Lyme Disease as a Model of Chronic Fatigue Syndrome
By Sam Donta, MD
Boston University Medical Center

With the discovery of the causative agent of Lyme disease, a new chapter has been opened in the understanding of chronic fatigue syndrome (CFS) and other multi-symptom disorders. Lyme disease, caused by spirochetal bacteria transmitted by the bite of an Ixodes (deer) tick, is now known to be one cause of a chronic fatigue disorder that cannot be readily distinguished from CFS, nor from what is termed fibromyalgia. These disorders have similar major symptomatology consisting of fatigue and neurocognitive dysfunction, along with numerous other symptoms that probably relate to altered neurologic function. Musculoskeletal symptomatology may be more frequent in fibromyalgia and in some patients with chronic Lyme disease than in CFS, but the definition of CFS also encompasses myalgias and arthralgias as part of the disorder.

Causative agents
In Lyme disease, following the bite of an infected deer tick, the Borrelia burgdorferi bacteria may spread locally and cause a variety of skin rashes, the most typical being an expanding circular rash with a clearing area and center resembling a bull's eye. Half of the rashes, however, are not typical, causing diagnostic problems for physicians. Patients who are infected may not develop or see the rash, and may not develop any future symptoms, remaining asymptomatic.

Some asymptomatic patients, however, may reactivate their infection following various stressors such as trauma, surgery, pregnancy, an intercurrent illness, taking an antibiotic for an unrelated reason, severe psychologic stress or having received the Lyme vaccine. Similar triggers such as trauma and other stresses are known to precipitate CFS and fibromyalgia.

It is likely that there are a number of other causes of CFS and fibromyalgia in addition to chronic Lyme disease. Epstein-Barr virus (EBV), the major cause of infectious mononucleosis, continues to be debated as a cause of CFS. It is uncertain whether EBV can cause symptoms other than fatigue, such as myalgias and arthralgias that are not seen during acute or reactivated EBV infection in patients who are being immunosuppressed, but it remains possible that EBV could cause one type of chronic fatigue disorder.

Some more recently recognized species of Mycoplasma (Mycoplasma fermentans, Mycoplasma genitalium) have been implicated in chronic fatigue and other multi-symptom disorders, including CFS itself, fibromyalgia and Gulf War Illness. These same bacteria have also been implicated as causative agents of rheumatoid arthritis, based on PCR-DNA evidence in patients with these disorders in which 50 percent are found to have the DNA of the Mycoplasma in circulating white blood cells, compared to 5-10 percent of a normal population. Whether the presence of this DNA represents past exposure or ongoing infection remains to be resolved. No longitudinal studies have yet been performed in patients with CFS to determine whether the finding of Mycoplasma DNA persists over months or years or whether such patients have any evidence of other infection such as Lyme disease or infection with Chlamydia species.

Gender effects
The effects of gender and host on susceptibility and expression of Lyme disease, CFS and other multi-symptom diseases are also in need of further study. In all these disorders, women appear to be more affected than men, usually at about 2:1 ratios. It seems notable that neural cells contain estrogen and progesterone receptors, and that herpes viruses can utilize estrogen receptors to gain access to the reservoir in the cell nucleus. Treatment of chronic Lyme disease also seems to be gender-dependent to some degree, with men generally having more speedy and complete recoveries compared to women. Gender relationships are known for a number of infectious diseases, so it would not be surprising that such a relationship exists for chronic Lyme disease, CFS and other multi-symptom disorders.

Disease targets
In Lyme disease, the nervous system seems to be the primary target for the bacteria causing the disease. Patients with the disease express many neurologic symptoms such as pain, paresthesias including numbness, tingling, crawling and itching sensations, as well as cognitive difficulties and mood changes. Even the joint pains and occasional arthritis (joint pain is much more frequent than actual swelling of joints) appear to be neuropathic in origin, as anti-inflammatory agents such as ibuprofen and other non-steroidal anti-inflammatory agents have little if any effect on the pain. Experimental evidence from animal models, primarily dogs and non-human primates, also affirm the localization of B. burgdorferi DNA to the nervous system.

The mechanisms underlying the pathophysiology of the disease remain to be defined, but could involve inflammatory responses, autoimmune responses or toxin-associated disruption of neural function. Any inflammatory responses appear to be weak, and there is no compelling evidence that Lyme disease is a result of immunopathologic mechanisms.

The target(s) for other causes of CFS remain to be defined. Without any animal models, it becomes more difficult to study its pathogenesis and pathophysiology. Nonetheless, the central nervous system would appear to be a logical target for other pathogens or other pathophysiologic processes. Any changes in immunologic function would not appear to be sufficient to explain the various symptoms, and are likely to be secondary to other pathogenetic processes.

