Tuesday, May 31, 2011

2 Wolfram Alpha On Lyme Disease Diagnosis

So, I'm not sure how familiar my readers are with Wolfram Alpha. If you've ever heard of the Mathematica software package, these are the guys that created it.

Wolfram Alpha is an online tool that uses computational algorithms and data modeling to output objective information on a variety of topics.

In other words: It takes statistics and facts from numerous sources and creates a database on given topics on the fly.

(To learn more about what Wolfram Alpha's online tool does, go here: http://www.wolframalpha.com/tour1.html)

You can go to their homepage and type any term into their search engine and it will build a page based on that term and nothing but that term. Instead of a list of different link results like you see on Google, you get one page with many different kinds of information on that term or topic.

So for fun, I typed "Lyme disease" into their homepage.

The link for that query is this: http://www.wolframalpha.com/input/?i=Lyme+disease

Now, as part of the output for that query, I received the following table of data:

This is one of those moments where my head is breaking, and I can see where they are drawing their data from in the notes below the table - so I need to follow up and see if I can look at the original source for this data.

But just based on what I'm looking at right now, the words "Oh my god, where are they getting these numbers?" escaped my lips.  

According to the footnote, the data is not CDC based, but is based on actual patient visits to US healthcare providers between 2006-2007. I have to wonder why Wolfram Alpha is mining data from this source and not more recent NAMCS/NHAMCS statistics or another source, but it is interesting to see something that is not CDC for a change.

The data in this table does and does not reflect what I've observed online in the Lyme disease patient community.

For one thing, the chart states far more men than women contract Lyme disease and are diagnosed for it than women.  Yet the number of women I see online who discuss Lyme disease outweighs the number of men a great deal.

After reading Polly Murray's book, The Widening Circle, why women are more active online participants and more activist in general has been made more clear to me: the children. If you are sick with Lyme disease, that's bad enough - but if your child is sick, that's worse, and mothers seem to be more likely than fathers to reach out for answers and support online to help not only themselves but their children. (Sorry dads, I don't like the dissing either, and I'm sure a lot of you are active in your child's health - but statistically speaking more women do end up dealing with their kids' health issues for whatever reason.)

This reaching out and forming support groups began with women way before the internet - the internet is just an extension of what happens in real life.

(By 1992 there were over 100 patient support groups for Lyme disease - which kinda chips away at this idea that Lyme disease is a disease spread by reading the internet. What was the internet in 1992? Usenet?*)

But in this table, it's saying far more men get Lyme disease, and I see fewer of them online.

Okay, so another thing about this table,  just so the reader is clear on what they're reading, it doesn't take 22 doctors for one woman to achieve a diagnosis for Lyme disease here, even though I've heard so many stories about this phenomenon - no, what the table means is that for every 22 office visits a doctor sees, one of them will be a woman that gets diagnosed with Lyme disease. 

That one in six visits for men seems really high to me - too high, if you ask me - but in reading the fine print these are estimates and estimates which are weighted for US demographics (how? in what manner?).

I think what's striking about this one year of data is the extrapolation of just how many patients were diagnosed with Lyme disease over the course of 131,748 doctor visits. 

86,700 people in one year... is that closer to reality than the CDC reported 40,000 or so?

I really don't know how much stock to put in this data at all. I feel like writing Wolfram and asking them what gives. How was the estimation made and weighed and why are they drawing their data from NAMCS/NHAMCS - and if so, can they get more recent data or is this it? 

I'm thinking it would be more accurate a head count to get diagnosis numbers from doctors rather than the CDC, because not all cases are reported - but I don't know how reliable these numbers are or how the estimation was computed.


Just to add to this, check out this other table generated from the same data set:


Now look at the ratio for the number of  men who are diagnosed with Lyme disease to the number of women.  And now look at the total number of estimated cases. 

The only factor changed for initial data output was from "primary diagnosis at visit" to "any diagnosis at visit". What exactly does this mean?

Update #2:

Well, isn't this interesting. I googled "NAMCS" and my first result was this:

On this page, we learn:
"The National Ambulatory Medical Care Survey (NAMCS) is a national survey designed to meet the need for objective, reliable information about the provision and use of ambulatory medical care services in the United States. Findings are based on a sample of visits to non-federal employed office-based physicians who are primarily engaged in direct patient care. 
The National Hospital Ambulatory Medical Care Survey (NHAMCS) is designed to collect data on the utilization and provision of ambulatory care services in hospital emergency and outpatient departments. Findings are based on a national sample of visits to the emergency departments and outpatient departments of noninstitutional general and short-stay hospitals."
So wait. This IS data from a survey the CDC knows about?

What percentage of these diagnosed cases are included in the CDC Lyme disease reported cases?

Why aren't these diagnosed cases mentioned on the reporting page for Lyme disease as a separate category of cases -  even if doctors did not fill out an official report?

Or are they mentioned somewhere on the CDC Lyme disease pages and I've missed it? Anyone want to confirm this for me?

Update #3:

Pointed out by an anonymous commenter on the blog just now - from the same page above:

Wow,  let's give the women lots of Ativan and give the guys none?

After reading this, we're all going to need Ativan.

Where they hell are these numbers coming from, though? The footnote here is really not useful.

And I'm sorry, if I am feeling sick with Lyme disease, getting it up is the last thing that would be on my mind... that must refer to a preexisting drug regimen. Even then... ouch.

I really have to wonder about these numbers.

Update #4 (hopefully the last?):

Okay, so I think I've answered some of my own questions here:

Q. How are the data used? 
A. NAMCS and NHAMCS data are used to statistically describe the patients that utilize physician services and hospital outpatient and emergency department services, the conditions most often treated, and the diagnostic and therapeutic services rendered, including medications prescribed. The data are used by public health policy makers, health services researchers, medical schools, physician associations, epidemiologists, and the print and broadcast media to describe and understand the changes that occur in medical care requirements and practices. The data are disseminated in the form of public health reports, journal articles, and microdata files. 
Q: Can the ambulatory medical care surveys be used to find out how many people have a certain diagnosis?
A: No. The ambulatory medical care surveys (NAMCS and NHAMCS) are not based on a sample of the population. They are based on a sample of visits rather than a sample of people. The data can be used to find out how many ambulatory care visits were made involving a certain diagnosis. To get an idea of utilization of ambulatory care in the population, the number of visits can be divided by the population of interest to get a rate of visits for a diagnosis of interest.
Okay, partially answered. I still have to wonder how public health policy makers, epidemiologists, etc. use this data, though... and how closely this sample of visits maps to reality.

I really don't think anyone has a true picture of how extensive Lyme disease is and how many people have persisting symptoms of Lyme disease pre- and post-antibiotic treatment, and it would be useful to know how many cases physicians actually diagnose and treat versus report to the CDC as those are different numbers.

Even then, these surveys are only representational of doctor caseloads over a one week period during a given year - they are not solid figures.

* This is not all there was, but there were only 26 web sites in the world at the end of 1992.

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Monday, May 30, 2011

0 Superbug Suit: Groups Sue FDA Over Risky Use of Human Antibiotics in Animal Feed

Approximately 70% of all antibiotics used in the United States are given to healthy farm animals at low doses to promote faster growth and compensate for unsanitary living conditions -- a practice that has increased over the past 60 years despite evidence that it breeds antibiotic-resistant bacteria dangerous to humans. The antibiotics, mixed into feed or water for pigs, cows, chicken, and turkeys, are used at levels too low to treat disease, leaving surviving bacteria stronger and resistant to medical treatment.

FDA concluded in 1977 that feeding animals low-doses of certain antibiotics used in human medicine -- namely, penicillin and tetracyclines -- could promote antibiotic-resistant bacteria capable of infecting people. However, despite this conclusion and laws requiring that the agency act on its findings, FDA failed to take any action to protect human health.

Read More Here >>>
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0 Paper: Factors Affecting Duration of CFS in Pediatric Patients

Indian J Pediatr. 2011 May 27. [Epub ahead of print]

Factors Affecting Duration of Chronic Fatigue Syndrome in Pediatric Patients.
Petrov D, Marchalik D, Sosin M, Bal A.

UMDNJ/Robert Wood Johnson Medical School, New Brunswick, NJ, USA.


To determine factors affecting duration of chronic fatigue syndrome (CFS) in pediatric patients.

This Retrospective cohort consisted of patients with CFS at the regional referral infectious disease clinic for evaluation of fatigue in children and adolescents. Demographic, clinical, and laboratory data were analyzed to identify the impact on duration and severity of pediatric CFS.

A total number of 53 predominantly white (98.1%) patients with CFS, aged 9-18 years, were included in the study. Other than fatigue, headaches and sleep disturbance were the most common symptoms of pediatric CFS. Seropositive status for Borrelia burgdorferi (B. burgdorferi) and Epstein-Barr virus (EBV) was identified in 66% of the patients with the diagnosis of CFS by CDC criteria. No association was found between the CFS symptoms, gender, or age at diagnosis and duration of fatigue symptoms. Duration of CFS was associated with high Body-Mass Index (BMI) in a regression model after adjustment for patient's age, gender, and seropositive status for B. burgdorferi and/or EBV (0.34 ± 0.15, P < 0.04).

BMI is significantly associated with prolonged duration of CFS.

CO Comments:

I really need to get hold of the full text of this paper.

Interesting how they pointed out that 66% of their patients were seropositive for Borrelia burgdorferi and Epstein-Barr Virus by CDC criteria, but the emphasis in the paper abstract conclusion is only on the correlation between Body-Mass Index and duration of CFS in patients.

What percentage of patients had Lyme disease versus EBV infections? The breakdown isn't clear.

And here comes an additional question: What relationship is there - if any - between BMI and duration of illness?
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Saturday, May 28, 2011

0 Administrivia: Most Recent Posts List Removed

Unfortunately, the service which provides the "Most Recent Posts" list plug-in has been down or at least producing code that isn't generating the list automatically - so I have had to remove that broken plug-in for now.

Sorry for the inconvenience for anyone who was relying on it. I recommend using the search function or scrolling down to the archive post section to find newer posts.
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4 Repost: Lyme Disease & Antibiotics: More Than Skin Deep

This is a repost from Thursday evening's Daily Kos.

Alexander Fleming discovered the first antibiotic, penicillin, in 1928. After the first clinical trials of antibiotics in the 1940s, they transformed medical care and dramatically reduced illness and death from infectious diseases.

I have to wonder if Alexander Fleming ever realized just how many purposes would be found for antibiotic use in the future - and if he would have ever predicted that their use would generate controversy.

A central controversy in treating people who have persisting symptoms of Lyme disease is whether or not they should receive more than three weeks of antibiotics to treat their condition.

And my question about this is why not treat them with longer courses of antibiotics if that is what is needed? Why is this such a big deal?

There are plenty of situations for which long term treatment with antibiotics is warranted. The most well known are tuberculosis (often treated for 9-12 months, sometimes longer) and Hansen's disease (leprosy, often treated for two years).

While I state upfront that overuse of antibiotics is not something I advocate - and use of antibiotics in general can lead to not only resistance but risk of acquiring secondary infections such as C. difficile - in a number of cases the benefit of taking antibiotics outweigh the risks.

That said, is there any hard and fast rule in the medical profession as to which conditions will be treated with antibiotics and for how long?

Let's look at a few conditions for which long term antibiotics have been used and studied.

For example: Acne.

What kind of treatment do patients with acne receive, and why do they need antibiotics in the first place? Let's take a look at that...

Antibiotic Use for Acne

Heather Brannon, MD, wrote that "Acne is caused by the effects of hormones on the pilosebaceous unit, consisting of a hair follicle, sebaceous gland, and a hair. The follicle becomes obstructed and an overgrowth of a normal skin bacteria, Propionibacterium acnes, causes destruction of the lining of the follicle. This process allows follicular material to enter the dermis, causing an inflammatory response." [1, 2]

Antibiotics work by several mechanisms. The most important is the decrease in the number of bacteria in and around the follicle. Antibiotics also work by reducing the irritating chemicals produced by white blood cells. Finally, antibiotics reduce the concentration of free fatty acids in the sebum, also reducing the inflammatory response.

Antibiotic Treatment For Acne

Tetracycline is the most widely prescribed antibiotic for acne, and 500 mg twice a day is used continued until a significant decrease in acne lesions is seen. The dose can then be decreased to 250 mg twice a day or discontinued.

Erythromycin varies with the type used, but it is typically prescribed as 250 - 500 mg twice a day.

Minocycline has been used effectively for decades as a treatment for acne. It is especially useful for pustular type acne. The usual starting dose is 50 to 100 mg twice a day.

Doxycycline is prescribed for 50 - 100 mg twice a day, and is often used for people who do not respond to or cannot tolerate erythromycin or tetracycline.[2]

So, you've got a good idea which dosages of what kind of antibiotics are used to treat acne.

Duration of Treatment For Acne and Risks

Some patients find they can improve their acne with oral antibiotics for 2-3 months to start, then decrease the dosage as they add a topical antibiotic for treatment. In some cases, oral antibiotic treatment must be extended for an additional 3 months or longer, depending on the patient's response to treatment.

Concern over the risk of long term antibiotic use for acne sparked some studies, which have mixed results:

  • A large study conducted by the British Journal of Dermatology studied 4274 acne patients and found that since 1991 an average of 51% of patients harbored colonies of resistant bacteria. Other studies have shown similar levels of antibiotic resistant acne bacteria. Interestingly, researchers are finding similar levels of resistance in both patients treated with antibiotics and those untreated as well, although those untreated have somewhat lower levels of resistance.[3]
  • There have been concerns that people who use antibiotics to treat their acne have a higher incidence of upper respiratory tract infections, however, followup studies have challenged that concern.[4]
  • A recent study has also shown that treating acne with antibiotics does not lead to antibiotic resistance: "Prolonged use of tetracycline antibiotics for the treatment of acne does not lead to increased antibiotic resistance, according to a study published online April 11 in the Archives of Dermatology." The study is specific to 3-4 months of tetracycline use, however, and other antibiotics like clindamycin and erythromycin show resistance after a couple months' use in patients.[5]

Clearly, more research is needed - but based on these studies, it at least looks like a draw, leaning somewhat towards "it depends on which antibiotic is used".

If in the future, bacteria involved in severe acne cases does become resistant to tetracycline use, there is evidence a bacteriophage of the bacteria causing it may be used in new treatment therapies.[6]

So What Does Acne Treatment Have To Do With Lyme Disease?

So here we are, after I've just given a detailed outline of how high antibiotic doses are to treat a bacterial infection that is skin deep for 3-4 months - sometimes longer - in order to help patients clear up their faces and have less irritated skin and less social ostracization.

In the transcript of an educational course on acne treatment, "Long-term Oral Antibiotics for Acne", dermatologists stated they have no problem giving their acne patients another 2 or 3 months worth of antibiotics to treat their acne if it isn't cleared up after the first 2-3 months of treatment.

And if patients have a flare up of symptoms, they advocate putting them back on antibiotics if they stopped taking them. They're pretty comfortable with using more antibiotics when they need to until patients symptoms improve.

Don't you think if patients who face ostracization for pimple-laiden skin can get more antibiotic treatment for an infection that is skin-deep, that Lyme disease patients should be able to get more antibiotic treatment for a bacterial infection which can move into major organs and the central nervous system in a few weeks after a tick bite?

Something is wrong here.

Other Conditions Using Longer Term Antibiotic Treatment

There are a number of other conditions for which long term antibiotics are used and they range anywhere from being inconvenient and irritating to being chronic and painful to live with. Research is ongoing in how antibiotics can be used to treat conditions which were once thought difficult to treat or never treated with antibiotics in the first place.


Rosacea is a skin condition that is treated with long-term antibiotics. One interesting thing about rosacea is that it has had an oral antibiotic specially formulated to treat it which has less risk of microbial resistance.[7]

Evidence has shown that long-term medical therapy increased the rate of remission in rosacea patients, and it should be noted that the specially formulated doxycycline used to treat rosacea now is used for months and years at a very low dose [8].

The Mayo Clinic states this about rosacea: "The duration of your treatment depends on the type and severity of your symptoms, but typically you'll notice an improvement within one to two months. Because symptoms may recur if you stop taking medications, long-term regular treatment is often necessary."[9]

Crohn's Disease

Antibiotics have been used to treat Crohn's disease, and a meta analysis concluded that long-term treatment with nitroimodazoles or clofazimine is effective in patients with Crohn's disease (median treatment length was 6 months; duration ranged from 3-24 months).[10]

Reactive Arthritis

Researchers from the University of South Florida College of Medicine found a combination of antibiotics can be an effective treatment for reactive arthritis caused by Chlamydia bacteria. Reactive arthritis symptoms usually last 3-12 months, although symptoms can return and develop into a long-term disease. In the past it was thought only a small percentage of people would experience chronic symptoms of reactive arthritis, but now more recent data suggests 30-50% of patients can develop a chronic form of the disease.[11]

Neurodegenerative & Inflammatory Disorders

Minocycline has used in other neurodegenerative and inflammatory disorders, such as multiple sclerosis, Parkinson's disease, Huntington's disease, rheumatoid arthritis and ALS for its non-antibiotic properties, and it and other antibiotics may be useful in long term treatment of such disorders.[12]

Questions To Consider

So those were just a few examples beyond acne, tuberculosis, and Hansen's disease of where more than a 2-3 week course of antibiotics has been recommended for various conditions which may be caused by a bacterial infection - and in the case of rosacea and other medical conditions - may not be. Antibiotics are used to treat rosacea and other conditions because of their anti-inflammatory properties.

