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.
[ 24. March 2008, 12:53 PM: Message edited by: sparkle7 ]
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sparkle7
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The optimal treatment of neurologic Lyme disease is not yet known.
Intravenous antibiotic therapy with Ceftriaxone or Cefotaxime is the accepted standard because these drugs more effectively penetrate the blood-brain-barrier.
In studies of Lyme arthritis in which patients were treated with oral antibiotics, the treatment failures often showed signs of neurologic involvement, suggesting that oral antibiotics may be insufficient to eradicate infection that may already be sequestered in the CNS compartment.
[ 24. March 2008, 12:52 PM: Message edited by: sparkle7 ]
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sparkle7
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Biochemistry of Lyme Disease: Borrelia burgdorferi Spirochete/Cyst by Prof. Robert W. Bradford and Henry W. Allen
excerpt:
Lyme Disease Toxin Because many of the symptoms of Lyme disease involve the nervous system, it was speculated that the spirochete produced a toxin that disrupted normal nerve function.
Through the use of DNA manipulations and a database of known protein toxin DNA sequences, a match was made with a selected Borrelia burgdorferi (Bb) gene and a specific toxin in the database.
Protein generated from this cloned Bb gene was examined biochemically and found to have characteristics similar to that of botulinum, the toxin of Clostridium botulinum, a zinc endoproteinase.1
The toxin from Bb belongs to a family of toxic proteins known as "zinc endoproteinases" or metalloproteases, and includes the toxin from the organism causing tetanus as well as those from many other well-known infectious diseases.
The structures of this family of toxins are all very similar, as determined by x-ray crystal analysis.2
They all contain zinc and perform the same proteolytic function, namely, cleaving the chemical (covalent) bond between two specific amino acids in a particular protein found in nerve cells.3
The substrate for this enzyme is very large, implying that any inhibitor of enzyme activity blocking the entry of the substrate into the active site must also be very large.
One reason for learning the structure of the toxin (including the active site) is to determine the geometry of this site, the exact positions of the atoms that bind other atoms in the substrate.
Knowing the arrangement of these atoms permits the development of inhibitors of the toxin, substances that compete with the normal substrate for active site occupancy.4
Action of Toxin The action of botulinum (as well as the toxin from the Lyme spirochete) is to prevent, through its action as a proteolytic enzyme, the release of the neurotransmitter acetylcholine.
Nerve endings may be associated with other nerves or muscles (the neuromuscular junction). To understand this mechanism in greater detail, consider the basic principles of nerve physiology described below.
Nerve Cells A typical nerve cell consists of a long filament or axon, the terminal end of which lies in close proximity to another nerve cell.
The space between them is known as the synaptic cleft (synapse).
One nerve cell communicates with another through the release of a chemical substance known as a neurotransmitter held within small sacs (vesicles) lying near the terminal end.
An electrical pulse travels the length of the axon and, when it reaches the nerve cell terminal, causes the vesicles to rupture through the presynaptic membrane and discharge the neurotransmitter into the synaptic cleft.
The neurotransmitter is bound by a protein (receptor) in the postsynaptic membrane of the adjoining nerve cell causing, in turn, the transmission of an electrical pulse down the axon of the second nerve cell.
By this mechanism, nerve cells communicate with one another through the action of a neurotransmitter.
One such neurotransmitter is a simple organic substance known as acetycholine.
[ 24. March 2008, 12:52 PM: Message edited by: sparkle7 ]
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sparkle7
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posted
- March 23, 2008 -
I'm posting this but I just want to say it's from a company that sells Samento (Cat's Claw).
I'm doing the Cowden protocol but I haven't gotten to taking the Samento, yet.
I do not profit from selling herbal supplements or making recommendations. I am just looking for alternative cures for Neuro Lyme.
-----
What Makes Lyme Disease Tick & How Samento� Eliminates It by Morton Walker, D.P.M. with Randall S. Walker
For almost two decades, intravenous (IV) therapy, usually with the once daily cephalosporin antibiotic, ceftriaxone (Rocephin), has been an option for various stages of LD.
Parenteral or IV therapy is, however, by nature more difficult, sometimes less accessible, potentially more hazardous, and clearly more expensive.
The current consensus for the role of IV antibiotics is that it should be reserved for the treatment of patients with prolonged and life altering neurological findings, whether CNS or peripheral.
By definition, these conditions reflect advanced neuroborreliosis. In recent years, a more controversial indication for the use of IV therapy has been employed, namely for treatment of the chronic or persistent LD or "post-LD syndrome", which involves much more subjective ailments such as fatigue, musculoskeletal pain and cognitive difficulties (see earlier discussion).
As reported in a summer 2001 article in the New England Journal of Medicine, approximately 125 individuals with "chronic LD" were randomized into two groups, one receiving placebo and the other 30 days of IV Rocephin followed by 60 days of oral doxycycline.
In essence, the trial showed no difference in benefit as gauged by Quality of Life (QOL) questionnaires (121).
Certain reviewers saw this as an affirmation of their belief that IV therapy was overused and wasteful, whereas others criticize various aspects of the trial, e.g. arbitrary length of IV antibiotics, the inherent faults in QOL reporting, etc.
It's safe to say that the trial has changed few minds and that opposing parties simply reaffirmed their pretrial bias. We regret that this trial did not include, for reasons unexplained, LD patients with documented neurological deficits.
On the other hand, the trial was so badly and fatally flawed that this point almost does not matter. Hopefully, better science will follow soon. We deserve it and we need it ...... maybe we'll have to do it.
The Jemsek Specialty Clinic has attempted to integrate various elements of what is known about persistent LD and the biology of the infection.
