Evaluation of Primary Chronic Autonomic Failure

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00059033
First received: April 16, 2003
Last updated: July 25, 2014
Last verified: October 2013

April 16, 2003
July 25, 2014
April 2003
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Complete list of historical versions of study NCT00059033 on ClinicalTrials.gov Archive Site
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Evaluation of Primary Chronic Autonomic Failure
Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure

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.

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, 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 18 F-dopamine, 18 F-DOPA, 13 N-ammonia, or 11 C-methylreboxetine.

Observational
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Autonomic Nervous System Diseases
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
380
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  • INCLUSION CRITERIA:

The subjects are patients with known or suspected primary CAF, based on referral information and confirmation of the clinical diagnosis at the intake evaluation. They are classified by results of the intake evaluation and then undergo comprehensive autonomic function testing.

Participation in this protocol is offered to people 18 years old or older, independently of gender, race, age, ethnicity, religion, or any other demographic or sociopolitical classifications.

Control patients have previously diagnosed PD or MSA without orthostatic hypotension, confirmed at the time of the intake evaluation.

EXCLUSION CRITERIA:

Age: People younger than 18 years old are excluded. Advanced age does not constitute an exclusion criterion.

Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator or Clinical Director, protocol participation would place the subject at substantially increased acute medical risk. This includes the risks associated with air travel to the NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or Clinical Director, the medical risk outweighs the potential scientific benefit.

Disqualifying Conditions: A candidate subject is excluded if there is a disqualifying condition. Examples of disqualifying conditions are hepatic or renal failure (defined by serum creatinine more than 1.5 g/dL), symptomatic congestive heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, and symptomatic coronary heart disease. A positive HIV test result does not necessarily exclude a patient from participating. Patients are excluded from further participation if the results of the intake evaluation lead to a diagnosis of a secondary form of CAF, such diabetic autonomic neuropathy. If a patient has a history of glaucoma, then an ophthalmology consult will be obtained, to determine whether exposure to any of the procedures or test drugs would place the patient at undue risk. If so, then the patient will be excluded from that part of the study.

Medications: A candidate subject is excluded if clinical considerations require that the patient continue treatment with a drug likely to interfere with the scientific results. An example would be treatment with a tricyclic antidepressant. Patients with known or suspected allergy or hypersensitivity to any test drug are excluded from receiving that drug. Patients who must take medications daily in the following categories may be excluded: anticoagulants, tricyclic antidepressants, barbiturates, aspirin, or acetaminophen. Subjects who must take aspirin daily will not undergo arterial catheterization; however, they may be allowed to participate in other aspects of the study. Patients unable to discontinue nicotine or alcohol temporarily are excluded. Patients are not to discontinue any medications before the patient or the patient s doctor discusses this with the Principal Investigator, Research Nurse, or Nurse Practitioner. . If it is decided that discontinuing medications would be unsafe, then the patient may be excluded from all or part of the study. Subjects must discontinue use of alcohol and tobacco throughout the period of testing in the protocol.

Herbal Medicines and Dietary Supplements: Certain herbal medicines or dietary supplements are known or suspected to interfere with the experimental results, and such herbal medicines or dietary supplements must be discontinued before enrollment in the study. For many herbal medicines or dietary supplements, the mechanisms of action and therefore the possible effects on the experimental results are unknown. In cases where the subjects wish to continue their herbal medicines or dietary supplements while on study, and search of the available medical literature fails to identify effects that are known or expected to interfere with the experimental results, then the subjects may participate.

Practical Limitations: Patients in whom we feel it would be difficult to insert a catheter into a vein are excluded. Subjects who are not expected clinically to tolerate lying still during the procedures are excluded.

Pregnancy: Pregnant women are excluded from the Protocol overall. In women with child bearing potential, blood testing for pregnancy will be done with 24 hours before initial testing (except for obtaining the medical history and physical examination) or any testing involving radioactivity under the Protocol. Repeat pregnancy testing will be done before any procedure or drug administration under the Protocol that takes place more than one week from a previous pregnancy test.

Termination of Participation: Subjects may refuse certain tests or procedures, or may terminate participation early, without loss of benefits to which they were previously entitled. The Investigators may also exclude a subject from further participation, such as in the event of known or suspect falsification of medical history information or refusal to undergo planned tests or procedures, without loss of benefits to which the subject was previously entitled.

Refusal to Undergo Certain Procedures: Candidate subjects are excluded if they refuse to undergo certain procedures. These are 1) i.v. catheter 2) electrocardiogram 3) blood drawing 4) DNA extraction and storage 5) DNA analysis

Both
18 Years and older
Yes
Contact: Janna Peries, R.N. (301) 435-5166 jperies@ninds.nih.gov
Contact: David S Goldstein, M.D. (301) 496-2103 goldsteind@ninds.nih.gov
United States
 
NCT00059033
030004, 03-N-0004
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National Institute of Neurological Disorders and Stroke (NINDS)
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Principal Investigator: David S Goldstein, M.D. National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health Clinical Center (CC)
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP