In a third study, the patients with chronic Lyme borreliosis received tetracycline for 1-11 months (mean, 4 months), and treatment failed in 10% of patients.[6]
- From: "CaliforniaLyme" <CaliforniaLyme@xxxxxx>
- Date: 23 May 2005 10:24:16 -0700
Lyme Neuroborreliosis: Recognition, Treatment, and Retreatment of
Relapse
Julie Rawlings, MPH
Introduction
On the first day of the 13th Lyme Disease Conference, Dr. Jarmo Oksi,
of the Department of Medicine, Turku University Central Hospital and
Department of Medical Microbiology, Turku University, Finland, examined
the issues involved in the diagnosis and treatment of Lyme
neuroborreliosis and the factors involved in relapse after antibiotic
treatment.
Vasculitis and Other Pathogenetic Mechanisms of Neuroborreliosis
Dr. Oksi began by reviewing the pathogenetic mechanisms of Lyme
neuroborreliosis, which are still poorly understood. It may be caused
either by the direct action of Borrelia burgdorferi or by indirect
immunologic reactions. As in another spirochetal disease, syphilis,
spirochetes in Lyme borreliosis can penetrate the blood-brain barrier
(BBB) early in the infection. Interaction with the intraluminal
endothelial surface by the spirochete, directly or via systemic
cytokines, has been shown to be necessary for the increase of the
permeability of BBB.
The dissemination of B burgdorferi to various organs depends on its
ability to adhere to and penetrate into the endothelium and the BBB. B
burgdorferi may also adhere in areas with endothelial damage. Recent
findings indicate that B burgdorferi can acquire proteolytically active
host components. This mechanism could facilitate the localization of
spirochetes to sites of vascular injury, followed by dissemination. The
affinity of the organism for astrocytes, the nearest neighbors of brain
capillaries, could facilitate its access to the nervous system.
Followed by the breakdown of the BBB, focal vasculitis may develop by
activation of endothelial cells and further release of inflammatory
mediators. CNS involvement is associated with scattered perivascular
mononuclear cell (mainly T-helper cell) infiltrates in the cerebral
cortex, sometimes accompanied by comparable focal changes in the
leptomeninges.
These observations by Dr. Oksi and colleagues support earlier reports
suggesting that vasculitis may be one of the primary pathophysiologic
mechanisms in Lyme neuroborreliosis. This is only logical, because B
burgdorferi infection frequently causes perivascular inflammation or
vasculitis in affected organs other than the CNS. This is also in
agreement with the recent finding that patients with chronic Lyme
encephalopathy have multifocally reduced blood perfusion to the
cerebral hemispheres, particularly in white matter; these patients also
show objective improvement in brain perfusion after antibiotic
treatment.[1]
Vasculitis also is a predominant finding in syphilis. Syphilitic
endarteritis may cause multiple small infarctions in the CNS or involve
the vasa vasorum of large or medium-sized vessels and lead to aneurysms
or ischemic infarction months or years after onset of infection.
Studies on experimental Borrelia infections have also shown prominent
lymphoplasmacellular infiltration in the microvasculature, endarteritis
obliterans, and spirochetes in and around blood vessels of synovial and
myocardial tissues.
Diagnostic Tests: Their Strengths and Limitations
The laboratory diagnosis of neuroborreliosis has usually been based on
nonspecific findings, serologic testing, and other indirect methods.
Intrathecal production of antibodies against B burgdorferi may confirm
the diagnosis of neuroborreliosis, although as an indirect method it
only can show that there is evidence of past or present infection
caused by B burgdorferi. However, evidence for the presence of B
burgdorferi can also be obtained by culture or polymerase chain
reaction (PCR) of cerebrospinal fluid (CSF), plasma, or brain tissue
specimens. Furthermore, direct demonstration of B burgdorferi in brain
lesions indicates that direct invasion of the spirochetes has obviously
been the pathogenetic mechanism in these cases.
