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Articles and Presentations
Controversies
in Neuroborreliosis
Audrey
Stein Goldings, M.D.
Updated
October, 2002
III. THE
ASSOCIATION BETWEEN MULTIPLE SCLEROSIS AND LYME DISEASE: THREE DIFFERENT
SCENARIOS
1) LYME CAN
LOOK LIKE MS BUT SYMPTOMS AND PATHOLOGY RESIDE OUTSIDE THE CENTRAL NERVOUS
SYSTEM
Lyme may present
as a MS-like illness, but on many occasions the pathology is not actually
in the CNS. Since chronic Lyme symptoms often are predominantly shifting,
vague, behavioral-psychological, psychiatric, and, as mentioned, neurological,
they are likely to conjure up the diagnosis of MS in patients and physician
alike. However, the existence of pathology outside the CNS should rule
out the diagnosis of MS. Some of the vague symptoms that can be mistaken
for MS include those that are better attributed to peripheral nervous
system damage, as part of the mononeuritis multiplex that may occur.
This might cause numbness, tingling, facial weakness, diplopia, etc.
The diagnosis of MS cannot be made in the absence of CNS symptoms and
signs. MRI and CSF findings would also help support the diagnosis of
MS. In addition, a significant CSF pleocytosis may occur with Lyme disease,
which should not be present with MS.
2) OTHER
LYME PATIENTS DO HAVE CNS LESIONS, BUT THESE ARE GENERALLY DISTINCTLY
DIFFERENT, CLINICALLY, AND PATHOLOGICALLY FROM MS
Patients
can have CNS lesions in the brain or spinal cord with Lyme disease.
The European literature includes many more cases than the American for
encephalomyelitis, strokes, etc. In those cases where there is focal
involvement of the brain or spinal cord, it may be more difficult to
distinguish neuroborreliosis from MS. Again, a brisk CSF pleocytosis
would help diagnose Lyme and the specific aforementioned test for CNS
Lyme antibodies. Simultaneous appearance of peripheral nervous system
abnormalities or arthritis should suggest the diagnosis of Lyme.
3) ANOTHER
GROUP OF PATIENTS HAS MULTIPLE SCLEROSIS AND LYME
There are some
patients who have a clear-cut preexisting history of MS before the onset
of Lyme disease. The Lyme appears to accelerate their clinical course.
For others, it appears to be the initiating infection that triggers
the MS. These patients are most likely genetically predisposed to MS
and the Lyme bacteria exerts its major effect by “turning on”
immunologically directed CNS injury. It is not uncommon to get a history
of the onset of an exacerbation of MS related to infections, so Lyme
exacerbating MS would be expected. HLA Class II molecules determine
the intensity of the immune response to pathogenic foreign or self-antigens.
With MS, the HLA-DR4 DQw8 haplotype has been associated with chronic
progressive MS and the HLA-DR2 DQw6 haplotype has been associated with
susceptibility to both chronic progressive and relapsing or remitting
MS. It is possible that in genetically predisposed patients of certain
HLA types that infection by Lyme bacteria would cause a high production
of cytokines that would mediate the demyelination and destruction of
oligodendrocytes.
Most recently,
researchers are studying positive outcomes when antibiotics that are
most useful in treating Lyme disease are used to treat “MS.”
IV. WHAT'S
WRONG WITH “CURRENT GUIDELINES FOR TREATMENT” OF NEUROBORRELIOSIS?
First, read the fine print.
It is interesting
to note that recommendations for treatment in the medical literature
may carry provisos in small print that can easily be overlooked but
are instrumental to understanding how important individualization of
therapy is at the current time. For instance, in the past and in small
print Dr. Alan Steere has written, “treatment failures have
occurred in all these regimens, and retreatment may be necessary; the
duration of therapy is based on clinical response, and the appropriate
duration of therapy with late neurological abnormalities may be longer
than two weeks.” A more recent article written by Rahn and
Malawista states “these guidelines are to be modified by new findings.
It should always be applied with close attention to the clinical course
of individual patients.” Dr. Katzel surveyed several Lyme Borreliosis
conferences, including international ones. He finds a trend towards
the use of antibiotics for longer periods than previously described
and lack of standardization of care worldwide. 50% of physicians responding
considered using antibiotics for time periods greater than one year
in symptomatic seropositive patients, with almost as many extending
therapy up to one and a half years when necessary.
THE CASE FOR PERSISTENT
INFECTION
Studies have shown
that Lyme bacteria can be an intracellular pathogen and may evade the
normal host immune response. The causative spirochete, B. burgdorferi,
for instance, may persist within fibroblasts and survive at least 14
days of exposure to ceftriaxone. In addition, B. burgdorferi
has been cultured from CSF more than a half year after a standard regimen
of IV antibiotics, according to Preac-Mursic. Logigian and Steere looked
at patients with chronic neuroborreliosis, evaluating them six months
after two weeks of IV ceftriaxone. Over one-half of the patients had
already been treated with therapy that was thought appropriate for their
stage of illness, yet the illness progressed. The majority of patients
studied had subacute encephalopathy and polyneuropathy. Most had persistent
fatigue, and almost one-half had headaches. One-third of these patients
had to stop working or had to go part-time, underscoring the disability
that may be seen with Lyme disease on an individual and societal level.
After therapy, two-thirds of patients improved markedly, but seldom
completely. Twenty-two percent improved but then relapsed, and fifteen
percent had no change in their condition.
