12th International Conference on Lyme Disease and Other Spirochetal and Tick-Borne Disorders

Day 2 - April 10, 1999

Differential Diagnosis in Lyme Disease
Brian A. Fallon, MD

Two presentations today addressed the overlap that exists between similar disorders one talk focused on diagnostic distinctions between fibromyalgia, Lyme disease, and Gulf War syndrome; the other was devoted to Chronic Fatigue Syndrome and Post-Lyme Disease.

Dr. Sam T. Donta of the Boston University Medical Center discussed fibromyalgia and Lyme disease, noting the increasing awareness of the similarities and differences between chronic Lyme disease and other chronic multi-symptom disorders (CMSDs) such as fibromyalgia, chronic fatigue, and Persian Gulf War illness.[1] Still, since all are characterized by fatigue, musculoskeletal pain, and neurocognitive dysfunction, discriminating one from the others is often difficult.

Historical Perspectives
In the early 1900s, fibromyalgia was referred to as "fibrositis". By the early 1990s, the term "fibromyalgia" began to be used more widely. Current epidemiologic studies indicate approximately a 0.1% to 0.2% incidence of fibromyalgia.

Descriptions of patients plagued by prominent fatigue states first appear in the 1850s, Dr. Donta said. These early references describe patients' symptoms as "bed cases" or "sofa cases," and physicians characterized such cases as neuromyasthenia. Following both World War I and World War II, epidemics of fatigue were reported and in 1988, the term "chronic fatigue syndrome" was first used. In Europe, the term "myalgic encephalomyelitis" is more commonly used than "chronic fatigue."

It is estimated that the incidence of chronic fatigue is approximately 0.1% -0.2% in the overall population, while in primary care settings the incidence is higher. A recent study indicated an incidence of 11.3% in a primary care sample of 2,376 patients. Following flu-like illness, 15% of patients developed post-infection chronic fatigue. A recent study from England demonstrated that after Q-fever, 42% of patients developed chronic fatigue.

Dr. Donta pointed out that Chronic Fatigue Syndrome shares a number of symptoms with Lyme disease. Symptoms of Lyme disease include fatigue, arthalgias, myalgias, headaches, cognitive problems, mood swings, and paresthesias.[2] Similarly, Chronic Fatigue Syndrome is characterized by a fatigue for 6 months, associated with at least 4 of 8 associated symptoms such as impaired memory, sore throat, tender or swollen lymph nodes, muscle pain, multi-joint pain, unrefreshing sleep, new onset headaches, and post-exertion malaise.

Chronic Lyme disease etiology may be multifactorial, Dr. Donta said. It may stem from a persistent relapsing infection, be an autoimmune-triggered disorder, or result from release of toxin during reactivation of infection.

The persistent infection hypothesis has also been applied to some of the other CMSDs. In recent studies of chronic fatigue syndrome, tests showed evidence of mycoplasma DNA in the WBC buffy coat in 50% of subjects. In another study -- this one of patients with Gulf War Syndrome -- similar findings were seen: mycoplasma fermentens in the blood of half the subjects.

Challenges in Differential Diagnosis
The diagnosis of these CMSDs relies largely on clinical criteria. Problems emerge given the non-specific nature of many of these symptoms; even in fibromyalgia, elucidation of tender points is not always reliable. Laboratory testing is of primary use as an adjunctive tool in clinical assessment. In Lyme disease, Western blot testing appears superior to the ELISA in detecting the illness, Dr. Donta said. In one of Dr. Donta's studies, conducted in a large cohort of patients with Western blot-positive serum results, only 35% (72/205) of the cohort had correspondingly positive ELISA results. These findings, Dr. Donta pointed out, are contrary to the recommendations of the CDC for a two-tiered approach to the serologic testing. The CDC recommendations say patients should not be tested by Western blot unless their screening ELISA results are either positive or equivocal.

Dr. Donta said that in formulating the standardized criteria for the interpretation of a Western blot, the CDC relied upon the number of bands that were most frequently seen rather than the specificity of the bands themselves. For this reason, he says, some of the most specific bands for Lyme disease (eg, the 31 and 34Kd bands) were excluded. Dr. Donta emphasized that a new set of criteria needs to be established for the interpretation of Western blot results, and that those criteria should include the specificity of the bands for Lyme disease.

Further, he said, the CDC case criteria for the diagnosis of Lyme disease do not include one of the more common late manifestations of neurologic Lyme disease: encephalopathy. SPECT imaging can be helpful in the differential diagnosis, demonstrating a pattern of heterogeneity, he said. DNA PCR studies may also be helpful, but Dr. Donta says that in his experience fewer than 5% of patients with chronic Lyme disease have positive PCR results.

Dr. Donta stressed that spinal fluid analysis is an important tool in the differential diagnosis of Lyme disease -- ruling out other disorders before the diagnosis of Lyme disease is firmly established.

