Autonomic Nervous System and Chronic Fatigue Syndrome

In Specific Aim 1, the investigators will use state-of-the-art measurements of sympathetic
activity (autonomic function tests, response to trimethaphan, direct nerve sympathetic
traffic recordings with microneurography, plasma norepinephrine, and intraneuronal
metabolites), inflammatory mediators (C-reactive protein, inflammatory cytokines), and
oxidative stress (isoprostanes) in patients with CFS-P. It is important that appropriate
control groups be included, and we will also study patients with CFS without orthostatic
tachycardia, patients with POTS without CFS, and normal controls.

The investigators have documented abnormalities in volume regulation in POTS patients.
Hypovolemia can contribute to sympathetic activation and, vice versa, sympathetic activation
can contribute to hypovolemia. Interrupting this vicious circle with acute saline infusion
is the most effective treatment to improve symptoms in POTS patients. Not surprisingly,
many POTS patients followed by the investigators, and CFS patients followed by Dr. David
Bell, are using saline pulse therapy as a way to alleviate symptoms. However, the efficacy
and safety of this approach has not been proven. The investigators propose to validate this
treatment in Specific Aim 2.

This group studies show that nitric oxide is arguably the most important metabolic factor
involved in cardiovascular regulation. Abnormalities in nitric oxide have been proposed to
contribute to CFS and POTS, but proving this has been challenging in part due to its
interaction with the sympathetic nervous system. In Specific Aim 3, the investigators
propose to investigate the importance of nitric oxide in CFS-P patients using an
experimental approach developed in our laboratory to eliminate nitric oxide/autonomic
interactions.

Finally, in Specific Aim 4, they propose a proof-of-concept study to test the hypothesis
that sympathetic activation contributes to many of the abnormalities found in CFS patients.
If our hypothesis is correct, inhibition of sympathetic tone will result in improvement of
the abnormalities described in volume, inflammation, and oxidative stress. More
importantly, it will result in symptomatic improvement in these patients. The investigators
believe, therefore, that the studies proposed in this application will improve the
understanding of the pathophysiology of CFS, and provide a rationale approach to the
treatment of this disabling condition.

Inclusion Criteria:

- Meet CDC diagnostic criteria of CFS (Fukuda et al., 1994)

- Meet diagnostic criteria of POTS (Raj et al., 2005)

- Age between 18-65 years

- Male and female are eligible (although the majority of patients with CFS-P are
female)

Exclusion Criteria:

- Presence of medical conditions that can explain postural tachycardia syndrome (e.g.,
dehydration, medications)

- Presence of medical or psychiatric conditions known to cause fatigue (Fukuda et al.,
1994). Inability to give, or withdrawal of, informed consent

- Inability to acquire or maintain adequate long-term intravenous access (peripheral
indwelling catheter, PIC)

- Pregnancy

- Other factors which in the investigator's opinion would prevent the subject from
completing the protocol

- Patients who are bedridden or chair-ridden