1 The Phenomenon Of ‘Chronic Lyme’; An Observational Study

Recently, the results of an observational study on chronic Lyme disease in Norway were published in the European Journal of Neurology. (The full text of the study is behind a pay wall on Wiley - but otherwise you can read the abstract online.) According to the National Institute of Health (NIH) clinical trials database, the purpose of the study was:

"... to chart clinical and laboratory findings in Norwegian patients with symptoms attributed by themselves or their doctor to ongoing chronic Bb infection. Objectives are to assess laboratory findings in relation to established diagnostic criteria and to form a picture of the burden of symptoms and illness perception in this group of patients. The study is essentially exploratory, and is supposed to raise rather than to test hypotheses."

Based on this, it sounds like the authors' original expectations for this study were that the researchers would find out in a given population that among those who either suspect they have chronic Lyme disease and have it - and those who suspect they have chronic Lyme disease and don't have it - that it would be discovered what clinical differences and diagnostic markers would set them apart.

But the abstract doesn't indicate what the criteria are for a case definition of chronic Lyme disease if the researchers had one in mind. Rather, it indicates that of the patients enrolled in the study, there was no evidence that any patient had an existing infection with Borrelia burgdorferi.

The following comments are strictly preliminary and based on the content of the abstract only - a more detailed review is in order once the full text has been read:

First, I was disappointed to find out that the total enrollment expected for this study was a mere 30 participants - and in the actual study, there were only 29 enrollees. This is a very small pool of applicants, and I don't think the data can be extrapolated to fit a large group of people - or even more so, a large group of people from an area which is highly endemic for Lyme disease.

Second, this study in no way set out to solve the problem of whether or not chronic Lyme disease is a real condition - I don't think that was the researchers' goal. Their goal was to characterize those people who either self-reported that they thought they had chronic Lyme disease based on their symptoms or their doctors suspected they had chronic Lyme disease based on their symptoms. Nothing less, nothing more.

It would have been more productive for patients had the researchers taken additional steps to determine what exactly the cause of these symptoms were. But the study was not designed to take those additional steps and just left us with these basic data points:

• Twenty patients (72%) had symptoms of an unknown cause; of them six met the criteria for Post Lyme disease syndrome (PLDS).

• Fourteen patients (48%) had the presence of anti-Borrelia burgdorferi antibodies.

• Eight patients (28%) had other well-defined illnesses.

The researchers stated, "None had evidences of persistent Bb infection, but whether current diagnostic criteria are functional in patients with longstanding complaints is controversial."

Looking at all of this, I'm not sure how to even interpret the initial data shared in the abstract... When those 72% are discussed - of which six patients met the criteria for Post Lyme disease syndrome - are those six patients exclusive of the fourteen patients with anti-Borrelia burgdorferi antibodies or are they inclusive?

If it's exclusive, then twenty of the twenty nine patients have evidence of some relationship to a Borrelia burgdorferi infection. If it's inclusive, then it's only fourteen patients who have evidence of this relationship.

But let's assume they are inclusive, and only fourteen had evidence of anti-Borrelia burgdoferi antibodies. Even if only 48% of the patients studied already have a history of exposure to Borrelia burgdorferi and continue to have persisting symptoms, I think that counts as evidence towards a relationship between Lyme disease and persisting symptoms. Either as a trigger or present causative agent. The researchers themselves state that this is at least partly the case, by reporting that, "sequelae from earlier Lyme disease were probable as main explanatory factor in some cases."

That said, a whopping 72% of patients had symptoms of an unknown cause. So what did they have? It is unknown to me if the issue of seronegativity was considered in patients' reports, whether or not patients with positive antibodies were tested for other conditions with cross reactive antibodies, or whether or not patients were studied for evidence of other tick-borne illnesses.

What is known, however, without having access to the full text is that patients had their blood tested and their CSF studied for any abnormalities and the presence of intrathecal antibodies, as shown in Table 1 of the Supporting Information section. And what is found there leaves me questioning the results - at least in part.

For example, the first patient mentioned in the "unknown causes" category is a 43 year old male who is both IgM and IgG positive for Borrelia burgdorferi antibodies, had 78 weeks of IV antibiotic treatment, and yet is not considered by their definition to have Post Lyme disease syndrome because there was "no documented episode of Lyme disease". This is puzzling - if someone has serological evidence of Lyme disease and they continue to have symptoms - wouldn't this indicate by the most conservative view that the patient at least has Post Lyme disease syndrome (regardless of the controversy over persistent infection)?

That there was no earlier documented acute case of Lyme disease seems to be at the heart of determining whether or not a patient is at least meeting the criteria for Post Lyme disease syndrome. According to this study, it seems that if there was no earlier record of an EM rash and evidence of a tick bite by a doctor, then the patient is disqualified from a Post Lyme disease syndrome diagnosis. Why this is the case when there is evidence patients do not always recall a tick bite, a rash is not always present (and this is even more likely in Europe based on some research), and there are documented cases of patients who are asymptomatic in the early stage - only to be profoundly disabled by symptoms later - is unknown. It doesn't make sense to me.

It would have been interesting had the researchers ran epitope and proteomic analysis of patients' CSF and confirmed earlier research completed by Chandra/Alaedini and Schutzer - so far, I see no evidence this was done; I would expect such an analysis would be included in the abstract. I would also like to know what - if any - immunological factors were examined in each of these patients.

After reading this abstract, what one is left with is are more questions about the nature of chronic Lyme disease than answers.

What is a good starting point for more research of this nature?

What is the relationship between persisting symptoms and infection with Borrelia burgdorferi?

The abstract for this study and its supporting information do not answer these questions. All this study does is begin to examine what relationship there is between Borrelia burgdorferi and persisting symptoms in a small group of people.