The low number of spirochetes in tissue samples and body fluids is one
of the reasons why it is difficult to demonstrate B burgdorferi by
culture or PCR. Therefore, a negative result obtained by these methods
can never exclude Lyme disease. However, a positive result can confirm
the diagnosis or treatment failure independently of results of antibody
tests.
Treatment of Neuroborreliosis: Unresolved Issues
Treatment of infection with B burgdorferi in its early, localized phase
is clinically successful in most cases. Treatment for neuroborreliosis
and disseminated infection is less successful and is therefore highly
variable between countries, study centers, and hospitals. Most
published recommendations favor intravenous antibiotics for 2-4 weeks
or, alternatively, oral therapy for 4 weeks. For neuroborreliosis, IV
treatment is usually recommended, with the exception of facial palsy or
peripheral neuropathy alone.
Dr. Oksi stated that B burgdorferi may invade the CNS early in the
infection, and possibly without causing severe symptoms. However, there
is also marked spontaneous recovery from the early phases of
neuroborreliosis. Therefore, assessment of the success of treatment is
difficult. According to a questionnaire study among doctors, about half
of the clinicians working in highly endemic areas in the United States
preferred to use treatments lasting for 3 or more months for patients
with chronic Lyme disease, contradictory to published
recommendations.[2] However, Dr. Oksi believes, there is no convincing
evidence showing that long-term treatment could prevent treatment
failures.
Relapsed Neuroborreliosis
Differentiating treatment failure from "post-Lyme syndrome" is
difficult, because they have both been poorly defined. However, it is
generally agreed that a true treatment failure means ongoing infection,
that is, the presence of live B burgdorferi. By contrast, "post-Lyme
syndrome" consists of residual symptoms lasting for several months
after therapy without evidence of the spirochete. Symptoms of
"post-Lyme syndrome" apparently arise via immunologic mechanisms
triggered by the infection.
Dr. Oksi reported on 13 patients with clinical relapse of disseminated
Lyme borreliosis after antibiotic treatment and culture or PCR
positivity for B burgdorferi.[3] These patients were a subgroup of 165
patients with disseminated B burgdorferi infection who were followed
for at least 1 year after 3 months of antibiotic treatment. Symptoms
reappeared in nearly 20% (32) of the original group of patients, 13 of
whom were PCR or culture positive.
These 13 patients (9 of them having multiorgan manifestations of the
disease) were initially treated for more than 3 months (median, 16
weeks) with IV and/or oral antibiotics. Antibody levels decreased or
changed to seronegative in 6 of the 13 patients after the first
treatment. For retreatment, patients received IV ceftriaxone 2 g daily
for 4-6 weeks, followed by oral antibiotics in 3 patients. The clinical
response to retreatment was considered good in 9 of the 13 patients (4
of them becoming symptomless) and poor in 4 patients. None of the
patients was PCR or culture positive after retreatment.
Previous studies. According to Dr. Oksi, the clinical relapse rate seen
in this study was slightly lower than levels reported earlier among
patients treated with shorter courses of antibiotics. However, at least
2 studies have shown better clinical outcome with a shorter duration of
antibiotic treatment. In one trial, Lyme neuroborreliosis patient
outcomes were excellent, with no treatment failures.[4] In the other
trial, in patients with acute disseminated Lyme borreliosis (mainly
multiple erythema migrans), clinical cure rates were 85% in patients
receiving ceftriaxone and 88% in those given doxycycline.[5] However,
the patients in the ceftriaxone group reported persistent symptoms at
the last follow-up visit more frequently (27%) than expected. In a
third study, the patients with chronic Lyme borreliosis received
tetracycline for 1-11 months (mean, 4 months), and treatment failed in
10% of patients.[6]
MRI findings. Before initial antibiotic treatment, 11 of the 13
patients had neurologic symptoms or findings, including meningitis in
3, encephalitis in 3, radiculitis or neuritis in 2; and other
neurologic symptoms, together with non-neurologic symptoms, in 5 of the
patients. Abnormal brain MRI findings were obtained in 5 of 8 patients
studied. One also had cervical myelopathy demonstrated by MRI.[3,7,8]
New foci. Dr. Oksi described brain lesions that developed in one
patient in previously intact areas during or after treatment, the last
one of them 16 months after the start of prolonged antibiotic therapy.
