Controversies in Neuroborreliosis
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Subject: Controversies in Neuroborreliosis
From: firstname.lastname@example.org (RitaStan)
Audrey Stein Goldings, M.D.
The objectives of this handout are to cover issues which are
not even handedly addressed in the current literature on Lyme
disease. I will:
Lyme Disease Conference
October 23, 1992
- present a practical approach for making
the diagnosis of neuroborreliosis,
- explore the other side
of the post-Lyme syndrome (ie: the likelihood of chronic
- discuss the relationship between MS
- critique the current regimens published for
treating neuroborreliosis and
- present my own approach
which may differ from some leading authorities.
"Anyone who in discussion relies upon authority uses,
not his understanding, but rather his memory."
I hope to provide the reader with a broader understanding of
neuroborreliosis so that he or she may better use current and
evolving knowledge for clinical decision making.
Leonardo Da Vinci -
Notebooks ( c. 1500)
I. NEUROBORRELIOSIS: MAKING THE DIAGNOSIS
Because of difficulties in making the diagnosis of
neuroborreliosis, the physician will need a familiarity
with the most common forms of presentations, which will be
emphasized. The following points will help evaluate the
patient for neuroborreliosis:
- For most patients, systemic features of disease
coexist with or predate neurologic manifestations.
- Both central nervous and peripheral nervous system
involvement is frequent with Lyme disease and typically
- Laboratory data may or may not confirm the diagnosis,
and other disease in the differential diagnosis must be
evaluated thoroughly in cases where diagnostic
- Although history of exposure to B. Burgorferi should
be sought, for various reasons, patients may not
remember a history of a tick bite, or the pathognomonic
rash particularly if the disease is presenting years
after the exposure.
CLINICAL DESCRIPTIONS OF NEUROBORRELIOSIS
CENTRAL NERVOUS SYSTEM (CNS)
MENINGISMUS WITH NORMAL CSF
Patients may present with
headache and stiff neck without evidence of CSF inflammation.
these symptoms probably indicate
- early CNS seeding has been described, as well as
- culture positivity during latent disease without concurrent
CNS inflammatory changes,
Stiff neck might alternatively be due to
axonal degenerative changes of the cervical paraspinal
musculature, but there should be other evidence
of a more widespread neuropathy when this is the case.
Lymphocytic Meningitis may
occur indistinguishable from aseptic meningitis during
early disseminated disease (weeks to months after
inocculation with B. burgdorferi).
- Most patients will have
headaches which will fluctuate in intensity.
features may include a cranial neuropathy in about 1/3 [of cases].
- A low grade encephalopathy is present in up to 1/2 [of cases] with
- mild memory concentration deficits,
- mood changes and
- sleep disturbance.
- Rarely, focal parenchymal
CNS lesions occur.
- The MRI may show punctate white matter
lesions best seen on T2-weighted images; larger lesions
- One brain biopsy showed
numbers of microglia cells,
- rare spirochetes and
- Transverse myelitis, movement disorders
(extrapyramidal cerebellar, chorea and myoclonus) and
hemiparesis can occur.
may occur. CSF may be normal.
- profound personality changes,
- anorexia nervosa, and
SUBACUTE ENCEPHALOPATHY (SAE)
The MOST COMMON
chronic CNS manifestation is a SAE,
- characterized by memory
problems and depression.
- Many patients will complain of
excessive daytime sleepiness and extreme irritability.
- These patients generally come to the office disorganized,
unable to give a coherent history. They will bring copious
notes which are invariably in the wrong order.
- The majority
complain of fatigue and about 1/2 [of them] have headaches.
- Coincident polyneuropathy is very common with
- Quantifiable deficits
- memory, learning and retrieval,
- attention and concentration,
- perceptual-motor skills and
- problem solving
- MMPI testing generally shows a stable psychological pattern without significant psychopathology, similar to other medically ill patients.
ADDITIONAL CNS TESTING: NEGATIVE TEST RESULTS DO
NOT RULE OUT THE DIAGNOSIS OF NEUROBORRELIOSIS
- Confirmation by CSF CULTURE is seldom practical because the
organism is very fastidious, present in small numbers, takes
a long time to grow out, and may undergo changes to forms
which cannot be cultured.
- CSF ANTIBODY TITERS may be present but are inconsistent
and therefore their absence does not rule out CNS infection.
- The MRI is seldom abnormal and the findings when present
are not specific for Lyme.
- CSF PCR may become a useful tool, but at present questions
regarding its sensitivity, specificity and reproducibility
need to be addressed. Furthermore, it is not known whether
PCR reactivity equates with active CNS disease. A recent
study using PCR methodology detected DNA of B. Burgdorferi
in CSF of patients with SAE, some of whom had both negative
blood serology and cell mediated immunoreactivity. Their
CSF was otherwise normal. An alternative explanation for SAE
is that it is due to soluble neuromodulators produced in
response to infection, so that even in the absence of
direct CNS infection neurologic dysfunction could occur.
- OLIGOCLONAL BANDS AND IgG INDEX - Looking for evidence
of an intrathecal immune response may be helpful, but it is
not specific. As a rule, oligoclonal bands and an elevated
IgG index are not present in North American Lyme disease
and their presence should suggest other disease, such as MS.