References:
http://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2012.03691.x/abstract
http://clinicaltrials.gov/ct2/show/NCT01151150
http://www.sciencedirect.com/science/article/pii/S1521661611001914
http://www.plosone.org/article/metrics/info%3Adoi%2F10.1371%2Fjournal.pone.0017287

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10 2011 Guidelines For Treating Lyme Disease...

... from Russia are here. With love.

This past weekend I got into a lengthy discussion with "radicale" on the Embers et al Issues a Statement post, and somewhere along the line, amid over 50 comments there (I highly recommend reading them, too), radicale advised that I check out documentation and research on Lyme disease from Russia and the Balkans.

So I did, and I did in part because he's the one who told me that treatment for both acute and disseminated Lyme disease in Serbia - particularly at two hospitals in the country - is more aggressive by default than it is either in the US or in Canada. He also stated that this treatment is backed by clinical studies (two of which are mentioned in the comments on the above post) - and because it was his home country and had this scientific backing, he went there for treatment for Lyme disease rather than in Canada.

He shared what he said was the standard antibiotic treatment schedule for Lyme disease given to patients in a few hospitals in Serbia:

"It is interesting that in Serbia, where every third tick is infected, amoxicillin is the drug of choice and it is routinely given for 6 weeks for early Lyme Disease.

In addition, disseminated Lyme Disease is treated in the following manner:

1) 4 weeks of ceftriaxone 2g/day plus metronidazole 500 mg bid
or three weeks of amoxicillin 1g tid followed by three weeks doxycycline 200mg bid plus metronidazole 500 mg bid
2) in case of persisting symptoms therapy is extended using pulsed doses up to 6 months

There are open-label control studies to support this type of treatment (in Serbian)."

I found this difference in approach to treatment interesting and I wanted a confirmation with a reliable source - so I have requested more information from him in terms of a citation for official guidelines using this antibiotic treatment.

While awaiting his response, I decided to see if I could find guidelines for other countries in the region and translate them. So far, I have found the 2011 guidelines for treatment of tickborne Borreliosis (they call it SDS) for Russia and ran them through Google Translate.

They are - as you will see - pretty bare bones relative to the guidelines document written up by either the IDSA or ILADS... And oh, OPTIONS... We have OPTIONS... did I say we have options? Yes, only I don't know what all the options actually are yet - I would have to figure out what all the drugs are by name.

Far as I can tell, Azitroks = azithromycin. doksitsi-wedge is, I think, some form of liquid doxycycline that is highly absorbent. klaforan = Claforan. Instructions at the bottom "per os" means "by mouth" or "orally".

I can figure out what some of the other drugs are due to their spelling coming close to the English word - but other drugs are unknown to me by the name being used...

APPROVED
Head of the Department of Health
Tomsk Oblast
O.S. Kobyakov
2011
Lepekhin A.
MD, Professor, Head of
Infectious Diseases and Epidemiology, State Educational Institution SSMU Health Ministry of Russia

Lukashova L.
MD, Professor, Department of Infectious Diseases and Epidemiology
GOU VPO SSMU Health Ministry of Russia

Ilyinskikh EN
MD, Professor, Department of Infectious Diseases and Epidemiology
GOU VPO SSMU Health Ministry of Russia

Zhukov, N.
MD, Professor of Neurology and Neurosurgery
GOU VPO SSMU Health Ministry of Russia

Portnyagina EV
PhD, Assistant Professor of Epidemiology and Infectious Diseases
GOU VPO SSMU Health Ministry of Russia

Dobkin, MN
PhD, chief freelance specialist in infectious
Health Department of the Tomsk region

Guidelines for Physicians
(Third edition, revised and enlarged)

Tomsk - 2011

THERAPY PROGRAM SDS

Schemes of causal treatment for tickborne Lyme Borreliosis

During the acute, manifest form (mild)

(Schema therapy - individual choice of doctor)
A. Amoxicillin 0.5 g three times daily per os (0.375 g of amoxiclav three times daily
per os), 14 days.
 or
Two. Azitroks 0.5 1 g once a day per os, 6 days.
 or
Three. Doxycycline 0.1 g 2 times a day per os, 14 days.

During the acute, manifest form (medium severity)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 1.0 g 2 times a day by intravenous drip, and 7 days, then - Amoxil-
penicillin of 0.75 g 3 times daily per os (0.375 g of amoxiclav three times daily per os),
7 days.
  or
Two. Ceftriaxone 1.0 g 2 times a day by intravenous drip, and 7 days, then - doksitsi-
wedge of 0.2 g 2 times a day intravenous drip, and 7 days.
 or
Three. 0.75 g of amoxicillin three times daily per os (0.560 g of amoxiclav three times daily
per os), 7 days, then - Azitroks 0.5 g of 1 time per day per os, 6 days.
 or
4. Doxycycline 0.2 g 2 times a day intravenous drip, and 7 days, then - Azitroks
0.5 1 g once a day per os, 6 days.

During the acute, manifest form (severe severity)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 2.0 g 2 times a day intravenous drip, and 10 days later - Amoxil-
penicillin at 1.0 g three times daily per os (amoxiclav, 0.625 g 3 times daily per os),
10 days.
 or
Two. Ceftriaxone 2.0 g 2 times a day intravenous drip, and 10 days later - doksitsi-
wedge of 0.2 g 2 times a day intravenous drip, and 10 days.
 or
Three. Amoxicillin 1.0 g three times daily per os (amoxiclav, 0.625 g 3 times a day
per os), 7 days, then - Azitroks of 1.0 g of 1 time per day per os in a 1-day and 0.5 g of 1
once a day per os for the next 5 days.
 or
4. Doxycycline 0.2 g 2 times a day intravenous drip, and 7 days, then - Azitroks 1.0 g of 1 time per day per os in 1-day and 0.5 g of 1 time per day per os for at- the next 5 days.