With all this in mind, why don't the standard guidelines state conditions for individual doctor discretion in using long term courses of antibiotics to treat patients with persisting symptoms of Lyme disease?

What about designing Lyme disease treatment studies which are similar to those for Crohn's disease (longer term treatment) and reactive arthritis (using a combination of antibiotics to treat symptoms)?

What about adding the study and treatment of tickborne coinfections such as Babesia and Ehrlichiosis into treatment trials, since polymicrobial infection can have an effect on treatment outcome?

In ongoing discussions of the use of long term antibiotic treatment for persisting symptoms of Lyme disease, only the same three clinical studies keep getting cited (Klempner, Krupp) which show low to no effective reduction of symptoms in patients using antibiotic treatment for Lyme disease after treatment is stopped.

These studies have their criticisms and are limited in what they could measure in terms of outcome and could not provide evidence of persistent infection one way or another.

Clearly more research is needed in this area - and with large random controlled studies.

If some researchers have proposed that the reason some Lyme disease patients experience persisting symptoms in what is labeled "Post-Lyme Disease Syndrome" due to inflammation from cytokines/a hyperactive immune response - why not use antibiotics for their anti-inflammatory properties?

So far, in my research, I've seen support for both Borrelia burgdorferi leading to persistent infection in patients - as well as inflammation being related to persistent symptoms in Post-Lyme Disease Syndrome.

Wouldn't treating these conditions with longer term antibiotics hit two birds with one stone?

If the reason for not treating persisting symptoms with longer courses of antibiotics is due to the concern for antibiotic resistance - which is a serious concern when one thinks of MRSA and VRSA - what about all these other conditions?

And surely some conditions merit antibiotic use with far more intensity and duration early on in order to prevent resistance and have a more favorable outcome for patients?

The bottom line:

The consequences of insufficient treatment for Lyme is not merely a painful memory of a prom photo with breakouts - it's people who have lost their ability to have careers and families and life fulfillment - and maybe even life, itself.

There's a reason Lyme patients feel that the people who have knee-jerk reactions to more than a month of abx are sentencing us to diminished lives, not just a lousy photograph in the scrapbooks of our lives.

Lyme disease bacteria can disseminate to different organs and into the central nervous system and brain shortly after infection. IT IS MORE THAN SKIN DEEP.

1. Pathophysiology of Acne vulgaris: http://www.aafp.org/afp/20001015/1823.html
2. http://dermatology.about.com/cs/antibiotics/a/acneabx.htm
3. Coates P, Vyakrnam S, Eady EA, Jones CE, Cove JH, Cunliffe WJ. "Prevalence of antibiotic-resistant propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study." The British Journal of Dermatology. 2002 May;146(5):840-8.
4. Antibiotic treatment of acne may be associated with upper respiratory tract infections.
5. http://www.medscape.com/viewarticle/740768
6. Farrar MD, Howson KM, Bojar RA, et al. (June 2007). "Genome sequence and analysis of a Propionibacterium acnes bacteriophage". Journal of Bacteriology 189 (11): 4161–7. doi:10.1128/JB.00106-07. PMC 1913406.PMID 17400737
7. http://www.rosacea.org/patients/faq.php#antibiotics
8. http://www.medscape.com/viewarticle/554690_4
9. http://www.mayoclinic.com/health/rosacea/DS00308/DSECTION=treatments-and-drugs
10. Long-Term Antibiotic Treatment for Crohn's Disease: Systematic Review and Meta-Analysis of Placebo-Controlled Trials
11. "Combination Antibiotics as a Treatment for Chronic Chlamydia-Induced Reactive Arthritis." J. D. Carter, L. R. Espinoza, R. D. Inman, K. B. Sneed, L. R. Ricca, F. B. Vasey, J. Valeriano, J. A. Stanich, C. Oszust, H. C. Gerard, and A. P. Hudson. Arthritis & Rheumatism; Published Online: April 29, 2010 (DOI: 10.1002/art.27394); Print Issue Date: May 2010.
12. Blum D, Chtarto A, Tenenbaum L, Brotchi J, Levivier M (2004). "Clinical potential of minocycline for neurodegenerative disorders". Neurobiol. Dis. 17 (3): 359–366. doi:10.1016/j.nbd.2004.07.012. PMID 15571972.

Other resources:
- Acne vulgaris: http://en.wikipedia.org/wiki/Acne_vulgaris
- CDC Antibiotic Resistance FAQ: http://www.cdc.gov/ghttp://www.cdc.gov/getsmart/antibiotic-use/anitbiotic-resistance-faqs.html
- Klempner MS, Hu LT, Evans J, et al. (July 2001). "Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease". N. Engl. J. Med. 345 (2): 85–92. doi:10.1056/NEJM200107123450202. PMID 11450676. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11450676&promo=ONFLNS19.
- Kaplan RF, Trevino RP, Johnson GM, et al. (June 2003). "Cognitive function in post-treatment Lyme disease: do additional antibiotics help?". Neurology 60 (12): 1916–22. PMID 12821733. http://www.neurology.org/cgi/pmidlookup?view=long&pmid=12821733.
- Krupp LB, Hyman LG, Grimson R, et al. (24 June 2003). "Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial". Neurology 60 (12): 1923–30. doi:10.1212/01.WNL.0000071227.23769.9E. PMID 12821734. http://www.neurology.org/cgi/content/abstract/60/12/1923.
- B. A. Fallon, MD, J. G. Keilp, PhD, K. M. Corbera, MD, E. Petkova, PhD, C. B. Britton, MD, E. Dwyer, MD, I. Slavov, PhD, J. Cheng, MD, PhD, J. Dobkin, MD, D. R. Nelson, PhD and
H. A. Sackeim, PhD. "A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy." Neurology March 25, 2008 vol. 70 no. 13 992-1003 http://www.neurology.org/content/70/13/992.short

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Wednesday, May 25, 2011

0 Daily Kos Posting Tomorrow At 6:30 PM EST

Please note that another entry will be posted on the Daily Kos tomorrow, May 26, Thursday at around 6:30 PM EST in observance of Lyme Disease Awareness month.

That is: 12:30 HST,  3:30 PM PST, 22.30 UTC (GMT)

The topic for this Daily Kos posting is going to be Long Term Antibiotic Treatment and asks why this is considered a controversial treatment for persisting symptoms of chronic Lyme disease as well as its named counterpart, Post-Lyme Disease Syndrome.

Check it out tomorrow at the below link - and comment there if you have a Daily Kos account:


As an extended side note, there will be discussion on the long term use of antibiotics to treat acne - and related to this, I really find this dialog on a Medscape transcript for a medical education credit class, "Long-term Oral Antibiotics for Acne: Focus on Safety (Slides With Transcript)" to be interesting and totally apropos to tomorrow's post:

Dr. Eichenfield: Yeah, and many times in practice I actually have the discussion with the patient where I've said, "Look, we don't want you on long-term antibiotics if we can help it. You're doing great." We have a decision to make here, and it's really a binary decision. Try to get them off the oral antibiotic at that time substituting topical or rolling it on a few more months. Depending upon how severe their disease was previously, I wouldn't mind another 2 or 3 months on balance in taking care of that patient.

Dr. Thiboutot: I think you really have to go by what their disease is telling you. That's absolutely important.

See the entire transcript and thumbnails from the slideshow at:

It's definitely food for thought when thinking about approaching the treatment of persisting symptoms of Lyme disease from different angles.
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Tuesday, May 24, 2011

4 The FDA Vault: Dr. Vijay Sikand On Lyme Disease & Lymerix

You know how I've said you can never guess what you're going to come across when you surf the net looking for other things?

Well, I came across this FDA transcript for a discussion on the Lymerix vaccine back in 1998. The original transcript contains an endorsement for the vaccine from the founder of Lyme Disease Foundation (LDF, not to be confused with the ADLF), who later determined the vaccine needed to be pulled from the shelves based on adverse reaction reports.

