): 307-324, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31456212

RESUMO

Parkinson disease (PD) is associated with a variety of motor and non-motor clinical manifestations, including cardiovascular autonomic dysfunction. Neurogenic orthostatic hypotension (nOH) is a potentially serious manifestation of cardiovascular sympathetic failure that occurs in approximately 30% of patients with PD. Here we review the pathophysiology and effects of the condition as well as treatment considerations for patients with PD and nOH. Screening for nOH using orthostatic symptom questionnaires, orthostatic blood pressure measurements, and specialized autonomic testing is beneficial for the identification of symptomatic and asymptomatic cases because cardiac sympathetic denervation and nOH can occur even at early (premotor) stages of PD. Symptoms of nOH, such as orthostatic lightheadedness, in patients with PD, have been shown to adversely affect patient safety (with increased risk of falls) and quality of life and should prompt treatment with non-pharmacologic and, occasionally, pharmacologic measures. Patients with nOH are also at increased risk of supine hypertension, which requires balancing various management strategies. FUNDING: Lundbeck (Deerfield, IL).

15.
Parkinsonism Relat Disord ; 66: 212-215, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31327626

RESUMO

OBJECTIVE: To determine whether smoking or alcohol use impacts the age of onset and disease duration in multiple system atrophy (MSA). METHODS: All patients diagnosed with MSA at Mayo Clinic, Rochester between 1998 and 2012 completed standardized questionnaires surveying smoking and alcohol use at the time of presentation. RESULTS: Of 551 patients with smoking and alcohol use data, 281 were past or present smokers with age of onset of 60.76 years compared to 62.97 years in controls (p = 0.0144). Age of onset in the 87 heavy alcohol users was 56.87 years compared to 62.97 years in controls (p = 0.0133). There was no difference in disease duration for smokers (p = 0.2758) or heavy alcohol users (p = 0.4820) compared to controls. CONCLUSION: Our findings show that smoking history and/or heavy alcohol use is associated with younger age of onset in MSA but do not influence survival.

16.
Neurology ; 93(1): e77-e87, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31152011

RESUMO

OBJECTIVE: This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). METHODS: Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS). RESULTS: Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect. CONCLUSIONS: Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.


Assuntos
Transplante de Células-Tronco Mesenquimais , Atrofia de Múltiplos Sistemas/terapia , Progressão da Doença , Feminino , Seguimentos , Humanos , Injeções Espinhais , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Resultado do Tratamento
17.
Auton Neurosci ; 219: 49-52, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31122601

RESUMO

To evaluate the influence of sex and gender on clinical characteristics and survival in multiple system atrophy (MSA), we reviewed MSA patients with autonomic testing 1998-2012. Of 685 patients, 52% were male. Median survival overall was 7.3 years for males, 7.6 years for females. Survival from diagnosis was 2.9 years in males, 3.8 years in females. Females were more likely to initially manifest motor symptoms. Males were more likely to have orthostatic intolerance and early catheterization. In conclusion, our data show longer survival from diagnosis in females and slight overall survival benefit which may be related to initial motor manifestations.

18.
J Neuropathol Exp Neurol ; 78(5): 453-459, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30861073

RESUMO

Skin biopsies have gained increasing popularity as a tool to evaluate disorders affecting small nerve fibers. While reports on sweat gland nerve fiber density (SGNFD) to quantitate sudomotor innervation have been promising, methodologies vary significantly. Although conventional stereology is commonly used, no standard technique has been established. We sought to develop an accurate and reproducible technique to quantify SGNFD. Skin punch biopsies from healthy individuals were cut and stained. Images of sweat glands (SGs) were acquired using confocal and widefield microscopes, and optimized using deconvolution. Nerve fibers were reconstructed and nerve fiber length (NFL) was quantified using three-dimensional (3D) automated software. SGNFD was obtained by dividing NFL by SG volume. SGNFD was also assessed using stereology for comparison. Ninety-two SGs from 10 healthy subjects were analyzed by independent observers. Using confocal microscopy, the software reliably traced nerve fibers. In contrast, rendering of nerve fibers was inferior using widefield microscopy. Interobserver reliability was suboptimal using widefield images compared to confocal (ICC = 0.82 vs ICC = 0.98). Correlation between 3D-reconstruction and stereology was poor (ICC = 0.38). The newly developed technique of SGNFD quantitation using 3D reconstruction of SG innervation with confocal microscopy reliably traces nerve fibers, shows outstanding reproducibility, is almost completely unbiased, and superior to conventional stereology methods.