8Podostroe for (mild)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 1.0 g of a once-daily intravenous infusion, and 10 days later - doksitsi-
wedge of 0.1 g 2 times a day intravenous drip, and 10 days.
 or
Two. Amoxicillin 0.5 g three times daily per os (amoxiclav, 0.625 g 3 times a day
per os), 10 days later - doxycycline 0.1 g 2 times daily intravenous-drip
10 days.

Subacute (medium severity)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 1.0 g of a once-daily intravenous infusion, and 10 days later - doksitsi-
wedge of 0.2 g 2 times a day intravenous drip, and 10 days.
 or
Two. Ceftriaxone 1.0 g of a once-daily intravenous infusion, and 10 days later - Amoxil-
penicillin of 0.75 g 3 times daily per os (0.375 g of amoxiclav three times daily per os),
10 days.

Subacute (severe severity)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - doksitsi-
wedge of 0.2 g 2 times a day intravenous drip, and 10 days.
 or
Two. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - Amoxil-
penicillin at 1.0 g three times daily per os (amoxiclav, 0.625 g 3 times daily per os),
10 days.

Chronic (phase compensation)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
amoxicillin 0.5 g three times daily per os (0.375 g of amoxiclav three times daily
per os), 7 days.
 or
Two. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
doxycycline 0.1 g 2 times a day by intravenous drip, and 10 days.

Chronic (Stage subcompensation)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
amoxicillin 0.5 g three times daily per os (0.375 g of amoxiclav three times daily
per os), 10 days.
 or
Two. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
doxycycline 0.2 g 2 times a day by intravenous drip, and 10 days.

9Hronicheskoe for (stage decompensation)

(Schema therapy - individual choice of doctor)
A. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
amoxicillin 0.5 g three times daily per os (0.375 g of amoxiclav three times daily
per os), 10 days.
 or
Two. Ceftriaxone 2.0 g of a once-daily intravenous infusion, and 10 days later - klaforan
2.0 g 2 times a day by intravenous infusion or intramuscular injection, and 10 days, then -
doxycycline 0.2 g 2 times a day by intravenous drip, and 10 days.

Scheme of pathogenetic and symptomatic therapy

Universal scheme of pathogenetic and symptomatic therapy
patients with SDS

(Drugs, marked with #, appoint, and the testimony of an individual selection, dosing regimen of drugs - depending on the severity of illness)

- Lineks 1-2 capsules three times daily per os, 30 days;
# 0.9% sodium chloride, 200 ml of intravenous-drip of 5% glucose solution
200-400 ml of intravenous-drip reopolyglukine 200-400 ml of intravenous-ka-
pelno;

# Immunomodulators (including data immunogram).

When neurological manifestations...

# Venotonicheskie tools
- 2.4% -10.0 aminophylline IV-drip, 10 days
or
- Cavinton (vinpocetine) 4-mL intravenous infusion, 10 days
# Neuroprotective drugs
- 10 ml Cerebrolysin intravenous-infusion, 10 days
or
- Actovegin 5-20 ml per day by intravenous drip, and 10 days later - on 0.2 g of 3
times a day per os, 30 days
or
- Cytoflavin 10 ml intravenous drip, in 100-200 ml of 5-10% solution of glucoside
goats, or 0.9% sodium chloride solution, 1 time per day, 10 days later - on 2
tablets 2 times daily per os, 25-30 days
or
- Nootropil 5 ml intravenous drip, and 10 days
or
- Lutset 10 ml intravenous bolus, and 10 days

# Metabolic means

- Mildronat 10% -5.0 (10.0) IV-bolus, 10 days
or
- Panangin 10-20 ml intravenous bolus, and 10 days, then - 1 tablet 3 times a
per day per os, 30 days

# Vitamin
- Milgamma 2 ml daily intramuscular injections of 10
or
1011
- Berokka plus 1 tablet daily per os, 30 days
or
- Benfolipen (combined multivitamin complex) 1 tablet 1.3
times daily after meals per os, 30 days

# Tranquilizers
- Nozepam of 0.01 g per os the night
or
- Grandaksin of 0.05 g 2 times a day per os
or
- Alprazolam 0,025 g per night per os, with a gradual increase in dose
0.025 g in 3-5 days
or
- Phenazepam of 0.005-0.01 g per night per os, 7-10 days
or
- Glycine, 0.1 g 4-6 times a day sublingually, long-term (period-rekonva
lestsentsii)
or
- Adaptol (mebikar) to 0.5 g 2-3 times a day per os, a few days to 2-3
months (the period of convalescence)

# Sedatives
- New-passive 1 tablet or 1 tsp. solution 3 times a day per os, 30 days
or
- Tincture of motherwort (peony, Valerian) or Corvalol (valokordin, valoser-
din)

otvornye tools
- Donormil to 0,015 g per night per os
or
- Radedorm to 0,005 g per night per os
or
- Ivadal of 0.010 g per os the night
or
- Imovan of 0.0075 g per night per os
or
- Sanval to 0,005 g per night per os

# antidepressants
- Amitriptyline to 0,025 g per night per os, with a gradual increase in dose
0.025 g, 30-40 days
or
- Luvox of 0.05-0.1 g per night per os, up to 3 months
or
- Agomelatine 0,025 g per night per os, up to 3 months
When arthrologic manifestations

# Non-steroidal anti-inflammatory drugs
- Diclofenac 3 ml intramuscular injections of 6 or 0.025-0.05 g 3 times
per day per os, up to 7 days
or
- Movalis 1.5 mL intramuscularly or 0.015 g of 1 time per day per os, up to 7 days
or 12
- Ksefokam of 0,008 g 1-2 times daily per os
or
- Celebrex to 0.2 g 2 times a day per os, up to 7 days
or
- Artrozan (meloxicam) to 0,015 g 1 a day per os

# Antispasmodics
- Midokalm of 0.05 g 2-3 times a day per os, with a gradual increase razo-
curve to the dose of 0.15 g (0.1 g 1-2 times a day intramuscularly or intravenously
slowly)
or
- Sirdalud 0,002 g 3 times a day

# With the express pain
- Diprospan 1 ml in 2-4 ml of 0.5% solution of novocaine or lidocaine 2%
an intramuscular injection once a week, 3-5 injections
or
- Combilipen (combined multivitamin complex in conjunction with the Do-
dokainom) 2 ml intramuscularly daily for 5-7 days, then - 2
ml 2-3 times a week for 2 weeks

# Massage, therapeutic exercise, physical therapy (in the period of convalescence)

When cardiac manifestations...