I'm setting aside any discussion of the Lymerix vaccine for now and just posting this statement from Dr. Vijay Sikand, an MD who practiced in Lyme, Connecticut... (items of interest are in bold)


Tuesday, May 26, 1998 

The meeting took place in Versailles Rooms I and II, Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland at 9:00 a.m., Patricia L. Ferrieri, M.D., Chair, presiding.  

VIJAY SIKAND, M.D., Sponsor Rep

"...As I was just saying, I included research in Lyme disease as part of a primary care practice for a number of years. In early 1995, 1,200 volunteers came to my office to enroll in the SmithKline Beecham vaccine trial which we are discussing today. Almost three and a half years later now, greater than 92 percent of those patients are still providing me with clinical follow-up.
Why do we need a vaccine for Lyme disease? It has been almost a quarter century since Lyme disease was first described as an emerging infection in this country. During these years a number of factors, epidemiologic factors and clinical factors, have resulted in considerable morbidity in burgeoning numbers of patients.This burgeoning load of disease as well as the increasing number of patients thus set the stage for prevention of this disease with a vaccine.Today, I will present to you some of the factors in a brief synopsis illustrating the need for a vaccine for Lyme disease.The illustrations which I will present to you, some of them are from my private practice and some of them are from the vaccine study.

The first factor is an epidemiologic factor,and this has already been discussed by Dr. Schoen. And that is that there is indeed a progressive increase in incidence of Lyme disease. The second factor also epidemiologic is the relentless geographic spread of this disease. There are new endemic areas being created annually and the disease burden is indeed growing.
The ineffectiveness of preventive measures which we attempt to practice is another important factor. We have tried various chemical and other means. Why have preventive measures, which are indeed important, not been effective in preventing an increase in cases of Lyme disease?  And before I answer that question, let me underline the fact that I indeed believe it is important that we continue to practice preventive measures because of co-infection with other illnesses besides Lyme disease. 

One obvious reason is that it is very impractical to practice certain protective measures.  This individual in the Lyme, Connecticut area desires to do some outdoor work and does not want to be bitten by a tick. But the point is it is very difficult to ask children or anybody else for that matter to tuck pants into socks, et cetera, in the middle of July and August when the ticks are questing. We can certainly check our pets, but checking one's dog is indeed a Sisyphean task when the dog goes in and out of the house all day long. Probably the best protective measure, I think, in preventing Lyme disease is checking for ticks.  Unfortunately, kids will only allow you to do this up to a certain age. And of course one must be vigilant with oneself.

More specifically, I think one of the important reasons to consider when thinking about why protective measures are difficult to utilize and be effective in preventing this disease is simply the nature of the Ixodid tick bite itself. The bite of this tick when it is infected transmits not only saliva infected with Borrelia burgdorferi, but the saliva also contains certain anti-inflammatory substances which have an anesthetic effect.The end result of that is that tick bites in general are not noticed. In one study, over 80 percent of the patients who presented with definite Lyme disease did not remember a tick bite. It is therefore very hard to correlate the incidence of definite Lyme disease cases with preceding tick bites, and this is well known.

Furthermore, as has been eluded to earlier, the recurrence of disease in individuals is also well known. Unfortunately, in the majority of patients, the vast majority of patients, natural infection with Borrelia burgdorferi does not confer protective immunity. 

Difficulties in clinical diagnosis of this disease are also well known, and it is not my place today to give you an overview or detailed presentation of the clinical aspects of Lyme disease.However, a couple of issues that do spring up and which I would like to address are as follows. In particular, the specter of asymptomatic infection is something that troubles me a great deal and troubles a great number of my colleagues who need to treat Lyme disease. The obvious analogy with syphilis infection with Treponema pallidus is there to consider. It is well known that Borrelia burgdorferi indeed after asymptomatic infection can lurk or secrete itself in certain areas of the body, perhaps the central nervous system or perhaps the joint spaces, only to reappear months or maybe years later in the form of late stages of illness which are harder to diagnosis and treat.

In terms of the variability of Lyme disease, it is indeed a very variable infection, if not a very complex infection.  In its very simplest form, it is erythema migrans, well localized, which we can all recognize and which we can all easily treat and from which most patients can get better. However, erythema migrans is not a single beast. Certainly this is the one which we easily recognize and which I just referred to.Before I continue with further slides, let me point out that the erythema migrans lesions you are about to see are all biopsy lesions which were laboratory proven to be caused by Borrelia burgdorferi.

Sometimes erythema migrans can present as a pustular lesion as is this one in the popliteal fossa inviting the scalpel of a surgeon. Sometimes the lesions are vesicular in nature, inviting a diagnosis perhaps of herpes simplex infection.  Sometimes our round lesion is actually triangular. Sometimes it doesn't even look round or red at all and invites a diagnosis of an intertriginous fungal infection in the groin of this patient who was biopsied and proven to have Lyme disease. Sometimes the lesion is more plaque-like, inviting diagnosis of nummular eczema, psoriasis, or other similar lesions. Sometimes it is in unusual locations. Sometimes it is large like this one. Sometimes it is small with satellite areas. Sometimes it is multiple, appearing almost like urticaria or erythema multiform. Sometimes, as in this individual who was a placebo recipient in the Lyme 008 SmithKline Beecham trial, it presents with other manifestations of early dissemination. This individual came in mainly because he was concerned about his face and it felt kind of funny and it was weak on one side. When I asked him whether he had had any unusual rashes, he said oh do you mean this one, and he showed me his arm with that EM. This is simply to illustrate the infranuclar 7th nerve palsy with which he presented. This patient, by the way, had no history of a tick bite or any unusual antecedent illness which he could remember.

The next slide is the electrocardiographic tracing of a 37-year-old mom from Lyme, Connecticut, mother of three. Generally healthy and no medical problems. Early on the day that this electrocardiogram was taken, she went to her local health club and did her usual work-out, which went fine. However, when she came home that day, she noticed that she had some palpitations, a little shortness of breath, malaise, and things just didn't seem quite right, but she wasn't sure what. When her husband came home, she told him that maybe she had worked out a little bit too hard at the club. A few minutes later, he was reading the newspaper in an armchair and he heard a thump on the floor above. He ran up the stairs to find his wife unconscious briefly on the floor and called 911. On arrival at the emergency department, the patient presented with this tracing, which in retrospect was a superventricular tachycardia representing an escape rhythm

There was fortunately a very vigilant emergency physician who didn't understand quite why a 37-year-old healthy woman had completely passed out, and she had what was a relatively benign rhythm at that point. But he was wise and admitted her to the coronary care unit for further monitoring. Late that night and the early hours of the following morning, the CCU nurse noted that the patient had gone through progressive degrees of AV block culminating in complete atrial ventricular dissociation. A cardiologist was summoned. He inserted a temporary transvenous pacemaker. The patient was started on intravenous antibiotics for about a week in the hospital followed by a few more weeks as an outpatient.This patient also had no history of a tick bite.

Besides the difficulties in clinical diagnosis, we are all aware that quandaries in laboratory diagnosis are rife.We rely pretty much on serologic testing in the United States today to assist us in diagnosing Lyme disease. Unfortunately, serologic testing, as with other infectious diseases, provides only indirect evidence of infection. When we order a serologic test, it just tells us that the patient has been exposed to Borrelia burgdorferi and doesn't tell us whether the infection is active or whether it is a past infection. It is probably worth noting, since I have learned a lot, that we don't have the clinical luxury in private practice that we had in the SmithKline Beecham trial in which we had baseline sera on all the patients who enrolled so that when they presented with symptoms, we could draw acute and convalescent serologies so as to compare them with each other and with baseline to better understand what symptoms they are presenting with. But your average physician in the office just can't do this. A patient comes in with symptoms or signs of Lyme disease and you have to make a clinical diagnosis and it is not always easy and serology doesn't help. The fact that in particular the ELISA creates a great deal of false positive results is also problematic. 

In particular and commonly in infectious mononucleosis and other spirochetal disorders, even healthy people, juvenile rheumatoid arthritis and other autoimmune disease all can produce false positive results. Indeed, even with Western blotting recent reports have shown that infection with the agent of human granulocytic Ehrlichiosis can cause false positive Western immuno-blots.The false negatives that we deal with are generally caused by use of serology testing in patients who have early Lyme disease and in whom the serologic response with immunoglobulin M has not occurred to the extent to which it can be measured.

