Michael VanElzakker, a researcher affiliated with the Tufts University PTSD neuroimaging laboratory as well as the Massachusetts General Hospital Psychiatric Neuroscience division, has published a novel hypothesis on the possible etiology of Chronic Fatigue Syndrome (CFS). In the paper, published in Medical Hypotheses, VanElzakker suggests that CFS may be the result of a pathological infection of the vagus nerve. Although VanElzakker proposes that any neutoropic virus or bacteria could trigger CFS, HHV-6 is at the top of his list.
For years, CFS researchers have been looking in plasma and blood cells for a pathogenic agent that causes the myriad of symptoms experienced by patients with the condition. However, according to VanElzakker, they may have been looking in the wrong place (plasma) and need to search instead in the tissues of the peripheral and central nervous system. During infection, the sensory vagus nerve sends a signal to the brain to initiate “sickness behavior,” an involuntary response characterized by fatigue, fever, myalgia, depression, and other symptoms that are often observed in patients with CFS. However, VanElzakker proposes that when sensory vagal ganglia or paraganglia are themselves infected with any virus or bacteria, these symptoms would be exaggerated. He notes that many of the symptoms of sickness behavior (such as fatigue, sleep changes, myalgia, cognitive impairment, depression and zinc depletion) are also mediated by proinflammatory cytokines and observed in CFS.
Herpesviruses and certain intracellular bacteria establish latency in the vagus nerve and reactivate during periods of stress or illness, causing the release of proinflammatory cytokines. HHV-6 is a highly neurotropic virus and potent inducer of cytokines such as IL-6 and NFkB, which many groups have proposed as an etiological theory for the role of HHV-6 in neurological conditions such as seizures and epilepsy. If this low-level “chronic” infection is localized to the vagus nerve it would be undetectable in the plasma, but could be demonstrated through analyzing tissue biopsies of the vagus nerve, VanElzakker suggests. HHV-6 is well-known for invading the hippocampus and other parts of the limbic system, and also establishes residence in the human sensory ganglia along with other neurotropic herpesviruses including HSV-1 and VZV (Hufner 2007).
To test his hypothesis, VanElzakker suggests that vagus nerve biopsy samples should be sought from CFS patients who have died prematurely from other causes. In addition, he also suggests that radiolabeled antibodies may be effectively designed and used to detect these CNS-localized infections. Radiolabeled antibodies are currently employed in fields such as tumor imaging, where they assist in locating clusters of specific virus in vivo.
Potential therapeutic options, he says, include virus-specific antiviral treatments, glial cell inhibitors such as lbudilast (used for asthma and stroke in Japan) and vagus nerve stimulation. Vagus nerve stimulation is currently used for refractory epilepsy, a condition that has been associated with HHV-6B reactivation.
VanElzakker points out that one potential problem with antivirals are that these drugs are not effective within immunoprivileged sites such as the vagal paraganglia. Also, any antiviral therapy would need to be broad spectrum since diagnosis of the specific pathogen(s) is challenging. An antiviral such as valacyclovir (Valtrex), for example, works well against HSV-1 but has limited if any effect on CMV or HHV-6. Two infectious disease specialists, Jose Montoya and Martin Lerner, have published previous studies suggesting that valganciclovir therapy may be effective for the subset of CFS patients suspected of having smoldering or low-level infections of HHV-6, EBV and CMV. Both Montoya and Lerner have shown that longer treatment terms (>6 months) have achieved greater success than short-term antiviral therapy (See HHV-6 & CFS). Ampligen, a drug that has undergone clinical assessment for use among CFS patients, also has antiviral properties. Of interest, lbudilast is a phoshpodiesterase inhibitor and several drugs in this pharmaceutical class have been shown to inhibit CMV replication.
While much is still unknown about the infectious etiology of ME/CFS, VanElzakker’s “vagus nerve hypothesis” offers a testable theory for researchers, animal models and specific diagnostic and treatment strategies moving forward.