# Metabolic means
- 10% mildronat -5,0-10,0 intravenous bolus, and 10 days (myocarditis, myocardial-
odistrofiya, ECG signs of repolarization, disturbances of rate)
- Panangin 10-20 ml intravenous bolus, and 10 days, then - 1 tablet 3 times a
per day per os, 30 days (arrhythmias and conduction)

# Sedatives
- New-passive 1 tablet or 1 tsp. solution 3 times a day per os, 30 days
(Syndrome of vegetative dystonia)
or
- Tincture of motherwort (peony, Valerian) or Corvalol (valokordin, valoser-
din)

# Antihypertensives
- Atenolol to 0.05-0.1 g per day, 20-30 days (arterial hypertension syndrome-
sion, cardiac arrhythmias, the syndrome of vegetative dystonia, stenokardicheskie
syndrome)

---

Comments? Questions? Thoughts?

My first thought on these guidelines are that the first thing I notice is that they are broken down into certain stages and conditional stages of Lyme disease/Borreliosis that are not defined here - perhaps they are defined in another document I have yet to locate, but just at first glance, medical professionals in Russia seem to break the stages down into finer grades of distinction with treatments to match.

My second thought is it seems their approach is to vary the kind of antibiotic used, and use the most bactericidal antibiotic first, followed by progressively less bactericidal and more bacteriostatic antibiotics. I am wondering if this is done for any specific reason.

My third thought is that the IDSA would probably not like part of these guidelines because they recommend using vitamins, massage therapy, and a little alternative medicine. That tincture of motherwort would probably be troubling to them. (Personally, I found valerian root to be a useful sleep aid, but it smells like dirty socks so I don't use it.)

My fourth thought is that this is pretty thorough in terms of intensive treatment for patients with cardiac and neurological manifestations of disseminated and late stage Lyme disease/Borreliosis, and I like that it offers ideas for supportive treatment for not only pain, anxiety, and depression - but for irregular heart rhythms.

There are some things that didn't translate well and I'm wondering what they are. "8Podostroe" for one thing."9Hronicheskoe" for another... I don't know what that is, either. Readers are invited to guess.

One thing I have learned while looking at various Russian and Balkans regional web sites on Lyme disease: They take it seriously.

You are considered an early mild case only within the first few days of a bite. After that, there is concern the disease has moved to the disseminated phase and it is treated more intensively. They also believe in relapses, and will give additional antibiotics if the initial course fails. In a number of places, you are expected to visit an infectious disease doctor as an outpatient 1, 3, 6, and 12 months after treatment in order to get follow up testing, report any relapsing, ongoing, or new symptoms, and give doctors more data for them to collect to understand how Lyme disease affects people.

There's more I've learned, but I'll share it later. Right now I just wanted to put these out here for you to see what other countries are doing to treat Lyme disease.

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10 Dr. Barthold Discusses Persistence On Diane Rehm Show

Several days ago,  Dr. Barthold was interviewed on the Diane Rehm Show on NPR. A full transcript to that show can be found on the WAMU radio/NPR web site, if you are interested in seeing what Dr. Auwaerter, Dr. Fallon, and Dr. Shor had to say about chronic Lyme disease.

I find what Dr. Barthold had to say about persistence to be very interesting.

(EDIT: Unfortunately, the strict terms about republishing any portion of the transcript were pointed out to me and I had to remove Barthold's quotes from this page - please refer to the transcript above in following what I say below.)

Did anyone else listen to the show or read the transcript and catch what he said about this:

The remaining organisms - potentially these persister cells - are in connective tissue and not eliciting inflammatory change. He sees very little inflammation in the animals he has tested and in which he found persistent spirochetes.

Yet when he removes the bacteria from a mouse and puts it in a new mouse, the spirochetes cause inflammation all over again.

What's up with that? Pretty strange, isn't it?

Can one form a hypothesis about why this is happening or at least take a shot at it?

I have a few ideas about this and will be putting them in comments in this post over the next few days, providing readers with the disclaimer that they are hypothetical and not to be taken as confirmed fact. Someone else will need to do the research on this issue.

Does anyone else here reading along have their own hypothesis about why this is happening - why after antibiotic treatment, he found persistent bacteria in these animals - yet they are not causing inflammation?

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6 Washington Post Article On Chronic Lyme Disease

The Washington Post has an article on chronic Lyme disease which is well written and touches upon not only how the disease can be insidious and slowly creep up on people with a wide range of symptoms - it also touches upon the science and the controversy around chronic Lyme disease. 

I consider an article such as this one to be a far better one than "Chronic Lyme: a dubious diagnosis" which was published in 2010 in the Chicago Tribune, because this one focuses on patients, their symptoms, and outcomes of their treatment in the face of information which contradicts their reality. 