What do we have in the way of direct testing to try to see if the organism itself is actually there or evidence of it? Well, culture and PCR are what are out there right now.  However, these are unreliable and impractical. Culture and PCR are certainly not warranted for the diagnosis of erythema migrans. The polymerase chain reaction is indeed sensitive in joint fluid. However, the diagnosis of Lyme arthritis does not require PCR testing since serology is almost invariably positive at that stage. Clinical conditions such as complex neurological conditions when a test like sensitive PCR would be useful, unfortunately cannot be diagnosed that way because PCR and indeed culture are not sensitive for cerebrospinal fluid, nor are they sensitive for urine, blood, and other body tissues when later in the disease one might care to employ these techniques.

Finally, there are indeed many dilemmas in therapy. In particular, untreated or inadequately treated Lyme disease may lead to the chronic morbidity with which we are very familiar. Most commonly arthritis and the not common but complex neurological syndromes are what often result and which confront the primary care physician in the office diagnostically and therapeutically.These particular outcomes result in much more intensive, long-term expensive therapy, often in the form of long-term intravenous antibiotics. These are the patients who often are refractory to treatment. Indeed, these are the patients in whom symptoms seem to persist despite what we have given in terms of adequate antibiotic therapy by any known measure.

            In conclusion, we need a vaccine for Lyme disease because it is increasing in incidence and geographic spread.We need a vaccine for Lyme disease because there are problems in clinical diagnosis, its laboratory evaluation, and its treatment. We need a vaccine for Lyme disease because preventive measures are unfortunately ineffective. Lyme disease is indeed vaccine preventable. Availability of this vaccine would lead to a significant reduction in chronic sequelae and substantive morbidity.  Lyme vaccine is thus a critical new public health approach to the primary prevention of Lyme disease in the United States. Thank you very much."

Dr. Sikand and Dr. Steere were at the same meeting. It's obvious Sikand knew Lyme disease could lead to serious late stage Lyme disease and chronic persistent symptoms of infection. If it could be easily resolved with 2-3 weeks of antibiotics, would they have spent this much time, effort, and money on developing a vaccine and running clinical trials?

Everyone at this meeting - including Lyme disease patient advocates - wanted a vaccine. That it would lead to adverse events in some patients and be pulled from the market later was not what everyone thought at first - at first it was welcomed as a solution to preventing the worst of what Lyme disease could do to a person because it was hard to diagnose and treat.

1998. Thirteen years ago.

How much have things changed since then?

Why are we still looking at the same problems and issues?
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Sunday, May 22, 2011

0 Video: The mystery of chronic pain

In this video from TED, Elliot Krane works with children in helping them with neuropathic pain and complex regional pain syndromes - nerve-related pain that continues from an injury long after the original accident occurred.

He practices at Stanford Hospital and Clinics and Lucile Packard Children's Hospital, and here is one story of how he helped a young girl stop the tremendous pain that made even a feather-light touch on her arm agonizing.

This may or may not relate to those who suffer from persisting symptoms of Lyme disease - either way, this story is something worth watching and considering in our challenges to understand and stop pain.

You might also want to read the comments on the original page for this video - the information found there may help you or someone else you love in tracking down another or an additional cause for pain:

[Time 08:14]

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Thursday, May 19, 2011

14 Chart: Ways To Discuss Your Position In An Argument

Referring back to this entry: http://campother.blogspot.com/2011/05/repost-lyme-disease-rant-wall-of.html, here is a chart that shows different kinds of interactions one can have during a discussion with opposing positions.

From observation, discussions where parties hold conflicting views tend to degenerate and become either flaming troll wars or stalemates when anything from contradiction on down through namecalling is applied.

When Counterargument, Refutation, or Refuting the Central Point are used, the discussion is far less likely to degenerate into a flaming troll war and is more likely to be productive - people are more likely to walk away from the discussion not only having a better understanding of others' views, but also having a clearer understanding of what they themselves do not understand or where they lack knowledge...

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Wednesday, May 18, 2011

6 Paper: Tired of Lyme borreliosis

I've decided that for the time being, I'm going to focus some of my time and energy on neuroborreliosis and late stage Lyme disease.

Is there a relationship between missing an early diagnosis of neuroborreliosis and later persisting symptoms? There seems to be, based on what Dr. Brian Fallon has stated in the past. This is something that interests me.

In my research on Lyme disease treatment guidelines,  I think this recent paper has been mentioned on Lymenet Europe:


Coumou J, van der Poll T, Speelman P, Hovius JW. Tired of Lyme borreliosis. Lyme borreliosis in the Netherlands. Neth J Med. 2011 Mar;69(3):101-11.

Man, these guys know what I'm thinking... I'm tired of Lyme borreliosis, too. And tired from it, as well as the entire stinking enchilada of controversy around the chronic issue.

But I digress... a lot of this paper echoes the IDSA treatment recommendations for Lyme disease, and later on, mentions this:

"In late manifestations of Lyme borreliosis, the same antibiotics are recommended, but with a longer duration of treatment (table 1).

[Ed. - table 1 mentions 30 days of IV ceftriaxone or oral doxycycline, depending on whether or not the patient exhibits pleiocytosis.]

"For selected individuals with aspecific symptoms in combination with positive Lyme serology antibiotic treatment could be considered. Although, to our knowledge, evidence-based guidelines for this are non-existent, treatment could be adjusted based on the duration of symptoms, e.g. short duration of symptoms (< 3 months) could be treated with 10-14 days of doxycycline 100 mg twice a day and longer lasting symptoms with 30 days of doxycycline 100 mg twice a day. In case of persistence of specific Lyme borreliosis symptoms, persisting B. burgdorferi s.l. infection, or re infection, should be considered and additional or prolonged therapy could be indicated."

Okay, so that's about individuals with positive Lyme serology. Positive Lyme serology and subjective measurements. Got that.

Then they mention PLDS patients:

"In stark contrast, patients with PLDS, or individuals with false-positive Lyme serology and aspecific symptoms, such as fatigue, myalgia, headache and joint pain, should not receive antibiotic treatment. However, some of these patients are occasionally unjustly treated for months to years with (multiple) intravenously administered antibiotics, for which no credible scientific evidence exists. Such approaches pose a great risk for serious adverse effects."

And so they're staying that individuals with false-positive Lyme serology and aspecific symptoms should not receive antibiotic treatment.

Right. So.

After rereading these paragraphs a few times, this leaves me with some questions and/or comments:

  1. How do you determine which patients have aspecific symptoms with positive Lyme serology versus patients with false-positive Lyme serology and aspecific symptoms?
  2. If evidence-based guidelines for patients with late manifestations for Lyme disease are non-existent, how are you coming up with this recommendation and what IS it based on? If you say opinion, what is that opinion based on?
  3. Which specific Lyme borreliosis symptoms must persist in order for prolonged therapy to be indicated?
  4. You're stating right there that the infection can persist. How do you know it persists?
I have a lot of unanswered questions about this, as I'm sure others might after reading this. 

At the close of the paper, the authors wrote this:

"Antibiotics are effective in all manifestations of Lyme  borreliosis and prognosis is usually excellent. However,  a minority of patients experience potentially severe, but aspecific symptoms after previous adequate treatment for Lyme borreliosis. In these individuals, additional antibiotics have no substantial beneficial effects compared with placebo.

 A challenge for the future is to develop a test to detect, or rule out, persistent active B. burgdorferi s.l. infection. This could reassure individuals who experience aspecific symptoms after previous recommended therapy for Lyme borreliosis, prevent unnecessary treatment and pave the way for research on the true aetiologies of aspecific symptoms after recommended antibiotic treatment for Lyme borreliosis."

And I agree,  a test is needed to detect and rule out persistent active B. burgdorferi infection. However, what are they doing right now to make that determination?

"In case of persistence of specific Lyme borreliosis symptoms, persisting B. burgdorferi s.l. infection, or re-infection, should be considered and additional or prolonged therapy could be indicated."

I just wonder... are we going in circles?

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Tuesday, May 17, 2011

8 Paper: Environmental Stress in Borrelia Burgdorferi

The things you find, just randomly surfing online...

So, this is someone's dissertation for their doctoral degree. In 2004.


A Dissertation Submitted to the Graduate Faculty of the University of Georgia in Partial
Fulfillment of the Requirements for the Degree

Should I forgive the typo, on a dissertation?

Well, I will. Just this once, because I am interested in commenting on more of the content inside and think this is a minor oversight. For all I know, there's a minor typo somewhere in my own publications that will come back to haunt me...