19.
Clin Auton Res ; 29(1): 105-112, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29492828

RESUMO

OBJECTIVE: To develop a scale to quantify and discriminate orthostatic from non-orthostatic symptoms. In the current study, we present validation and reliability of orthostatic and non-orthostatic symptom scores taken from the orthostatic discriminate and severity scale (ODSS). METHODS: Validity and reliability were assessed in participants with and without orthostatic intolerance. Convergent validity was assessed by correlating symptoms scores with previously validated tools [autonomic symptom profile (ASP) and the orthostatic hypotension questionnaire (OHQ)]. Clinical validity was assessed by correlating scores against standardized autonomic testing. Test-retest reliability was calculated using an intra-class correlation coefficient. RESULTS: Convergent validity: orthostatic (OS) and non-orthostatic (NS) symptom scores from 77 controls and 67 patients with orthostatic intolerance were highly correlated with both the orthostatic intolerance index of the ASP (OS: r = 0.903; NS: r = 0.651; p < 0.001) and the composite score of the OHQ: (OS: r = 0.800; NS: r = 0.574; p < 0.001). Clinical validity: symptom scores were significantly correlated with the total composite autonomic severity score (OS: r = 0.458; NS: r = 0.315; p < 0.001), and the systolic blood pressure change during head-up tilt (OS: r = - 0.445; NS: r = - 0.354; p < 0.001). In addition, patients with orthostatic intolerance had significantly higher symptom scores compared to controls (OS: 66.5 ± 18.1 vs. 17.4 ± 12.9; NS: 19.9 ± 11.3 vs. 10.2 ± 6.8; p < 0.001, respectively). Test-retest reliability: Both orthostatic and non-orthostatic symptom scores were highly reliable (OS: r = 0.956 and NS: r = 0.574, respectively; p < 0.001) with an internal consistency of 0.978 and 0.729, respectively. INTERPRETATION: Our initial results demonstrate that the ODSS is capable of producing valid and reliable orthostatic and non-orthostatic symptom scores. Further studies are ongoing to test sensitivity, specificity and symptom severity.

20.
Handb Clin Neurol ; 157: 715-725, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30459035

RESUMO

Autonomic dysfunction in Parkinson disease encompasses thermoregulatory symptoms and was first noted by Gowers in the late 19th century when he described abnormal temperature sensation and sweating in Parkinson disease patients. These thermoregulatory symptoms became more recognized in the postlevodopa era when Parkinson disease patients were more readily tested with objective autonomic function tests. Objective thermoregulatory testing in Parkinson disease reveals deficits of sweating and vasomotor tone which often correlate with the severity of other autonomic deficits. Tests of thermoregulatory function can also be used to differentiate Parkinson disease from other neurodegenerative disorders. The pathophysiology of thermoregulatory dysfunction in Parkinson disease encompasses both central and peripheral mechanisms; involvement of the brainstem and hypothalamus with alpha-synuclein pathology is well recognized with increasing evidence of peripheral neuropathy in Parkinson disease that influences thermoregulation. Medications used to treat Parkinson disease also affect thermoregulatory symptoms. Disorders of thermoregulation significantly affect the quality of life for patients and their caregivers and can be severe and even life threatening, such as in the parkinsonism-hyperpyrexia syndrome.


Assuntos
Regulação da Temperatura Corporal/fisiologia , Doença de Parkinson/fisiopatologia , Humanos
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