Fifty (32%) of the 156 patients were evaluated because they developed
joint
symptoms months or, in most instances, years after Lyme disease. The
most
common
picture was that of an elderly patient who had degenerative arthritis
in the
finger joints, lower spine, hips, or knees. Most of the other patients
with
rheumatic symptoms had noninflammatory regional pain syndromes, such as

subacromial bursitis or chondromalacia patellae. In most cases, the
joints with
degenerative changes were not those affected by attacks of Lyme
arthritis, but
in some patients, previous Lyme arthritis may have been a factor in the

development of chondromalacia patellae or degenerative arthritis of the
knees.
A
few patients had other types of inflammatory arthritis after Lyme
disease, such
as rheumatoid arthritis or gout.

Fifteen additional patients were evaluated for neurological symptoms
that
developed 1 year or more after Lyme disease. For the most part, these
patients
had illnesses of unknown cause, such as a seizure disorder or vertigo,
but
neurological test results for Lyme disease were negative. In one
patient,
detailed neurological evaluation led to the diagnosis of a cerebellar
tumor
rather than neuroborreliosis. The remaining patients had disorders
affecting
other systems. Of the 156 patients with previous Lyme disease and
another
current illness, 134 (86%) had a positive antibody response to B
burgdorferi in
our laboratory at the time of our evaluation; the remaining 22 had a
history of
erythema migrans.

Patients With Another Illness

We thought that 452 (57%) of the 788 patients had another illness
rather than
Lyme disease. They had had symptoms for a mean duration of 3 years
(range, 1
month to 22 years) at the time of our evaluation. More than half of
these
patients had chronic illnesses with prominent subjective symptoms, such
as
chronic fatigue syndrome or fibromyalgia Table 4. The sex ratio among
these
patients was 2 to 1 in favor of women, but the age distribution was
similar to
that in patients with past or current Lyme disease Table 1. Although
psychiatric
disorders such as anxiety, depression, or somatization clearly played a
role in
the illness of some of these patients, we did not attempt to make
psychiatric
diagnoses. Approximately 30% of the patients had other rheumatic
diseases,
including rheumatoid arthritis or osteoarthritis, or regional pain
syndromes.
The remaining patients had neurological diseases, such as multiple
sclerosis,
or
disorders affecting other systems, such as chronic urticaria or chronic

uveitis.

----------------------------------------------
Table 4. Patients With Other Diseases
----------------------------------------------

Most of the 452 patients had had multiple serological tests for Lyme
disease
done in multiple laboratories. Of the 452 patients, 203 (45%) had
previously
had
at least one positive result in another laboratory, often in a
borderline-positive
range. In our laboratory, none of these patients was seropositive.

Results of Retreatment in Previously Treated Patients

Prior to referral, 409 of the 788 patients had received recommended
treatment
courses of oral or intravenous antibiotic therapy for Lyme disease, and
some
had
been retreated multiple times. Of the 409 patients, 31 (8%) had chronic

encephalopathy or polyneuropathy of Lyme disease, and 25 of these
patients had
improvement or resolution of their symptoms within 2 to 6 months after
retreatment with 2 g of ceftriaxone per day for 14 or 30 days. Another
42
patients (10%) had chronic fatigue syndrome or fibromyalgia following
soon
after
Lyme disease. Of the 22 patients with these syndromes whom we
retreated, only
one, whose only symptom was fatigue, improved after ceftriaxone therapy
and did
not relapse. Fourteen patients (3%) had chronic Lyme arthritis of one
or both
knees. Of the eight patients in this category whom we retreated, none
responded.
The remaining 322 patients (79%) had another illness, and we did not
recommend
further antibiotic therapy for these patients.

COMMENT

The greatest diagnostic problem demonstrated in this study was
distinguishing
Lyme arthritis, encephalopathy, or polyneuropathy from chronic fatigue
syndrome
or fibromyalgia. The most common picture in Lyme arthritis is marked
swelling
of
one or both knees. Lyme encephalopathy and polyneuropathy, which
probably
result
from direct infection of the nervous system with B burgdorferi, are
usually
associated with subtle memory deficit, localized radicular pain, or
distal
paresthesias [6,7,8,9]. These symptoms, which are often accompanied by
CSF or
electromyographic abnormalities, improve gradually over a period of
months
following intravenous antibiotic therapy [6].