These two paragraphs tidily sum up the sort of information chronic Lyme disease patients are faced with when they first receive their diagnosis and begin treatment:

"I began my research on the Web site of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. “Lyme disease can usually be successfully treated with 3 to 4 weeks of antibiotic therapy,” it stated. “After being treated for Lyme disease, some patients still report non-specific symptoms, including persistent pain, fatigue, impaired cognitive function . . . . These patients . . . may be diagnosed with post-Lyme disease syndrome. Studies have shown that more antibiotic therapy is not beneficial and the risks outweigh the benefits.” 

I was puzzled. Why did the NIH say long-term antibiotic therapy was not effective? Although it was only one case, my friend’s daughter had apparently been cured by it. And at this point, Pat had been taking a single antibiotic for about six weeks and was clearly getting better. After a week on the drug, the numbness in his hands started to recede. After a month, he stopped gagging while he drank. But he was still extremely sick, and it seemed clear that stopping the treatment would be a disaster."

This is, as they say, where the rubber meets the road.

Once you begin antibiotic treatment and your symptoms begin to improve, the decision to stop them earlier doesn't make sense. When your symptoms are so severe that you cannot function and other alternatives you have tried have not worked, what else are you doing to do?

I have stopped treatment during the course of my disease - only to find my symptoms returning within a few days after antibiotics were stopped. Even after the worst of my symptoms began to fade, I have also gone without treatment for months, where I hovered back and forth between a state of flu and arthritis to fibromyalgia and functional fatigue - never living, just vaguely existing - only to improve when I began antibiotics again.

Inbetween the antibiotics, I tried painkillers and sleeping pills. I tried trigger point release therapy, gentle massage, and acupuncture. Of these, acupuncture worked the best. But beginning antibiotics again often not only brought the pain down - it gave me some energy and focus back.

As one person without a control version of myself, I can't really tell you how my control version would have fared without antibiotic treatment. But it's not a thought I want to contemplate, because I do remember just how much more worse off I was when I first found myself ill with Lyme disease and how I declined without treatment:

I could not understand what I read even if I read it multiple times and could not follow conversations around me. I remember crawling on my hands and knees to the bathroom, and not being able to wash my own back. Raising my arms became impossible. They were too heavy to lift. And at one point, I would fall asleep sitting up against many pillows and try hard not to move even the slightest amount because even that would send severe pain jolting through my entire body. From my head down to my fingertips; from my neck down to my toes. Every.single.joint. Every.single.muscle.

With antibiotics, I went from nearly bedridden to being able to walk. At first to the front door. Then to the mailbox. It was slow going. Agonizing.

But eventually, I did manage to get out more and walk further, and have life become at least a little closer to something resembling normal. Not in every respect - but not the hell it was when I first contracted Lyme disease, either. And I still have some distance to travel before I am more or less back to my old self.

This is just one report from one person. It's anecdotal. It's not the result of a clinical trial or published in a peer-reviewed well-established journal - unless we consider Rita, TicksSuck, Joanne, Heidi, Claudia, and others who comment here to be peers and this blog to be the journal.

I wish I had evidence I could give everyone to tell people that they helped me. That I improved, and when I went off of them for extended periods of time, it was like turning the clock back. Progress could be undone.

But I don't have hard scientific evidence to hand you on this one. I can say, though, that I went from doing next to nothing and wanting to die from severe pain to beginning to think again, read and write again, and sleep through the night without stabbing pain waking me. That, for me, was evidence enough that more antibiotic treatment helped. That's why I continued when I did.

Anyway... quit hanging out around here and go check out the entire Washington Post article, "The doctor diagnosed chronic Lyme disease, but many experts say it doesn’t exist": http://www.washingtonpost.com/national/health-science/the-doctor-diagnosed-chronic-lyme-disease-but-many-experts-say-it-doesnt-exist/2012/02/06/gIQA4aMHtR_story.html

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11 Why Aren't Persisting Spirochetes Enough Evidence Of Infection?

On the heels of Embers et al having published their statement on PLoSONE, a number of patients are already questioning its content.

Some are claiming that Embers et al statement about how their findings should not be used to oppose current IDSA treatment guidelines for Lyme disease is something they were asked to write - rather than something the authors included on their own.

I don't know. For this claim - whether it's true or not - I have no evidence. However, one thing I do know is that there are solid scientific reasons which back the need for more research on spirochetes which survive after prolonged antibiotic treatment.

The question, of course, which weighs heavily on every patient's mind has been this one:

Why aren't persisting spirochetes enough evidence of infection?

It's become a political hot button question, and it's a scientific question. But most people think that as long as the spirochetes Embers found are alive and metabolically active, that is enough evidence to state that yes, Lyme disease is a chronic infection - let's stop all this nonsense right now and change the treatment guidelines!

Given my own experience and how longer than standard treatment helped me improve, I totally get this. I've been there, done that - and I think that a standard course of antibiotic treatment does not work for everyone. Particularly if there is a delay in proper diagnosis and treatment. Particularly if a coinfection is present. Particularly if there is some abnormality in one's immune system.

But if you are a scientist and you are researching this phenomenon of persistence - whether you as a scientist suspect these spirochetes can cause persisting infection or not; whether the above claim by other patients is true or not - you will be called upon by other scientists to support your findings.

It isn't just going to be the IDSA or the ALDF or other organizations which deny the possibility of persistent infection as a cause of chronic Lyme disease which are going to want to know the outcome of your study.

It's going to be the American Society for Microbiology (ASM) that wants to know the outcome. It's going to be researchers in Europe like the Brorsons who study the "cyst" form of Borrelia burgdorferi and want confirmation of their own findings about persistence.

It's also going to be universities and health departments and many different organizations which may not have any particular position on whether or not Lyme disease can be chronic who will want to know the outcome of your study.

They're all going to want to know the outcome of a study such as Embers et al, so these researchers must be certain about what they found and its significance, and conduct additional research related to their findings in order to confirm them.