THE PERIPHERAL NERVOUS SYSTEM
- Generally the following are seen and reflect different clinical
presentations of mononeuritis multiplex (polyneuropathy).
- Cranial neuropathy,
- painful radiculitis,
- distal neuropathy and
- Bell's Palsy occurs in almost 11% of all Lyme patients
and is bilateral in up to 1/3. Therefore, a bilateral Bell's
Palsy is very suspicious for Lyme in an endemic area.
- Painful radiculitis or cranial neuropathy can be seen with meningitis but also with normal CSF due to axonal neuropathy.
- Myositis may occur with Lyme as well as
- poly - myalgia rheumatica.
In a series of patients with
chronic neurologic manifestations of Lyme disease symptoms of chronic involvement
- of the
peripheral nervous system developed
a median of 16 months after the onset of infection while
involovement began a median of 26 months after the onset
PERIPHERAL NERVOUS SYSTEM TESTING
Electrophysiological testing may show evidence of a mild peripheral
neuropathy. Axonal degeneration and perivascular inflammatory infiltrates are noted on pathological specimens.
A. THE MOST COMMON PRESENTATION IS SAE, POLYNEUROPATHY, AND ARTHRITIS.
TRIAD OF SAE, POLYNEUROPATHY AND ARTHRITIS IS HIGHLY
SUSPICIOUS FOR NEUROBORRELIOSIS.
typically patients present with SAE, most often combined with
- Brief episodes of arthritis, primarily
involving the knees, generally predate the symptoms and may
persist after onset of neurological abnormalities.
Since serologies may be contradictory or negative, the
physician will have to settle for treating if clinical suspicion
is strong enough and assess whether the patient has "possible"
or "probable" neuroborreliosis. Vigilant attempts to rule
out other disorders should be undertaken. Screening should be
definite diagnosis can not be made.
- collagen vascular disease,
- other infections,
- metabolic or endocrinological disturbances, etc.
B. CURRENT MEDICAL MYTHOLOGY:
"YOU HAVE FIBROMYALGIA.
YOU MIGHT HAVE HAD LYME DISEASE IN THE FIRST PLACE, AND
EVEN IF YOU DID, YOU WERE GIVEN ENOUGH ANTIBIOTICS.
RETREATMENT WILL NOT HELP".
PERSISTENT INFECTION VERSUS POST-LYME SYNDROME
Many patients are sent home with antidepressants, muscle
relaxers but no antibiotics from doctors' offices because
they have symptoms of fibromyalgia. Pictures similar to,
or identical to fibromyalgia may be part of the constellation
of symptoms of Lyme; it may occur more rarely as an isolated
symptom, or surface after what would otherwise be
considerated successful treatment.
Symptoms of fibromyalgia due to Lyme disease have not been
cured with short term oral or intravenous antibiotics, so
some argue fibromyalgia is not due to active infection. I
would question whether those particular antibiotic regimens
were adequate to eliminate the infection, rather than assume
the patient has developed "Post-Lyme Syndrome" (some yet
to be defined immunologically triggered disorder).
THE SCOPE OF THE PROBLEM
Bujak et al. evaluated patients a mean of almost 5 years
- 15% of these patients had symptoms of
fatigue and arthralgia.
- Almost 1/2 [of the cases] met criteria for
fibromyalgia or chronic fatigue syndrome. Fibromyalgia
is thought to be a variant of the chronic fatigue syndrome.
Of note, nearly all patients continued to complain of memory
loss or concentration difficulties.
- 1/4 [of the cases] had objective
evidence of cognitive impairment and
- 15% manifested
C. SYMPTOMS OF FIBROMYALGIA AND CHRONIC FATIGUE
SYNDROME IN LYME DISEASE MAY BE ATTENUATED FORMS
OR CHRONIC MANIFESTATIONS OF THE FLU-LIKE SYMPTOMS
ASSOCIATED WITH EARLY DISSEMINATION.
All physicians experienced with treating Lyme disease have
had patients who present with a recurrence of flu-like
symptoms, months to years after they have completed
the usual antibiotic course of therapy, oral or intravenous,
and re-exposure had not occurred.
- These patients describe their
flu-like symptoms as identical to their early disseminated
stage of Lyme disease.
- The flu-like symptoms may reoccur
following what appears to be a trivial stressor, such as an
uncomplicated viral URI.
- Patients may be able to "contain"
their symptoms without specific antimicrobial therapy,
but many will have to resume antibiotics.
- These patients
complain of having to go to bed due to excessive fatigue or
- They cannot think straight,
- their muscles
and joints ache, and
- they may have a low grade fever.
symptoms sound like a "fibromyalgia-like syndrome" or
"acute fatigue syndrome"?
