blood -brain barrier / why it isn't always easy to cure Lyme disease

From: JWissmille (jwissmille_at_aol.com)
Date: 06/23/04 

Date: 23 Jun 2004 00:48:31 GMT

" Scientific reasoning is a kind of dialogue between the possible and the
actual, between what might be and what is in fact the case."

Sir Peter Medawar

".......Neither the clinical presentation nor routine
laboratory tests accurately predicted which patients had B. burgdorferi DNA in
their CSF
.......Our findings demonstrate that B. burgdorferi can disseminate to
the CNS very early on in the course of the infection with little or no clinical
evidence of CNS involvement....."

"......This raises the possibility that the CNS may act as a sanctuary for B.
burgdorferi, protecting it from the action of systemic anti-biotics and
immunity and thereby allowing it to reseed the periphery intermittently..."

from: Invasion of the Central Nervous System by Borrelia burgdorferi in Acute
Disseminated Infection
JAMA. 1992;267:1364-1367
authors: Benjamin J. Luft, ......Raymond J. Dattwyler

"...........In this prospective study of unselected patients, we found two
thirds of the patients with disseminated infection had B. burgdorferi DNA in
their CSF. Although the presence of spirochetal DNA does not necessarily mean
that viable B. burgdorferi were present in the CNS of these patients, this is
very likely, given the fact that these patients had evidence of active clinical
infection. The parameters have been used in the past to diagnose acute CNS
infection may have greatly underestimated the true incidence of CNS involvement
in this group of patients. Neither the clinical presentation nor routine
laboratory tests accurately predicted which patients had B. burgdorferi DNA in
their CSF
.......Our findings demonstrate that B. burgdorferi can disseminate to
the CNS very early on in the course of the infection with little or no clinical
evidence of CNS invovement. Acute primary and secondary infections due to
Treponema pallidum (syphilis) are also associated with a high rate of
dissemination to the CNS......This study has important therapeutic implications
as well. In the past, the recommended treatment of acute Lyme disease
consisted of low doses of oral tetracycline or penicillin, even in patients
with signs and symptoms of systemic and therefore potential meningeal
involvement...an inordinately high failure rate....when ceftriaxone, an
antibiotic that is highly active against B. burgdorferi, achieves high CSF
levels, and has a prolonged half-life, was compared with penicillin for the
treatment of late Lyme disease, ceftriaxone had a significantly higher success
rate.........Among four patients with chronic Lyme arthritis, B. burgdorferi
was found in the CSF of one patient with relapsing arthritis. This patient had
no clinical evidence of CNS involvement and no intrathecal antibody production
. This raises the possibility that the CNS may act as a sanctuary for B.
burgdorferi, protecting it from the action of systemic anti-biotics and
immunity and thereby allowing it to reseed the periphery intermittently. This
finding is especially important when considering the appropriate treatment of
the chronic phase of this disease and whether the use of oral antibiotics
alone, as suggested by some for chronic arthritis, is
appropriate."
________________________

".........persistence of brain infection after treatment with antibiotics that
do not readily penetrate the blood-brain barrier..."

Neuroborreliosis during relapsing fever: review of the clinical manifestations,
pathology, and treatment of infections in humans and experimental animals.
 
Clin Infect Dis 1998 Jan;26(1):151-64 (ISSN: 1058-4838)
Cadavid D; Barbour AG
Department of Neurology, Georgetown University School of Medicine, Washington,
D.C. 20007, USA.

The spirochetal disease relapsing fever is caused by different Borrelia
species. Relapsing fever is well recognized as an infection of the blood, but
little is known about its predilection for the nervous system and the eyes. To
investigate neurological and ocular involvement during relapsing fever, we
reviewed the clinical manifestations, pathology, and treatment of relapsing
fever of humans and experimental animals. The results indicate that Borrelia
turicatae and Borrelia duttonii, the agents of tick-borne relapsing fever in
southwestern North America and sub-Saharan Africa, respectively, cause
neurological involvement as often as Borrelia burgdorferi in Lyme disease.
Evidence of this is the frequent occurrence of lymphocytic meningitis and
peripheral facial palsy in human disease; the identification of spirochetes in
the brain and other nervous tissues of humans, animals, and arthropod vectors;
and the persistence of brain infection after treatment with antibiotics that do
not readily penetrate the blood-brain barrier.
 