They must find evidence that no one can argue against - even the most skeptical - if they are to support their own hypotheses. And it may be that at this stage they genuinely do not know what to make of these persistent spirochetes and not only their ability to cause disease - but how they cause it.

I can easily imagine that Embers et al is being very cautious about the interpretation of their results and wanting further studies as easily as it is for other people to imagine that Embers at al were somehow instructed to downplay the significance of their spirochetes surviving antibiotic treatment.

Why do I say this? I say this because I have learned a few things about these stealthy bacteria and think there is good reason for Embers et al to be cautious about the interpretation and approaching their results either way.

Borrelia burgdorferi spirochetes, plasmids, and infectivity

After doing some research on this issue, the issue of whether or not these spirochetes were infectious and pathogenic or not is a more complex issue than it at first appears.

First, here's a refresher of some basic microbiological definitions. (Bear with me, I'll try to get through this part quickly.)

Infection = the replication of organisms in the tissue of a host; when defined in terms of infection, disease is overt clinical manifestation. In an inapparent or subclinical infection, an immune response can occur without overt clinical disease.

Colonization = A carrier (colonized individual) is a person in whom organisms are present and may be multiplying, but who shows no clinical response to their presence.

Pathogenicity = The pathogenicity of an agent is its ability to cause disease; pathogenicity is further characterized by describing the organism's virulence and invasiveness.

Virulence = refers to the severity of infection, which can be expressed by describing the morbidity (incidence of disease) and mortality (death rate) of the infection.

Invasiveness = invasiveness of an organism refers to its ability to invade tissue.

Now that we're past these definitions, I'll cut to the chase and say there are two important things to know upfront:

1) During in vitro passage or certain stressors, Borrelia burgdorferi can lose some of their plasmids. How soon this happens varies depending on the strain and particular isolates of Borrelia. 

2) When Borrelia burgdorferi loses specific plasmids with specific genes on them, it can lose infectivity and pathogenicity. It should be noted that specific genes for specific purposes can show up on different plasmids on different strains. (For example: Bb strain N40's VlsE locus is different from the one found on commonly studied B31, and it shows up on a different plasmid than on B31.) 

The essential bit of information here is that the loss of a particular gene or set of genes can affect spirochetes' ability to cause infection - and even if these genes are lost, spirochetes may still survive for a while. They can become attentuated or less infectious.

Numerous studies on Borrelia burgdorferi's plasmids have shown that lp28-1 is a linear plasmid which makes Borrelia burgdorferi infectious. VlsE genes found on lp28-1 are thought to be essential for mammalian infection with Borrelia burgdorferi.

When the lp28-1 and yet a different plasmid, lp25, are missing from spirochetes, they are unable to infect mice. The lack of lp25 completely abolishes infectivity since this plasmid encodes a gene (bbe22) which is essential for Borrelia burgdoferi's survival in mice.

Spirochetes which lose lp28-1 plasmids will still live for a while - but the immune system tends to mop them up in a few weeks without antibiotic usage.

Specific research on mutant spirochetes with a lack of the lp28-1 plasmid has shown the following:

"While the wild-type B. burgdorferi persisted in tissues for the duration of the study, the lp28-1− mutant began clearing at day 8, with no detectable bacteria present by day 18. As expected, the wild-type strain persisted in C3H/HeN mice despite a strong humoral response; however, the lp28-1− mutant was cleared coincidently with the development of a modest immunoglobulin M response. The lp28-1− mutant was able to disseminate and persist in C3H-scid mice at a level indistinguishable from that of wild-type cells, confirming that acquired immunity was required for clearance in C3H/HeN mice. Thus, within an immunocompetent host, lp28-1-encoded proteins are not required for dissemination but are essential for persistence associated with Lyme borreliosis."

To translate the above:

Normal Bb spirochetes infected C3H/HeN (mice which are specifically bred for the ability to demonstrate joint swelling and arthritic symptoms similar to those found in the average person who gets Lyme disease) mice and these spirochetes could not be cleared by the immune system despite the fact that these mice had a strong humoral response.

However, mutant Bb spirochetes which did not contain linear plasmid 28-1 were completely cleared by these C3H/HeN mice.

What's fascinating about this study is even though the mutant Bb spirochetes lacked lp28-1, these spirochetes could still disseminate. Only in severely compromised immune deficient mice (scid mice) could the spirochetes both disseminate and persist - acquired immunity must be functional in animals infected with such mutants in order to clear the spirochetes.

So, here is one example of how you can have spirochetes which are alive and metabolically active and  can even disseminate - yet they are no longer causing disease. In this instance, they were cleared by the immunocompetent mice without the use of any antibiotics within a mere 18 days. (I wish I were that lucky!)

More recently, other plasmids have been found to contribute to infectivity in mammalian hosts - such as lp36. lp36 is viewed as being another major contributor to persistent infection in mice, and spirochetes become attenuated when lp36 is removed.

Linear plasmid 28-1 and lp25 have a much longer history of their role in infectivity and pathogenicity, and they are two of the most studied linear plasmids thus far - lp28-1 the most because of its VlsE genes in strain B31.

So, keep this in mind when you think of the Embers et al study, and realize why this part of their paper on Rhesus macaques caught my attention:

"A few spirochetes grew in cultures of organ tissues collected post-mortem from each animal after  > 9 weeks, but we were unable to subculture any spirochetes from either treated or untreated animals due to their slow growth. We therefore pelleted these cultures to confirm their identity and test their viability by DNA/RNA analysis. Transcription was detected in culture pellets and the tissues of treated animals, indicating that the bacteria were metabolically active (Figure 6C, D). Figure 6D shows ospA transcription detected directly in tissues harvested from treated and untreated animals. We also hypothesized that persistent spirochetes may lose linear plasmid 28-1 (lp28-1), which encodes the VlsE antigen bound by the anti-C6 antibody. Transcription of a lp28-1 gene (bbf26) was verified in organ tissue from both untreated animals and one treated animal (Figure 6D).