First, this section on serological tests for Lyme disease:

"ELISA assays are the most widely available and commonly performed tests, and have replaced IFA which are both labor intensive and subjective in interpretation (54, 77, 176, 192).  However, both ELISA and IFA are prone to both false positives and false negatives.  False positives generally result from the cross reactivity of B. burgdorferi proteins with proteins of other infectious agents (spirochetal, bacterial, rickettsial, rocky mountain spotted fever, EBV) (54, 77, 176, 192)."

 Yes, it's important to know what you're infected with, but in this case, with the exception of EBV - everything there is a bacterial infection requiring antibiotic treatment. So patient history plus serology is more than likely going to nab this one for treatment.

Next, let's look at this section on antibiotic resistance:

"Antibiotic resistance in B. burgdorferi has been investigated in vivo, in vitro, as well as in clinical reports.  B. burgdorferi is resistant to aminoglycosides, ciprofloxacin, rifampin, most first generation cephalosporins and some clinical isolates are erythromycin resistant (40, 134, 136, 138, 154, 192, 199, 220, 293)."

See, that's a lot of different drugs to which it's resistant. Note, please, that aminoglycosides are the first drug mentioned there.

And then we look at which antibiotics affect Borrelia burgdorferi:

"In contrast, it is  sensitive to penicillin and penicillin derivatives along with some macrolides and second generation cephalosporins (9, 40, 134, 136, 138, 154, 199, 220, 273, 277, 310).  To effectively treat B. burgdorferi located in deep tissue, CNS, eye, and within tendons, higher doses are often required (9, 40, 199, 220, 273, 277, 310)."

Okay, I think you could have expected this... this statement is totally within the standard guidelines and on research done to date on these particular antibiotics in vitro.

But then there's this part of the paper:
"Treatment of disseminated and late Lyme disease is much more difficult.  The duration of treatment is longer, the response is often slower and treatment failure is higher due to the presence of B. burgdorferi in the CNS, eye, within tendons and deep tissue (192, 306).  For patients with neurological complications, intravenous treatment regimens can last many months and includes 2 grams daily of ceftriaxone or 20 million units per day of penicillin G in divided doses (192, 306, 309). "
Hm. Okay. This isn't something that's included in the guidelines. Fascinating. This sounds more like the treatment plan that many Lyme disease patients with persisting symptoms have been taking, and getting some flack for from some medical professionals.

So why? If this is good enough for a doctoral dissertation, why isn't it good enough for patients?

Did something happen in 2004 I don't know about? I'm pretty sure the guidelines for treatment at this point did not include this treatment recommendation.

So what are papers 192, 306, and 309?

192. Nocton, J. J., and A. C. Steere. 1995. Lyme disease. Adv. Intern. Med. 40:68-115
306. Wilson, M. E. 2002. Prevention of tick-borne diseases. Tick-Borne Diseases 86:219-238.
309. Wormser, G., R. Nadelman, J. Dattwyler, D. Dennis, E. Shapiro, A. C. Steere, T.
Rush, D. W. Rahn, P. K. Coyle, D. H. Persing, D. Fish, and B. J. Luft. 2000. Practice
guidelines for the treatment of Lyme disease. Clin. Infect. Dis. 31:S1-S14.

Wait. I'm really seeing this?

I need to go look at these papers and have a stiff drink.

Okay, paper 192 is http://www.ncbi.nlm.nih.gov/pubmed/7747659 on PubMed, but there is no option to view an abstract of it, or pay for full text access  through PubMed. Advances in Internal Medicine stopped publishing in 2001, so you'll have to get a hard copy elsewhere (Elsevier doesn't have it, either.)

On to the next paper... http://www.ncbi.nlm.nih.gov/pubmed/11982299 which one has to pay for access online, though there is a limited abstract.

And then 309, which is this http://www.ncbi.nlm.nih.gov/pubmed/10982743  Which is the IDSA Lyme disease guidelines for 2000.

And, well, they say about what I expected:

"Late neuroborreliosis affecting the CNS or peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (B-II).

Alternative parenteral therapy may include administration of cefotaxime (2 g iv every 8 h) (B-II) or iv penicillin G (18–24 million units daily, divided into doses given every 4 h for patients with normal renal function) (B-II). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, a 14–28-day course of treatment with ceftriaxone (75–100 mg/kg/d in a single daily iv dose; maximum, 2 g) is recommended (B-II). An alternative is cefotaxime (150–200 mg/kg/d iv, divided into 3 or 4 doses; maximum, 6 g/d) (B-II). Another alternative is iv penicillin G (200,000–400,000 units/kg/d, divided into doses given every 4 h for those with normal renal function; maximum, 18–24 million units/d) (B-II)."

As has been said other places at other times: Why aren't these "reliable objective measures" spelled out in this document?

And how does one determine whether to dose out 2 weeks, 3 weeks, or 4 weeks of ceftriaxone? What's the objective measurement they use to decide between giving a patient 2 weeks versus 4 weeks of IV?

And the next section is...

"Chronic Lyme disease or post–Lyme disease syndrome..."

Yeah, well, let's not even go there right now. Most people reading along already know what that section says...

I suspect that the 2002 Wilson paper is what mentions long term treatment protocols in the dissertation I began writing about - but I'm going to have to look for it elsewhere and see if I can find access available for all my readers. For what it's worth, there is some mention of Sam Donta in the same publication, so perhaps this is where the extended IV protocol in bold came from?

At any rate,  getting back to reading  the 2000 guidelines (and I have yet to reread the 2006 ones), it appears that there weren't many studies back then on large numbers of patients with neuroborreliosis and late stage Lyme disease including encephalopathy. We're talking 7 patients for this one case series, 48 for another... small numbers.

And amid all that, there are studies like this which were conducted:

"From 1986 through 1991, 48 adult and pediatric patients with Lyme arthritis were randomly assigned to receive either doxycycline (100 mg orally twice a day) or amoxicillin and probenecid (500 mg of each 4 times a day), in each instance for 30 days [87]. Eighteen of the 20 evaluable patients treated with doxycycline and 16 of the 18 evaluable patients who completed the amoxicillin regimen had resolution of arthritis within 13 months after enrollment in the study. However, neuroborreliosis later developed in 5 patients, 4 of whom were treated with the amoxicillin/probenecid regimen.

The concomitant use of probenecid with amoxicillin may be inadvisable, because probenecid may impair penetration of b-lactam antibiotics into brain parenchyma [72, 88].

In retrospect, it was noted that all 5 patients reported subtle distal paresthesias or memory impairment at the time of enrollment. It was concluded that patients with Lyme arthritis can usually be treated successfully with oral antibiotics, but practitioners must be aware of subtle neurological symptoms that may require treatment with iv antibiotics."

Hope that test got a do-over, and they found out what was wrong with those 5 patients and they got the help they needed. Would you have included patients with that background in this study? I wouldn't have. Their symptoms match those of neuroborreliosis. Why weren't they excluded from the study earlier on?

I underlined "subtle neurological symptoms" to make a point, by the way: The panelists are always mentioning that they need objective evidence of infection, yet here they are urging practitioners to be aware of subtle neurological symptoms. Which are subjective evidence.

So... what else can you look at as objective measurements other than serology? Because after the first two weeks of infection, CSF tests don't have good yields. And if your patient already had some antibiotics but they were undertreated, will they produce a robust ab response on tests? Can someone tell me?

Okay, here's another study from the 2000 guidelines:

"Patients with late Lyme disease associated with prominent neurological features also respond to antibiotic therapy. In trials conducted from 1987 through 1989, 27 adult patients with Lyme encephalopathy, polyneuropathy, or both were treated with iv ceftriaxone (2 g/d for 2 weeks) [93]. In addition to clinical signs and symptoms, outcome measures included CSF analyses and neuropsychological tests of memory. Response to therapy was usually gradual and did not begin until several months after treatment. When response was measured 6 months after treatment, 17 patients (63%) had uncomplicated improvement, 6 (22%) had improvement but then relapsed, and 4 (15%) had no change in their condition."

So right there, the study outcome was that 6 of 27 patients improved but relapsed, and 4 just didn't get any better.  In this study, 37% of the patients did not have "uncomplicated improvement". (What does that mean, "uncomplicated improvement"? Why not use the words "were cured"? )

No, in this study, 37% did not improve at all as far as we know. Some followup report here would be good.

Moving on to another study from the 2000 guidelines (are you bored yet?):

"In 1987, a case series of 7 patients with Lyme arthritis or chronic neuroborreliosis, who were refractory to oral or iv penicillin therapy were then treated with iv ceftriaxone (2 or 4 g/d for 2 weeks) [83]. All 5 patients who had arthritis responded to ceftriaxone therapy, and for 5 of the 6 patients with limb paresthesias, a reduction in symptoms and improvement of nerve conduction study findings were noted."

