Plasma Exchange for Autoimmune Autonomic Failure
Condition: Plasma Exchange; Autonomic Failure
MeSH terms: Pure Autonomic Failure
Study type: Observational

Summary: 
      This study will explore whether an antibody is influencing the autonomic nervous system, and
      if its removal will eliminate signs and symptoms of failure in that system. The autonomic
      nervous system is responsible for many automatic changes involved in everyday activities,
      such as standing up, digesting food, and exercising in the heat. Antibodies fight germs but
      sometimes cause health problems. Removal of the antibody is done through a procedure called a
      plasma exchange.

      Patients with primary chronic autonomic failure and a circulating antibody to what is called
      the neuronal nicotinic receptor may be eligible for this study. To be eligible, patients will
      have participated in an earlier study, protocol number 03-N-0004. Patients will undergo tests
      and procedures that include an electrocardiogram, and blood collection for hepatitis, HIV,
      and pregnancy. Blood will be tested for a complete blood count, clotting factors, and
      chemistries. There will also be tests for liver function, kidney function, cortisol, and
      thyroid. Participants will be tested for signs and symptoms of autonomic failure, and will be
      asked to complete questionnaires about various symptoms before the plasma exchange, 1 or 2
      weeks afterward, and then monthly or bimonthly for up to 1 year. Patients will undergo a
      series of other tests. In one test, a patient is upright and blows against a resistance
      (Valsalva maneuver). The quantitative sudomotor axon reflex test (QSART) uses iontophoresis,
      involving application of acetylcholine, a chemical messenger, and a small amount of
      electricity. QSART examines the regulation of sweating, a particular aspect of the autonomic
      nervous system. There will be a test using edrophonium, given intravenously (IV), to evaluate
      that drug's effects on the heart, skin, glands, gastrointestinal activity, bladder tone, and
      salivation. A glucagon test, also by IV, will show patients' ability to release the hormone
      adrenaline.

      The plasma exchange will be performed by use of an automated cell separator. Patients' blood
      will be removed continuously through a needle in the arm. Blood cells will be separated from
      the plasma by a spinning process and continuously returned to circulation through a needle in
      the patients' opposite arm. Blood cells that are returned will be mixed with albumin, a
      sterile replacement solution. A blood thinner, citrate, will be given, to prevent clotting of
      blood. This whole procedure will take about 2 hours. Patients will typically undergo five
      exchange procedures in about 10 days while they are inpatients at the NIH Clinical Center.
      The amount of plasma removed in a single session and the number of sessions will be set by
      the NIH Blood Bank. It is expected that patients' autonomic failure will improve after
      several days of starting the plasma exchange. Testing for symptoms of autonomic failure and
      autonomic function testing will occur about 1 month after the plasma exchange and monthly or
      bimonthly for up to 1 year. For each visit of testing, patients will be inpatients for about
      2 days. If autonomic failure recurs, patients may have a second plasma exchange, with the
      same follow-up tests, for about 1 year.
    

Detailed description: 
      Background: Until recently, it was thought that primary chronic autonomic failure occurring
      without central neurodegeneration (pure autonomic failure, PAF) reflected diffuse loss of
      catecholamine-producing cells (sympathetic noradrenergic nerves and adrenomedullary
      chromaffin cells) outside the brain. Rarely, however, PAF patients have clinical laboratory
      findings suggesting decreased post-ganglionic nerve traffic in intact autonomic nerves,
      rather than denervation. To date, all of four such patients have also had a high titer of a
      circulating antibody to the nicotinic receptor mediating ganglionic neurotransmission. In one
      case, studied by another group, plasma exchange reversed signs and symptoms of autonomic
      failure, consistent with the antibody being pathogenic.

      Purpose: In this Protocol, we will carry out plasma exchange in patients we identify as
      having PAF, intact cardiac noradrenergic innervation, and a circulating antibody to the
      neuronal nicotinic receptor, to determine whether antibody pathogenicity is a consistent
      finding in this condition. We will assess the extent of relationship between symptoms, signs,
      and clinical laboratory indices of autonomic function with the titer of the antibody and
      obtain abundant plasma for antibody characterization and target protein identification.

      Methods: Autonomic function testing will be done before plasma exchange, 1-2 weeks after
      plasma exchange, and monthly or bi-monthly thereafter for up to one year. Plasma exchange may
      be repeated once, when symptoms of autonomic failure return as the antibody level builds up,
      to verify in individual patients whether repetition of plasma exchange produces reproducible
      amelioration of clinical and laboratory measures of autonomic failure.
    

Keywords: Plasmapheresis; Auto-antibodies; Autonomic Nervous System; Dysautonomia; Sympathetic Nervous System; Autonomic Failure