 
Indexing Check Tags: Animal; Human; Support, U.S. Gov't, P.H.S.
Language: English
MEDLINE Indexing Date: 199803
Publication Type: Status: Completed
Publication Type: Journal Article; Review; Review, Academic
Grant ID: AI24424
PreMedline Identifier: 0009455525
Unique NLM Identifier: 98116703
Journal Code: IM
__________________________

_____________________________

"................. This
finding is especially important when considering the appropriate treatment of
the chronic phase of this disease and whether the use of oral antibiotics
alone, as suggested by some for chronic arthritis, is
appropriate."....

from: A Perspective on the Treatment of Lyme
 Borreliosis
authors: Benjamin J. Luft, Gorevic, Halperin,
 Volkman, and Raymond J.
Dattwyler
source: Reviews of Infectious Diseases Vol. II
  Supplement 6 September,
October 1989

".....It is apparent that B. burgdorferi disseminates
 hematogenously in a
sizable group of patients ...and that high tissue levels of antimicrobial
agents may be needed to eradicate the infection.....If CNS involvement is
discovered or there is significant compromise of
 an organ system as a result of
infection, the patient should receive parenteral
 therapy so that adequate CNS
drug levels are attained. .......Recently, Weber
 et al reported the congenital
transmission of B. burgdorferi to an infant whose
 mother had been treated with
1 million units of oral penicillin for 7 days.
 Given the significant failure
rate described by Steere et al. in patients
 treated with 250 mg of oral
penicillin (more than 50% of whom developed
 'minor'and 'major' disease), it
would seem reasonable to administer more
 vigorous......to pregnant patients with
acute EM. No study has established the
 optimal treatment in this instance;
.....Further studies must establish the duration
of therapy necessary to
eradicate this infection and thus to prevent
 congenital transmission..."

".....We
 do not believe this high incidence to be an artifact of patient selection,
 since these patients were all studied before this neurologic syndrome was
 widely appreciated, and since all were initially referred by a
rheumatologist, not a neurologist..."

".....However, following treatment the most distal portion of nerves
 seemed to improve first--even in nerves that were intially apparently
 normal---suggestive of a dying back neuropathy...."

"........we have been
 unable to identify either spirochetes or evidence of active inflammation in
 the nerve, nor have we been able to demonstrate antibody compliment, or immune
 complex deposition. However, we have been struck by the rapid clinical and
 neurophysiologic recovery following antibiotic treatment as well as to
treatment with other agents
 known to cross into the nervous system......"

"....This resolution of
 symptoms has occurred before there has been any appreciable drop in antibody
 titer, suggesting the problem is a direct effect of infection with spirochetes
 and not a purely immune-mediated phenomenon..."
_______________________________

............"Of the many patients we have seen with chronic Lyme disease (most
of whom
 had worsened despite treatment with recommended oral antibiotics)..."

"................Our observations led us to conclude that many patients with
Lyme
 disease have significant abnormalities of the peripheral nervous system, not
 attributable to other causes, and that many of these abnormalities can resolve
 following APPROPRIATE antibiotic treatment............"

"...................This syndrome clearly may evolve
 despite treatment with currently recommended antibiotic
regimes................"

"................the use of sequetial studies in affected patients emphasizes
the
 utility of using patients as their own "controls............"

Lyme Disease: Cause of a treatable peripheral neuropathy
Authors: Halperin, Little, Coyle, Dattwyler
Neurology 1987;37:1700