So here, again, "reduction in symptoms" and "improvement of nerve conduction study findings were noted"... but I'm not seeing the phrase, "resolution of symptoms". Is this the most patients can hope for with these conditions?

I'm hoping I missed something, and just need to find the original case series paper and read it. But I see this as 5-6 people out of 7 did not have resolution of their symptoms. How else can I read it?

More from the 2000 guidelines:

"In a follow-up study, 23 patients with Lyme arthritis or late neuroborreliosis were randomly assigned to receive penicillin (20 million units per day iv for 10 days) or ceftriaxone (4 g/d iv for 14 days) [84]. Of the 13 patients who received ceftriaxone none had objective evidence of persistent disease after treatment, although 3 had mild arthralgias and 1 complained of fatigue and memory difficulty. In contrast, 5 of the 10 patients who received iv penicillin continued to have fatigue, memory deficit, or recurrent oligoarthritis. For 4 of these 5 patients, symptoms resolved after repeat treatment with ceftriaxone."

Better outcome. Good. I'm glad they figured out ceftriaxone worked better than penicillin.

Still, what happens if ceftriaxone didn't work? Do you try another antibiotic or say, "that's it"? I'm wondering what happened to that fifth person and how they're doing today. And I do wonder what happened to those 3 patients with mild arthalgias and 1 with fatigue and memory problems... were they followed up later on? Did their symptoms resolve or continue? Do they know what caused them? Unanswered questions.

And also:

"In a subsequent study, 31 patients with Lyme arthritis or chronic neuroborreliosis were randomly assigned to receive 2 or 4 g/d of ceftriaxone for 2 weeks [84]. After treatment, 3 of the 31 patients had persistent encephalopathy, 2 had persistent neuropathy, and 3 had no diminishment of their arthritis. The overall frequency of persistent symptoms among patients was 13%, which was similar in both treatment groups."

And... and... oh, here's one with more people, and it's randomized:

"In an open-label, randomized, multicenter study, 143 evaluable patients with manifestations of late Lyme disease, primarily Lyme arthritis, were treated with iv ceftriaxone (2 g/d for either 2 or 4 weeks) [85]. In 76% of those treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved after treatment (the P value was not significant). The most common persistent symptoms were arthralgia, pain, weakness, malaise, and fatigue."

Okay, so 76% of patients treated for 2 weeks and 70% of those treated for 4 weeks, symptoms resolved. Now what about the other 24% and 30% respectively? Their symptoms must not have resolved?

Now I can't keep going on with posting all of these, it's getting tedious - there are more examples of the work they were doing in the guidelines and you can check them out for yourself.

Let's review the treatment recommendation for Late stage Lyme neuroborreliosis, shall we?

"Late neuroborreliosis affecting the CNS or the peripheral nervous system. For patients with late neurological disease affecting the CNS or peripheral nervous system, treatment with ceftriaxone (2 g once a day iv for 2–4 weeks) is recommended (tables 3 and 4) (B-II). Alternative parenteral therapy may include administration of cefotaxime (B-II) or penicillin G (BII). Response to treatment is usually slow and may be incomplete. However, unless relapse is shown by reliable objective measures, repeat treatment is not recommended. For children, treatment with ceftriaxone is recommended (tables 3 and 4) (BII). Cefotaxime or penicillin G administered iv are alternatives (B-II)."

So this is the recommendation for 2000.

I really need to take a look at the guidelines for 2006 and compare them.

But just looking at the 2000 guidelines as their own sort of universe, what is puzzling me is why they are recommending treatment guidelines which don't lead to resolution of symptoms for everyone. At least a greater number of people?

If the reason these other cases failed - and with the bigger studies, we're looking at 24-37% of patients did not have resolution of their symptoms - was because they had this particular human leukocyte antigen–DR4 specificity and antibody reactivity with OspA of the spirochete... that isn't stated for ANY of these studies.

It is stated for one study they mentioned later on with 16 patients though - but it's the only one mentioned where they tested for this marker. One study. Sixteen people.

I'm hoping when I look at the next set of guidelines, it will be data rich. Right now, I'm just reeling a bit from this, and wondering if the author of the dissertation saw these results and wondered about them, too.

How do you tell the difference between late stage Lyme disease that relapsed or continued versus what they are calling PLDS?

Getting back to the dissertation (remember the dissertation I first began writing about? It's okay if you don't - I almost forgot it myself):

I found this bit of microbiology trivia for those interested:

"Finally, in contrast to most bacteria, B. burgdorferi phospholipids, lipoproteins and glycolipids contain unsaturated fatty acids, such as linoleic, linolenic, and arachidonic acids, which are derived from the host (35, 38, 121, 171)."

The damned things are just parasites, really.

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0 Repost: Lyme Disease: Money & Chronic Mayhem

The following is a repost of an entry from yesterday's Daily Kos.

This past February, the Republican-led House of Representatives proposed a budget that would have cut millions of dollars from science agencies that fund Lyme disease research as well as research for other infectious diseases. These cuts would have not only lead to funding levels well below those proposed by Obama when he tabled his budget request more than a year ago, but also well below the 2010 levels they have been operating under since October.

At the National Institutes of Health (NIH), a cut of just over 1% amounts to a loss of $323 million, including $50 million that Congress has specified will come out of funding for buildings and facilities on the agency's campus in Bethesda, Maryland.[1]

At the same time, the Centers for Disease Control and Prevention (CDC), in Atlanta, Georgia will have its budget cut this year by 11.5%, or $742 million.

These two agencies, NIH and CDC, are largely responsible for nationally funded surveillance and research on Lyme disease in the United States today. They are at risk for the more serious proposed cuts to be carried out in 2012, which is likely to have a major impact on Lyme disease research since there is very little privately funded research on tickborne diseases.

Lyme Disease Surveillance, Diagnosis, and Funding

The following chart depicts the steady increase of Lyme disease cases which are reported to the CDC by state health departments and physicians across the country.

It should be noted that back in 2002, the CDC stated that in highly endemic areas, for every case you see depicted on this chart, there could be at least six to twelve times more cases which are not reported.[2]

If one were to extrapolate that each case reported came from an endemic area, that would mean anywhere from 180,000 to nearly 480,000 actual cases of Lyme disease were contracted in 2009, and the number is growing.

Given there are variations in which tickborne diseases are most likely to be contracted nationwide, the average number of unreported cases may be more than twelve times higher in highly endemic regions and less than six times higher in regions which are not as suitable for tick habitat expansion.

But this misses a point.

Even at the baseline of roughly 40,000 reported cases (through testing, both confirmed and considered probable) per year, that is a LOT of cases of Lyme disease.

That's almost up there with how many people get the flu every year - 43,696 cases of Novel A influenza were reported in 2009.[3]

That's right up there with HIV - of which 36,870 diagnosed cases were reported in 2009.

But the actual reported cases are only a slice of the whole - it only documents instances where people have been TESTED for Lyme. Just as with the flu and HIV, what the actual number of people is who contract Lyme disease is not entirely known.

Even the CDC has stated in its own report:

"Between 2008 and 2009 there was a 3.6% increase in confirmed cases and 35.6% increase in probable cases. Much of the increase can be attributed to variability in surveillance practices, although evidence of true emergence exists in certain areas. Because of the burden on endemic states posed by Lyme disease surveillance, some states have modified surveillance protocols to better manage limited resources. States using modified methods, including case estimation, might report decreased case counts."[3]

Also, it is important to note that reporting of nationally notifiable diseases to CDC by the states is voluntary. Reporting is currently mandated (i.e., by state legislation or regulation) only at the state level, so the list of diseases that are considered notifiable varies slightly by state.

There are reasons why getting a grip on the scope of the problem is elusive for patients as well - it's not just an issue of surveillance and affects people individually:

Some tickborne diseases which look like Lyme disease in all respects may not show up in current standard Lyme disease blood tests.

For example, Borrelia lonestari produces a disease very similar to Lyme disease known as Master's Disease - which most Lyme disease patients just lump under "Lyme disease" on support groups because it pretty much causes the same symptoms for people. They get a rash, but test negative on standard Lyme disease blood tests.

Some tickborne diseases which look like Lyme disease in all respects may never have a rash.