Several reports have been published on the occurrence of new foci and
paradoxical enlargement of CNS lesions during the treatment of
mycobacterial CNS infections.[9] The direct effects of mycobacterial
products or the host's immunologic reactions elicited by microbial
components have been suggested as the most likely explanation for the
appearance of new foci in mycobacterial infections.
A similar mechanism could explain the development of new lesions during
therapy for Lyme borreliosis. However, DNA of B burgdorferi in the
plasma of the patient more than 16 months after the initiation of first
antibiotic treatment suggests the presence of ongoing infection. The
route of entry to the new sites could have been the vascular wall after
occurrence of subclinical spirochetemia.
An alternative explanation is that the spirochetes were already at the
site of lesions before antibiotic treatment. Because of metabolic
inactivity, they were not affected by antibiotics. After a latent
period, the spirochetes could have activated and caused changes visible
on brain MRI. The disappearance of all lesions after repeated therapy
further supports the theory that the lesions were directly related to B
burgdorferi infection. Our experience with this patient suggests that,
in rare cases, extended or repeated antibiotic treatments may be
necessary to eradicate the spirochete from sites where it has acquired
a latent state.
Conclusions
Thus, Dr. Oksi stated, MRI findings compatible with vasculitis
associated with a positive PCR result from the CSF or plasma, even
without direct demonstration of the spirochete in the brain lesions,
might be an indication for antimicrobial treatment against B
burgdorferi. In addition, because treatment response may not be
apparent for months after cessation of treatment, length of treatment
should probably be decided at the start of therapy.
PCR offers a practical means to differentiate patients with "post-Lyme
syndrome" or with "serologic scars" from those who definitely need
retreatment. Randomized studies with long-term follow-up are warranted
to determine the most successful regimens and adequate durations of
antibiotic treatments for disseminated Lyme borreliosis.
References
Logigian El, Kaplan RF, Steere AC. Successful treatment of Lyme
encephalopathy with intravenous ceftriaxone. J Infect Dis.
1999;180:377-383.
Ziska M, Demarest F, Donta ST. Physicians preferences in the diagnosis
and treatment of Lyme disease in the United States. Infection.
1996;24:182-186.
Oksi J, Marjamäki M, Nikoskelainen J, Viljanen MK. Borrelia
burgdorferi detected by culture and PCR in clinical relapse of
disseminated Lyme borreliosis. Ann Med. 1999;31:225-232.
Karlsson M, Hammers-Berggren S, Lindquist L, Stiernstedt G, Svenungsson
B. Comparison of intravenous penicillin G and oral doxycycline for
treatment of Lyme neuroborreliosis. Neurology. 1994;44:1203-1207.
Dattwyler RJ, Luft BJ, Kunkel MJ, et al. Ceftriaxone compared with
doxycycline for treatment of acute disseminated Lyme disease. N Engl J
Med. 1997;337:289-294.
Donta ST. Tetracycline therapy for chronic Lyme disease. Clin Infect
Dis. 1997;25(suppl 1):S52-S56.
Oksi J, Kalimo H, Marttila RJ, et al. Inflammatory brain changes in
Lyme borreliosis. A report on three patients and review of literature.
Brain. 1996;119:2143-2154.
Oksi J, Nikoskelainen J, Viljanen MK. Comparison of oral cefixime and
intravenous ceftriaxone followed by oral amoxicillin in disseminated
Lyme borreliosis. Eur J Clin Microbiol Infect Dis. 1998;17:715-719.
Afghani B, Lieberman JM. Paradoxical enlargement or development of
intracranial tuberculomas during therapy: case report and review. Clin
Infect Dis. 1994;19:1092-1099.
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