In contrast, chronic fatigue syndrome or fibromyalgia, which may be
variants of
the same disorder, tend to produce more generalized and disabling
symptoms.
They
include marked fatigue, severe headache, widespread musculoskeletal
pain,
multiple symmetric tender points in characteristic locations, pain and
stiffness
in many joints, diffuse dysesthesias, difficulty with concentration,
and sleep
disturbance [32,33,34,35]. These patients lack evidence of joint
inflammation;
they have normal neurological test results [36]; they usually have a
greater
degree of anxiety and depression [37,38]; and their illness is not
cured by
antibiotic therapy. We did not find age, sex, or duration of symptoms
to be of
help in distinguishing neuroborreliosis from fibromyalgia, but the
presence of
tender points on examination and lack of response to antibiotic therapy
were
important clues in diagnosing fibromyalgia.

The problems in distinguishing neuroborreliosis from fibromyalgia are
compounded
by the fact that some patients develop fibromyalgia in association with
or soon
after Lyme disease, suggesting that B burgdorferi is one of the
infectious
agents that may trigger this chronic pain syndrome. When the syndrome
develops
years after Lyme disease, we suspect that it is due to the chance
occurrence of
two diseases. In many ways, the development of fibromyalgia as a
consequence of
infection with B burgdorferi is now the worst complication of this
disorder
since, in our experience, the pain syndrome does not respond to
antibiotic
therapy [20]. Although some patients with fibromyalgia noted
improvement while
on antibiotic therapy, they invariably relapsed within several months
after
treatment was stopped. We suspect that such improvement may be due to
the
potential placebo effect of therapy. Regardless of whether Lyme disease
is the
triggering cause, the safest and most effective approach to the
treatment of
fibromyalgia includes low-dose tricyclic medications, analgesic agents,
an
exercise program, and stress reduction techniques [39,40].

The remaining patients who had illnesses other than active Lyme disease
usually
had other rheumatic or neurological diseases for which specific
diagnostic
tests
are lacking. Several common problems were distinguishing degenerative
arthritis
or regional pain syndromes from Lyme arthritis. Determining the correct

diagnosis was more problematic in patients who had neurological
syndromes after
Lyme disease, such as vertigo, seizure disorder, or idiopathic
peripheral
neuropathy. Although we sometimes decided to treat these patients with
antibiotic therapy, their symptoms did not improve.

The limitations of laboratory testing in Lyme disease include the
insensitivity
of culture methods, the inability of serological tests to distinguish
active
from inactive infection, and the marked interlaboratory and
intralaboratory
variability in test results [24,25]. Of the 452 patients referred here
with
presumptive Lyme disease in whom we diagnosed another illness, 45% had
had a
positive serological test result for B burgdorferi in another
laboratory, but
were seronegative in our laboratory. Discrepant serological results,
particularly
if only one test result is positive, must be interpreted with caution.
Physicians should also be aware that more and more of the population in
endemic
areas are becoming seropositive due to past or asymptomatic infection
with B
burgdorferi. A positive serological test result in these patients is
often
interpreted as evidence of active Lyme disease rather than as
seropositivity
due
to past infection. If these patients develop another illness, which was
the
case
in 20% of the patients referred to the clinic, it may be attributed
incorrectly
to Lyme disease. In the future, tests that detect antigen, such as the
the
polymerase chain reaction, may help to distinguish active from inactive

infection; these tests are currently being researched.

Patients were usually referred to the clinic because of persistent or
recurrent
symptoms following standard antibiotic regimens for Lyme disease
[1,12,13].
Although persistent or recurrent symptoms in Lyme disease may result
from
incomplete eradication of spirochetes, only the current patients with
Lyme
encephalopathy or polyneuropathy responded to retreatment with
intravenous
antibiotic therapy, and they accounted for a small percentage of the
patients
referred to the clinic. Another small percentage of the current
patients seemed
to have immune-mediated chronic arthritis or a parainfectious
fibromyalgia
syndrome triggered by infection with B burgdorferi, but they did not
respond to
additional antibiotic therapy.