Post-Lyme Disease and Chronic Fatigue Syndrome
The other presentation that highlighted how other clinical syndromes share symptomology with Lyme disease was delivered by Dr. Lauren Krupp, of the State University of New York at Stony Brook and principal investigator of the Stop Lyme Disease NIH-funded research study.[3] She described her work comparing Post-Lyme Syndrome with Chronic Fatigue Syndrome. She said her studies are based on observations that a small percentage of patients (5-16%) experience a constellation of symptoms following early disease treatment: headache, myalgia, fatigue, paresthesias, arthralgias, and mood disturbance. Prior studies have demonstrated that risk factors for the development of sequelae from Lyme disease include lengthy duration of disease (>1 year) prior to treatment, high specific IgG antibody titers, and multiple bands on the Western blot (which have been correlated with poor verbal memory performance).

The term "Post-Lyme Syndrome" encompasses chronic or intermittent problems that begin at the time of clinical Lyme disease and persist for months to years despite adequate antibiotic therapy. Synonymous terms include "post treatment Lyme disease" and "chronic Lyme disease". Similar in symptomology to other disorders, Post-Lyme Syndrome (PLS) may produce cognitive disturbances (encephalopathy), fatigue/malaise (Chronic Fatigue Syndrome), joint and muscle pain (fibromyalgia), headache, and other features such as hearing loss, vertigo, mood disturbances, paresthesias, sleep disturbances, and stiff neck.

Dr. Krupp said estimates of the frequency of PLS range from 13% (in a 1993 study of 788 patients), to 53% (in a 1993 study of 215 patients). In a population-based study by Shadick in 1994 comparing Lyme disease patients to community controls, the significantly more common and distinguishing clinical symptoms between the two groups respectively were severe fatigue (26% vs 9%), concentration problems (47% vs 16%), emotional lability (18% vs 5%), difficulty sleeping (47% vs 16%), and objective cognitive impairment (12% vs 5%).[4]

Dr. Krupp said that in addition to persistent infection, reinfection, or a post-infectious immune or inflammatory process, other causes of Post-Lyme Syndrome need to be considered. These include incorrect diagnosis, slow resolution of symptoms, residual damage, and unmasked prior pathology.

In one post-treatment Lyme disease study, Dr. Krupp compared patients with PLS to patients with Chronic Fatigue Syndrome (CFS). The PLS patients had a history of seropositivity, a compatible clinical syndrome, severe fatigue persisting for 6 months or more, and no other explanation for fatigue. The CFS patients had no history of Lyme disease. Although all of the CFS patients met the 1994 CFS criteria, as many as 84% of the PLS patients also met the same criteria. The clinical symptoms that significantly distinguished the two groups, comparing CFS and PLS respectively, were: fever (72% vs 28%), sore throat (76% vs 28%), unrefreshing sleep (96% vs 36%) and tender cervical or axillary lymph nodes (60% vs 26%). In the CSF analyses of these two patient groups, 21-40% of the PLS patients were Borrelia antigen positive vs 0% of the CFS patients. In regards to cognitive performance, both groups had more deficits than the controls, with the PLS patients having more deficits on verbal fluency, verbal memory, and digit span than the CFS patients.

Determining Efficacy of Therapy
In the Stop Lyme Disease Study, which is ongoing, the goal has been to characterize the clinical and laboratory findings of patients with PLS and to determine the efficacy of one month of parenteral ceftriaxone therapy. All patients met the CDC case definition of Lyme disease. This placebo-controlled study has 3 primary endpoints: fatigue, cognitive speed, and CSF infection markers. Neurologic, CSF, psychiatric, fatigue, and cognitive measures were applied at baseline and at 6 month follow-up. Of 45 enrolled subjects, 27 have completed treatment and the 6-month follow-up, 13 are in phase, 3 had allergic reactions and 2 have dropped out of the study. Most patients are working full time (77%) and there are slightly more women (55%) than men (45%). About 25% of the patients had only an initial EM rash on presentation, while 55% had an EM and late manifestations, and 20% had only late manifestations (such as arthritis).

At baseline, 100% of the PLS patients had severe fatigue, 63% had objective cognitive impairment, 22% were OspA CSF-antigen postive, and 32% had a current psychiatric disorder. Dr. Krupp said the treatment results thus far from the study could not be divulged because the trial is ongoing.

Dr. Krupp noted that there is considerable overlap between PLS and CFS and that cognitive deficits and psychiatric comorbidity are common.

Donta ST: Fibromyalgia, Lyme disease, and Gulf War Syndrome. 12th International Conference on Lyme Disease and Other Spirochetal and Tick-Borne Disorders, New York, NY, 1999.
Donta ST. Tetracycline therapy for chronic Lyme Disease. Clin Infect Dis 1997 25(Suppl 1): 52-6, 1997 Jul.
Krupp L: Chronic Fatigue Syndrome and Post-Lyme Disease. 12th International Conference on Lyme Disease and Other Spirochetal and Tick-Borne Disorders, New York, NY, 1999.
Shaddick NA, Phillips CB, Logigian EL, et al: The long-term clinical outcomes of Lyme disease. Ann Intern Med 1221: 560-67, 1994