Diagnosis
The diagnosis of Lyme disease is primarily based on clinical grounds. Just as with CFS, the combination of symptoms over months and years, in the absence of an obvious alternative diagnosis, is sufficient to make a presumptive clinical diagnosis. The diagnosis of Lyme disease is made easier if a typical rash is present during the early phase of infection. After that, it is difficult to distinguish the flu-like illness that can occur a few weeks later, or can recur over a number of months. Some patients develop severe headaches and an aseptic meningitis, which frequently is diagnosed instead as "viral" meningitis. If a Bell's palsy occurs, causing drooping of one side of the face, the possibility of Lyme disease should occur to the physician. If an unprovoked arthritis occurs, causing swelling of a single joint, especially the knee, but sometimes more than one joint, then the possibility of Lyme disease should also be given high consideration.

But it is the chronic phase of the disease that causes most of the problems for physicians and patients, because of the lack of "objective" signs and the presence of so many symptoms that it causes some doctors to invoke psychologic reasons for the patients' symptoms. Many such patients receive a diagnosis of CFS or fibromyalgia, when they may have underlying Lyme disease as the cause of their symptoms.

The laboratory has been helpful in some patients with Lyme disease, especially those with arthritis, in whom there are stronger antibody responses than in those with the chronic, multi-symptom form of the disease. The criteria for the laboratory diagnosis has been patterned after the arthritic form of the disease, and not the chronic form; thus, there are many physicians who are misinformed about the test's lack of value in chronic disease. The Lyme Western Blot is helpful when it shows reactions against specific proteins of B. burgdorferi, but can be negative in 25-30 percent of patients who otherwise have chronic Lyme disease. PCR-DNA tests for Lyme in blood, urine and spinal fluid are rarely positive, most likely because the bacteria and their DNA are not present in those body fluids, but inside nerve cells.

The MRI exam of the brain in about 10 percent of patients with chronic Lyme disease can show some white spots in various areas, similar to those seen in multiple sclerosis, a neurologic disease of unknown cause that has some overlapping symptoms with Lyme disease, such as the paresthesias. It is unclear how many patients who have Lyme disease as a cause of CFS have such MRI findings, or how many patients with CFS have these findings. The brain SPECT scan, a variation of a PET scan, shows some changes in blood flow to various parts of the brain, primarily the temporal (cognitive processing) and frontal (mood) lobes in about 75 percent of patients with chronic Lyme disease. Patients with CFS have also been reported to have some brain SPECT scan changes, frequently involving the occipital lobe. No comparative studies have been made among patients with chronic Lyme disease, CFS and fibromyalgia. The mechanisms underlying these changes remain to be defined, but may be due to a mild vasculitis or to a signaling problem within the nerve network of the brain in those specific areas. It is promising, though, that these changes are reversible in most patients treated with antibiotics that appear to be effective in treating the chronic Lyme disease.

Treatment
Treatment of chronic Lyme disease, CFS, fibromyalgia and other chronic multi-symptom disorders has been primarily symptom-based. Although some of these treatments (e.g., amitryptiline, other sleep medications, antidepressants, pain medications) can offer some relief, they rarely lead to resolution of the chronic symptoms. In chronic Lyme disease, there continues to be controversy whether antibiotics can be of value. In our studies, intracellular-type antibiotics such as tetracycline or the combination of one of the erythromycin-type antibiotics (e.g., clarithromycin-Biaxin, azithromycin-Zithromax) and hydroxychloroquine (a drug which changes the pH inside cells to be less acid, thus allowing the erythromycin-type antibiotics to be effective) given over a number of months (6-18 months, sometimes longer) has resulted in substantial improvement and cures in most patients with chronic Lyme disease. Similar results have been noted in some patients with CFS of unknown cause, supporting the hypothesis that some patients with CFS have an underlying infection responsive to those antibiotics. Antibiotic trials in CFS have been limited to one month, a duration inadequate to more properly evaluate the potential of certain antibiotics to exert a positive effect on the disease. Additional studies, examining both potential etiologic agents of CFS and treatment trials, should lead to a better understanding of both the cause and treatment of patients with CFS.

Selected Readings

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Choppa PC et al. "Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis, and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome." Mol Cell Probes, 1998; 12:301-8.

Donta ST. "Treatment of chronic Lyme disease with macrolide antibiotics." In: Program and abstracts of the VIIIth International Conference on Lyme Borreliosis; June 20-24, 1999; Munich, Germany. Abstract P193.

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