The most important point of this report is that misdiagnosis, either by
the
physician or the patient, was by far the most common reason for the
apparent
lack of response to antibiotic treatment. Before retreating a patient
with
persistent or recurrent symptoms who is thought to have Lyme disease,
the
physician should first reconsider whether the diagnosis is correct.

We thank the many physicians who referred patients to the clinic; Hal
Dinerman,
MD, Nancy Liu, MD, Robert Kalish, MD, Elena Massarotti, MD, James
Abraham, MD,
and Bernadette Muldoon, RN, for help in the evaluation of patients;
Bruce
Reinhardt and Jennifer Whalen for excellent laboratory assistance; and
Sandra
Gomes for help in preparation of the manuscript.

REFERENCES

1. Steere AC. Lyme disease. N Engl J Med. 1989;321:586-596. [Medline
Link]

2. Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical
manifestations
of Lyme disease. Ann Intern Med. 1983;99:76-82. [Medline Link]

3. Pachner AR, Steere AC. The triad of neurologic manifestations of
Lyme
disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology.

1985;35:47-53. [Medline Link]

4. Steere AC, Batsford WP, Weinberg M, et al. Lyme carditis: cardiac
abnormalities
of Lyme disease. Ann Intern Med. 1980;93:8-16. [Medline Link]

5. Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme
arthritis.
Ann
Intern Med. 1987;107:725-731. [Medline Link]

6. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations
of Lyme
disease. N Engl J Med. 1990;323:1438-1444. [Medline Link]

7. Halperin JJ, Luft BJ, Anand AK, et al. Lyme neuroborreliosis:
central
nervous
system manifestations. Neurology. 1989;39:753-759. [Medline Link]

8. Logigian EL, Steere AC. Clinical and electrophysiological findings
in
chronic
neuropathy of Lyme disease. Neurology. 1992;42:303-311.

9. Halperin JJ, Little BW, Coyle PK, Dattwyler RJ. Lyme disease: cause
of a
treatable peripheral neuropathy. Neurology. 1987;37:1700-1706. [Medline
Link]

10. Dattwyler RJ, Volkman DJ, Conaty SM, Platkin SP, Luft BJ.
Amoxycillin plus
probenecid versus doxycycline for treatment of erythema migrans
borreliosis.
Lancet. 1990;336:1404-1406. [Medline Link]

11. Massarotti EM, Luger SW, Rahn DW, et al. Treatment of early Lyme
disease.
Am
J Med. 1992;92:396-403. [Medline Link]

12. Rahn DW, Malawista SE. Lyme disease: recommendations for diagnosis
and
treatment. Ann Intern Med. 1991; 114:472-481. [Medline Link]

13. Treatment of Lyme disease. Med Lett. 1992;34:95-97.

14. Liu NY, Dinerman H, Levin RE, et al. Randomized trial of
doxycycline vs
amoxicillin/probenecid for the treatment of Lyme arthritis: treatment
of
non-responders with intravenous penicillin or ceftriaxone. Arthritis
Rheum.
1989;32:S46. Abstract.

15. Steere AC, Pachner A, Malawista SE. Neurologic abnormalities of
Lyme
disease: successful treatment with high-dose intravenous penicillin.
Ann Intern
Med. 1983;99:767-772. [Medline Link]

16. Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late
Lyme
borreliosis--randomized comparison of ceftriaxone and penicillin.
Lancet.
1988;1:1191-1194. [Medline Link]

17. Steere AC, Dwyer E, Winchester R. Association of chronic Lyme
arthritis
with
HLA-DR4 and HLA-DR2 alleles. N Engl J Med. 1990;323:219-223. [Medline
Link]

18. Kalish RA, Leong JM, Steere AC. Association of treatment-resistant
chronic
Lyme arthritis with HLA-DR4 and antibody reactivity to OspA and OspB of

Borrelia
burgdorferi. Infect Immun. In press.