On reflection, it seems reasonable to assume that a chronic CNS infection with a slowly replicative organism like Bb will require prolonged therapy, preferably with an antibiotic with a delivery that allows for the highest drug levels possible in the CNS.
For this reason, we treat severe and chronic CNS manifestations of neuroborreliosis with IV antibiotics for as long as 16-32 weeks and have noted repeatedly that clinical improvement may not become apparent until several months into therapy, although we generally see some effect by the third month and certainly the fourth month of therapy (more on concepts of therapy below).
The emerging research on a cystic form of Bb has changed the long-term treatment picture. In theory, biologic and environmental stress promotes conversion or "morphing" of the spirochetal form to a cystic form, apparently within hours, and this form exhibits different surface antigens and therefore a different presentation to the immune system.
The converse is documented, i.e. the cystic form can readily convert back to the spirochetal form (122).
It is known that antibiotic pressure, utilizing medications effective against the spirochetal form, accelerates cyst formation (123).
In vitro, incubation of Bb with ceftriaxone, for example, leads to Bb cyst formation after just four hours, much faster and more completely than doxycycline exposure (123). As expected, neither of these compounds (or any other commonly used antibiotics in LD) have any effect of the cyst.
On the other hand, many studies indicate that metronidazole is effective in killing the cystic form, but not the spirochetal form, of the Bb bacteria (124).
For that reason, many Lyme aware physicians have begun to see the value of using combination antibiotic therapy with the addition of the agent metronidazole. In our experience, patients with Bb infection routinely develop a Herxheimer reaction (see below) in response to treatment with metronidazole and occasionally these reactions may be severe and limiting.
Long term suffering neuroborreliosis patients seem to have the most difficult time with this therapy, suggesting that the cyst load may be higher in this patient group, particularly in the CNS.
If this is the case, one might assume that conversion to a cyst form is a natural evolution of the illness for at least some Bb strains.
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map1131
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posted
Well, josh I could of given this speech with first hand knowledge. Shoot I don't need a degree. I've lived it. Nothing like having the experience to tell it?
I've been studying so long on this lyme & company, someone should give me a degree as lyme specialists.
Oh shoot, I need to study the drugs more. I wouldn't want to kill someone with the wrong abx or some other script? I need to learn more on some of those big words too. Spelling and pronouncing them is difficult.
Oh well, maybe I do need to go to college to learn it properly.
Pam
-------------------- "Never, never, never, never, never give up" Winston Churchill Posts: 6495 | From Louisville, Ky | Registered: Jan 2002
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sparkle7
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As reported by RICHARD SADOVSKY, M.D., American Academy of Family Physicians, "The diagnosis of Lyme disease is clinical.
Early infection is often accompanied by false-negative serologic tests, although this can occur late in the disease.
The positive predictive value of serologic testing is low in patients with vague symptoms unaccompanied by any objective signs."
Some infected individuals have dormant illness (asymptomatic infection has been determined by serological testing) later manifesting from trauma or immuno-suppression, or manifest only non-specific symptoms such as fever, malaise, tingling/numbness sensations, meningitis, encephalitis, headache, fatigue, or myalgia.
The patient may in many cases not recall a tick bite. Ticks, especially in the nymph stage may feed undetected and fall off leaving behind only a sinister calling card...borrelia burgdorferi (Lyme disease) and possible co-infections (echlirosis, babesiosis, bartonella).
Lyme disease spirochetes disseminate from the site of the tick bite by cutaneous, lymphatic and blood borne routes.
The signs of early 'disseminated' infection can occur within days to weeks.
Symptoms may also slowly reveal themselves over a long period of time with patients showing up at their doctors with vague, varied symptoms and no knowledge of a tick bite nor rash.
In addition to possible multiple (secondary) erythema migrans lesions, early disseminated infection may be manifest as disease of the nervous system in varying degrees (ie. muscle twitches, tics, numbness/tingling, lower back/neck pain), the musculoskeletal system, or the heart.
Early neurologic manifestations include aseptic meningitis (infection in the cerebrospinal fluid also called lymphocytic meningitis), cranial neuropathy (changes in nerve sensation of the skull , face/jaw region, especially facial full/partial nerve palsy), and radiculoneuritis (nerve root involvment).
Musculoskeletal manifestations may include migratory joint and muscle pains with or without objective signs of joint swelling.
Cardiac manifestations may include rapid/fluctuating heart rate (tachycardia), slowing of the heart rate below 60 bpm (bradycardia), myocarditis (inflammation of the muscular walls of the heart) and transient atrioventricular blocks [the inappropriate delay (or complete inability) of an electrical impulse, generated in the atria, to reach the ventricles (via the atrioventricular node)].
B. burgdorferi (Lyme) infection in the untreated or inadequately treated patient may progress to late disseminated disease weeks to years after infection.
Manifestations of late disseminated Lyme disease are intermittent swelling and/or pain of one or a few joints (asymetrically), chronic axonal polyneuropathy, or encephalopathy, the latter usually manifested by cognitive disorders, eye disturbances, sleep disturbance, fatigue, memory and personality changes (including depression, bi-polar disorder and psychiatric manifestations).
More frequently, Lyme disease morbidity may be severe, chronic, and disabling.
An ill-defined post-Lyme disease syndrome is said to occur in some persons following treatment for Lyme disease.
But this is clearly an 'active' not 'post' lyme infection and further treatment must continue if resolution is to be gained.
[ 28. March 2008, 02:30 AM: Message edited by: sparkle7 ]
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bettyg
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sparkles thanks so much for adding the dates to each of the 3 top articles AND breaking them each up so they are readable to us with problems reading!!!
we appreciate it for anyone copying this to have ALL important info!
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thanks so much for adding the dates to each of the 3 top articles AND breaking them each up so they are readable to us with problems reading!!! 
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