This study suggests
that additional antibiotics greatly helped the majority with neuroborreliosis
but they were insufficient to cause long lasting remission in those
patients who subsequently relapsed. Persistent residual or irreversible
disease may explain the fifteen percent who had no change in their condition.
For those
clinicians who have had extensive experience with chronic neuroborreliosis,
more recent recommendations suggesting that a regime of only 20 to
28 days or even 6 weeks of intravenous antibiotics is sufficient for
cure proved contrary to clinical experience. That brief dosing does
not appear to prevent relapse or improve long-term outcome dramatically
in many cases. Perhaps, as recent information has instructed, that
is because the immune system does not begin to repair itself until
the beginning of the fourth month of antibiotic treatment. A trial
of prolonged use of oral antibiotics seems more reasonable in many
cases, given these circumstances.
Antibiotics
used for chronic neuroborreliosis should be able to penetrate the
blood-brain barrier, express activity against intracellular organisms,
and assure good intraphagocytic penetration. It is anticipated that
the microbe during late disease has achieved maximal adaptation to
its host environment. Also, because of the long generation time of
the organism, lengthier therapy is warranted.
V. WE
DON'T HAVE ALL THE ANSWERS BUT HERE’S WHAT IS RECOMMENDED
If a patient has
meningitis or appears acutely ill, particularly with possible arrhythmia,
admit him or her to the hospital for intravenous antibiotics and observation.
Generally, however, in patients with stable late disease, oral antibiotics
can be tried first. The majority of patients will have some improvement
or gradual resolution of encephalopathic symptoms with a better energy
level. After a six-week trial of appropriate antibiotics, the patient
is re-evaluated. If there is no Herxheimer response or some clinical
improvement during this interval, it is worrisome, and the physician
needs to be concerned about: 1) misdiagnosis, 2) noncompliance, and/or
3) permanent end organ damage. These possibilities should be addressed
with the patient before proceeding with intravenous antibiotics since
they may not be maximally beneficial either
Over the long haul,
whether intravenous antibiotics are used for two weeks or longer, with
chronic refractory disease, ultimately other methods are necessary.
A lengthier use of oral antibiotics seems more logical than intravenous
antibiotics for some patients. Unfortunately, there are no current tests
that adequately measure disease activity with neuroborreliosis in all
patients.
We are sorely in
need of a test similar to the CSF VDRL for syphilis that would give
us a measure of disease activity. Culture negativity or disappearance
of a specific immune response in the serum or CSF has not been useful
at this time to establish cure. CSF antibodies may persist for years
after otherwise successful treatment. Particularly in the CNS, judging
response of therapy is problematic because pathological changes may
incompletely or, at least, very slowly reverse. Any clinical improvement
would be expected to occur in a delayed fashion after therapy is given.
Likewise, one would expect neuropathy related to axonal degeneration
to remit slowly and/or incompletely. Formal neuropsychiatric testing
is of value in documenting pathology and following the patient. It also
helps delineate what the patient can and cannot do. It also can help
to define the disease for the patient, family, insurer, and the employer.
The patient needs to be told that his or her symptoms should remit slowly
and incompletely, when on antibiotic treatment. This is particularly
important when the symptoms have been chronic.
VI. IN
SUMMARY
The premise of
this approach to diagnosing and treating neuroborreliosis needs to be
reinforced.
- There is no
current laboratory test that makes or breaks the diagnosis of neuroborreliosis.
It is a clinical diagnosis substantiated by laboratory data when possible.
Fortunately, the majority of cases are fairly uniform in their lack
of uniformity, and other diagnoses are easily ruled out. In situations
where the physician simply cannot achieve diagnostic certainty, he
or she should notify the patient that the diagnosis is “possible”
or “probable” neuroborreliosis. This has been done previously
with MS (i.e., possible, probable, and definite MS), another disease
where laboratory testing does not make the diagnosis in and of itself.
- There is no
perfect current laboratory test to monitor success of therapy, and
this is critically needed. Until better testing is available, assessing
progress, or lack thereof, will largely be determined with clinical
acumen.
- The infection
is difficult to eradicate and may require long-term treatment. The
spirochete, particularly in later stages, becomes well adapted to
survival within its host environment. There are some patients that
we may not be able to cure, but will be able to palliate with currently
available antibiotics.
- Although immunopathogenic
factors may play a crucial role in disease presentation, the presence
of chronic infection appears necessary to perpetuate the process and
play a causative role in persistence of immunologically triggered
symptoms.
- There is no
Diagnostic and Statistic Psychiatry Manual (DSM IV) category for “antibiotic
seeking behavior.” It is common for physicians who are unable
to explain patients’ symptoms or effect their cure to ascribe
a psychiatric cause to their malady. This is easily done with Lyme
since objective findings may be subtle or non-existent. Because neuropsychiatric
symptoms may pre-dominate, it is easy in some patients to attribute
their symptoms to depression or secondary gain. These patients do
not in any other way seek other medication that would be associated
with habituation or addiction (i.e., pain medicine).
Many patients suffer
unfairly at the hands of physicians who refuse to make the diagnosis
because blood tests are either contradictory or negative. “Lyme
bashing,” for instance, referring to Lyme disease as “yuppie
flu,” is demeaning. The “just say no” attitude of certain
physicians towards Lyme patients who request retreatment with antibiotics
should not be condoned in the face of continuing experience with this
potentially chronically disabling infectious disease.
Audrey Stein Goldings,
MD is a private practice neurologist in Dallas. She is member of ILADS
and a founding member of the Board of Directors.
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