19. Sigal LH. Summary of the first 100 patients seen at a Lyme disease
referral
center. Am J Med. 1990;88:577-581. [Medline Link]

20. Dinerman H, Steere AC. Lyme disease associated with fibromyalgia.
Ann
Intern
Med. 1992;117:281-285. [Medline Link]

21. Russell H, Sampson JS, Schmid GP, Wilkinson HW, Plikaytis B.
Enzyme-linked
immunosorbent assay and indirect immunofluorescence assay for Lyme
disease. J
Infect Dis. 1984;149:465-470. [Medline Link]

22. Magnarelli LA, Meegan JM, Anderson JF, Chappell WA. Comparison of
an
indirect fluorescent-antibody test with an enzyme-linked immunosorbent
assay
for
serological studies of Lyme disease. J Clin Microbiol. 1984;20:181-184.

[Medline
Link]

23. Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in
the
serodiagnosis of Lyme disease. J Infect Dis. 1993;167:392-400. [Medline
Link]

24. Hedberg CW, Osterholm MT, MacDonald KL, White KE. An
interlaboratory study
of antibody to Borrelia burgdorferi. J Infect Dis. 1987;155;1325-1327.

25. Bakken LL, Case KL, Callister SM, Bordeau NJ, Schell RF.
Performance of 45
laboratories participating in a proficiency testing program for Lyme
disease
serology. JAMA. 1992;268:891-895. [Medline Link]

26. Shrestha M, Grodzicki RL, Steere AC. Diagnosing early Lyme disease.
Am J
Med. 1985;78:235-240. [Medline Link]

27. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly
MG.
Seronegative Lyme disease: dissociation of the specific T- and
B-lymphocyte
responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-1446.
[Medline
Link]

28. Dressler F, Yoshinari NH, Steere AC. The T cell proliferative assay
in the
diagnosis of Lyme disease. Ann Intern Med. 1991;115:533-539. [Medline
Link]

29. Hanrahan JP, Benach JL, Coleman JL, et al. Incidence and cumulative

frequency of endemic Lyme disease in a community. J Infect Dis.
1984;150:489-496.
[Medline Link]

30. Steere AC, Taylor E, Wilson ML, Levine JL, Spielman A. Longitudinal

assessment of the clinical and epiodemiologic features of Lyme disease
in a
defined population. J Infect Dis. 1986;154:295-300. [Medline Link]

31. Steere AC, Berardi VP, Weeks KE, Logigian EL, Ackermann R.
Evaluation of
the
intrathecal antibody response to Borrelia burgdorferi as a diagnostic
test for
Lyme neuroborreliosis. J Infect Dis. 1990;161:1203-1209. [Medline Link]

32. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a
working
case definition. Ann Intern Med. 1988;108:387-389. [Medline Link]

33. Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue
syndrome.
Rev
Infect Dis. 1991;13(suppl 1):S8-S11. [Medline Link]

34. Reilly PA, Littlejohn GO. Fibromyalgia and chronic fatigue
syndrome. Curr
Opin Rheumatol. 1990;2:282-290. [Medline Link]

35. Goldenberg DL. Fibromyalgia syndrome: an emerging but controversial

condition. JAMA. 1987;257:2782-2787. [Medline Link]

36. Buchwald D, Komaroff AL. Review of laboratory findings for patients
with
chronic fatigue syndrome. Rev Infect Dis. 1991;13(suppl 1):S12-S18.
[Medline
Link]

37. Kaplan RF, Meadows ME, Vincent LC, Logigian EL, Steere AC. Memory
impairment
and depression in patients with Lyme encephalopathy: comparison with
fibromyalgia
and nonpsychotically depressed patients. Neurology. 1992;42:1263-1267.
[Medline
Link]

38. Lane TJ, Manu P, Mathews DA. Depression and somatization in the
chronic
fatigue syndrome. Am J Med. 1991;91:334-344.

39. Goldenberg DL, Felson DL, Dinerman H. A randomized, controlled
trial of
amitriptyline and naproxen in the treatment of patients with
fibromyalgia.
Arthritis Rheum. 1986;29:1371-1377. [Medline Link]

40. McCain GA, Bell DA, Mai FM, Halliday PD. A controlled study of the
effects
of a supervised cardiovascular fitness training program on the
manifestations
of
primary fibromyalgia. Arthritis Rheum. 1988;31:1135-1141. [Medline
Link]