In a similar scenario, investigators in southern Spain identified several patients with atypical Lyme borreliosis, who were serologically reactive with Borrelia burgdorferi antigens, but who lacked classical erythema migrans skin lesions and who originated from a region of the country where the recognized tick vector of Lyme borreliosis was distributed sparsely. Indeed, blood cultures subsequently revealed a relapsing fever Borrelia sp., genetically distinct from B. burgdorferi and transmitted by an entirely different tick species. In this case, discovery of a novel disease agent occurred because these patients did not meet the established case definition for Lyme borreliosis (Anda, et al., 1996; Guy, 1996).

If people contract a tickborne illness and no EM rash is seen, and they get a blood test that does not meet the CDC case definition for Lyme disease - they aren't reportable even if history and symptoms match.

This is important for anyone reading along to know: If you or a loved one is bitten by a tick and gets sick with symptoms of Lyme disease, you need to know that Lyme disease is ultimately a clinical diagnosis. In other words, if you or a loved one does not meet criteria for surveillance purposes that does not mean you do not have Lyme disease. See: http://www.cdc.gov/ncidod/dvbi/lyme/ld_humandisease_diagnosis.htm

In a number of cases, a doctor will see that a patient has a rash and just treat the patient for a skin infection - not knowing that it is Lyme disease.

Not all Lyme disease EM rashes look exactly like a bull's eye. They can come in somewhat different shapes, be solid up to the bite mark, and even be somewhat bluish or look like a bruise. [4] (See: Variations on Lyme disease rashes.)

Not all cases of Lyme disease which are treated are reported.

A person could be sick with all the symptoms except an obvious EM rash and have a history of a tick bite - but still have a negative blood test. This can happen early in infection with a hidden rash - it can also happen due to recent antibiotic treatment for something else.

Some people are misdiagnosed with other conditions in the first place.

Their doctors either think they have a viral infection, chronic fatigue syndrome, fibromyalgia, or some other condition which is not Lyme disease. This diagnosis could lead to another uncounted case as Lyme disease was not suspected and no tests were conducted - maybe no rash was found nor a tick bite recalled. Later blood tests may reveal the disease once it has already moved to the late stage when it is harder to treat effectively.

Knocking On Neuroborreliosis' Door

To add to the troubles of diagnosing garden variety Lyme disease in its acute stage, it is estimated that in the United States and Europe, roughly 12-20% of Lyme disease patients will go on to develop neurological complications of Lyme disease or neuroborreliosis (IOM Report; HPA, 2011).

The actual number of people who develop neuroborreliosis is less certain because of the same factors listed above - and lumbar puncture tests are only somewhat accurate at detecting Lyme disease within the first two weeks of infection, which is much earlier than blood tests detect it.

I've speculated that the reason why so many patients complain of neurological and cognitive symptoms with Lyme disease is that they were misdiagnosed or undertreated for Lyme disease early on, when the infection already affected the central nervous system and brain.

Data on Lyme disease with persisting symptoms would be good to have in this instance -especially if one can look at case histories, symptoms, and serology and determine if roughly 4,000-8,000 people a year (or more, not knowing actual cases) who are projected to get neuroborreliosis are, in fact, those who are most likely to suffer with persisting symptoms.

Early detection and treatment of neuroborreliosis in specific (which requires higher doses of antibiotics and IV treatment for a month is recommended) may prevent the number of people who have developed persisting symptoms and eliminate a lot of suffering, pain, and hardship for thousands of individuals and families.

During the time of the 2010 Institute of Medicine conference on tickborne infection, Dr. Brian Fallon, head of Columbia University's Lyme and Tick-borne Disease Research Center stated:

"The NIH does not fund trials on treating chronic Lyme disease and the IOM are hesitant to push for further studies on antibiotic treatments, because the jury is still out on whether chronic Lyme disease results from an extended inflammatory reaction to the Lyme bacteria Borrelia burgdorferi in the United States after it has been eradicated by a short course of antibiotics."[5]

This - even though as mentioned in a previous diary here - animal studies have found Lyme disease bacteria DNA through PCR and spirochetes in autopsies performed on animals after antibiotic treatment. And those were just a fraction of the studies.

In the most recent Institute of Medicine report on tickborne illnesses ([6] p.7-15), it stated:

"Turning to the literature pertaining to patients with chronic persistent symptoms, Fallon noted a number of areas need additional research. A European study compared patients with neurologic Lyme disease to those with erythema migrans 3 years later and found that 50 percent of those with neuroborreliosis experienced persistent symptoms versus 16 percent of the EM patients (Vrethem et al., 2002). These results suggest that follow up studies on chronic symptoms, rather than focusing solely on early EM, should focus on the subpopulation of patients who present with neurologic or other disseminated symptoms."

So perhaps my speculation is worth following up on.


But all of this takes money. All of this takes a concerted effort from researchers to look at Lyme disease not just from a position where they are encouraged to improve vaccine development and tests - but encouraged to look at how the infection affects hosts and treatment.

The majority of Lyme disease studies conducted by federal agencies are by the NIH-NIAID.

The NIH-NIAID has funded the greatest amount of tick-borne disease studies - a total of 404 studies comprising 85% of the funding from all agencies and organizations. The CDC has funded 19 tick-borne disease studies from 2006 to 2010, 7% of the funding from all agencies and organizations. NIH-NIAMS has funded 15 tick-borne disease studies all between 2006 and 2009. The remaining agencies USDA-ARS, NSF, NIH-NINDS, US Army Public Health Command, and USDA-NWRS have each funded five or less studies between 2006 and 2010.[6 (B-1)]

The above chart shows that after 2009, funding for all tickborne disease research was combined - so how research funds were allocated for different purposes in 2010 is unclear based on this report which was included in the Institute of Medicine's October 2010 workshop on tickborne diseases.[6]

What is known is how spending for tickborne disease research has been allocated in the recent past, and that requested budgetary increases or even requesting funding at the same rate is threatened by budget cuts.

In 2009, in terms of tickborne infections, Francisella studies received the most funding at $190m (52%) followed by Borrelia studies at $122m (33%). [6 (B-7)]

In 2010, Borrelia research (Lyme disease plus other Borrelia bacterial infections) ate the largest portion of the NIH research pie for the first time in history.

While $122m would take care of all my financial worries (and a good portion of yours!) for my lifetime, when it comes to your research dollar - $122m does not go very far - and really not that far for certain populations and subjects if you slice it a certain way.

In terms of the total tickborne diseases pie:

Microbiological studies received the most amount of funding at $210m (57%) with a total of 304 studies. The next highest study type was Prevention/Education studies, which were allocated $83.8m in funding (23%) for a total of 73 studies. Combination of study types were allocated $47.2m (13%), Treatment studies were allocated $17.1m (5%), Environmental studies were allocated $5.8m (1%), and Surveillance studies were allocated $3.5m (1%).

So looking at this, keep in mind that those treatment studies are aimed at acute cases of all tickborne diseases - and not aimed at studies for treatment of those with Lyme disease who have persisting symptoms. $17m on the face of it is not that much of a budget. This is our national program for study on tickborne infections... and it might run a few high schools for a year.

And in terms of surveillance studies - getting an accurate count of probable and confirmed cases for all tickborne infections in United States - funding surveillance is only 1% of the budget. That's only $3.5m (which is about what it costs for some guy's sweet brownstone in New York City or a fine little Victorian in San Francisco).

While I could never afford that - especially after having my health ruined by Lyme - surely there can be more funding allocated for accurate surveillance, including followup studies to ensure those with chronic symptoms are evaluated for neuroborreliosis? Surely there is more money that could be reallocated for studies to help Lyme disease patients with persisting symptoms?

[1] Nature News: US budget a taste of battles to come Nature 472, 267-269 (2011)
[2] CDC: Lyme Disease -2001-2002 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5317a4.htm
[3] CDC Summary of Notifiable Diseases (MMWR) - 2009 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5853a1.htm
[4] Lyme Disease Foundation: Variations on Lyme disease rashes. http://www.lyme.org/gallery/rashes.html
[5] Nature News: Scientists push for Lyme disease trials http://www.nature.com/news/2010/101014/full/news.2010.542.html
[6] Institute of Medicine. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases.

Addtional References:
Dr Pedro Anda PhD, Waldo Sánchez-Yebra PhD, Maria del Mar Vitutia Dvm, Esperanza Pérez Pastrana Bsc, Isabel Rodríguez BA, Nancy S Miller MD, P Bryon Backenson MSc, Jorge L Benach PhD. A new Borrelia species isolated from patients with relapsing fever in Spain. The Lancet. Volume 348, Issue 9021, Pages 162 - 165.

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