".....Of the many patients we have seen with chronic Lyme disease (most of whom
 had worsened despite treatment with recommended oral antibiotics) many have
 noted intermittent tingling paresthesias of their extremities, yet had no
 demonstrable neurologic deficits. These symptoms were distinctly different
 from, and more commonplace than, those described in the literature, leading us
 to study this population in greater detail.......
Materials and methods. Subjects. Between October 1985 and March 1986, 36
 patients with proven late Lyme disease were evaluated in the Lyme Disease
 Clinic at University Hospital, SUNY, Stony Brook. All patients had clinical
 histories consistent with diagnosis and had immunologic evidence of reactivity
to B.
 burgdorferi.......Three of the 22 patients with clinical and immunological
 evidence of Lyme disease but without the typical history of limb paresthesias
 also underwent neurophysiologic testing to determine if similar abnormalities
 occurred in asymptomatic patients. One of these patients, a carpenter, had a
 history suggestive of carpal tunnel syndrome at the time his arthritis had
 been most active, but these symptoms were no longer present. Another, a
 mechanic, had a history of left arm tingling and back pain since a driving
 accident in which several cervical vertebrae had been fractured. The third
 had no paresthesia of any sort..........
...............Discussion. Several distinct syndromes involving the peripheral
 nervous system have been described in patients with Lyme disease. Although we
 see large numbers of patients with Lyme disease, we have only rarely observed
 these syndromes . None of our patients had severe radicular pain, brachial
 neuritis, or obvious mononeuropathy multiplex. Only one had
 electrophysiologic findings suggestiive of a Gullian-Barre-like syndrome.
...... the electrophysiologic testing
failed
 to reveal any more subtle evidence of cranial nerve dysfunction. Yet, almost
 one half of the patients we have seen with late Lyme disease have had
 neurologic difficulties, the most common of which has been the presence of
 intermittent paresthesias. Therefore, we believe this syndrome to be a very
 common entitiy, but one quite different from those previously described. We
 do not believe this high incidence to be an artifact of patient selection,
 since these patients were all studied before this neurologic syndrome was
 widely appreciated, and since all were initially referred by a
rheumatologist, not a neurologist.
    The reason that this syndrome has not been previosly recognized may be that
 the neurologic examination is usually not strikingly abnormal in these
 patients. In the few previous reports of neurophysiologic testing in this
 disease, this was performed on patients with clinical abnormalities. Because
 of the consistent and persistent subjective symptoms, and in spite of the
 normal clinical examinations, we chose to study these patients
 neurophysiologicallly.
.........Our observations led us to conclude that many patients with Lyme
 disease have significant abnormalities of the peripheral nervous system, not
 attributable to other causes, and that many of these abnormalities can resolve
 following appropriate antibiotic treatment. This syndrome clearly may evolve
 despite treatment with currently recommended antibiotic regimes......However,
 it is striking that several patients have responded to more prolonged or
 higher dose penicillin regimes, as well as to treatment with other agents
 known to cross into the nervous system.......
The pathogenesis of this peripheral neuropathy remains unclear. It appears to
 be quite separate from the CNS manifestations of Lyme disease--its occurrence
 does not coincide with the acute meningoencephalitis, nor does its response to
 treatment necessarily parallel that of encephalopathy. The neurophysiologic
 abnormalities are multifocal in nature such as might be seen in mononeuritis
 multiplex. However, following treatment the most distal portion of nerves
 seemed to improve first--even in nerves that were intially apparently
 normal---suggestive of a dying back neuropathy.....Finally, we have been
 unable to identify either spirochetes or evidence of active inflammation in
 the nerve, nor have we been able to demonstrate antibody compliment, or immune
 complex deposition. However, we have been struck by the rapid clinical and
 neurophysiologic recovery following antibiotic treatment. This resolution of
 symptoms has occurred before there has been any appreciable drop in antibody
 titer, suggesting the problem is a direct effect of infection with spirochetes
 and not a purely immune-mediated phenomenon.
    This study leads to two very different but equally important sets of
 conclusions. First, it serves to emphasize the sesitivity and utility of
 neurophysiologic testing, making posssible the demonstration significant
 abnormalities of peripheral nerve fuction in clinically normal patients.
 Furthermore , the use of sequetial studies in affected patients emphasizes the
 utility of using patients as their own "controls," demonstrating significant
 changes where values before and after were both well within the rather broadly
 defined "normal
range".
Second, these techniques have enabled us to
 characterize a clinical syndrome quite distinct from those previously
 described in Lyme disease and to demonstrate that it is one of the small
 number of neuropathies that is readily reversible. Since the neurophysiologic
 abnormalities improve with effective treatment, they have provided a
 quantitative, objective assessment of the efficacy of different antibiotic
 regimes in this disease. Since the best antibiotic regime to treat Lyme
 disease remains to be determined, having such a means of objectively comparing
 different agents will be invaluable."

_______________
".......; the identification of spirochetes in
the brain and other nervous tissues of humans, animals, and arthropod vectors;
and the persistence of brain infection after treatment with antibiotics that DO
NOT READILY PENETRATE THE BLOOD-BRAIN BARRIER..." i.e. IV or IM

  Neuroborreliosis during relapsing fever: review of the clinical
manifestations,
pathology, and treatment of infections in humans and experimental animals.
Cadavid D, Barbour AG
Clin Infect Dis 1998 Jan 26:1 151-64

Abstract
The spirochetal disease relapsing fever is caused by different Borrelia
species. Relapsing fever is well recognized as an infection of the blood, but
little is known about its predilection for the nervous system and the eyes. To
investigate neurological and ocular involvement during relapsing fever, we
reviewed the clinical manifestations, pathology, and treatment of relapsing
fever of humans and experimental animals. The results indicate that Borrelia
turicatae and Borrelia duttonii, the agents of tick-borne relapsing fever in
southwestern North America and sub-Saharan Africa, respectively, cause
neurological involvement as often as Borrelia burgdorferi in Lyme disease.
Evidence of this is the frequent occurrence of lymphocytic meningitis and
peripheral facial palsy in human disease; the identification of spirochetes in
the brain and other nervous tissues of humans, animals, and arthropod vectors;
and the persistence of brain infection after treatment with antibiotics that do
not readily penetrate the blood-brain barrier.

Author Address
Department of Neurology, Georgetown University School of Medicine, Washington,
D.C. 20007, USA.

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