In the case of Embers et al study on Rhesus macaques, one antibiotic treated animal was found to have evidence of transcription of a lp28-1 gene (bbf26 - protein; purpose unknown) from a sample taken from heart tissue (Fig. 6D) and that transcription should only be able to occur if the lp28-1 plasmid is intact and functional. lp28-1 is a linear plasmid which is very specific to infection both in vitro and in vivo, whether a tick or needle inoculation is used.

In Embers study, in addition to transcription of a gene from lp28-1, OspA transcription from lp54 was found in three treated animals. OspA transcription was detected in two tissue samples taken from the bladder and one tissue sample taken from the spleen. Additional OspA transcription was found in different organs in two out of three of the same animals using organ tissue culture pellets.

Overall, this sounds interesting and points to the possibility of chronic infection after antibiotic treatment.

 But if I have seemed cautiously optimistic about this study, it's because of a few factors*:

1) Only one treated animal had evidence of a infection where lp28-1 transcription was taking place - had more treated animals shown evidence of transcription on this plasmid, I would have been more excited. How long could spirochetes maintain these plasmids while being treated? What about lp25?

2) It is unknown to me if the genetic background and/or immune system of the treated Rhesus macaques somehow played a role in their inability to clear the spirochetes which remain after antibiotic treatment. (Refer to this post on HLA-DR types, read what's before and after the "=" signs, and you'll see what I mean.)

3) it is unknown to me how different the results would be if the Rhesus macaques had been infected using ticks instead of needle inoculations. It seems to make sense to me to do this study again using ticks because that mimics what happens in nature.

On the other hand, I find it very interesting that three animals showed evidence of transcription of OspA. Given how much inflammation people experience during Lyme disease - plus evidence of later stage antibody reactivity to OspA - it at least gives me pause to think about how often OspA has been a culprit for my own symptoms, directly or indirectly.

The only kind of spirochete
you don't mind getting close to.

So it's a mixed bag how I look at the results of the Embers Rhesus macaque study. I think it's a positive step in the right direction establishing what happens with spirochetes in their host after antibiotic treatment. And yet the unanswered questions for me seem related to the same unanswered questions the researchers themselves wrote in their paper.


Is There Anything Positive To Glean From Dr. Baker?


Of Dr. Baker's two major stated issues with the Embers study, the only one now left is whether or not the spirochetes which were transmitted by ticks to new hosts (xenodiagnosis) were in fact infectious. His other concern was over the use of ceftiofur in the study rather than ceftriaxone - however, the authors of the study have since posted a correction to PLoSONE stating that ceftriaxone - not ceftiofur - was used throughout the entire study.

If there are any remaining minor issues he has with the study, he has yet to share them on the Lyme Policy Wonk blog. Mostly, he seemed to reiterate his concern about these two issues and focused on the single mention of ceftiofur in the paper repeatedly.

About the most positive response I heard from Dr. Baker on that blog thus far was about his view of how Lyme disease research should be conducted:

"...I favor a multi-disciplinary approach that moves the field in a different direction, rather than solutions based on the assumed yet to be proved existence of a persistent infection that can only be cured by antibiotics. I don’t really discount such a view; rather, I feel we are neglecting other possibilities that may provide the answers we all are looking for. A case in point, would be the recent work of good friend, Armin Alaedini — who I helped support when I was at the NIH– using specimens collected by Mark Klempner as part of his clinical trial. These valuable specimens are being maintained by Mark in a specimen repository for use in just such cutting-edge research. They are available free of charge on request."

Like Pamela Weintraub, I agree that a multi-disciplinary approach to research on Lyme disease is important. And while Dr. Baker also supports a multi-disciplinary approach to research on Lyme disease and he states he doesn't discount the view of persistent infection in the above paragraph - his direct responses to patients suffering with CLD/PTLDS state that most patients are suffering from some other non-Lyme disease related condition - something I find particularly unhelpful to my situation. That and a lack of sufficient research on other treatment approaches has been an issue for ages.

In my opinion, Dr. Baker's response to the Embers Rhesus macaque study was more negative than it warranted. I wouldn't have viewed it negatively at all - I see it as a stepping stone in getting a better understanding about Lyme disease.  And just because it leaves unanswered questions does not mean it was inherently flawed - which was what Dr. Baker seemed to suggest.

To quote someone else on that blog:

"My question to Dr. Baker is why don’t you and your colleagues offer some expert advice, according to your best opinions and hunches if science really has proven inadequate for your epistemic standards of validity, without having to officially disclose any sensitive data that might get you in trouble with your career, that could actually HELP these affected people lessen their pain and disability? Just disparaging some controversial or technically flawed research as being invalid does not seem helpful enough to me."

Yes. This.

Regardless of anyone's opinion - Dr. Baker, or LLMDs, or my friends and family - researchers will be expected to provide evidence to the world that these remaining spirochetes are pathogenic. They will need to provide evidence that that they can cause infection and reproduce - even if they are already proven to be alive.

Researchers who are trying to work without bias will want to cover all the bases and check their postulates twice to be 100% certain that Borrelia burgdorferi either causes a chronic infection or it does not after standard antibiotic treatment.

This may be so - but I'm impatient about it.


References:

The Absence of Linear Plasmid 25 or 28-1 of Borrelia burgdorferi Dramatically Alters the Kinetics of Experimental Infection via Distinct Mechanisms. Maria Labandeira-Rey, J. Seshu, and Jonathan T. Skare. Infect Immun. 2003 August; 71(8): 4608–4613. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC166013/

Correlation between plasmid content and infectivity in Borrelia burgdorferi. Purser JE, Norris SJ. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13865-70. http://www.ncbi.nlm.nih.gov/pubmed/11106398

High- and low-infectivity phenotypes of clonal populations of in vitro-cultured Borrelia burgdorferi. Norris, SJ, Howell, JK, Garza, SA, Ferdows, MS, and Barbour, AG. Infect. Immun. 63:2206-2212.