- Prior medical experience suggests
reactivation of infection. Despite what may appear to have
been a previous "cure", relapse of symptoms in this context
would appear to be due to failure to eradicate the infection
with reactivation after a period of dormancy.
of symptoms due to immunologically triggered disease,
INDEPENDENT of persistent infection seems unlikely.
reality, DISTINCTIONS BETWEEN FLU-LIKE SYNDROME,
FIBROMYALGIA, AND CHRONIC FATIGUE BLUR. It seems more
logical to me to postulate that fibromyalgia and chronic
fatigue syndrome, when seen with Lyme disease, may be
attenuated forms of chronic manifestations of earlier
flu-like symptoms associated with early dissemination.
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
Lyme symptoms are often predominantly neurological and
vague, 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
- facial weakness,
- diplopia, etc.
- The diagnosis of MS cannot
be made in the absence of CNS symptoms and signs.
and CSF findings would also help support the diagnosis
- In addition, a significant CSF pleocytosis may
occur with Lyme 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,
- 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 HAVE 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 exacerabating MS would be
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 infectioon by Lyme bacteria would cause a high
production of cytokines that would mediate the demyelination
and destruction of oligodendrocytes.
IV. WHAT'S WRONG WITH "CURRENT GUIDELINES FOR TREATMENT" OF NEUROBORRELIOSIS.
It is interesting to note that recommendations for treatment in the medical literature may in small print carry
provisos that can easily be overlooked but are instrumental
to understanding how important individualizaiotn of therapy
is at the current time. For instance,
First, read the fine print.
- in small print Dr. 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" (he now recommends up to
- 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 1 year in symptomatic seropositive patients,
with almost as many extending therapy up to 1 1/2 years
THE CASE FOR PERSISTENT INFECTION
Studies have shown that Lyme bacteria may be an intracellular
pathogen and may evade the normal host immune response.
B. burgdorferi, for instance, may persist within fibroblasts
and survive at least 14 days of exposure to Ceftriaxone.
- B. burgdorferi has been cultured from CSF more
than 1/2 year after a standard regimen of IV antibiotics,
according to Preac-Mursic.
- Logigian and Steere looked at
patients with chronic neuroborreliosis, evaluating them
6 months after 2 weeks of IV Ceftriaxone.
This study suggests that additional antibiotics helped the
majority with neuroborreliosis but it was insufficient to
cause long lasting remission in those patients that subsequently relapsed. Persistent residual or irreversible
disease may explain the 15 % who had no change
in their condition.
- Over 1/2
of the patients had already been treated with therapy
thought appropriate for their stage of illness, yet the illness
- The majority of patients studied had subacute
encephalopathy and polyneuropathy.
- Most had persistent
fatigue, and almost one half had headaches.
- 1/3 of
these patients had to stop working or had to go part-time,
underscoring the disability that may be seen with Lyme on an
individual and societal level.
- After therapy, 2/3 of
patients improved markedly, but seldom completely.
- 22 % improved but then relapsed, and
- 15 %
had no change in their condition.
- For those clinicians that have had extensive experience with
- more recent recommendations suggesting
20 to 28 days of intravenous antibiotics does not appear to
be the answer to prevent relapse or improve outcome in any
- Instead, the prolonged use of oral antibiotics
seems more reasonable. These antibiotics should be able to
- penetrate the blood-brain barrier,
- express activity against
intracellular organisms, and
- assure good intraphagocytic
- It is anticipated that the microbe during late
disease has achieved maximal adaptation to its host
- Also, because of the long generation time of
the organism, lengthier therapy is warranted.
V. I DON'T HAVE "THE ANSWER" BUT HERE'S WHAT I DO.
- If a patient has meningitis or appears acutely ill, partcularly with possible arrhythmia, I will admit him or her
to the hospital for intravenous antibiotics and observation.
- Generally, however, in patients with stable late disease, I
will try oral antibiotics 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
- If there is no Herxheimer response or some
clinical improvement during this interval, it is worrisome
and the physician needs to be concerned about:
- noncompliance and/or
- permanent end organ damage.
- These should be addressed with the patient before proceeding with intravenous antibiotics since these may not
be beneficial either.
- Over the long haul, whether intravenous
antibiotics are used two weeks or longer, "the juice isn't
worth the squeeze" and ultimately, with chronic refractory
disease, other methods are necessary.
- A lengthier use of
oral antibiotics seems more logical than intravenous antibiotics.
- Unfortunately, there are no current tests that
adequately measure disease activity with neuroborreliosis.
We are sorely in need of a test similar to the CSF VDRL
for syphillis 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
- 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.
testing may be of value in documenting pathology and following the patient. It also helps delineate what the
patient can and cannot do. It helps to define the disease for
the patient, family, and the employer.
- The patient needs to
be told that his or her symptoms may remit slowly and incompletely, regardless of antibiotic treatment. This is
particularly important when the symptoms have been chronic.
VI. IN SUMMARY
I would like to reinforce the premises of my approach to
diagnosing and treating neuroborreliosis.
- 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 monotonous
in presentation, 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 current laboratory test to monitor success of
therapy which 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
- Although immunopathogenic factors may play a crucial
role in disease presentation, chronic infection may be
necessary to perpetuate the process and play a causitive
role in persistence of immunologically triggered symptoms.
- There is no DSM III 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 nonexistent. Because neuropsychiatric symptoms may predominate, 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 (ie; 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 chronic disabling
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