Last updated on October 2017

Evaluation of Primary Chronic Autonomic Failure


Brief description of study

This study will conduct tests in patients with primary chronic autonomic failure (CAF) to learn more about these disorders, which include pure autonomic failure, multiple system atrophy, Parkinson's disease with autonomic failure, and autoimmune autonomic neuropathy. Healthy volunteers and patients with primary CAF 18 years of age or older may be eligible for this study. Participants undergo some of the following tests: - Blood studies, including arterial catheter insertion to measure blood pressure and collect arterial blood samples, blood flow studies using sensors applied to the skin and a pressure cuff around a limb, and blood draw for genetic studies. - Bladder motility: Ultrasound test of bladder function. - Electrocardiogram and heart ultrasound. - Responses to changes in temperature: Warm water and then room temperature water are passed through watertight pads applied to the back and front of the body and body temperatures are measured. - Gastrointestinal motility: Bowel sounds are recorded using a microphone placed on the abdomen. - Lower body negative pressure: The lower body is placed into an airtight barrel-like chamber. Some air is sucked out of the barrel, causing blood to pool in the legs, as occurs during standing. - Lumbar puncture: A needle is inserted in the space between the bones in the lower back to collect a small sample of cerebrospinal fluid. - Microdialysis to measures levels of chemicals in the body fluid of certain tissues. A solution is passed through a thin tube inserted into the skin. Chemicals in the body tissues enter the solution. The solution is collected and the chemical levels are measured. - PET scanning: A nuclear medicine test to produce images of body organs. For patients with urinary problems, a catheter is inserted into the bladder before starting the scan. - Pupillometry: The pupil of the eye is measured using a special camera in a light-controlled room. - QSART. A small amount of a brain chemical is applied to the skin with a tiny amount of electricity, and the sweat in a nearby patch of skin is measured. - Measurement of saliva production, using a cotton-like material placed between the teeth and gums to absorb saliva. - Skin electrical conduction test, using sensors on the skin to measure sweat production. - Skin and core temperature measurements using sensors on the skin and in the ear canal. - Speech and swallowing assessment for patients with speech and swallowing difficulties. - Stress echocardiogram: A catheter is placed in the subject's arm for sampling blood or giving a drug while the subject exercises. During the test, blood pressure, pulse rate, and EKG are continuously monitored.

Detailed Study Description

Objective: In dysautonomias, altered functions of one or more components of the autonomic nervous system adversely affect health. Primary dysautonomias have been classified clinically into chronic autonomic failure (CAF) syndromes that include pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure (manifested especially by neurogenic orthostatic hypotension (OH)). Clinical assessment alone is often inadequate for correct diagnosis and does not provide insights into mechanisms or identify new therapeutic targets. This protocol calls for continuous development and assessment of physiological, neuropharmacologic, neurochemical, neuroimaging, and other clinical laboratory approaches, to identify lesion types and sites in CAF and improve diagnosis, increase mechanistic understanding, and incite novel therapeutics. PAF, MSA, and PD exemplify alpha synucleinopathies, in which deposits of the protein alpha-synuclein occur in Lewy bodies in catecholamine-producing neurons (PD, PAF) or in the cytoplasm of glial cells (MSA). Only the Lewy body forms of synucleinopathy are consistently associated with loss of catecholaminergic neurons. Under this protocol we have obtained evidence that patients with Lewy body diseases have decreased ability to take up intra-neuronal catecholamines from the cytoplasm into storage vesicles. Cytoplasmic catecholamines are cytotoxic, such as by enzyme-catalyzed conversion to highly reactive catecholaldehydes. By studying CAF patients we hope to make discoveries that will yield a unifying, integrative concept for the pathogenesis and different clinical manifestations of Lewy body diseases. Autonomic function testing under this protocol is also required for screening purposes for entry into other protocols of the Clinical Neurocardiology Section. Moreover, comprehensive autonomic function testing is requested in patients of the NIH Undiagnosed Diseases Program. Finally, in a long-term project as a member of the Autonomic Rare Diseases Clinical Research Consortium we are applying this testing to study the natural history of neurogenic OH. Study Population: The study population consists of patients with idiopathic, or primary, CAF, with emphasis on PAF, MSA, and PD. Comparison groups include healthy volunteers (HVs), patients with PD who do not have OH, and patients with iatrogenic CAF such as from bilateral thoracic sympathectomies. Design: Subjects undergo multiple physiological, neuropharmacologic, neurochemical, and neuroimaging, and other tests, to see if the results by different modalities agree and point to specific sites and types of lesions. Outcome Measures: Physiological outcome measures include hemodynamic responses to the Valsalva maneuver, orthostasis, and altered temperature at skin of the back. Neuropharmacologic measures include cardiovascular responses to test drugs that probe specific components of the autonomic nervous system. Neurochemical measures include plasma, cerebrospinal fluid, microdialysate, urine, and skin biopsy tissue levels of catecholamines and related compounds. Neuroimaging measures include positron emission tomographic scanning after injection of 18F-dopamine, 18F-DOPA, 13N-ammonia, or 11C-methylreboxetine.

Clinical Study Identifier: NCT00059033

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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, MD United States
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