Plasmid Stability during In Vitro Propagation of Borrelia burgdorferi Assessed at a Clonal Level. Dorothee Grimm, Abdallah F. Elias, Kit Tilly and Patricia A. Rosa. Infect. Immun. June 2003 vol. 71 no. 6 3138-3145 http://iai.asm.org/content/71/6/3138.full

Experimental assessment of the roles of linear plasmids lp25 and lp28-1 of Borrelia burgdorferi throughout the infectious cycle. Grimm D, Eggers CH, Caimano MJ, Tilly K, Stewart PE, Elias AF, Radolf JD, Rosa PA. Infect Immun. 2004 Oct;72(10):5938-46. http://www.ncbi.nlm.nih.gov/pubmed/15385497

The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi. Mollie W Jewett, Kevin Lawrence, Aaron C Bestor, Kit Tilly, Dorothee Grimm, Pamela Shaw, Mark VanRaden, Frank Gherardini, and Patricia A Rosa. Mol Microbiol. 2007 June 1; 64(5): 1358–1374. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1974800/?tool=pubmed

Basic Epidemiology. Beaglehole R, Bonita R, Kjellstrom T. World Health Organization, Geneva, Switzerland, 1993

* Factors which concern others but I did not originally think of are included in comments below.

[Edited March 9, 2012 - Removed item above about brain tissue after reviewing Embers paper again - multiple brain samples were taken; one treated animal was positive for B. burgdorferi RNA in both heart and brain.]

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64 Embers et al Issues Statement On PLoSONE

Embers et al has issued the following author statement on PLoSONE:

Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection

Author statement
Posted by membersla on 02 Mar 2012 at 15:19 GMT

We recently published this article entitled “Persistence of Borrelia burgdorferi in Rhesus Macaques Following Antibiotic Treatment of Disseminated Infection.” The subject and content of this work may be viewed very divergently, given the controversy surrounding Lyme disease treatment. Specifically, the phenomenon of post-treatment Lyme disease syndrome and its cause (s) have been viewed with much contention.

Our work, which was funded by several grants from the National Institutes of Health, is composed of two major experiments. Experiment 1 entailed a very comprehensive and time-consuming study that indicated the possibility that spirochetes could persist after antibiotic treatment, but only nucleic acid or antigen of these bacteria were detected, leaving open the question of persistence by intact organisms. Experiment 2 was intended to answer that question. The authors elected to publish these 2 studies together, as they mutually enhance the validity and scientific merit of the work.

In our study, we provide evidence demonstrating the post-treatment persistence of the B. burgdorferi spirochete that has been reported previously in a mouse model. We further demonstrate through multiple detection methods that intact spirochetes can survive antibiotic treatment in a nonhuman primate host. It is not our intent to present data in opposition of current antibiotic treatment regimens for humans, but rather to report what we believe to be objective, well-performed experiments on antibiotic efficacy in a nonhuman primate model.

These data are by no means a referendum on long-term antibiotic therapy, nor should they serve to oppose current IDSA guidelines for the treatment of Lyme disease. From the medical standpoint, these results may or may not warrant testing of additional treatments or regimens. This depends heavily on the results of further inquiry as to the duration of persistence, the viability and phenotype of persistent organisms, and the answer to the key question of whether persisters are pathogenic. Current practices could only be challenged by solid proof of better treatment options; these are currently not available.

For several decades, basic scientists and medical doctors have collaborated to understand and improve Lyme disease treatment, diagnosis and prevention. As we proceed with further inquiry into the phenomenon of PTLDS, these collaborations are essential. The continued discussion, commentary and debate will additionally be of benefit when conducted without bias.

Source Link: http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607&root=info%3Adoi%2F10.1371%2Fannotation%2Fbe820481-edcb-457e-8d20-c0a904b91607

Bolded emphasis mine.

My comments? I could have predicted that such a statement would be issued. The researchers in question are making a string of inquiries where they must be certain of the outcome and not make a statement about the nature of Lyme disease prematurely - even if the chronic infection model of Lyme disease makes sense to many people and is the experience which a number of patients report having.

It comes as a disappointment to many patients that there is a specific statement here against long term antibiotic treatment, with the explicit statement that the results of this study are not intended to oppose current IDSA treatment guidelines. However, it is also stated that "these results may or may not warrant testing of additional treatments or regimens". The future regarding changes in antibiotic usage is uncertain.

Statements above and within the original study reflect a certain amount of uncertainty.

And in order for this team to avoid becoming cargo cult scientists, they must be willing to look at all the possible causes for persisting symptoms. They must be willing to challenge themselves and question the strength of their suspicions and poke holes at their assumptions. This must be done not only to assure them they are on the right track - but to be prepared to answer questions coming from any critics.

They may repeat their experiments to confirm their findings and conduct another study where tick inoculation is used and not needle inoculation. A study is needed that examines what would happen in an actual case of infection under conditions found in nature - not in a lab. This experiment would not only involve the use of ceftriaxone and doxcycline - but use infected ticks on hosts and involve the complex immune interactions that take place after a tick infection which do not occur the same way as they would after injection with a bacteria-laiden needle.

I'm looking forward to more research from Embers et al. That they close their statement with the phrase, "The continued discussion, commentary and debate will additionally be of benefit when conducted without bias," means a lot to me. It indicates to me that they are seeking the truth - which is something I can get behind. I only hope they find it soon.

Image credit: Morphology of Borrelia burgdorferi by Jeffrey Nelson, Microbe Library. Use under Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

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